Neurotoxicity

Neurotoxicity: Identifying and ControllingPoisons of the Nervous System

April 1990

OTA-BA-436NTIS order #PB90-252511

Recommended Citation:

U.S. Congress, Office of Technology Assessment, Neurotoxicity: Identifying and ControllingPoisons of the Nervous System, OTA-BA-436 (Washington, DC: U.S. Government PrintingOffice, April 1990).

For sale by the Superintendent of DocumentsU.S. Government Printing Office, Washington, DC 20402-9325

(order form can be found in the back of this report)

.

Foreword

Extraordinary developments in the neuroscience in recent years have been paralleled bya growing congressional interest in their policy implications. The designation of the 1990s bythe 101st Congress as the “Decade of the Brain” is one indication of the promise shown byscientific advances for treating diseases of the nervous system and for increased generalunderstanding of the human mind. Other advances, however, have led us to the disturbingrealization that many commonly used chemicals can adversely affect the human nervoussystem. Concern about this issue provided the motivation for hearings held in October 1985on ‘‘Neurotoxins in the Home and in the Workplace’ by the Subcommittee on Investigationsand Oversight of the House Committee on Science and Technology.

Another result of heightened congressional interest was a request that OTA undertake aseries of assessments on major public policy issues related to the neuroscience. Requestingcommittees included the House Committees on Science, Space, and Technology; Energy andCommerce; Appropriations; and Veterans’ Affairs; and the Senate Subcommittee on Science,Technology, and Space of the Committee on Commerce, Science, and Transportation. Inaddition, the Senate Committee on Environment and Public Works recently requested a studyof the noncancer health risks posed by toxic substances. This Report, the first of theneuroscience series, discusses the risks posed by neurotoxic substances—substances that canadversely affect the nervous system—and evaluates the Federal research and regulatoryprograms now in place to address these risks.

One finding of this Report is that considerably more research and testing are necessaryto determine which substances have neurotoxic potential. Neurotoxic effects can often gounrecognized because symptoms are varied and may not appear for months or even years.Adverse effects range from impaired movement, anxiety, and confusion to memory loss,convulsions, and death. Another important finding is the need for greater public awareness.Neurotoxic chemicals constitute a major public health threat; the social and economicconsequences of excessive exposure to them are potentially very large. Minimizing exposurerequires action not just by regulatory and other public officials, but also by individual citizenswho can take steps to avoid these substances both at home and in the workplace.

Many individuals and institutions contributed their time and expertise to the project.Scientists and regulatory officials in several Federal agencies and experts in academia andindustry served on the project’s advisory panel, in workshop groups, and as reviewers. OTAgratefully acknowledges the assistance of these contributors. As with all OTA assessments,however, responsibility for the content of the Report is OTA’s alone and does not necessarilyconstitute the consensus or endorsement of the advisory panel or the Technology AssessmentBoard.

JOHN H. GIBBONSDirector .

.,.Ill

New Developments in Neuroscience Advisory Panel

Peter S. Spencer, ChairOregon Health Sciences University, Portland, OR

Robert H. Blank Laurane G. MendelssohnNorthern Illinois University Lilly Research LaboratoriesDeKalb, IL Indianapolis, IN

James F. Childress Franklin E. MirerUniversity of Virginia United Auto WorkersCharlottesville, VA Detroit, MI

Fred H. Gage Albert S. MoraczewskiUniversity of California-San Diego Pope John XXIII CenterLa Jolla, CA Houston, TX

Bernice Grafstein Herbert ParolesCornell University Columbia UniversityNew York, NY New York, NY

Ronald Kartzine} Richard M. RestakCIBA-GIGY Corp. Neurological Associates, P.C.Summit, NJ Washington, DC

Alan KrautAmerican Psychological AssociationWashington, DC

Neurotoxic Substances Study Panel

Stanley H. AbramsonKing & SpaldingWashington, DC

Louis W. ChangUniversity of ArkansasLittle Rock, AR

Alan M. GoldbergJohns Hopkins UniversityBaltimore, MD

Marion MosesUniversity of California-San FranciscoSan Francisco, CA

John O’DonoghueEastman Kodak Co.Rochester, NY

Bernard WeissUniversity of RochesterRochester, NY

NOTE: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the advisory and study panelmembers. The panels do not, however, necessarily approve, disapprove, or endorse this report. OTA assumes full responsibilityfor the report and the accuracy of its contents.

iv

Neurotoxicity

Roger C. Herdman, Assistant Director, OTA, Health and Life Sciences Division

Gretchen S. Kolsrud, Biological Applications Program Manager1

OTA Project StaffMark Schaefer, Study & Project Director

Timothy P. Condon, Project Director2

Peter R. Andrews, Research AssistantJoyce Ann Brentley, Analyst

Claire L. Pouncey, Research AssistantE. Blair Wardenburg, Research Analyst3

Monica Bhattacharyya, Research AssistantCatherine A. Laughlin, NIH Detailee4

Gladys B. White, Analyst5

Support StaffCecile Parker, Office Administrator

Linda Rayford-Journiette, Administrative SecretaryJene Lewis, Secretary

Sharon Oatman, Administrative Assistant6

Lori B. Idian, Secretary7

Contractors

Zoltan Annau, Johns Hopkins UniversityJacqueline Courteau, Hampshire Research Associates

Warren R. Muir, Hampshire Research AssociatesGeorge Provenzano, University of Maryland at Baltimore

Brenda Seidman, Environ Corp.Ellen Widess, University of Texas

Ronald Wood, New York University Medical CenterJohn S. Young, Hampshire Research Associates

Jeffrey L. Fox, Washington, DCBlair Potter (editor), Bethesda, MDJulie Phillips (indexer), Vienna, VA

Raymond Driver (graphics artist), Damascus, MD

OTA Publishing Staff

Kathie Boss, Publishing OfficerDorinda Edmondson, Desktop Publishing

Christine Onrubia, Graphic Designer/IllustratorSusan Zimmerman, Graphic Artist

lmou~ September 1989.2mou@ August 1989.3~ou~ August 1989.

4Th17Nl@ hdy 1989.fThrough June 1989.

%ough February 19897ThOU#l July 1989.

Contents

PageChapter 1. Summary, Policy Issues, and Options for Congressional Action . . . . . . . . . . . . . . . . 3

Chapter 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Chapter 3. Fundamentals of Neurotoxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Chapter 4. Research and Education Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Chapter 5. Testing and Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

Chapter 6. Assessing and Managing Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

Chapter 7. The Federal Regulatory Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

Chapter 8. Economic Considerations in Regulating Neurotoxic Substances . . . . . . . . . . . . . . . . 211

Chapter 9. International Regulatory and Research Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

Chapter 10. Case Studies: Exposure to Lead, Pesticides in Agriculture, andOrganic Solvents in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

Appendix A, The Food Additive Approval Process: A Case Study . . . . . . . . . . . . . . . . . . . . . . . . 315

Appendix B. Workshop on Federal Interagency Coordination of NeurotoxicityResearch and Regulatory Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321

Appendix C. Decade of the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

Appendix D. Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332

Appendix E. List of Contractor Documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

Appendix F. Glossary of Terms and List of Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

Chapter 1

Summary, Policy Issues, andOptions for Congressional Action

CONTENTSPage

SUMMARY .. ... .. .. ... .. .. .. .. ... .,. .....+. . . . . . . .....,, . . . . . . . . . . . . . . . . . . . . . . . .Scope of This Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .. .. .. +.. ... .+.+...,What Is Neurotoxicity? . . . . . . . . . . . . . . . . . . . . . . . . . . . .+ .. .. .. .. .. ..+. . . . . . . . . . . . . . . .Who Is At Risk? ... ... ...+.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Research and Education Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Testing and Monitoring .. .. .. .. .. .. .. .. ... ....+... .. .. .. .. .. .. .. .. ... ... ... ...~.Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .. ... ... +......Federal Regulatory Response . . . . . . . . . . . . .. .. .. .. .. .. ... +.. ....+...Federal Interagency Coordination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Economic Considerations in Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . .International Issues . . . . . . . . . . . .

POLICY ISSUES AND OPTIONS

Box

~ o R. 6 0 i e k i . l o N. k . A c. t i. 6 N

Boxes

I-A. Vulnerability of the NervousSystem to Toxic Substances . . . . . . . .

,...,.. . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . .

34489

12131519192122

Page. . . . . . . . . . . . . . . 5

l-13. MPTP and Parkinson’s Disease ......+..........++.. . .. .. .. .+ . . . . . . . . . . . . . . . . . . 6l-C. had: A Continuing Threat to the Nation’s Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8l-1). Cocaine and the Developing Fetus . . . . . . . . . . . . . . . . . . .+ . . . . . . . . . . . . . . . . . . . . . . . . 10l-E. Neurotoxic Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26l-F. Limitations of FDA’s Postmarked Monitoring System for

Adverse Drug Reactions: Halcyon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29I-G. Organic Solvents in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..+.. 30

FiguresFigure Page

l-1. Average Annual Motor Neuron Disease Mortality in the United States,White Males . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,..,.... . . . . . . . . . . . . . . . . . . . . . 3

l-2. The Fundamental Structure of the Nerve Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5l-3. Neurotoxic Effect of MDMA on Serotonin Nerve Fibers in the Cerebral Cortex

of the Monkey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . + . . . . . +........ . . . . . . . . . . . . . . 9l-4.Neurotoxic Substances Are Prominent Among the Toxics Release Inventory’s

Top 25 Chemicals Emitted Into the Air 1987 .. .. .. .. .. .. .. .. .. .. ... ... ..+...+ 14

TablesTable Pagel-1. Federal Funding for Civilian Neurotoxicity-Related Research . . . . . . . . . . . . . . . . . . . .l-2+ Major Federal Laws Controlling Toxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1116

Chapter 1

Summary, Policy Issues, and Options for Congressional Action

SUMMARYChemicals are an integral part of our daily

lives and are responsible for substantially im-proving them. Chemicals can also endanger ourhealth, even our survival. This assessmentfocuses on neurotoxic substances, those chemi-cals that adversely affect the nervous system.Included among such substances are industrialchemicals, pesticides, therapeutic drugs, abuseddrugs, food, food additives, cosmetic ingre-dients, and naturally occurring substances. Whethera substance causes an adverse health effectdepends on many factors, including the toxicityof the substance, the extent of exposure, and theage and state of health of an exposed individual.Minimizing public health risks requires infor-mation about the properties and mechanisms ofaction of potentially toxic substances to whichhumans may be exposed. This informationprovides the foundation for safety standards.

More than 65,000 chemicals are in the U.S.Environmental Protection Agency’s (EPA) inven-tory of toxic chemicals; and the Agency annu-ally receives approximately 1,500 notices ofintent to manufacture new substances. Since fewof these chemicals have been tested to determineif they adversely affect the nervous system, noprecise figures are available on the total numberof chemicals in existence that are potentiallyneurotoxic to humans. Some estimates havebeen developed, however, based on analyses ofcertain subsets of chemicals. These estimatesvary considerably, depending on the definitionof neurotoxicity used and the subset of sub-stances examined. For example, some 600active pesticide ingredients are registered withEPA, a large percentage of which are neurotoxicto varying degrees. One investigator estimatedthat 3 to 5 percent of industrial chemicals,excluding pesticides, have neurotoxic potential.Another investigator found that 28 percent ofindustrial chemicals for which occupationalexposure standards have already been devel-oped produce neurotoxic effects. In addition, a

substantial number of therapeutic drugs haveneurotoxic potential.

In recent years, concern about the neurotoxiceffects of chemicals has increased as evidencehas become available linking exposure to chem-icals and drugs with long-term changes in thenervous system. Some scientists believe thatneurotoxic substances play a role in triggeringsome neurological disorders, including Parkin-son’s disease, Alzheimer’s disease, and amyotro-phic lateral sclerosis. For example, investigatorsrecently found evidence that the incidence ofmotor neuron disease (primarily amyotrophiclateral sclerosis) is increasing particularly in theelderly (figure 1-1 ). Exposure to toxic chemicalsmay be one of the factors contributing to thisincrease. More research is necessary to confirmthis trend and to determine the underlyingcausative factors.

Human exposure to significant concentra-tions of most known neurotoxic substances isnormally quite limited. Consequently, the num-ber of substances that pose an actual threat topublic health is considerably less than the total

Figure l-l—Average Annual Motor Neuron Disease*Mortality in the United States, White Males

Rate per 1001000 population12

10

8

8

4

2

0 I -1o11

m

c 40 40-4445-4950-5455-59 60-6465-6970-7475-79 80-84 85.Age

@ Between 1962-1964 m Between 1980-1984

“Most motor neuron disease is diagnosed as amyotrophic lateral sclerosis(ALS) or Lou Gehrig’s disease.

SOURCE: Adapted from D.E. Lilienfeld, et al., “Rising Mortality FromMotoneuron Disease in the U. S., 1962-1884,” The Lancet, Apr.1, 1989, pp. 710-713.

-3 -

4 ● Neurotoxicity: Identifying and controlling poisons of the Nervous System

number of neurotoxic substances in existence.The number of substances that pose a signifi-cant risk to public health and the extent ofthat risk are unknown because the potentialneurotoxicity of only a small number ofchemicals has been evaluated adequately.

Scope of This Study

This study examines many, but not all, of theclasses of neurotoxic substances. The assess-ment includes discussion of industrial chemi-cals, pesticides, therapeutic drugs, substancedrugs, foods, food additives, cosmetic ingre-dients, and such naturally occurring sub-stances as lead and mercury. It does notinclude radioactive chemicals, nicotine (fromcigarette smoke), alcohol (ethanol), biologicaland chemical warfare agents, microbial, plant,and animal toxins, and physical agents such asnoise.

What Is Neurotoxicity?

The nervous system comprises the brain, thespinal cord, and a vast array of nerves andsensory organs that control major body func-tions. Movement, thought, vision, hearing,speech, heart function, respiration, and numer-ous other physiological processes are controlledby this complex network of nerve processes,transmitters, hormones, receptors, and channels(figure 1-2).

Every major body system can be adverselyaffected by toxic substances, but the nervoussystem is particularly vulnerable (see box l-A).Many toxic substances can alter the normalactivity of the nervous system. Some produceeffects that occur almost immediately and lastfor several hours. Examples include an alcoholicbeverage or fumes from a can of paint. Theeffects of other neurotoxic substances mayappear only after repeated exposures over weeksor even years: e.g., regularly breathing the

Photo credit: W Eugene Smith and Aileen Smith

A child victimized by mercury poisoning during the Minamata Bay, Japan, incident in the 1950s is bathed by his mother.This is one of the most dramatic poisoning incidents involving a neurotoxic substance.

Chapter l---Summary, Policy Issues, and Options for Congressional Action ● 5

Figure 1-2—The Fundamental Structure of the Nerve Cell

VkL \ A x o nterm[nal

Cell body

2 /

/// -- SynapseMyelin

SOURCE: Office of Technology Assessment, 1990. ‘1

ndri

Box l-A—Vulnerability of the Nervous System to Toxic Substances

The nervous system is particularly vulnerable to toxic substances because:. Unlike other cells that make up the body, nerve cells, or neurons, normally cannot regenerate once

lost—toxic damage to the brain or spinal cord, therefore, is usually permanent.● Nerve cell loss and other regressive changes in the nervous system occur progressively in the second half

of life—toxic damage may therefore progress with aging.● Certain regions of the brain and nerves are directly exposed to chemicals in the blood, and many neurotoxic

chemicals cross the blood-brain barrier with ease.● The peculiar architectural features of nerve cells, with their long processes, provide a vast surface area for

chemical attack and are therefore inherently susceptible to chemical interference,● The dependence of the nervous system on a delicate electrochemical balance for proper communication of

information throughout the body provides numerous opportunities for foreign chemicals to interfere withnormal function.

● Even minor changes in the structure or function of the nervous system may have profound consequencesfor neurological, behavioral, and related body functions.

SOURCE: P.S. Spencer, personal communication, 1989.

tes

6 ● Neurotoxicity: Identifying and controlling Poisons of the Nervous System

fumes of a solvent in the workplace or eatingfood or drinking water contaminated with lead.Some substances can permanently damage thenervous system after a single exposure-certainorganophosphorous pesticides and metal com-pounds such as trimethyl tin are examples (boxl-B). Other substances, including abused drugssuch as heroin and cocaine, may lead toaddiction, a long-term adverse alteration ofnervous system function. Many neurotoxic sub-stances can cause death when absorbed, inhaled,or ingested in sufficiently large quantities.Neurotoxic substances play a significant causalrole in the development of some neurologicaland psychiatric disorders; however the pre-cise extent of the contribution is unclear.

Care must be taken in labeling a substanceneurotoxic because factors such as dose and

intended effects must be taken into considera-tion. A substance may be safe and beneficial atone concentration, but neurotoxic at another.For example, vitamins A and B6 are required inthe diet in trace amounts, yet both causeneurotoxic effects in large doses. In other cases,a substance that is known to be neurotoxic mayconfer benefits that are viewed as outweighingthe risk of adverse side-effects. For example,thousands of individuals suffering from schizo-phrenia have been able to live relatively normallives because of the beneficial effects of antipsy -chotic drugs. However, chronic use of pre-scribed doses of some of these drugs may giverise to tardive dyskinesia—involuntary move-ments of the face, tongue, and limbs—side-effects so severe that they may incapacitate apatient.

Box 1-B—MPTP and Parkinson’s Disease

In recent years, the hypothesis that Parkinson’s disease and other neurological disorders might be triggered byenvironmental factors has become more widely accepted. Although toxic substances have long been consideredpossible contributors to the cause of some disorders of the nervous system, the MPTP incident has focused moreattention on this environmental hypothesis.

MPTP is the abbreviation for l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, a compound that can be createdduring the production of synthetic heroin. Remarkably, in just 5 to 15 days, this highly neurotoxic substance caninduce a syndrome virtually identical to Parkinson’s disease—a disease that usually occurs late in life and developsslowly over a period of years. Both Parkinson’s disease and the MPTP-induced syndrome are characterized bytremors and lack of muscular control that stem from degeneration of neurons in the substantial nigra, a region deepin the central area of the brain. Neurons in the substantial nigra synthesize and secrete the neurotransmitter dopamine,hence Parkinson’s patients are treated with levodopa, a precursor of this neurotransmitter.

The discovery of the link between MPTP and Parkinson’s disease has dramatically changed the nature ofresearch on this disease. Much work has focused on MPP+, a metabolize of MPTP that is responsible for the adverseeffects on the brain. Recently, researchers discovered that a monoamine oxidase inhibitor, a type of drug sometimesused to treat depression, blocks the conversion of MPTP to MPP+. Other researchers have shown that themonoamine oxidase inhibitor Deprenyl, administered to Parkinson’s patients in combination with levodopa,reduces the symptoms of the disease and extends their lives. It was found that Deprenyl slows the rate ofdegeneration of neurons in the substantial nigra, perhaps making it useful in the treatment of Parkinson’s disease.

The MPTP story illustrates how a neurotoxic substance might cause or contribute to the development ofneurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. Therelative contributions of environmental and genetic factors to the causes of these diseases are not understood andare the subject of considerable research and debate within the scientific community. Although the extent to whicha neurotoxic substance contributes to the cause of Parkinson’s disease is unclear, the MPTP story serves as anexample of how neurotoxicological research can lead to abetter understanding of the causes of neurological diseaseand ways to treat it.

SOURCES: I.J. Kopin and S.P. Markey, ‘‘MPTP Toxicity: Implications for Research in Parkinson’s Disease,’ Annual Review o~~ewoscknce11:81-96, 1988; J.W. Langston, P. Ballard, J.W. Tetrud, et al., “Chronic Parkinsonism in Humans Due to a Product ofMeperidine-Analog Synthesis, ” Science 219:979-980, 1983; R. Lewin, “Big First Scored With Nerve Diseases,” Science245:467468, 1989.

Chapter 1-Summary, Policy Issues, and Options for Congressional Action ● 7

Broadly defined, a substance is considered tohave neurotoxic potential if it adversely affectsany of the structural or functional components ofthe nervous system. At the molecular level, asubstance might interfere with protein synthesisin certain nerve cells, leading to reduced produc-tion of a neurotransmitter and brain dysfunction.At the cellular level, a substance might alter theflow of ions (charged molecules, e.g., sodiumand potassium) across the cell membrane, therebyperturbing the transmission of information be-tween nerve cells. Substances that adverselyaffect sensory or motor function, disrupt learn-ing and memory processes, or cause detrimentalbehavioral effects are neurotoxic, even if theunderlying molecular and cellular effects on thenervous system have not been identified. Expo-sure of children to lead, for example, leads todeficits in I.Q. and poor academic achievement;however, the mechanisms by which this occursare not understood. In addition, researchersrecently found evidence that phenobarbital, adrug prescribed to children to prevent seizuresassociated with fevers, reduces intellectual abil-ity. But as is the case for lead, the underlyingmechanism is unknown.

For the purposes of this study, the Office ofTechnology Assessment (OTA) defines neurotoxic-ity or a neurotoxic effect as an adverse changein the structure or function of the nervoussystem following exposure to a chemicalagent. This is the definition currently used byEPA. However, as the preceding discussionillustrates, this definition should be used inconjunction with information on the in-tended use of the substance, the degree oftoxicity, and the dose or extent of exposure ofhumans or other organisms. The definitionhinges on interpretation of the word "ad-verse,” and there is disagreement amongscientists as to what constitutes “adversechange.” Determining whether a particularneurological or behavioral effect is adverserequires a comprehensive analysis of allavailable data. Although certain effects are

clearly adverse (e.g., hallucinations, convul-sions, loss of memory, permanent neurologicaldamage, death) others are more difficult todefine (e.g., temporary drowsiness, a briefheadache). The circumstances of exposure anda variety of other factors must be taken intoaccount in borderline cases. For example, drows-iness in the evening at home may be of littleconsequence, but drowsiness during the daywhile operating machinery in the workplacemay be detrimental or even life-threatening.

———.— — — A

——-————— .

—— ——~ -“1’. . . . . -

Illustrated by: Ray Driver

8 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Who Is At Risk?

Everyone is at risk of being adversely affectedby neurotoxic substances, but individuals incertain age groups, states of health, and occupa-tions face a greater probability of adverseeffects. Fetuses, children, the elderly, work-ers in occupations involving exposure torelatively high levels of toxic chemicals, andpersons who abuse drugs are among those inhigh-risk groups.

The developing nervous system is particu-larly vulnerable to some neurotoxic substances,for several reasons. It is actively growing andestablishing cellular networks, the blood-brainbarrier that protects much of the adult brain andspinal cord from some toxic substances has notbeen completely formed, and detoxificationsystems are not completely developed. Lead isa potent neurotoxic substance that is particularlyharmful to children (box l-C). Toxic substancescan contribute to neuropsychiatric disorders inchildren. The National Academy of Sciences

recently reported that 12 percent of the 63million children under the age of 18 in theUnited States suffer from one or more mentaldisorders, and it identified exposure to toxicsubstances before or after birth as one of theseveral risk factors that appear to make certainchildren vulnerable to these disorders.

The elderly are more susceptible to certainneurotoxic substances because decline in thestructure and function of the nervous systemwith age limits its ability to respond to orcompensate for toxic effects. In addition, de-creased liver and kidney function increasessusceptibility to toxic substances. Aging mayalso reveal adverse effects masked at a youngerage. Persons who are chronically ill, especiallythose suffering from neurological or psychiatricdisorders, are at risk because neurotoxic sub-stances may exacerbate existing problems. Also,many elderly Americans take multiple drugsthat may interact to adversely affect nervoussystem function. According to the Department

Box l-C—Lead: A Continuing Threat to the Nation’s Children

Lead is an especially troublesome neurotoxic substance because it occurs naturally in the environment andtherefore may be found in food, water, and air, as well as in the byproduct.. of manufacturing and industry.Environmental Protection Agency (EPA) and Food and Drug Administration (FDA) measures to reduce lead ingasoline and food have been largely successful, but some sources of exposure remain, and some sources that arenot major contributors now may become so in the future.

Despite lead reduction in a number of areas, lead poisoning remains a major public health problem, particularlyamong children, who are both more sensitive to lead’s neurotoxic effects and more likely to be exposed to certainsources, such as paint chips from older houses, school water coolers containing lead-lined tanks, and home watersupplies contaminated with lead from old piping. According to the Department of Health and Human Services, 17percent of the Nation’s children (in standard metropolitan statistical areas) have levels of lead in their blood thatmay be adversely affecting their nervous systems. The percentage is much higher for urban children from poorfamilies. As tests become more sensitive, neurotoxic effects become apparent at progressively lower levels of leadin children’s blood. In addition, relatively low exposures to lead in early years appear to have developmental andneurobehavioral effects that persist into young adulthood. Because of the widespread nature of the problem, it wouldbe prudent to consider a nationwide screening program of lead poisoning in children.

There is some concern that existing EPA regulations cannot adequately remove lead from drinking water, andit is unclear whether water suppliers or property owners bear the responsibility for removing lead plumbing. Thesame problem of responsibility exists for the removal of lead-based paint from older houses. Without any centralreporting system, it is difficult to ascertain the extent of lead poisoning in individual States; and since funding forlead poisoning prevention was placed under the block grant umbrella, it is difficult to determine the extent to whichFederal funds are being spent on lead poisoning prevention.

SOURCES: H.L. Needleman, A. Schell, D. Bellinger, et al., “The Long Term Effects of Exposure to Imw Doses of Lead in Childhood,” NewEnglandJournalofh4edicine 322:83-88, 1990. K.L. Florini, G.D. Krumbhaar, Jr., and E.K. Silbergeld, “Ugacy of Gad: America’sContinuing Epidemic of Childhood Lead Poisoning,’ Environmental Defense Fund, Washington, DC, 1990.

Chapter l--Summary, Policy Issues, and Options for Congressional Action ● 9

of Health and Human Services (DHHS), peopleage 60 and older represent 17 percent of theU.S. population but account for nearly 40percent of drug-related hospitalizations andmore than half the deaths from drug reac-tions. Common adverse effects include de-pression, confusion, loss of memory, shakingand twitching, dizziness, and impairedthought processes.

Workers in industry and agriculture oftenexperience substantially greater exposures tocertain toxic substances than the general popula-tion does. Neurotoxic pesticides and solventsare common sources of exposure in theworkplace. The National Institute for Occupa-tional Safety and Health (NIOSH) has identifiedneurotoxic disorders as one of the Nation’s 10leading causes of work-related disease andinjury. Other leading causes of work-relateddisease and injury include noise-induced hear-ing loss and psychological disorders, both ofwhich are mediated by the nervous system.NIOSH has estimated that several million work-ers are exposed to neurotoxic substances on aregular basis.

Persons who abuse psychoactive drugs mayface particularly severe neurotoxic effects. TheNational Institute on Drug Abuse (NIDA) re-ported that in 1986 drug abuse led to more than119,000 emergency room visits and 4,138deaths. Some drugs can permanently damagethe nervous system. Damage may be so severeas to cause personality changes, neurologicaldisease, mental illness, or death. Persons whoabuse drugs are often not aware of, or do not takeseriously, the threat these substances pose totheir health. Drugs such as cocaine, heroin,MDMA (ecstasy), and phencyclidine (PCP) areneurotoxic and threaten the health of manyAmericans. Figure 1-3 illustrates how oneabused drug, MDMA, can destroy nerve fibersin the brain. Abuse of psychoactive drugs bypregnant women poses a major risk to thedeveloping nervous system of the fetus (seebox l-D).

Figure 1 -3--Neurotoxic Effect of MDMA on SerotoninNerve Fibers in the Cerebral Cortex of

the Monkey

A. Control

B. MDMA

Repeated administration of MDMA (5mg/kg, 8 doses) to aCynomolgus monkey produced degeneration of most serotoninnerve fibers in this region of the cortex, which is involved in theperception of touch and position sense. Similar toxic effects areseen in most areas of the cerebral cortex.SOURCE: M.A. Wilson and M.E. Molliver, Department of Neuroscience,

Johns Hopkins University School of Medicine.

Research and Education Programs

Federal research related to neurotoxic sub-stances is conducted primarily at the NationalInstitutes of Health (NIH), the Alcohol, DrugAbuse, and Mental Health Administration(ADAMHA), and EPA. Limited research pro-grams are under way at the Food and DrugAdministration (FDA), the Centers for DiseaseControl (CDC), the Department of Energy, theDepartment of Agriculture, and other agencies.


Box l-D-Cocaine and the Developing Fetus

When a pregnant women abuses a psychoactive drug, she alters not only the activity of her nervous system,but that of her unborn child as well. Depending on the abused substance, the frequency of use, the dose, and otherfactors, the mother’s quest for a high can lead to permanent damage of the rapidly developing fetal nervous system.According to a recent survey by the National Association for Perinatal Addiction Research and Education, each yearas many as 375,000 infants may be adversely affected by substance abuse, Maternal substance abuse is frequentlynot recognized by health-care professionals during pregnancy. Consequently, treatment or prevention programsoften come too late. According to the National Institute on Drug Abuse, approximately 6 million women ofchildbearing age (15 to 44) are current users of an illicit drug, about 44 percent have tried marijuana, and 14 percenthave used cocaine at least once.

A recent study of 50 women who used cocaine during pregnancy revealed a 31 percent incidence of pretermdelivery, a 25 percent incidence of low birthweight, and a 15 percent incidence of sudden infant death syndrome.These types of parameters are easy to quantify. The biochemical and neurobehavioral effects are more difficult todocument, but they are just as real. Early research indicates that cocaine babies suffer abnormal development of thenervous system, impaired motor skills and reflexes, seizures, and abnormal electrical activity in the brain.

Cocaine is so addictive that it can suppress one of the most powerful human drives-maternal care. As onepregnant crack addict put it: “The lowest point is when I left my children in a park for like 3 or 4 days. I had leftmy kids with a girl that I know and told her. . . ‘watch them. . . I’ll be back’ and I didn’t come back. So that waslike—when I finally came down off of that high, I realized that I needed help. ” Sick and abandoned children ofcocaine mothers have placed a heavy burden on a number of the Nation’s hospitals. During a l-week period at onehospital, 1 in 5 black infants and 1 in 10 white infants were born on cocaine. Taxpayers usually end up paying thehealth-care bill—a bill that can exceed $100,000 per infant.

SOURCES: National Association for Perinatal Addiction Research and Education, News, Aug. 28, 1988; J.H. Khalsa, “Epidemiology ofMatemat Drug Abuse and Its Health Consequences: Recent Finding,’ National Institute on Drug Abuse, in preparation; CBS News,“Cocaine Mothers: Suffer the Children,” West57th Street, July 15, 1989.

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Photo credit: Courtesy of Dr. Emmaiee S. Bandstra, M. D., Division of Neonato/ogy, University of MiamtiJ&son Memorial ikfedkal Canter

Chapter I-Summary, Policy Issues, and Options for Congressional Action 11

Table l-l-Federal Funding for CivilianNeurotoxicity-Related Research

Agency Researcha ($ millions)

National Institutes of Healthb . . . . . .Alcohol, Drug Abuse, and Mental

Health Administrationc . . . . . . . . . .Environmental Protection Agency. . .National Institute for Occupational

Safety and Health . . . . . . . . . . . . .Food and Drug Administration . . . . .Department of Energyd . . . . . . . . . . .Department of Agriculture . . . . . . . . .

Total . . . . . . . . . . . . . . . . . . . . . . . .

32.6

26.63.9

0.71.80.50.4

66.5aTotals are based primarily on fiscal year 1988 data.bExcludes resewch related to nicotine and smoking.GExcl@es research related to alcohol and a~oholism.

dEx~udes research related to radiation.SOURCE: Office of Technology Assessment, 1990.

As indicated in table 1-1, total Federal fundingfor civilian neurotoxicology -related research(excluding research related to nicotine andsmoking, alcohol and alcoholism, and radiation)is about $67 million. The bulk of this funding(89 percent) is through ADAMHA and NIH andtends to focus on the toxicity of drugs and thebiochemical mechanisms underlying neurologi-cal and psychiatric disorders. A number of otherFederal agencies and organizations providelimited funding for research related to neurotox-icity as well. Given the threat that neurotoxicsubstances pose to public health and the lackof knowledge of the mechanisms by whichthese substances exert adverse effects, OTAfound that, in general, Federal researchprograms are not adequately addressingneurotoxicity concerns.

Research related to environmental neurotoxicol-ogy is confined primarily to the intramuralprogram at EPA and the extramural program atthe National Institute of Environmental HealthSciences (NIEHS) within NIH. The NIEHSextramural grants program supports a substan-tial number of research projects in academia.However, OTA found that, with the exception ofthe neurobehavioral section of the Laboratory ofMolecular and Integrative Neuroscience withinNIEHS, NIEHS intramural research programsare focused on the basic neuroscience ratherthan on environmental neurotoxicology, result-ing in a prominent intramural research gap at

NIH in the environmental neurotoxicology field.Of the approximately $3 million NIEHS spenton intramural research in the neuroscience infiscal year 1988, OTA found that only aboutone-fourth was devoted to studies in whichneurotoxicology was the primary focus.

Academic research in neurotoxicology issupported almost exclusively by NIH andADAMHA. Most extramural research fundedby NIH is through NIEHS and the NationalInstitute of Neurological Disorders and Stroke(formerly the National Institute of Neurologicaland Communicative Disorders and Stroke),although several other Institutes have substan-tial programs. The extramural grants program atNIEHS has been particularly effective in fund-ing research grants in the neurotoxicity field.ADAMHA funds grant programs through NIDAand the National Institute of Mental Health.

EPA has a relatively large intramuralresearch program in neurotoxicology whichhas been limited in recent years by lack offunding for supplies and equipment. EPAlacks an extramural grants program in neu-rotoxicology. The Agency has only a smallgrants program that has rarely funded neurotoxi-cology-related projects. Traditionally, Federalagencies have supported both intramural andextramural efforts to ensure a balanced, compre-hensive, and cost-effective program.

In recognition of the need to expand itsresearch programs in the neurotoxicology area,EPA recently submitted to the Office of Man-agement and Budget (OMB) a request to expandits research budget by $1.5 million. Approxi-mately $1.0 million was requested for thedevelopment of in vitro neurotoxicology tests;another $0.5 million was requested to examineadverse effects associated with cholinesteraseinhibition and the utility of cholinesterase inhibi-tion as a biomarker for exposure. However,OMB allowed no funding for either researcheffort. In vitro test development is often cited asa high-priority research need because of therequirement to rapidly screen toxic chemicals

12 ● Neurotoxicology: Identifying and controlling Poison of the Nervous System

and to try to minimize the use of animals inresearch. A technical EPA panel recently recom-mended that the Agency initiate studies toexamine the relationship between cholinesteraseinhibition and other adverse effects on thenervous system.

FDA funds a small number of researchprojects related to neurotoxicology, primarilythrough its intramural research programs. TheNational Center for Toxicological Research isconducting a number of intramural researchprojects related primarily to developmentalneurotoxicology. The Center for Food Safetyand Applied Nutrition has a small in-houseprogram and is supporting three extramuralresearch projects.

Within CDC, NIOSH has small intramuraland extramural programs devoted to the identifi-cation and control of neurotoxic substances inthe workplace. CDC’s Center for Environ-mental Health and Injury Control conductsepidemiological investigations of human expo-sure to environmental hazards, but few studiesfocus on neurotoxic effects.

Industry supports neurotoxicology -related re-search through several mechanisms, includingin-house scientists, contract laboratories, con-sortia, contracts with universities, and grants touniversities. Toxicity evaluations conducted aspart of internal applied research are necessary todevelop safe and effective products, to protectemployees, to protect the environment, and tocontrol liability costs. Research programs varyconsiderably depending on the types of productsmanufactured and various economic considera-tions.

OTA found that education of researchscientists in the neurotoxicology field islimited, in part, by inadequate Federal sup-port for training programs. Part of the diffi-culty in obtaining funding is due to the nature ofneurotoxicology-the intersection of neuroscienceand toxicology. Few academic departmentsdevote significant resources to neurotoxicology,and few Federal research organizations devotemajor efforts to it. NIEHS supports training in

the neurotoxicology field; however, fundinglimitations allow for support of only a relativelysmall number of trainees.

Millions of American workers are exposed toneurotoxic substances in the workplace, butillness stemming from these exposures oftengoes undetected and untreated. The subtlety ofneurotoxic responses is one reason for thissituation; for example, complaints of headacheand nervousness are often ascribed to othercauses. Another reason is the lack of adequatelytrained health-care professionals to diagnoseand treat neurotoxic disorders. Medical schools,in general, devote little of their curricula tooccupational health issues. After medicalschool, physicians may undertake residencytraining in occupational medicine, but in 1987only about 1 in every 1,000 residents wasspecializing in occupational medicine. Nursesare also needed in the occupational health fieldto provide emergency services, to monitoremployee health, and to provide counseling andreferral to physicians. In addition, industrialhygienists are needed to evaluate and controlhealth hazards in the workplace.

Testing and Monitoring

Controlling toxic substances is a two-partprocess. The first step is to identify existingsubstances that adversely affect the nervoussystem and take action to minimize humanexposure to them. The second step is to identifynew neurotoxic substances in use and eitherprevent their manufacture (if they cause seriousneurotoxic effects) or limit human exposure tothem and release of them into the environment.Very few new and existing chemicals havebeen evaluated specifically for neurotoxicity.

The effects of toxic substances on the nervoussystem may be evaluated through animal tests,cell and tissue culture (in vitro) tests, and humantests. Each approach has advantages as well aslimitations. The best way of predicting adverseeffects on human health is to test potentiallytoxic substances directly on human subjects.However, this approach is often difficult and inmany situations is unethical. Therefore, it is


usually necessary to rely on animal and in vitrotests to predict effects on human health. In somecases, in vitro tests can be used to detectneurotoxic effects; at present, however, animaltesting is used to obtain a neurotoxicologicaland behavioral evaluation. As more in vitrotesting techniques become available and arevalidated, they may be used in the initialscreening process or to complement animaltests.

Several industrial and Federal organizationshave developed animal tests to evaluate theeffects of known and potential neurotoxic sub-stances. In industry, several testing methods arecurrently used on a limited basis to assess theneurotoxic potential of some toxic substances.In the Federal arena, EPA recently developedguidelines for a series of neurotoxicity tests tosupplement its general toxicological tests. Coreneurotoxicological tests used in initial screeningfor toxicity include the functional observationalbattery (a series of rapid neurological tests toevaluate toxic effects on animals), tests of motoractivity, and neuropathological examinations.Additional tests that may be used includeschedule-controlled operant behavior tests, acuteand subchronic delayed neurotoxicity tests fororganophosphorous substances, and developmentalexaminations. Neurophysiological evaluationsare also useful in identifying neurotoxic sub-stances and in evaluating their adverse effects.

Several human tests are in use to determinethe neurotoxic potential of suspected and knowntoxic substances. These include neurobehav-ioral evaluations and various neurophysiologi-cal tests. In addition, computer monitoringdevices are rapidly advancing to aid in studies ofneurotoxicity.

Monitoring the release of toxic substances iscritical to regulatory programs. In 1986, Con-gress enacted the Federal Emergency Planningand Community Right-to-Know Act, whichmandated that EPA develop a Toxics ReleaseInventory of more than 300 toxic chemicalsreleased by industry into the environment. Thefirst data were published in 1989, and the

inventory will be updated annually. Such adatabase will undoubtedly prove to be veryuseful in monitoring releases of neurotoxicsubstances. As indicated in figure 1-4, 17 of thetop 25 toxic substances released into the envi-ronment have neurotoxic potential.

Monitoring exposure to neurotoxic substancesis a critical component of public health andenvironmental protection efforts. Monitoringmay be conducted by regularly surveying con-taminants in the food supply, banking animalspecimens, and collecting biological data onhumans. Biological specimens can be used tomeasure contamination levels over periods ofmany years and to document adverse effects.Human biological monitoring programs can beundertaken to detect exposure to toxic sub-stances and to aid in making decisions abouthealth risks. Such programs may be particularlyuseful in monitoring exposures in the workplace.

Risk Assessment

Risk assessment is the analytical process bywhich the nature and magnitude of risks areidentified. Risk, as it pertains to the healtheffects of toxic substances, is the probability ofinjury, disease, or death for individuals orpopulations undertaking certain activities orexposed to hazardous substances. It is some-times expressed numerically (e.g., 1 in 1 mil-lion); however, quantification is not alwayspossible, and risk may sometimes be expressedin qualitative terms such as high, medium, orlow risk. Risk management, a process guided byrisk assessment, and by political, social, ethical,economic, and technological factors as well,involves developing and evaluating possibleregulatory actions and choosing among them.

Some degree of risk is associated with almostevery aspect of modern living. For example,traveling in an automobile involves a risk ofaccidental death of 1 in 4,000, a relatively highrisk. In contrast, the risk of being killed bylightning is 1 in 2 million. Whether a risk isacceptable or not depends on many factors,including benefits. Defining acceptable risk isthe task not only of scientists and regulatory

14 ● neurotoxici(-y: Identifying and Controlling Poisons of the Nervous System

Figure l-4-neurotoxic Substances Are Prominent Among the Toxics Release inventory’s Top 25

360

300

250

200

160

100

50

0

Chemicals Emitted Into the Air in 1987

Millions of pounds

Listed as a neurotoxIc substance by

_ A n g e r end Johnson ( 1985], orsu bje cl to TSCA Sect Ion 4 les I r u I etor neurotox IC subs l a n c e s

n Not I I a ted a8 a neurotox Ic su bsla nc e

Dlm_lAM TO ME AC IT MK XY CD DI CH AO ET F R HA TR PR GE NA TE ST BE Ml CL CS SA

AM - Ammonl a M K - Mnthvl Fthv I KaInnc, F R - F reon 113 ST - SI yrene- ~ ., - r --- -TO - Tol u e n e X V - Xy I e n e ( m I xe d I s o mer a ] H A - H yd-roc h I Or IC AC I d

CD - Car bon Dlsu I t i d e

BE - Benzene

ME - Mel hanol T R - Tr Ich Ioroel hy Iene Ml - Met hyl Isobu t y I Ke tone

AC - AcetoneDI - Dlch Ioromethane P R - P ropy I ene CL - Ch Iorotor mCH - Ch I or Ine G E - G I Ycol Ethers CS - Car bony I SU I fide

1 T - 1,1.1- Tr I - AO - A l um inum Ox ide NA - N-Bu 1 y I A lcoho l 5A - Sul fur IC Ac8d

ch Ioroethane ET - E thy lene T E - Te I r ach I o ro e t h y I e ne

SOURCES: Data obtained from W.K. Anger and B.L. Johnson, “Chemicals Affecting Behavior,” neurotoxicity of Industrial and Commercial Chemicals, vol.1, J.L. O’Donoghue (cd.) (Boca Raton, FL: CRC Press, 1965), tables 1 and 2, pp. 70-141; TSCAsec. 4,52 FR 31445; TSCAsec. 4,53 FR 5932;54 FR 13470; 54 FR 13473; U.S. Environmental Protection Agency, Office of Pesticides and Toxic Substances, The Toxics Release Inventory:A National Perspective, 1987, EPA 560/4-89-006 (Washington, DC: 1989).

officials, but of society in general. Everyoneevaluates risks on a daily basis and makesindividual choices depending on experience andother factors.

Risk assessment practices are the subject ofongoing debate within the regulatory and scien-tific communities, and in the last two decadesstrategies to regulate toxic substances havechanged considerably. In the early 1970s, envi-ronmental legislation focused on regulating arelatively small number of pollutants of knowntoxicity. Today, concern is focused on thou-sands of toxic substances, for many of whichlittle information is available. This change hasbeen forced in part by improved methods ofdetecting toxic substances in the environment,

improved capabilities for identifying the ad-verse effects of these substances, and thedifficulty of determining threshold levels belowwhich no adverse effects occur.

Policies regarding risk assessment have beencontroversial. Some people believe that Federalagencies overestimate risk by making overlyconservative assumptions in developing riskassessments. Others feel that risk assessmentpractices do not take into account the complexinteractions of multiple pollutants that oftenoccur in the environment. Still others point outthat risk assessments focus primarily on adverseeffects on human health and devote little atten-tion to other organisms and the environment ingeneral. Critics of established risk assessment

—. — . . . . . . -Chapter 1-Summary, Policy Issues, and Options for Congressional! Action ● 15

w.

IIllustrated by: Ray Driver

procedures believe that too little attention isbeing paid to the potential effects of toxicsubstances on children, infants, and the unborn.Regardless of the various viewpoints, riskassessment has become an integral componentof regulatory strategies, and it is important toappreciate the scientific issues underlying thisprocess in order to understand how toxic sub-stances are controlled.

Concerns about carcinogenicity have domi-nated discussions about the risks posed bytoxic substances. However, the adverse ef-fects on organs and organ systems, particu-

larly the nervous system, may pose an equalor greater threat to public health. Conse-quently, it is important to devise risk assess-ment strategies to address noncancer healthrisks. An important difference between neuro-toxicity and carcinogenicity is the extent towhich the effects are reversible. The endpoint ofcarcinogenicity is considered to be irreversible(although some argue that, strictly speaking, a‘‘cure’ would render the effect reversible),whereas the endpoints of neurotoxicity may beeither reversible or irreversible, depending onthe specific effect, the duration and frequency ofexposure, and the toxicity of the substance.Reversibility requires the introduction of a newvariable into the risk assessment equation.

Since the nervous system is perhaps the mostcomplex organ system of the body, evaluatingthe neurotoxic potential of environmental agentsis a particular challenge. For example, testingfor a toxic effect on one component of thenervous system (e.g., hearing), may or may notreveal a toxic effect on another component (e.g.,vision). Furthermore, an effect on one nervoussystem function is not necessarily predictive ofan effect on another nervous system function.

The results of toxicological analyses arestrongly influenced by the age of the organismbeing examined. For example, mice exposed tomethylmercury during prenatal developmentmay not exhibit adverse effects until late in theirlives. With age, the functional capacity of thebrain declines significantly, and chronic expo-sure to some neurotoxic substances is thought toaccelerate this process. Hence, some scientistsand regulatory officials believe that risk analy-ses should consider adverse effects over a rangeof ages and should take into account latenteffects.

Federal Regulatory Response

It is the task of regulatory agencies to limitpublic exposure to toxic chemicals throughprograms mandated by law. Because of the greatdiversity of toxic substances, many statutes existto control their use. These laws are administeredby various Federal agencies, but primarily by


Table 1-2--Major Federal Laws ControllingToxic Substances

Agency primarilyAct responsible

Toxic Substances Control Act . . . . . . . . . . . . . . . . .Federal Insecticide, Fungicide, and Rodenticide

Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Federal Food, Drug, and Cosmetic Act . . . . . . . . . .Occupational Safety and Health Act . . . . . . . . . . . .Comprehensive Environmental Response,

Compensation, and Liability Act . . . . . . . . . . . . .Clean Air Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Federal Water Pollution Control Act and

Clean Water Act . . . . . . . . . . . . . . . . . . . . . . . . . .Safe Drinking Water Act . . . . . . . . . . . . . . . . . . . . . .Resource Conservation and Recovery Act . . . . . . .Consumer Product Safety Act . . . . . . . . . . . . . . . . .Federal Hazardous Substances Act . . . . . . . . . . . .Controlled Substances Act . . . . . . . . . . . . . . . . . . . .Federal Mine Safety and Health Act . . . . . . . . . . . .Marine Protection, Research, and Sanctuaries

Act . . . . . . . . . . . . . . . . . . . . ... , . . . . . . . . . . . . .Lead-Based Paint Poisoning Prevention Act . . . . .Lead Contamination Control Act . . . . . . . . . . . . . . .Poison Prevention Packaging Act . . . . . . . . . . . . . .

EPA

EPAFDA

OSHA

EPAEPA

EPAEPAEPA

CPSCCPSCFDA

MSHA

EPACPSCHHS

CPSCKEY: CPSC-Consumer Product Safety Commission; EPA-Environ-

mental Protection Agency; FDA-Food and Drug Administration;HHS--Department of Health and Human Services; MSHA—MineSafety and Health Administration; OSHA-Oocupational Safety andHealth Administration.

SOURCE: Office of Technology Assessment, 1990.

EPA, FDA, and the Occupational Safety andHealth Administration (OSHA) (table 1-2).OTA found that very few substances have beenregulated as a result of neurotoxicity concerns.

New and existing industrial chemicals areregulated by the Toxic Substances Control Act(TSCA). Pesticides are controlled by the FederalInsecticide, Fungicide, and Rodenticide Act(FIFRA), and toxic substances in the workplaceare regulated by the Occupational Safety andHealth Act (OSH Act). The Federal Food, Drug,and Cosmetic Act (FFDCA) regulates food andfood additives, drugs, and cosmetics. Theselaws address the vast majority of toxic sub-stances, and more than a dozen other acts focuson other substances and sources of exposure.Although neurotoxicity is generally not explic-itly mentioned in legislation mandating theregulation of toxic substances, it is implicitlyincluded as a toxicity concern.

Under the authority of this diverse frameworkof legislation, regulatory agencies have promul-gated equally diverse regulations for protecting

human health. Some regulatory programs re-quire substantial testing of chemicals to screenfor toxic effects; others are not empowered torequire any such testing. Some regulations callfor screening substances before they are allowedto enter the marketplace; other regulations arereactive, coming into effect only when evidenceindicates that an existing chemical can or doescause harmful effects.

Federal laws governing toxic effects can bedivided into three general categories:

1.

2.

3.

licensing and registration laws for newand existing chemicals, which entail ex-plicit review processes and may includerequirements for toxicity testing;standard-setting laws for chemicals usedin specific situations, under which regula-tory agencies determine recommended orrequired limits on toxic substances invarious environmental media (air, water,or soil) or emitted by a given source, ordictate appropriate labeling of productsthat contain toxic substances; andcontrol-oriented measures for dealingwith chemicals, groups of chemicals, orchemical processes that are explicitly iden-tified in the laws as targets of concern.

Distinctions among the three categories are notabsolute—there is more of a continuum than adiscrete grouping in the legislative language—but this classification indicates the basic types ofapproaches that have been developed to protectthe public and the environment from the adverseeffects of toxic substances.

Consistency of the Federal Regulatory Effort

There are numerous differences in regulatorypractice under different laws, even within thegroup of Incensing laws (TSCA, FIFRA, FFDCA).These differences do not, for the most part,apply specifically y to the regulation of neurotoxiceffects, but rather to regulation of all toxiceffects. Thus, consistency of regulation forspecific neurotoxic effects hinges on consis-tency of regulation in a more general sense.

Chapter 1-Summary, Policy issues, and Options for Congressional Action ● 17

Statutory requirements for chemical regula-tory programs differ in several important re-spects, among them the number of chemicalsevaluated, the time available for review, theamount and type of data available at thebeginning of the review process, the ability ofthe reviewer to acquire additional data afterreview has begun, and the burden of proofregarding safety. For example, the Premanufac-ture Notice (PMN) process under TSCA neces-sitates review of hundreds of chemicals everyyear; each review is allotted only 90 days(although an extension is possible), and substan-tive toxicity data are rarely submitted. EPA canobtain additional data or impose controls onchemicals only if it finds that there may be anunreasonable risk associated with use of thechemical. Without significant toxicity data,predicting risk is difficult and must rely onhypothetical relations between chemical struc-ture and biological activity. However, little isknown about structure-activity relationshipswith respect to neurotoxicity. Applicants forregistration of a pesticide under FIFRA mustsubmit extensive general toxicological dataaccording to specified test protocols, the reviewprocess extends over a period of years, theapplicant is required to submit additional data ifthe basic data raise concerns, and the applicantmust establish that the pesticide will be both safeand effective under the proposed conditions ofuse. Few data relating to neurotoxicity concernsare presently required. However, the agency isconsidering expanded testing requirements.

That there are differences in the degree ofregulatory scrutiny under the various Federalregulatory programs is widely acknowledged.Often, these disparate regulatory requirementsreflect real differences in the potential risksrepresented by the chemicals each programregulates. It may be that the more intensescrutiny reserved for some types of chemicals isan appropriate reflection of the likelihood thatthey will threaten human health or the environ-ment.

Current laws are generally based on thepremise that chemicals for which there is a

greater probability of exposure should meet ahigher standard of safety. This is most clearlyillustrated by the prohibition of carcinogenicsubstances as direct food additives and ofpesticides that concentrate in foods (the Delaneyclause of FFDCA). No such general prohibitionapplies to general industrial or commercialchemicals under TSCA or the OSH Act.

The stringency of the evaluation process fornew chemicals under the various laws generallymatches the presumption of risk—the combina-tion of hazard and exposure potential-posed byeach class (in the view of regulatory officials)and the number of new class members intro-duced each year. Thus, drugs are not to bepermitted on the market until proven safe andeffective in clinical trials. New pesticides andfood additives are evaluated nearly as strin-gently; however, human trials are not per-formed. Commercial chemicals, whether in-tended for industrial or consumer use, receivethe least scrutiny.

There are two exceptions to these trends, oneminor and one significant. Consumer chemicalshave not received any procedurally differentscrutiny than those intended for industrial use,despite the fact that larger numbers of personsmay be exposed as consumers than as industrialworkers. Moreover, FFDCA does not requirethat cosmetics and cosmetic ingredients undergopremarket toxicity testing. Industry voluntarilytests cosmetic ingredients for acute toxic effects,but few are examined for chronic toxicity. Somehave been found to have acute and chronicneurotoxic effects on laboratory animals.

While many scientists find some comfort inthe observation that the stringency of review ofa chemical matches its presumptive risk (exceptfor cosmetics), public interest groups havevoiced concerns over such odds playing. Forexample, the chemicals regulated under TSCAmake up the largest classes of chemicals, yetthey receive relatively little scrutiny by EPA.TSCA does offer options for selecting high-riskchemicals for further scrutiny, but the vastmajority of chemicals receive only a limited

18 ● Neurotoxcity: Identifying and Controlling Poisons of the Nervous System

review. Critics of EPA argue that regulatoryresource considerations and a desire not toburden industry, rather than presumptiverisk, are in fact driving chemical reviewcriteria. They raise the question of whetherthe minimal screening given to the majorityof chemicals is adequate to deal with high-risk chemicals that are not members ofknown risk categories.

Regulation of New v. Existing Chemicals

Existing chemicals are subject to varyingdegrees of review and reevaluation. In contrastto procedures for reviewing new chemicals,however, procedures for reexamining existingchemicals do not necessarily reflect the inherentrisks of the chemical classes involved.

EPA attempts to ensure the adequacy of thedata supporting continued pesticide registrationthrough a regular review process. The registra-tion standards program, which examines 25chemicals per year, has thus far addressed onlya small portion of the active ingredients ofregistered pesticides and has been the subject ofconsiderable concern. At the present rate, activepesticide ingredients would be reviewed on anaverage of only once every 12 years or more.The 1988 FIFRA amendments mandated thatthe review schedule be accelerated so that allactive ingredients are reviewed by 1997. Tomeet this goal, EPA will need to streamline itsexisting review process.

Under section 4 of TSCA, existing chemicalsare ranked for probable risk or high exposuresprior to entering the test rule or consent orderregulatory process. In the period from 1977 to1988, final rules were issued on only 25chemicals or related sets of chemicals, con-sent agreements were reached on three, withnine proposed rules pending. Clearly, theserules address only a very small fraction of the60,000 chemicals in the TSCA inventory.

FDA’s various procedures for reviewingexisting drugs and food and color additives areless formal than those for pesticides or toxicsubstances. FDA tracks physicians’ reports of

adverse drug reactions and reports them to theoriginal evaluators of the drugs. Food and coloradditives have been notable exceptions to thereview of existing chemicals. Until recently,once an additive was registered, there was nomonitoring of adverse reactions. For aspartame,FDA established voluntary reporting programs,but most food additives are not the subject offormal reporting programs. Although FDA doesnot require reporting on the use of approvedfood and color additives, i t could track suchinformat ion and use i t to assess the r i sksassociated with approved uses.

Specific neurotoxicological Considerations

Regulatory differences in general strategiesfor eva lua t ing toxic i ty en ta i l cor respondingd i f f e r e n c e s i n t h e e v a l u a t i o n o f n e u r o t o x i ce f f e c t s . T h u s f o r h u m a n d r u g s , p r e c l i n i c a ltoxicity tests are only used to guide observationson c l in ica l t r ia l s and to e luc ida te poss ib lemechanisms of toxicity, rather than to directlyassess toxic potential. For pesticides and foodand color additives, in contrast, animal toxicitydata are used directly in predicting human risk.H o w e v e r , e v e n w i t h i n p r o g r a m s t h a t h a v eessentially similar approaches to assessing toxicr isks , there are d i f ferences wi th respect toconsideration of neurotoxic risks.

Regula tory programs have adopted one ofthree basic approaches to toxicity evaluation,depending on which of three under ly ing as-sumptions they hold. One approach is based onthe assumption that general toxicity tests usinghigh doses a re adequate to de tec t neurotoxicpotent ia l and tha t neuro toxicologica l eva lua-tions are needed only if general tests, data onstructural analogues, or other specific knowl-edge about a chemical indicate a potential forneurotoxicity. Among these are FDA’s preclini-cal testing program for drugs and its currentp r o g r a m f o r a p p r o v i n g f o o d a d d i t i v e s . T h esecond approach, represented by the pesticider e g i s t r a t i o n p r o g r a m u n d e r F I F R A , a c c e p t smore general structural information in guidingneurotoxic i ty tes t ing . Al l organophosphorouscompounds are evaluated for the potential to

Chapter l-Summary, Policy Issues, and Options for Congressional Action ● 19

induce delayed neuropathy, but nonorgano-phosphorous compounds are not specificallyevaluated for neurotoxic potential. All pesti-cides undergo a general toxicity screen; how-ever, specific neurotoxicity tests are not pres-ently required. Finally, under section 4 ofTSCA, specific neurotoxicity testing is requiredfor any chemical with high exposure potential,as well as for chemicals specifically suspectedof being neurotoxic. Such testing presumes thatstandard toxicity tests are not adequate toevaluate neurotoxic effects.

OTA found that Federal efforts to controlneurotoxic substances varied considerably be-tween agencies and between programs withinagencies. Improving the Federal response willrequire increased neurotoxicity testing, im-proved monitoring programs, and more aggres-sive regulatory efforts.

Federal Interagency Coordination

Interviews with toxicologists and neurotoxicolo-gists in various Federal agencies indicated thatthere is little formal coordination among agen-cies, although neurotoxicologists at differentagencies maintain regular informal contacts.There are also several coordinated researchefforts mediated by interagency agreements andby personal contac t .In the spring of 1989,OTA and EPA cosponsored a workshop onFederal interagency coordination at whichAgency representatives decided to establishan Interagency Working Group on Neu-rotoxicology to foster increased interactionamong Federal agencies responsible for re-search and regulatory programs.

neurotoxicologists at different agencies main-tain regular informal contact, but this contacthas not fostered a consensus on the bestapproach to regulating neurotoxic hazards. Realdifferences of scientific opinion remain, anddata that would resolve these differences havenot been developed by the agencies involved.Restrictions on revealing confidential businessinformation hinder the transfer of potentiallyuseful toxicological information, both to thepublic and between Federal agencies. Moreover,

even wi th in agencies , neurotoxicologis t s andother toxicologists sometimes disagree on theproper role of neurotoxicity in safety evalua-tions.

An agency’s approach to neurotoxicity evalu-a t i o n o f t e n c o r r e s p o n d s t o t h e p r e s e n c e o ra b s e n c e o f n e u r o t o x i c o l o g i s t s o n t h e s t a f f .Al though th is presumably ref lec ts personnelconsiderations—if an agency is not evaluatingneurotoxicologica l da ta , i t does not requi rep e o p l e t r a i n e d t o d o s o - i t d o e s r a i s e t h eq u e s t i o n o f w h e t h e r p e r s o n s w h o e v a l u a t egeneral toxicological data understand the contribu-tions of directed testing to the prediction ofneurotoxic ef fec ts . Genera l toxicologis ts a reessential to the review process; however, indi-v iduals wi th specia l ized exper t i se are of tennecessary to ensure a comprehens ive evalua-tion. Variations in the hiring of neurotoxicolo-gists by Federal agencies reflect a more generalproblem of toxicologica l assessment , tha t ofd e t e r m i n i n g t h e a p p r o p r i a t e d e g r e e o f s p e -cialization required to evaluate the many organsys tems potent ia l ly a f fec ted by a toxic sub-stance. OTA found that effectiveness in ad-dressing neurotoxicological concerns at Fed-eral agencies is dependent on the presence ofneurotoxicologists in regulatory program of-fices. Improving Federal programs will re-quire increased employment of neurotoxicol-ogists trained in risk assessment and regula-tory procedures.

The Federal regulatory response to neurotox-icity is fragmented not only by differences inscientific judgment, but also by differences inregulatory responsibility. The decision to evalu-ate drugs, pesticides, and food additives bystricter standards than are applied to commercialchemicals is based not only on the views ofscientists, but also on national consensus. Thus,the perception of risk by the public can stronglyinfluence regulatory policies related to toxicsubs tances .

Economic Considerations in Regulation

Regula t ing neurotoxic subs tances involvesconsideration of both the economic benefits of

20 Neurotoxicity: ldentifying and Controlling Poisons of the Nervous System

using these substances and their actual orpotential costs. The problem of balancing bene-fits, costs, and risks of regulation is not uniqueto the control of neurotoxic substances; it arisesin all forms of health, safety, and environmentalregulation. Regulations that are designed toreduce or prevent neurotoxic risks can benefitsociety through improvements in public healthand environmental amenities. In most cases,however, society incurs costs to achieve theseregulatory ends. The costs of complying withhealth and safety regulations may also result inincreases in market prices, reductions in indus-try profits, and declines in new product innova-tion.

Many of the key Federal laws under whichneurotoxic substances are regulated requireagencies to ascertain the positive and negativeeconomic consequences of regulation. In imple-menting these laws, Congress has generallyintended that agencies prepare regulatory analy-ses and document the balancing of benefits,costs, and risks of proposed alternatives.

The Costs and Benefits of neurotoxicity Testing

Experience with neurotoxicity testing is stillrelatively limited, creating uncertainty regard-ing the available cost estimates for this type oftesting. Because of the uncertainty regardingthese costs, OTA obtained estimates of the costsof several types of neurotoxicity tests from anumber of individuals in government, industry,and academia.

The median estimates derived from OTA’ssurvey indicate that a complete set of neurotox-icity tests, including a functional observationalbattery, motor activity, and neuropathology,may add from 40 to 240 percent to the costs ofconventional toxicity tests currently required byEPA. By far the largest portion of the added costcomes from the neuropathology evaluations,which are needed to determine whether struc-tural change in the nervous system has occurredand the nature and significance of the change.Based on its survey, OTA found that acuteneurotoxicity tests (including EPA’s functionalobservational battery, motor activity test, and

neuropathology evaluations) may add a total ofabout $50,000 to standard toxicity test costs.Subchronic neurotoxicitytests may add $80,000,and chronic tests may add about $113,000. TheEPA subchronic schedule-controlled operantbehavior test may add about $64,000. However,the functional observational battery alone wouldadd only $2,500 to the cost of a conventionalacute toxicity test. A conventional acute test oforal exposure presently costs about $21,000.

Testing costs should be viewed in the contextof the health benefits of minimizing publicexposure to neurotoxic substances, the total costto industry of marketing a new product, poten-tial profits resulting from the sale of the product,and the impact high initial costs have on theinnovation process.

The benefits of regulating neurotoxic sub-stances can be measured in terms of the humanand monetary values placed on reduction of risk.A number of approaches have been used toassign monetary values to reduction of the risksof mortality, morbidity, and disability. Lead hasbeen the subject of an in-depth economicanalysis. A 1985 study estimated that the totalhealth benefits of reducing the neurotoxiceffects of lead on U.S. children would amountto more than $500 million annually between1986 and 1988. If adult exposure to lead,including workers’ exposure, were included,the benefits would be considerably larger.Although the health and economic benefits oflimiting public exposure to neurotoxic sub-stances are more difficult to estimate than thecosts of regulation, the example of leadillustrates the importance of considering thepotentially large monetary benefits of regula-tory actions. Like other toxicity testing, neuro-toxicity testing is conducted to prevent adversehealth effects; hence, the benefits of such testingmay not be readily apparent and may accrue wellinto the future. Often, the immediate costs oftesting receive considerable attention by regula-tory officials, but the sizable potential economicbenefits of preventing public exposure to ahazardous substance receive comparatively lit-tle attention.

Chapter 1-Summary, Policy Issues, and Options for Congressional Action . 21

As indicated earlier, neurotoxic substances, inparticular abused drugs, play a significant,causal role in the development of neurologicaland psychiatric disorders; however, the preciseextent of the contribution remains unclear.Mental disorders and diseases of the nervoussystem contribute substantially to healthcosts in the United States. In 1980, theyranked as the third and fifth most expensivemedical conditions in terms of personalhealth-care expenditures. The estimate ofnearly $40 billion (1980 dollars) for these twocategories of morbidity does not include valuesfor lost productivity, restricted activity, andother social costs (e.g., criminal activity, lawenforcement, and rehabilitation for drug andalcohol abuse) that frequently accompany men-tal illness or other forms of mental impairment.

International Issues

Like most environmental concerns, neurotox-icity is a problem that is not limited by nationalboundaries. Pollutants readily cross nationalborders, hazardous chemicals are frequentlyimported and exported between industrializedand developing nations, and adulterated foodand commercial products enter the United Statesdespite current regulatory efforts. Strategies tolimit human exposure to neurotoxic substancesshould be devised in the context of both nationaland international regulatory and research initia-tives.

International Regulatory Activities

Despite numerous regulations governing theexport and import of neurotoxic chemicals andproducts containing them, some countries do nothave the regulatory framework and resources toadequately protect human health and the envi-ronment from these substances. Many nations,including the United States, have policies andprocedures in place, but too often they workonly on paper. In practice, they may allowneurotoxic substances to slip through the regula-tory cracks. Some developing nations haveregulations to protect workers and consumersfrom the adverse effects of neurotoxic sub-stances, but these nations often lack the re-

sources to enforce them. This lack of effectiveregulation and enforcement in developing na-tions has a negative impact not only on publichealth and environment in the user country, butalso in industrialized nations, including theUnited States, where people process and con-sume products imported from developing na-tions.

Both TSCA and FIFRA contain provisionsexempting certain U.S. products produced forexport from the requirements that apply toproducts sold for use in the United States. Inmost instances, the requirements of TSCA donot apply to substances manufactured, proc-essed, or distributed for export. The require-ments will, however, apply if it is determinedthat the mixture or article will present anunreasonable risk of injury to health within theUnited States or to the environment of theUnited States. In addition, because pesticidesintended solely for export are exempt from thepublic health protection provisions of FIFRA,pesticide manufacturers can legally exportbanned, severely restricted, or never-registeredsubstances that have been deemed too hazardousfor use in this country. Companies that do so arerequired to notify the importing country that thepesticides in question have been banned, se-verely restricted, or never registered for use inthe United States. Sometimes such pesticidesare used on food crops that are imported backinto the United States for consumption. Criticsof this practice have termed it the ‘‘circle ofpoison. ’

On January 15, 1981, several days before theend of his term, President Jimmy Carter issuedan Executive Order that set controls on exportsof substances that were banned or severelyrestricted in the United States. Several days afterbecoming President, Ronald Reagan revokedthis order.

International Research Activities

Active interest in neurotoxicity began in theUnited Kingdom during and after World War II.Since that time, research efforts in the UnitedStates have gradually increased. The United


States is now the world leader in environmentallegislation and government funding of neuro-toxicology research.

International research activities tend to focuson the heavy metals (lead and mercury), organicsolvents, and pharmaceutical agents. Scandi-navian countries have been active in research onthe neurotoxicity of organic solvents. OtherEuropean countries have supported research oncompounds of particular concern in occupa-tional settings, such as pesticides and heavymetals. Foreign neurotoxicology -related scien-tific papers published in international journalsmost often originate from authors in Canada,England, Italy, Australia, and Japan. A numberof papers originate from authors in France,India, Sweden, Finland, and Mexico, as well.

neurotoxicology research has been primarilyan intranational effort. In recent years, someinternational cooperation has been initiated bythe World Health Organization and the U.S.National Toxicology Program, but thus farcooperation has occurred only in specific areassuch as lead toxicity, solvent toxicity, and thedevelopment of testing methodologies. Thelimited scope of international cooperation islargely due to the lack of funds available forsuch efforts.

In some European countries, notably theFederal Republic of German and Sweden,environmental movements are becoming in-creasingly influential. It is likely that thesenations will play leading roles in supportingresearch and in developing regulations to con-trol toxic substances. The Federal Republic ofGermany has already acted to remove lead fromgasoline and to fund studies of lead toxicity inchildren. All of the Scandinavian countries(Sweden, Denmark, Norway, and Finland) havetraditionally supported research on solvents.These patterns are likely to continue and maybroaden to include the investigation of othertoxic substances as environmental movementsgrow. Political events in the Soviet Union haveled to the emergence of an environmentalmovement, and it appears that the Soviet

government will also take a more active role inthese issues. Finally, in the Far East, both thePeople’s Republic of China and Japan are facingmajor pollution problems and are becomingincreasingly involved in toxicological issues.

POLICY ISSUES AND OPTIONS FORCONGRESSIONAL ACTION

Six broad policy issues related to the identifica-tion and regulation of neurotoxic substanceswere identified during the course of this assess-ment:

1.

2.

3.

4.

5.

6.

adequacy of the Federal regulatory frame-work,adequacy of Federal and federally spon-sored research programs,coordination of Federal regulatory andresearch programs,availability of adequately trained researchand health-care professionals,communication of information to workersand the public, andadequacy of international regulatory andresearch programs.

Associated with each policy issue are severaloptions for congressional action, ranging in eachcase from taking no action to making substantialchanges. Some of the options involve directlegislative action. Others involve the executivebranch, but with congressional oversight ordirection. The order in which the options arepresented does not imply any priority. More-over, the options are not, for the most part,mutually exclusive; adopting one does notnecessarily disqualify others within the samecategory or in any other category. A carefulcombination of options might produce the mostdesirable effects. It is also important to keep inmind that changes in one area may haverepercussions in other areas.

ISSUE 1: Is the current Federal regulatoryframework addressing neurotoxicity ade-quately?

The Federal regulatory framework has beenbuilt on the foundation established by four


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major Acts: 1) Toxic Substances Control Act; 2)Federal Insecticide, Fungicide, and RodenticideAct; 3) the Federal Food, Drug, and CosmeticAct; and 4) Occupational Safety and Health Act.At least a dozen other acts address generaltoxicological concerns. Many of them explicitlyor implicitly mandate regulation of neurotoxicsubstances. Options related to this issue areorganized around the Federal agency with leadresponsibility for implementing a particular law.

Environmental Protection Agency

EPA is responsible for implementing two ofthe major acts, TSCA and FIFRA, and several

others pertaining to neurotoxic substances, in-cluding the Clean Air Act; the Federal WaterPollution Control Act and Clean Water Act; theSafe Drinking Water Act; the ComprehensiveEnvironmental Response, Compensation, andLiability Act; the Marine Protection, Research,and Sanctuaries Act; and the Resource Conser-vation and Recovery Act.

Option 1: Take no action.

If no congressional action is taken, EPA willcontinue to be responsible for carrying out theprovisions of the existing statutes, which implic-itly address neurotoxicity in the context ofgeneral toxicological concerns. The degree towhich neurotoxic substances are regulated willvary according to program priorities, resources,the expertise of Agency personnel, and interpre-tation of pertinent laws by Agency officials. Todate, few toxic substances have been regulatedon the basis of known or suspected adverseeffects on the nervous system. Even in theabsence of congressional action, this situation islikely to change, given greater public andAgency awareness of neurotoxicological con-cerns and the institution of new neurotoxicitytesting guidelines under TSCA and FIFRA. Forexample, EPA is actively considering requiringfunctional observational battery, motor activity,and neuropathological tests for all new pesti-cides and for all existing pesticides undergoingreregistration.

Option 2: Mandate more extensive neurotoxicity“ testing under TSCA and FIFRA.

neurotoxicity test guidelines developed byEPA to support regulatory programs mandatedby TSCA and FIFRA will allow the Agency torequire neurotoxicity testing of a wide range ofindustrial chemicals and pesticides. The extentand frequency of testing EPA may require is notclear at this time.

If it wishes to mandate additional neurotoxic-ity testing, Congress could require EPA to testnew and existing chemicals if certain productionvolume and human exposure levels are reachedand if structure-activity relationships or other


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information suggests that the substance may beneurotoxic. Volume and exposure levels can beeffective triggers for testing. Production volumeis currently being used as a trigger by the FederalRepublic of Germany, and this testing approachhas been considered by EPA in the past.However, triggered testing does have importantlimitations-some substances may have potentneurotoxic effects at low doses. Congress mayalso wish to request that EPA consider novel

approaches to obtaining more extensive datafrom industry under TSCA, perhaps through theuse of economic incentives. EPA could workwith industry representatives to devise incen-tives for voluntary neurotoxicity testing. EPAcould also work more closely with scientists inindustry and academia to develop and validateneurotoxicity tests.

Congress could amend FIFRA, mandatingthat new and existing pesticides being consid-ered for registration undergo neurotoxicity test-ing under the newer, more extensive guidelines.This would formalize EPA’s pending policy andwould underscore congressional concern re-garding the potential adverse effects of neuro-toxic pesticides on public health. Currently,EPA plans to require the use of three neurotoxic-ity tests: the functional observational battery,motor activity, and neuropathological evalua-tions. Congress could also mandate that certainclasses of inert ingredients undergo neurotoxic-ity evaluations as well. Congress may wish torequest that EPA consider developmental neurotoxi-cological and behavioral tests in addition to thethree core neurotoxicity tests for certain pesti-cides. Such tests are considered by some scien-tists to be particularly important in evaluatingthe effects of neurotoxic substances on children.Congress could also mandate that risk assess-ments devote increased attention to the potentialadverse effects of pesticides on children.

Option 3: Require that EPA and other Federalagencies revise the confidential businessinformation provisions of various toxic sub-stances control laws and regulations to allowgreater access to toxicological information.

Under TSCA, for example, much of theinformation submitted to EPA by chemicalmanufacturers or processors can be claimed tobe confidential business information. Informa-tion covered by such a claim cannot be divulgedto anyone outside the small group of EPAemployees who have been granted a specialclearance, primarily selected EPA staff andcontractors. The aim of confidentiality provi-sions is to prevent commercially valuable infor-

Chapter 1-Summary, Policy Issues, and Options for Congressional Action . 25

mation from being disclosed to the submitter’scompetitors. Other environmental statutes con-tain similar provisions regarding confidential ortrade secret information.

Toxicity data per se cannot be claimed asconfidential under TSCA, but much of the otherinformation relevant to assessing toxic riskscan—including the identity of the chemical forwhich toxicity data are presented, its physical-chemical properties, and its intended uses. Thisrenders the health and safety data of little use toanyone without a special clearance.

The strong confidentiality provisions in TSCAcan present significant barriers to efficientregulation. The requirement for a special clear-ance prevents the use of confidential data byanyone without a clearance, even if they areEPA officials or officials of other Federalagencies who are attempting to regulate thesame chemical or closely related chemicalsunder different laws. The limited exchange ofinformation can lead to duplication of effort,particularly when several agencies are con-strained by confidentiality provisions.

The inability to share information, eitherinside the government or with outside parties,often interferes with research efforts. For exam-ple, much of the information on a chemical’sstructure-activity relationship is covered byclaims that it is confidential business informat-ion. Scientists in industry, academia, and othergovernment agencies cannot gain access to thisinformation, even when it might contain valua-ble data for developing improved methods ofpredicting neurotoxicity and other toxic effects.At the same time, claims of confidentiality mayprevent EPA from obtaining expert advice orconsensus opinions from academic or industrialscientists.

Public interest groups and other interestedindividuals do not have access to informationthat would allow them to question-or toaccept—EPA’s actions on many toxic sub-stances. Nor can individuals take action toprotect themselves if they do not have access toinformation regarding the identity of toxic

chemicals or the products that might containthem.

Few persons would dispute the need for someform of protection for trade secrets. However,many persons believe that there is good reasonto question whether the burden imposed bystrong confidentiality provisions and similarstatutes on the government, the public, andindustry is justifiable.

Congress could disallow certain kinds ofinformation, including the precise chemicalidentification of a substance and all toxicologi-cal data on a substance, from claims of confiden-tiality. It could mandate that more informationabout the chemical properties, potential adverseeffects, and production and release of toxicsubstances be made available to the public. Itcould amend existing laws or write new laws toenable sharing of information between Federalregulatory programs. Congress could also createa centralized confidential database, admini-stered by one designated agency, or a consor-tium of agencies, and divert all reporting to thedesignated agency. In addition, it could requiremore extensive labeling of the contents ofchemical products.

Option 4: Take action to provide agriculturalworkers with greater protection from theadverse effects of pesticides.

Congress could amend FIFRA, giving EPAgreater regulatory authority to protect farm-workers and others from the adverse effects ofpesticides (see box l-E).

Option 5: Mandate that neurotoxicity concernsbe addressed in regulatory activities undervarious other laws for which EPA has regula-tory responsibilities.

Congress could mandate that neurotoxicityreceive greater attention under any or all of thefollowing laws: the Clean Air Act; the CleanWater Act; the Safe Drinking Water Act; theComprehensive Environmental Response, Com-pensation, and Liability Act; and the ResourceConservation and Recovery Act. Each lawaddresses toxicological concerns in a different


Box l-E—neurotoxic Pesticides

Organophosphorous and carbamate insecticidesare the most neurotoxic classes of pesticides used inthe United States and are the most common causes ofagricultural poisoning. They pose a significant threatto a substantial portion of the 4 to 5 million Americanswho work in agriculture. At the biochemical level, theymay affect humans in the same manner that they affectthe insects for which they are intended-throughinhibition of the enzyme that breaks down the neuro-transmitter acetylcholine. The acute health effects oforganophosphorous and carbamate insecticides in-clude hyperactivity, neuromuscular paralysis, visualproblems, breathing difficulty, restlessness, weakness,dizziness, and possibly convulsions. The organo-chlorine class of pesticides is also very toxic becausethese substances accumulate in the body and causepersistent overstimulation of the central nervous sys-tem. Acute or subacute intoxication from organo-chlorines produces excitability, apprehension, dizzineweakness, muscle twitching, tremors, convulsions, and

Photo credit.’ Doug/as Watts/Christopher Brady

ss, headache, disorientation, confusion, loss of balance,coma.

What scientific and epidemiological data there are suggest pesticide poisoning prevails despite existingprotective measures. The Environmental Protection Agency (EPA) is aware of the shortcomings of the protectionscurrently in effect for farmworkers and others who work with pesticides. The Agency has proposed regulations toimprove them, but critics have already deemed the proposals inadequate. EPA claims to be restricted by the FederalInsecticide, Fungicide, and Rodenticide Act, which grants the Agency only limited regulatory power. Inadequatefunding has also contributed substantially to the weaknesses of Agency programs.

The possible occurrence of neurobehavioral disorders after chronic low-level exposure or acute poisoningdeserves further study. Neuropsychological assessments of occupational groups have yielded inconsistent results,perhaps reflecting differences in the type and scope of tests used. Few studies have had an adequate follow-up toassess the length of impairment. Field studies have not provided sufficient data on levels of pesticides in children’sblood or duration of exposure to understand dose-response relationships, nor have most studies controlled for age,education, or other potential confounding factors. Few or no studies have examined exposed workers prospectively,subgroups of women or aging workers, interactions between pesticides, or interactions between pesticides andpharmacological agents (including ethanol and common medications).


reamer. Congress could take action as these levels of pesticide residues in foods. Potentiallaws are amended, as funds are appropriated,and/or through various oversight activities.Such action might include making specificreference to neurotoxic substances or the ad-verse effects of chemicals on the nervoussystem, or both, in legislation addressing toxicsubstances and requiring that neurotoxic poten-tial be considered when conducting risk assess-ments. With respect to FIFRA specifically,Congress could mandate that neurotoxic poten-tial be carefully considered in setting tolerance

adverse effects of pesticides on the developingnervous system could be cited as a particularconcern.

Congress could also request that EPA reviewthe effectiveness of agency programs in regulat-ing neurotoxic substances and examine ap-proaches to improve existing activities.

Food and Drug Administration

The Federal Food, Drug, and Cosmetic Actcovers a wide range of substances. It authorizes


FDA to require submission of specific toxicitytest data before permitting food additives, drugs,and other substances to be marketed. Thisauthority could be used to incorporate neurotox-icity evaluations in FDA test guidelines or torequire neurotoxicity testing during the applica-tion process if initial toxicological data indicatepotential neurotoxic effects. FDA does not haveauthority to require premarket toxicity testing ofcosmetic ingredients.


If Congress chooses to take no action, FDA islikely to continue to address the potentialneurotoxicity of food additives, drugs, and othersubstances in the context of general toxicologi-cal concerns. FDA does not routinely requirespecific neurotoxicity testing for food additivesand drugs; instead, it evaluates the potential forneurotoxic effects in the context of a broadtoxicological profile. Some scientists, includingmost FDA officials, believe that specific neuro-toxicity testing of drugs and food additives is notnecessary and that existing general toxicologicaltesting approaches adequately detect adverseeffects on the nervous system. Other scientistsbelieve that existing general toxicological ap-proaches are not sensitive enough to detectmany neurotoxic effects and that specific neuro-toxicity tests are essential for a complete toxico-logical evaluation.

Option 2: Commission an independent study bythe National Academy of Sciences to deter-mine whether specific neurotoxicity testsshould be routinely required by FDA inevaluating the safety of drugs, food additives,and other substances regulated under FFDCA.

This option would address the issue of theadequacy of existing testing approaches. Such astudy could include a retrospective analysis todetermine whether conventional toxicologicaltests have failed to detect neurotoxic effects. Itcould also include a symposium at whichscientists from academia, industry, government,and elsewhere could present varying views onthis subject and attempt to reach a consensus onthe proper course of action.

Option 3: Mandate more extensive neurotoxicitytesting under FFDCA for drugs, food addi-tives, and other substances.

Congress could mandate that FDA revise its‘‘Toxicological Principles for the Safety Assess-ment of Direct Food Additives and ColorAdditives Used in Food,” commonly referred toas the ‘Red Book, ’ to require routine neurotox-icological screening of new food additives andto formulate improved processes for postmarkedsurveillance of new and existing additives.Congress could also require that some generallyregarded as safe (GRAS) compounds undergoneurotoxicity testing. It could require that newdrugs, particularly psychoactive drugs, undergoincreased neurotoxicity testing through the useof specific neurotoxicological tests. In particu-lar, Congress could mandate that FDA requirecomplete neurotoxicity testing of psychoactivedrugs that may be prescribed to children andpregnant women. Choosing this option wouldinvolve agreeing with scientists who believe thatpresent toxicological testing practices at FDAdo not adequately address potential adverseeffects on the nervous system and that specificneurotoxicological tests are necessary to estab-lish the safety of food additives and drugs.

Option 4: Amend FFDCA to require premarkettoxicity testing of cosmetics and cosmeticingredients.

FDA does not have the statutory authority torequire premarket toxicity testing of cosmeticsand cosmetic ingredients. Industry voluntarilyconducts general testing of many products. IfFDA finds that a cosmetic product has not beenadequately tested, it can require that it bepackaged with a warning label stating that ‘thesafety of this product has not been determined. ’In addition, FDA can take regulatory actionagainst any poisonous or deleterious substancein cosmetics. Congress could amend FFDCA torequire that cosmetics and cosmetic ingredientsundergo premarket toxicity tests consistent withthose required of drugs. Testing requirementscould include a screen for neurotoxicologicaleffects. A general toxicological evaluation, at

28 ● neurotoxic@: Identifying and Controlling Poisons of the Nervous System

least, would ensure a degree of safety compara-ble to that of other products regulated underFFDCA.

Option 5: Mandate more extensive postmarkedsurveillance and monitoring of the adverseeffects of drugs, food additives, cosmetics,and other substances and require that suchinformation be made more readily availableto the public.

Congress could mandate that FDA substan-tially expand postmarked surveillance and moni-toring of the adverse effects, particularly neuro-toxic effects, of drugs, food additives, cosmet-ics, and other substances. Congress could man-date that health-care professionals report ad-verse effects directly to FDA. Congress couldmandate that surveillance and monitoring databe made more readily available to the public. Itcould also mandate expanded patient packaginginformation in drug products. Additional infor-mation could be provided to patients on poten-tial adverse neurotoxic effects of drugs, particu-larly at higher than recommended doses, and onadverse effects that should be reported to ahealth-care professional (box l-F).

Occupational Safety and Health Administration

OSHA is authorized under the OSH Act toregulate toxic substances in the workplace inorder to ensure that no employee suffers mate-rial impairment of health or functional capacity.Recently, OSHA promulgated a far-reachingrevision and update of existing standards. Thenew standards affect 428 chemicals, loweringexisting permissible exposure limits for 212substances and establishing new exposure limitsfor 164 others. However, in devising the newstandards, OSHA relied to a large extent on therecommendations of the American Conferenceof Governmental Industrial Hygienists, a privateorganization, instead of NIOSH, the Federalscientific advisory organization on occupationalhealth issues. The advisability of this approachis likely to be a subject of continuing contro-versy in the occupational health field (box l-G).The adequacy of OSHA’s efforts to protect theNation’s workers from toxic substances in

general and neurotoxic substances in particularis a controversial issue. There are varying viewson the extent to which OSHA regulatory actionstake into account neurotoxicological concernsand the adequacy of industrial programs tomonitor worker exposure to neurotoxic sub-stances. There is also the question of whyfarmworkers, a segment of the work force thatregularly comes into contact with pesticideswith neurotoxic properties, are not afforded thesame legal protections as most other U.S.workers.


If no congressional action is taken, OSHAwill continue to be responsible for carrying outthe existing provisions of the OSH Act, whichassure that no employee suffers “materialimpairment of health or functional capacity. ”Under these provisions, neurotoxic effects areimplicitly, but not explicitly, covered. There-fore, the limited attention given to neurotoxicitywill continue to be determined by agencypriorities, resource considerations, public con-cerns, and the expertise of regulatory officials.

Option 2: Mandate that neurotoxicity concernsreceive greater attention under the OSH Act.

Congress could use the authorization andappropriations process to communicate to OSHAits concern regarding neurotoxicity. The currentlaw could be strengthened by incorporating anexplicit reference to neurotoxic substances orthe adverse effects of chemicals on the nervoussystem, or both. Congress could mandate thatMaterial Safety Data Sheets clearly describepotential adverse affects on the nervous system.Congress could encourage industry to assurethat health-care professionals, safety officers,and employee supervisors are aware of theneurotoxic potential of the chemicals to whichemployees are exposed. In addition, Congresscould request that the General AccountingOffice evaluate the effectiveness of OSHA’senforcement program with respect to neurotoxicsubstances.


Box l-F—Limitations of FDA’s Postmarked Monitoring System for Adverse Drug Reactions:Halcion, A Case Study

Halcion, the most widely prescribed sleeping medication in the United States, was first approved for use in late1982 with a recommended usual adult dose of 0.25 to 0.50 mg. Its package insert included mentions of amnesia,confusion, agitation, and hallucinations as possible side-effects. Over the next few years, FDA’s adverse reactionmonitoring system recorded an excess of adverse reports for Halcion in comparison to other benzodiazepinehypnotics--even after correcting for market share of the drug. In 1987, as a result of the reports and the apparentdose-relatedness of some adverse effects, several labeling and marketing changes were made. The usual adult dosewas changed to 0.25 mg, two paragraphs mentioning the apparent dose-relatedness of some side-effects were addedto the package insert, and a “Dear Doctor” letter was issued detailing the labeling changes. In early 1988, Upjohn,the manufacturer, discontinued the 0.50 mg tablet.

Following these changes, public concern about possible problems associated with Halcion use increased,largely because of a September 1988 article in California Magazine and a story on the ABC television program20/20 in February 1989. The number of adverse reports received, which was expected to decline as a result of thelabeling changes and Halcion’s status as an “older” drug (the number of adverse reports associated with a drugnormally decreases over time), rose. In September 1989, FDA convened an expert panel to review the reporting dataon Halcion and to discuss whether further changes should be made in the labeling or marketing of the drug.

Discussion at that meeting illustrates the difficulties of drawing conclusions from the spontaneous adversereporting process. In a comparison of adverse reports for Halcion (45 million prescriptions written since 1982) withadverse reports for Restoril (35 million prescriptions written since 1980), a drug prescribed to patients with similarsleeping problems, the following data were presented:

Total number of reports received by FDAAdverse event Halcion RestorilAmnestic events 267 4Hallucinations, paranoid behavior 241 12Confusion and delirium 304 17Hostility and intentional injury 48 2

Overall, an average of 38 adverse reports per million prescriptions was received for Halcion, while 7.5 adversereports per million prescriptions were received for Restoril.

These seemingly dramatic results, however, were tempered by myriad complicating variables. The influenceof publicity, differences in reporting rates by manufacturers, lack of dosage information in about one-half of theadverse reports for Halcion, and ‘‘new drug’ v. ‘‘older drug’ effects all obscured the significance of differencesbetween the sets of data. The 4-week period following the 20/20 episode, for example, produced twice as manyadverse reports for Halcion as the 4-week period preceding the show. The FDA panel finally concurred that the datawere too unreliable to warrant action, except possibly in the case of amnesia.

The unreliable data generated by the postmarketing monitoring system now in place effectively limit FDAreview to premarket trials. Unexpected interactions with other medications or long-term side-effects may easily bemissed. This is particularly disturbing from the standpoint of neurotoxicity, since drugs not expected to haveneuropharmacological effects are not necessarily subjected to specific neurotoxicity testing. Changes which couldimprove the present system might include a requirement that all adverse report forms be sent directly to FDA aswell as a requirement that physicians submit reports for all ‘‘serious” adverse reactions observed.

Because of the inherent limitations in FDA’s drug approval and adverse reaction monitoring systems, it isimportant that physicians and patients be aware of the possible adverse effects of the medications they prescribeand consume. Drugs are approved for use under certain conditions and at certain doses, and complicating factorssuch as age, other medications, or illness may significant y alter the effects of these drugs. In most cases, the decisionto take any medication is a personal choice for the patient; an individual cannot make an informed decision withoutaccess to information about potential adverse effects.

SOURCES: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, PsychopharmacologicalDrugs Advisory Committee, Transcript o~l’roceedings, Thirty-First Meeting (Rockville, MD: September 1989); “When SleepBecomes a Nightmare, ” 20/20, ABC, Feb. 17, 1989; Pharmaceutical Data Services, ‘‘Top 200 Drugs of 1989,’ American Druggisr,in press.

30 ● neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 1-G-Organic Solvents in the Workplace

Organic solvents and mixtures of solvents with other organic solvents or other toxic substances are widely usedin the workplace. Millions of workers come into contact with solvents every day through inhalation or contact withthe skin, Some solvents profoundly affect the nervous system. Acute exposure to organic solvents can affect anindividual’s manual dexterity, response speed, coordination, and balance. Chronic exposure of workers may leadto reduced function of the peripheral nerves and such adverse neurobehavioral effects as fatigue, irritability, lossof memory, sustained changes in personality or mood, and decreased ability to learn and concentrate.

The National Institute for Occupational Safety and Health (NIOSH) recommends that employers inform andeducate workers about the materials to which they are exposed, potential health risks involved, and work practicesdesigned to minimize exposure to these substances. NIOSH also recommends that employers assess the conditionsunder which workers may be exposed to solvents, develop monitoring programs to evaluate the extent of exposure,establish medical surveillance for adverse health effects resulting from exposure, and routinely examine theeffectiveness of control methods being employed.

The Occupational Safety and Health Administration has recently updated the permissible exposure limits forapproximately 428 substances, including many solvents. The new ruling established lower exposure limits forapproximately 212 substances already regulated by the agency. Permissible exposure limits are established for thefirst time for another 168 substances, while existing limits for 25 substances are reaffirmed. This marks the first timein 17 years that a new set of exposure standards has been established. For many companies, meeting the newstandards may require stricter engineering controls or more frequent use of respirators and other personal protectivedevices, or both. Continued education of workers, improved methods of preventing exposure, and plans orprocedures to maintain compliance with the new ruling are required.


Option 3: Mandate increased efforts to monitor which they are exposed, access to exposure andadverse neurological and behavioral effectsof substances in the workplace.

Congress could mandate increased monitor-ing of adverse neurological and behavioraleffects of toxic substances in the workplace.This would include enhanced efforts to detecttoxic chemicals and improved reporting ofknown or potential adverse effects of chemicalson the nervous system, including the incidenceof neurological or psychiatric disorders ordiseases. Congress could mandate improvedpostmarketing surveillance of new products.

Congress could also mandate that OSHAconduct a review of its regulatory programs andexamine ways to more effectively protect work-ers from neurotoxic substances.

Option 4: Mandate the extension to farmwork-ers of legal rights under the OSH Act.

Congress could mandate the OSH Act toinclude farmworkers under its provisions. Thiswould give workers the right to know about thetoxicity of pesticides and other chemicals to

medical records, and protection against retalia-tion by employers for taking steps to protecttheir health. Congress could consider extendingthese rights without preempting the more exten-sive standards that now exist in some States.

Consumer Product Safety Commission

The Consumer Product Safety Commission(CPSC) is an independent regulatory commis-sion charged with protecting the public from“unreasonable risks of injury associated withconsumer products.’ Risk of injury is defined as‘‘risk of death, personal injury, or serious orfrequent illness.’ The Federal Hazardous Sub-stances Act provides for the protection of publichealth by requiring that hazardous substances belabeled with various warnings, depending on thenature of the hazard. The Poison PreventionPackaging Act requires that CPSC preventinadvertent poisoning of small children byspecially packaging hazardous substances tomake it “significantly difficult for childrenunder 5 years of age to open or obtain a toxic or


harmful amount of the substance therein withina reasonable time. ’


Present laws treat neurotoxic substances inthe context of general toxicological concerns.Therefore, the degree to which CPSC specifi-cally addresses neurotoxic substances dependson program priorities, resources, and the exper-tise of regulatory officials. Views regardingCPSC’s current degree of concern about neuro-toxic effects vary.

Option 2: Mandate that neurotoxicity concernsreceive greater attention under various Fed-eral laws for which CPSC has regulatoryresponsibilities.

Congress could mandate that a private commis-sion or organization examine the effectivenessof CPSC’s present regulatory activities in pro-tecting the public, especially high-risk groupssuch as children, from neurotoxic and othertoxic substances. In addition, congressionalauthorization and appropriations committeescould request that CPSC programs place ahigher priority on concerns related to theadverse effects of toxic substances on thenervous system, including a requirement that theCommission ensure that products with neuro-toxic potential be clearly labeled.

Department of Housing and Urban Development

The Lead-Based Paint Poisoning PreventionAct of 1971 required that the Department ofHousing and Urban Development (HUD) elimi-nate as far as practicable the hazards of leadpaint in existing houses, and mandated that theDepartment promulgate necessary regulations.However, the General Accounting Office re-ported in 1981 that HUD had not fulfilled itsresponsibility to eliminate lead-based paint inFederal housing. Following litigation and acourt order, HUD revised its regulations in 1986and 1987, and in 1988 Congress amended thatAct requiring that HUD promulgate additionalregulations to address the problem.


HUD is making progress in meeting congres-sional mandates to address lead-based paint inhousing, however, the pace of progress is slow.In the absence of congressional action, HUDwill continue to move forward, but large num-bers of children will continue to be exposed tolead-based paint in older homes.

Option 2: Amend the Lead-Based Paint Poison-ing Prevention Act to better address theproblem of lead paint in older homes.

If Congress wished to take action to expediteremoval of lead-based paint from older homes,it could amend the had-Based Paint PoisoningPrevention Act establishing new programs toaddress the problem and providing funds to support paint removal efforts.

Option 3: Establish a major new program toprovide findingfor the removal of lead-basedpaint from older homes.

Congress may wish to enact a new law tofacilitate removal of lead-based paint from olderhomes. One proposal recently developed by theEnvironmental Defense Fund (EDF) recom-mends establishment of a trust fund financed byan excise fee on the production and importationof lead. The EDF proposal calls for a programjointly administered by EPA and the Depart-ment of Health and Human Services.

ISSUE 2: Is the current Federal researchframework addressing neurotoxicity ade-quately?

The current Federal research framework foraddressing neurotoxicity is composed of majorextramural programs sponsored by NIH andADAMHA. A sizable intramural program islocated at EPA, and more limited intramuralprograms are under way at ADAMHA and NIH.FDA has a substantial developmental neurotoxi-cology program at its National Center forToxicological Research, but research effortselsewhere are very limited in scope. OTA foundthat, in general, Federal research programs arenot adequately addressing neurotoxicologicalconcerns.

32 ● neurotoxiciq: Identifying and Controlling Poisons of the Nervous System


EPA has a large intramural research programdevoted to environmental neurotoxicology. Al-though the Agency has a small extramural grantsprogram, it is not currently supporting anyprojects in which neurotoxicology is a majorfocus. EPA supports intramural program initia-tives through a small number of contracts andcooperative agreements.


Without congressional action, EPA intramu-ral programs will continue at moderate levels.However, in the absence of an Agency policychange, lack of funding for supplies and equip-ment may continue to hamper some researchefforts. Failure to expand EPA’s intramuralprogram will make it difficult to move into new,priority areas such as the development of in vitroneurotoxicity testing approaches and the analy-sis of structure-activity relationships of chemi-cals.

Option 2: Provide funding for expansion ofintramural research programs.

Congress could choose to provide greatersupport to EPA’s Office of Research andDevelopment to fund additional research in theenvironmental neurotoxicology field. Budgetincreases would also alleviate problems associ-ated with the lack of funds for supplies andequipment. Substantial increases would allowEPA to move into new areas of research thatwould strengthen its regulatory capabilities,including its efforts to understand the relation-ship between chemical structure and neurotoxiceffects and further development and validationof neurotoxicity testing protocols, particularlyin vitro and developmental tests.

Option 3: Provide funding for extramural grantprograms to support neurotoxicological andneuroepidemiological research.

EPA’s total extramural grants program forenvironmental issues is small; fiscal year 1989funding for the entire program (addressing allenvironmental concerns) was $8.2 million to

support individual academic investigators and$4.5 million to support eight EnvironmentalResearch Centers (in addition, the Superfundprogram provides $2.5 million in grants toinvestigators and $5.0 million to support fivehazardous substances research centers). Cur-rently, EPA is funding no neurotoxicology-related research grants to individual investiga-tors through its extramural program. Federalresearch programs are normally composed ofboth intramural and extramural efforts: extra-mural programs enable talented investigators inacademia and elsewhere to carry out research ofinterest to the sponsoring agency. They alsoallow an agency to complement its short-termintramural efforts, required to meet regulatoryneeds, with long-term studies that will helpguide future research.

EPA is considering substantial expansion ofits extramural programs. Congress could sup-port such expansion or mandate programs thatgo beyond EPA’s plans, or both. A grantsprogram in neurotoxicology would greatly im-prove the scientific foundation of the Agency’sregulatory decisionmaking. Areas that wouldparticularly benefit from increased support aremonitoring and neuroepidemiology, which aidin tracking the contribution of environmentalcontaminants to adverse human effects, includ-ing neurological and psychiatric disorders. Inaddition, extramural research designed to im-prove the Agency’s ability to predict neurotoxiceffects (e.g., through a better understanding ofchemical structure-activity relationships) wouldgreatly benefit regulatory programs. Researchon the neurotoxicological properties of specificsubstances would aid in regulatory decision-making, and would enhance the Agency’sability to understand and predict the neurotoxic-ity of other substances.

National Institutes of Health

NIH supported more than 200 neurotoxicology-related research projects in fiscal year 1988.Most of the projects were extramural competi-tive grants to investigators in public and private


institutions. A few intramural projects wereconducted.


In the absence of congressional action, NIHwill continue to conduct limited intramuralresearch related to neurotoxicology, primarily atthe National Institute of Neurological Disordersand Stroke (NINDS) and the National Instituteon Deafness and Other Communication Disor-ders (NIDCD). The very small intramural re-search effort in environmental neurotoxicologyat NIEHS might be enhanced. Institute manag-ers could require that existing basic neuro-science research efforts change their focus toneurotoxicological concerns.

Extramural programs that fund neurotoxicologi-cal research projects are sponsored by severalInstitutes, particularly the three mentioned above.Without congressional action, these programswill continue to fund a core group of neurotoxi-cologists in academia at moderate levels. It isunlikely that the number of individual researchprojects funded would increase significantly.

Option 2: Enhance National Institutes of Healthresearch efforts related to neurotoxicology,

If Congress wishes to enhance the NIH effort,it could mandate development of a 5-year planto address neurotoxicological concerns. Such aplan could include an analysis of current NIHintramural and extramural programs, as well asdevelopment of an integrated and comprehen-sive approach to neurotoxicological research inthe years ahead. NIH would also benefit from anoutside review of the missions of individualInstitutes and the current intramural and extra-mural programs supporting those missions.Increased interaction among Institutes and be-tween Institutes and other Federal agencieswould improve NIH’s response to neurotoxicityconcerns. Congress could expand the 5-yearplan to include all relevant programs in theDepartment of Health and Human Services.This would include NIH, ADAMHA, FDA,NIOSH, the Agency for Toxic Substances andDisease Control, and other organizations. De-

velopment of such a plan would lead to acoordinated Federal effort to address the neuro-toxicity issue.

Congress could provide additional funding toNIH to expand extramural grant programs,allowing various Institutes to enhance researchefforts on such subjects as the mechanisms bywhich drugs cause adverse neurotoxic effects,the mechanisms by which environmental con-taminants adversely affect the nervous system,and the extent to which toxic substances contrib-ute to neurological and psychiatric disorders.High-priority research goals might include thestructure-activity relationships of toxic chemi-cals, the vulnerability of developing and agingnervous systems to toxic substances, and thevariation in sensitivity of individuals to thesesubstances.

Congress could fund additional intramuralresearch into high-priority areas of neurotoxi-cology research. It could also mandate rees-tablishment of an intramural neurobehavioraltoxicology program at the National Institute ofEnvironmental Health Sciences and request thatthe National Toxicology Program give a higherpriority to neurotoxicity concerns.

Alcohol, Drug Abuse, and Mental HealthAdministration

ADAMHA funds extensive neurotoxicity re-search at all three of its Institutes (OTA hasexcluded research on alcohol and alcoholismfrom this study). The National Institute on DrugAbuse (NIDA) and the National Institute ofMental Health (NIMH) both fund a substantialnumber of extramural research grants. Intramu-al research programs related to neurotoxicol-ogy are somewhat limited in size and scope.


If Congress chooses to take no action,ADAMHA programs will continue at moderatelevels. However, without budget increases orsignificant reprogramming of funds, it will bedifficult for these institutes to expand researchefforts in the neurotoxicology field.

34 ● Neurotoxicity : Identifying and Controlling Poisons of the Nervous System

Option 2: Encourage greater research empha-sis on the impact of abused drugs on thenervous system and on the potential contribu-tions of toxic substances to neuropsychiatricdisorders.

Congress may wish to encourage ADAMHAto devote increased resources to the potentiallong-term and permanent adverse effects of drugabuse, particularly the effects of maternal drugabuse on the developing nervous system of thefetus. Congress could also encourage greateremphasis on research to understand the mecha-nism by which psychoactive drugs and othertherapeutic drugs act on the central nervoussystem, and particularly on how to preventmoderate to severe adverse side-effects of thesedrugs. ADAMHA could also focus more atten-tion on neurotoxicity issues associated with theuse of multiple psychoactive drugs for longperiods of time by the elderly. Research ad-vances in these areas would promote the devel-opment of safer, more effective drugs. Congresscould support expanded research on the bio-chemical processes underlying addiction toabused drugs at NIDA’s Addiction ResearchCenter.


Research programs within FDA are con-ducted at the National Center for ToxicologicalResearch (NCTR) in Jefferson, Arkansas, and atthe Center for Food Safety and Applied Nutri-tion in Washington, D.C. Research programsrelated to neurotoxicology are very small, withthe exception of the intramural developmentalneurotoxicology research program at NCTR.


Without congressional action, neurotoxicol-ogy research programs within FDA will remainvery limited in scope. Relatively little researchis currently devoted to neurotoxicological con-cerns. This is of particular significance becauseso many substances regulated under the Food,Drug, and Cosmetic Act have neurotoxic poten-tial. Although some funds, particularly at NCTR,could be redirected to this area, present fiscal

limitations on FDA research leave little roomfor flexibility.

Option 2: Provide funding to expand or initiateintramural and extramural research pro-grams related to the adverse effects on thenervous system of drugs, cosmetics, foodadditives, naturally occurring toxic substancesin food, and other substances.

Congress could choose to provide FDA withfunds to support both intramural and extramuralresearch related to the potential neurotoxiceffects of substances regulated under FFDCA. Asizable research effort in this area would sub-stantially improve FDA’s ability to protectpublic health through an improved understand-ing of the effects of toxic substances on thenervous system. To promote substantive re-search efforts in critical areas, Congress couldconsider establishing research centers at aca-demic institutions to focus on specific neurotoxi-cological concerns (e.g., structure-activity rela-tionships, development of neurotoxicologicaltests, epidemiological studies, mechanisms ofaction). Congress could also provide funds tosupport a major neurotoxicology research unitwithin FDA.

National Institute for Occupational Safetyand Health

NIOSH, located within CDC, has identifiedneurotoxic disorders as one of the Nation’s 10leading causes of work-related disease andinjury. To aid in understanding the extent andnature of this problem, NIOSH supports a smallnumber of intramural and extramural researchactivities. The intramural program is devotedprimarily to evaluation of testing approachesand to analysis of selected neurotoxic sub-stances found in the workplace. The NIOSHextramural program funds a very small numberof grants devoted to understanding the mecha-nisms by which toxic substances adverselyaffect the nervous system.


If no action is taken, NIOSH research pro-grams related to neurotoxicity will continue at a

Chapter l-Summary, Policy Issues, and Options for Congressional Action . 35

low level. Given the magnitude of the problemof exposure to neurotoxic substances in theworkplace, the present level of effort will notensure an adequate database to support theanticipated needs of the Occupational Safetyand Health Administration.

Option 2: Expand intramural and extramuralneurobehavioral research programs at NIOSH.

This option would lead to improvements inunderstanding the extent to which workers areexposed to neurotoxic substances, the mecha-nisms by which these substances exert adverseeffects, and means of preventing exposures inthe workplace. Substantive increases in fundingfor research would provide a better foundationfor OSHA’s regulatory activities related toneurotoxicity. Priority research needs include abetter understanding of dose-response relation-ships, mechanisms of action, and structure-activity relationships. Methods for evaluatingworker exposures need to be developed, im-proved, and validated. Epidemiological studiesare needed to reveal the extent of workplaceexposure to neurotoxic substances and thecontribution of such exposure to neurological,psychiatric, and other disorders and injuries.More research is needed on latent neurologicaldisorders that may result from chronic, low-level exposure to neurotoxic substances.

Substantially increased NIOSH funding ofextramural neurotoxicology and neurobehav-ioral research would improve scientific under-standing of workers’ exposure to toxic chemi-cals. Such an increase would encourage researchscientists to enter the field of environmentalneurotoxicology by supporting laboratories thatfocus on occupational health issues. It wouldalso be an important source of training forphysicians.

Other Federal Agencies and Organizations

Other Federal agencies and organizations thatundertake neurotoxicity-related research includethe Center for Environmental Health and InjuryControl and the National Center for HealthStatistics within CDC, the Agency for Toxic

Substances and Disease Registry, the Depart-ment of Energy, the Department of Agriculture,the Department of Veterans Affairs, and theNational Aeronautics and Space Administra-tion. The Department of Defense conductsneurotoxicology -related research, particularlyas it relates to chemical warfare; however,defense-related research is not included in thisreport. The National Science Foundation pres-ently supports very little research in this area.


If Congress chooses to take no action, smallresearch programs in these organizations arelikely to continue. In some of them, limitedefforts may be appropriate; in others, particu-larly those within DHHS, small efforts mayhamper the ability of other agencies and individ-uals to address neurotoxicity-related issues. Forexample, the National Center for Health Statis-tics provides most of the current information onthe prevalence, mortality, and morbidity associ-ated with neurological and other diseases in theUnited States. Because of budget cuts in recentyears, neuroepidemiologists have had difficultyin obtaining the statistical information neces-sary for studies of how neurotoxic substancescontribute to neurological and psychiatric disor-ders.

Option 2: Mandate that various Federal organi-zations and agencies undertake or expandresearch programs addressing neurotoxicity -related concerns.

Several organizations could support researchefforts in neurotoxicology that would enhancetheir own programs and those of others. Con-gress could mandate that these agencies adjustprogram priorities to better address neurotoxicity-related concerns, it could selectively provideincreased funds for these programs, or it coulddo both. For example, enhanced efforts at theCenter for Environmental Health and InjuryControl, National Center for Health Statistics,and Agency for Toxic Substances and DiseaseRegistry would benefit many Federal and Stateagencies and would provide support to academicinvestigators. The Department of Energy has

36 ● neurotoxici~: Identifying and Controlling Poisons of the Nervous System

recently reemphasized research on the toxico-logical effects of chemicals. Its existing pro-grams are focused on nuclear-related healthconcerns; support of nonnuclear, neurotoxicity -related research is minimal. Studies of theneurotoxic substances generated by energy-producing technologies would be beneficial.The National Science Foundation could spuracademic research into the mechanisms bywhich toxic substances adversely affect thenervous system by providing support for basicresearch in the neurotoxicology field,

ISSUE 3: Should Congress take steps toimprove interagency coordination of Fed-eral research and regulatory programsrelated to neurotoxicity?

Until recently there was little coordination ofFederal research and regulatory programs re-lated to neurotoxic substances. At a workshopsponsored by OTA and EPA, representatives ofvarious Federal agencies decided to establish anInteragency Working Group on neurotoxicol-ogy l to aid in interagency coordination.


Without congressional action, the new inter-agency coordinating group may succeed inenhancing the exchange of regulatory and re-search information among Federal agencies.The success of an initiative of this kind is largelydetermined by the willingness of senior agencyadministrators, program managers, and tech-nical personnel to participate and voluntarilyshare information. Whether an adequate level ofinterest will be maintained is not clear. Anotherimportant question is whether the group willhave sufficient support at the senior manage-ment levels to carry out research and regulatoryinitiatives.

Option 2: Mandate and formalize the establish-ment of an organization to foster coordina-tion of Federal interagency research and

regulatory programs related to neurotoxicol-ogy.

Congress could formalize the existing inter-agency coordinating group by mandating establish-ment of an organization to ensure maximum useof U.S. research and regulatory resources.Congress could mandate that all significantFederal programs be represented in the organi-zation, and it could require the submission of areport every 5 years on the state of the Federalneurotoxicology research and regulatory effort.This interagency organization would benefitfrom a board of advisors from academia, indus-try, and elsewhere who could evaluate existingprograms and provide guidance on future direc-tions. Choosing this option would require theredirection of existing agency funds or theappropriation of new funds.

ISSUE 4: Are current Federal educationaland research policies and programs ensur-ing an appropriate number of adequatelytrained research and health-care profes-sionals to address neurotoxicity concerns?

A significant portion of our current under-standing of the effects of toxic substances on thenervous system comes from application of basicresearch to environmental health problems.However, too few scientists are trained in bothneuroscience and toxicology to provide anadequate supply of neurotoxicologists. In addi-tion, other environmental health professionalsare needed to address neurotoxicological con-cerns, including neuroepidemiologists, occupa-tional physicians, and nurses with training inneurotoxicology.


Without congressional action, the focus offederally supported training programs will con-tinue to be determined by individual agencies,and funding will continue at low levels. Inade-quate Federal support of training is partlyresponsible for the shortage of adequately

I@ ~t. 26, 1989, tie ~me ~m changed t. the “Interagency Committee on Ne~otoxicology ” (ICON). The committee is administered ~OU@the neurotoxicology Division of EPA’s Health Effects Research Laboratory in Research Triangle Park, NC.


trained research and health-care professionals inthe field of neurotoxicology.

Option 2: Take steps to encourage individuals toestablish careers in research and health-carefields that address toxicological, particularlyneurotoxicological, concerns.

If Congress wishes to take this approach, itcould mandate expansion of pre- and post-doctoral research training programs in neurotox-icology by increasing the number of traininggrants to individuals and/or research centers.This would primarily involve expansion ofexisting programs supported by NIH and NIOSH.Congress could encourage training of medicalstudents in occupational medicine, includingcourse work in neurotoxicology. It could pro-mote training of graduate students in neurotoxi-cology by providing additional funds to NIH,ADAMHA, and NIOSH for this purpose or byfunding a new training program that would beadministered by EPA. It could also encouragephysician residency training in occupationalmedicine by increasing the funds (through TitleVII of the Health Professionals Education Act)for establishing such programs. Finally, it couldencourage training of occupational safety andhealth specialists through continued or in-creased funding of the NIOSH training grantsprogram, in particular the Educational ResourceCenters.

ISSUE 5: Are workers and the public receiv-ing sufficient information to allow them tomake informed decisions about exposureto neurotoxic substances?

Preventing adverse effects of exposure toneurotoxic substances depends largely on un-derstanding the threat that neurotoxic sub-stances pose to human health and knowing howto limit exposure to these substances. In recentyears, Congress has taken steps to increase thequantity and quality of information available tothe public concerning health risks posed by toxicsubstances. For example, the Federal Emer-gency Planning and Community Right-to-KnowAct of 1986 has resulted in a large database,

Photo credit: UnitedAutomobik, Aerospace, and Agricultural ImplementWorkers of America-UAW Public Relations Department

Respirators may be useful in minimizing exposure tosolvent vapors when engineering or work practice controls

are inadequate.

accessible to the public, on the release of morethan 300 toxic chemicals at facilities throughoutthe United States. In 1987, the Department ofLabor expanded the OSHA hazard communica-tion standard. This standard gives employees theright to know what chemicals they may encoun-ter in the workplace. In general, information istransmitted through hazard communication pro-grams, which use labels on containers and otherwarning signs; post appropriate safety informa-tion, including material safety data sheets; andtrain and educate employees about the chemicalproperties and hazardous effects of the toxicsubstances to which they are or may be exposed.


38 . neurotoxicity: Identifying and Controlling Poisons of the Nervous System

In the absence of congressional action, exist-ing hazard communication and right-to-knowlaws will provide the public and workers withuseful information about the health risks posedby neurotoxic substances. The relevance of thisinformation to neurotoxicity concerns will con-tinue to be determined to a large degree by theperceptions and priorities of officials in thevarious agencies with regulatory responsibili-ties. Federally mandated worker informationprograms tend to focus on the carcinogenic andteratogenic potential of toxic substances; non-cancer health risks such as neurotoxicity tend toreceive less attention, even though they maypose an equal or greater health threat.

Option 2: Take action to ensure that the risksposed by neurotoxic substances are explicitlydescribed to the public through hazard com-munication and right-to-know laws.

Choosing this option will result in enhancedcommunication of neurotoxic health risks to thepublic. Congress could require that informationprovided to workers under the Hazardous Communi-cation Standards of the Occupational Safety andHealth Act include a description of significanthazards posed by neurotoxic substances, and itcould mandate improved enforcement of thehazardous communication provisions of thisAct. Congress could also require that neurotox-icity concerns be explicitly addressed in infor-mation developed and released under the Fed-eral Emergency Planning and Community Right-to-Know Act. Information on trends in annualdata would also be useful in monitoring pro-gress, in limiting releases, and in minimizingpublic exposure.

Option 3: Take additional steps to inform thepublic of the short- and long-term adverseeffects of abuse of psychoactive drugs on thenervous system.

Congress could provide NIDA with fundingfor an aggressive campaign to inform the publicof the potential long-term consequences of drugabuse on the nervous system. Congress couldmandate that particular attention be devoted tothe abuse of psychoactive drugs by pregnant

women and the severe effects these substancesmay have on the nervous system of the develop-ing fetus.

Option 4: Mandate improved labeling of con-sumer products with respect to potentialneurotoxic effects.

Congress could take steps to assure thatsubstances purchased by consumers that haveneurotoxic potential are appropriately labeledand contain appropriate warnings when neces-sary. Congress could request that agenciesdevote particular attention to substances that

\ ’\ \ , ’ - - - -=.. \‘\ \ “.



may adversely affect the developing nervoussystem.

In addition, Congress could mandate that alltoxic product ingredients, including those some-times referred to as ‘inert’ substances, be listedon product labels. This is particularly importantwith respect to pesticide products.

ISSUE 6: Should the United States moreactively encourage and participate in inter-national regulatory and research programsrelated to neurotoxic substances, andshould the United States revise its policieswith regard to the export of neurotoxicsubstances?

The adverse effects on the nervous system ofoccupational and environmental exposure totoxic chemicals are a major problem in thedeveloping regions of the world. The UnitedStates is the leader in the international researcheffort to understand the health risks posed byneurotoxic substances. Because of this exper-tise, many persons believe that the United Statesshould participate more actively in cooperativeinternational efforts to address the problem. Inaddition, many question current U.S. policiesregarding the export of neurotoxic substancesthat have been banned, severely restricted, ornever registered for domestic use.


At the present time, U.S. scientists activelyparticipate in international conferences pertain-ing to toxic substances and human health risks.To a more limited extent, public and privateagencies in the United States and foreigncountries cooperate in research and regulatoryactivities. In the absence of congressional ac-tion, informal international activities will con-tinue, but significant formal arrangements forcoordinating research and regulatory efforts areunlikely.

Even though the United States is capable oftraining individuals from foreign countries inthe fields of neurotoxicology and neuroepidemi-ology, it is very difficult for U.S. academic

institutions to obtain funds to support suchefforts. In the absence of congressional action,little funding will be available for training of thiskind.

Without congressional action, the UnitedStates will continue to export neurotoxic sub-stances that are banned, severely restricted, ornever registered for use in this country. Personswho support current export policies believe thatsuch practices are appropriate as long as thehealth risks posed by the chemical are communi-cated to the receiving country. Persons whooppose these policies believe that, despite ef-forts at hazard communication, many receivingnations do not have the expertise to judge thenature of the health risks; further, they argue thatrisk-related information is often not adequatelycommunicated to users. The use of banned,severely restricted, or never-registered pesti-cides in developing countries is often cited as aparticular problem.

Option 2: Encourage Federal agencies to initi-ate and participate in joint internationaltesting efforts to evaluate the toxicity of newand existing chemicals.

Because so many chemicals have not beenadequately tested for neurotoxicity, some per-sons believe it would be advantageous to testcertain chemicals under joint international agree-ments. If standardized testing procedures couldbe agreed on, such an approach might result ina more equitable sharing of the chemical testingburden throughout the international community.The International Program on Chemical Safety(a joint venture of the United Nations Environ-ment Program, the International Labor Organi-zation, and the World Health Organization) hassponsored efforts to develop methods for assess-ing the neurotoxic effects of exposure to chemi-cals. Congress could encourage and supportinternational programs of this kind. It could alsoencourage the development of an internationaltoxicity database accessible to developing coun-tries at minimal cost.

Option 3: Provide or redirect finding to encour-age neurotoxicological and epidemiological

40 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

research and information exchange betweenpublic and private U.S. organizations andthose offoreign nations.

This option would promote internationalprograms to evaluate the health risks posed byneurotoxic substances and would encouragecooperative efforts to minimize human exposureto chemicals and naturally occurring substancesthat pose a public health risk. It is currentlydifficult for U.S. researchers to obtain grantsupport for projects involving internationalcollaboration. Modest funding to encouragesuch collaboration would lead to mutuallybeneficial research efforts. U.S. neurotoxicolo-gists and other scientists have few contacts inThird World countries, where their expertisecould promote research and training of foreignpersonnel. Creation of a grants program to fosterthese relationships would not only respond tothese needs, but also enlarge the perspective ofU.S. scientists and promote international coop-eration.

This option would encourage Federal agen-cies to provide grant support to academicinstitutions for partial sponsorship of interna-tional conferences and working groups onneurotoxicological questions. In addition, Con-gress could encourage continued U.S. participa-tion in international toxicological research andpolicy planning activities. In particular, it couldencourage the design and implementation ofeducational programs to inform people in devel-oping countries about the risks posed by expo-sure to neurotoxic substances.

Option 4: Allow academic institutions receivingFederal funds for training grants to use adesignated percentage of funds to supportnon-U.S. residents.

At the present time, NIH can support foreignresearch fellows through various mechanisms;however, Federal funds are not available to helpsupport foreign students at U.S. academic insti-tutions. Allowing U.S. institutions to use adesignated percentage of training funds tosupport non-U.S. nationals and residents would

facilitate the exchange of graduate students andpostdoctoral fellows and aid foreign nations indeveloping their own research and regulatoryprograms. Congress could also make Federalfunds available to encourage public and privateinstitutions to sponsor research and training ofpersons in developing countries by U.S. person-nel working in those countries.

Option 5: Revise existing laws governing theexport of hazardous substances.

Congress could take action under variouslaws to ensure that regulations limiting theexposure of U.S. citizens to toxic substances areextended to individuals in foreign nations. Thiscould involve prohibiting or limiting the exportof neurotoxic substances that are banned, se-verely restricted, or never registered for domes-tic use. Such action would address the ethicalconcerns of persons who believe that currentpolicies place the United States in a position ofprofiting from the export of chemicals that areconsidered to be too hazardous for domestic use.It would also help to minimize the exposure ofU.S. citizens to hazardous chemicals through theimport of foods, food products, and otherconsumer goods containing toxic substancesthat have been banned, severely restricted, ornever registered in the United States.

Specifically with respect to pesticides, Con-gress could take steps to ban or restrict theexport of those products that are not registeredin the United States. It could prohibit or restrictthe export of particularly hazardous pesticidesto countries that do not have adequate regula-tory, monitoring, and public and worker healthprotection programs. Congress could also re-quire proper labeling of all exported pesticideproducts, including clearly written warnings inappropriate languages. Warning labels could berequired to include the use of generally under-stood poison and health protection symbols.Steps could be taken to prohibit or restrict theimport of food products containing the residuesof pesticides not registered for use in the UnitedStates.

Chapter 2

Introduction

‘‘Chemicals are an everyday fact of life in modern society. They enhance our lives in ways too numerous tocount, but progress has its price, and too often the price of the role of chemicals in our society is human illnessand disease.

Representative Harold L. VolkmerCommittee on Science and Technology

U.S. House of RepresentativesOctober 8, 1985

‘‘Nervous system dysfunction during advanced age seems destined to become the dominant disease entity ofthe twenty-first century. Neither I, nor anyone else, can tell you how much of that dysfunction might beattributable to toxic chemicals in the environment. So far, hardly anyone has looked. ”

Bernard Weiss, Ph.D.Testimony before the Committee on Science and Technology


WHAT IS NEUROTOXICITY? .SCOPE OF THIS STUDY . . . . . .WHO IS AT RISK? . . . . . . . . . . . .EXAMPLES OF neurotoxic

Industrial Chemicals . . . . . . . . .Pesticides . . . . . . . . . . . . . . . . . . . .Therapeutic Drugs . . . . . . . . . . .Abused Drugs . . . . . . . . . . . . . . . .Food Additives . . . . . . . . . . . . . . .Cosmetics . . . . . . . . . . . . . . . . . . .

CONTENTS

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......’ ...*.*. ● .@

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. . . . . . . . . . . . . . . . . . . . . . . ..+..... ..+.*,*. ........ “.

SUBSTANCE S. . . . . . . . . . . . . .. .+ .. .. ... ..+. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ ~.....+. ● ☛☛

✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ .....$+, -....... .......+ . . . . . , , . . . . .

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TOXIC SUBSTANCES AND NEUROLOGICAL AND PSYCHIATRICDISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

IDENTIFYING neurotoxic SUBSTANCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . + . . . . . . .REGULATING neurotoxic SUBSTANCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ECONOMIC CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . + . . . . . . . . . . . . . . .INTERNATIONAL CONCERNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . +CHAPTER 2 REFERENCES . . . . . . . . . . . . + . . . . . . . . . . . . . . . . . . . + . . . . . . . . . . . . . . . . . . . . . .

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Fibers in the Cerebral. . . . . . . . . . . . . . . . . . . . .the United States,. . . . . . . . . . . . . . . . . . . . .in the United States,. . . . . . . . . . . . . . . . . . . . .

to Toxic Substances .. . . . . . . . . . . . . . . . . . . . .

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Chapter 2

Introduction

Chemicals are an integral part of our daily livesand are responsible for substantially improvingthem. Yet chemicals can also endanger our health,even our survival. This report focuses on neurotoxicsubstances, those chemicals that adversely affect thenervous system. Included among such substancesare industrial chemicals, pesticides, therapeutic drugs,abused drugs, foods, food additives, cosmetic ingre-dients, and naturally occurring substances. Whethera substance causes an adverse health effect dependson many factors, including the toxicity of thesubstance, the extent of exposure, and an individ-ual’s age and state of health. Minimizing publichealth risks requires knowledge about the propertiesand mechanisms of action of potentially toxicsubstances to which humans may be exposed. Thisknowledge provides the foundation for safety stan-dards.

More than 65,000 chemicals are in the Environ-mental Protection Agency’s (EPA’s) inventory oftoxic chemicals, and each year the Agency receivesapproximately 1,500 notices of intent to manufac-ture new substances (30). Since few of thesechemicals have been tested to determine if theyadversely affect the nervous system (or other sys-tems), no precise figures are available on the totalnumber of chemicals in existence that are potentiallyneurotoxic to humans. Some estimates have beendeveloped, however, based on analyses of certainsubsets of chemicals. These estimates vary consider-ably, depending on the definition of neurotoxicityused and the subset of substances examined. Forexample, some 600 active pesticide ingredients areregistered with EPA (27), a large percentage ofwhich are neurotoxic to varying degrees. Oneinvestigator estimated that 3 to 5 percent of indus-trial chemicals, excluding pesticides, have neuro-toxic potential (41). Another investigator found that28 percent of industrial chemicals for which occupa-tional exposure standards have already been devel-oped demonstrate neurotoxic effects (1). In addition,a substantial number of therapeutic drugs and manyabused drugs have neurotoxic potential.

Human exposure to most known neurotoxicsubstances is normally quite limited. Consequently,the number of substances that pose an actual threatto public health is considerably less than the total

number of neurotoxic substances in existence. Thenumber of neurotoxic substances that pose asignificant public health risk is unknown becausethe potential neurotoxicity of only a small num-ber of chemicals has been evaluated adequately.

WHAT IS neurotoxicITY?The nervous system comprises the brain, the

spinal cord, and a vast array of nerves that controlmajor body functions. Movement, thought, vision,hearing, speech, heart function, respiration, andnumerous other physiological processes are con-trolled by this complex network of nerve processes,transmitters, hormones, receptors, and channels.

20-812 -90 - 2 : QL 3 -43-


Although every major body system can be ad-versely affected by toxic substances, the nervoussystem is particularly vulnerable to them. Unlikemany other types of cells, nerves have a limitedcapacity to regenerate. Also, many toxic substanceshave an affinity for lipids, fat-like substances thatmake up about 50 percent of the dry weight of thebrain, compared to 6 to 20 percent of other organs(8).

Many toxic substances can alter the normalactivity of the nervous system. Some produce effectsthat occur almost immediately and last for a periodof several hours: examples include a drug thatprevents seizures, an alcoholic beverage, and fumesfrom a can of paint. The effects of other neurotoxicsubstances may appear only after repeated exposuresover weeks or even years, for example, regularlybreathing the fumes of a solvent in the workplace oreating food or drinking water contaminated withlead. Some substances can permanently damage thenervous system after a single exposure: certainorganophosphorous pesticides and metal compoundssuch as trimethyl tin are examples. Other substances,including abused drugs such as heroin and cocaine,may lead to addiction, a long-term adverse alterationof nervous system function. Many neurotoxic sub-stances can cause death when absorbed, inhaled, oringested in sufficiently large quantities.

Care must be taken in labeling a substanceneurotoxic because factors such as dose and in-tended effects must be taken into consideration. Asubstance may be safe and beneficial atone concen-tration but neurotoxic at another. For example,vitamins A and B6 are required in the diet in traceamounts, yet both cause neurotoxic effects in largedoses (50). In other cases, a substance that is knownto be neurotoxic may confer benefits that are viewedas outweighing the adverse effects. For example,thousands of individuals suffering from schizophre-nia have been able to live relatively normal livesbecause of the beneficial effects of the antipsychoticdrugs. However, chronic use of prescribed doses ofsome of these drugs may give rise to tardivedyskinesia-involuntary movements of the face,tongue, and limbs—side-effects so severe that theymay incapacitate the patient (50).

Another factor that complicates efforts to evaluateneurotoxicity is the potential additive effects of toxicsubstances. For example, independent exposure totwo toxic substances may lead to no observable

adverse effects, but simultaneous exposure couldresult in damage to the nervous system. In addition,the body has an effective but limited capacity fordetoxifying many chemical agents. Some chemicalsthought to be relatively nontoxic may cause adverseeffects if exposure occurs after the body’s detoxify-ing systems have been saturated (17). Such situa-tions might occur following chronic exposure to acomplex mixture of chemicals in the workplace or tochemicals at hazardous waste sites.

Broadly defined, any substance is considered tohave neurotoxic potential if it adversely affects anyof the structural or functional components of thenervous system. At the molecular level, a substancemight interfere with protein synthesis in certainnerve cells, leading to reduced production of aneurotransmitter and brain dysfunction. At thecellular level, a substance might alter the flow ofions (charged molecules such as sodium and potas-sium) across the cell membrane, thereby perturbingthe transmission of information between nerve cells.Substances that adversely affect sensory or motorfunctions, disrupt learning and memory processes,or cause detrimental behavioral effects are neuro-toxic, even if the underlying molecular and cellulareffects on the nervous system have not beenidentified. Exposure of children to lead, for example,leads to deficits in I.Q. and poor academic achieve-ment (40). Behavioral effects are sometimes theearliest signs of exposure to neurotoxic substances(56). In addition, there is evidence that the adverseeffects of some toxic substance-induced neurodegen-erative diseases may not become apparent untilyears after exposure (49).

For the purposes of this study, the Office ofTechnology Assessment (OTA) defines neurotoxic-ity or a neurotoxic effect as an adverse change inthe structure or function of the nervous systemfollowing exposure to a chemical agent. This is thedefinition currently used for regulatory purposes byEPA (50 FR 188). However, as the precedingdiscussion illustrates, this definition should be usedin conjunction with information on the intended useof the substance, the degree of toxicity, and the doseor extent of exposure of humans or other organisms.The definition hinges on interpretation of theword “adverse,” and there is disagreementamong scientists as to what constitutes “adversechange.” The nature and degree of impairment, theduration of effects (especially irreversible effects),and the age of onset of effects are among the many

Chapter 2-Introduction .45

factors taken into account in determining whether ornot an effect is adverse. The definition is furthercomplicated by the possibility that adverse effectson the nervous system maybe secondary effects ofthe action of a toxic substance on other organs. Forexample, kidney or liver damage may lead toadverse effects on the nervous system (26). Deter-mining whether a particular neurological or behav-ioral effect is adverse requires a comprehensiveanalysis of all available data, including considera-tion of social values (1 1).

SCOPE OF THIS STUDYThis study examines many, but not all, of the

classes of toxic substances. The assessment in-cludes discussion of industrial chemicals, pesti-cides, therapeutic drugs, substance drugs, foods,food additives, cosmetic ingredients, and suchnaturally occurring substances as lead and mer-cury. It does not include radioactive chemicals;nicotine (from cigarette smoke); alcohol (ethanol);biological and chemical warfare agents; microbial,plant, and animal toxins; and physical agents such asnoise.

WHO IS AT RISK?Everyone is at risk of being adversely affected by

neurotoxic substances, but individuals in certain agegroups, states of health, and occupations face agreater probability of adverse effects. The develop-ing nervous system is particularly vulnerable tosome neurotoxic substances, for several reasons. Itis actively growing and establishing cellular net-works, the blood-brain barrier that protects much ofthe adult brain and spinal cord from some toxicantshas not been completely formed, and detoxificationsystems are not fully developed. Consequently,fetuses and children are more vulnerable to theeffects of certain neurotoxic substances than areadults (44). The National Academy of Sciences(NAS) recently reported that 12 percent of the 63million children under the age of 18 in the UnitedStates suffer from one or more mental disorders andidentified exposure to toxic substances before orafter birth as one of the several risk factors thatappear to make certain children vulnerable to thesedisorders (31).

The elderly are more susceptible to certainneurotoxic substances because decline in structureand function of the nervous system with age limits

its ability to respond to or compensate for toxiceffects (17). In addition, decreased liver and kidneyfunction increases susceptibility to toxic substances.Aging may also reveal adverse effects masked at ayounger age. Persons who are chronically ill,especially those suffering from neurological orpsychiatric disorders, are at risk because neurotoxicsubstances may exacerbate existing problems. Also,many elderly Americans take multiple drugs thatmay interact to adversely affect nervous systemfunction. According to the Department of Health andHuman Services (DHHS), people 60 and olderrepresent 17 percent of the U.S. population butaccount for nearly 40 percent of drug-related hospi-talizations and more than half the deaths resultingfrom drug reactions (19). Common adverse effectsinclude depression, confusion, loss of memory,shaking and twitching, dizziness, and impairedthought processes.

Workers in industry and agriculture often experi-ence substantially greater exposures to certain toxicsubstances than the general population. The Na-tional Institute for Occupational Safety andHealth (NIOSH) has identified neurotoxic disor-ders as one of the Nation’s 10 leading causes ofwork-related disease and injury. Other leadingcauses of work-related disease and injury includenoise-induced hearing loss and psychological disor-ders, both of which are mediated by the nervoussystem. Evaluating the risk posed by neurotoxicsubstances is critical to the regulatory process. Riskassessment issues are discussed in chapter 6.

EXAMPLES OF neurotoxicSUBSTANCES

neurotoxic substances include naturally occur-ring elements such as lead and mercury, biologicalcompounds such as botulinum toxin (produced bycertain bacteria) and tetrodotoxin (found in thepuffer fish, a Japanese delicacy), and syntheticcompounds, including many pesticides and indus-trial solvents. Some commonly encountered sub-stances are neurotoxic but may not be recognized assuch. For example, certain antibiotics and hexachlo-rophene (once frequently used as an antibacterialagent in soaps) are neurotoxic when sufficientlylarge quantities are ingested or absorbed through theskin; however, exposures to large quantities are rare.Many therapeutic drugs and abused substances alsohave neurotoxic potential.



neurotoxic substances can cause a variety ofadverse health effects, ranging from impairment ofmuscular movement to disruption of vision andhearing, to memory loss and hallucinations. Somesubstances can cause paralysis and death. Often,neurotoxic effects are reversible, that is, the effectsdiminish with time after exposure ceases and noadverse effects on the nervous system are thought toremain. At times, the effects are irreversible and leadto permanent changes in the nervous system. Table2-1 summarizes some of the most frequently re-ported neurobehavioral effects of exposure to toxicsubstances (2). The adverse effects of neurotoxicsubstances and the mechanisms through which theyoccur are discussed in chapter 3.

neurotoxicity has been an important public healthconcern for many years, and incidents of humanpoisoning have occurred periodically throughout theworld for centuries. Some of the major incidents are

Table 2-l-Neurological and Behavioral Effects ofExposure to Toxic Substances

Motor effects:convulsionsweaknesstremor, twitchinglack of coordination,

unsteadinessparalysisreflex abnormalitiesactivity changesMood and personality effects:sleep disturbancesexcitabilitydepressionirritabilityrestlessnessnervousness, tensiondeliriumhallucinations

Sensory effects:equilibrium changesvision disorderspain disorderstactile disordersauditory disordersCognitive effects:memory problemsconfusionspeech impairmentlearning impairmentGenera/ effects:loss of appetitedepression of neuronal activitynarcosis, stuporfatiguenerve damage

SOURCE: Adapted from W.K. Anger, “Workplace Exposures,” Neurobe-havioral Toxicology, Z. Annau (cd.) (Baltimore, MD: JohnsHopkins University Press, 1986), pp. 331-347.

indicated in table 2-2. The neurotoxicity of heavymetals, widely distributed in the soil of the Earth’ssurface, has been recorded in fable and fact for manycenturies. The toxicity of lead, for example, has beena concern since Hippocrates first recognized it in themining industry (39).

Lead is a widely distributed metal. In its naturalstate, it is referred to as inorganic lead. Majorsources of inorganic lead include industrial emis-sions, lead-based paints, food, and beverages. Or-ganic lead compounds include the anti-knock gaso-line, tetraethyl lead. had has profound effects on thenervous system. At relatively low levels it can causea variety of neurobehavioral problems, includinglearning disorders (54). Despite years of researchand considerable regulatory action, the extent andconsequences of lead poisoning in children remaina major public health problem. In 1988, a Federalagency reported that about 17 percent of Ameri-can children in metropolitan statistical areas(MSAs) have concentrations of lead in their bloodabove 15 micrograms per deciliter, a concentra-tion that may adversely affect the nervous system(54). The percentage is much higher for urbanchildren from poor families. Over the years, numer-ous Federal regulations have been developed todecrease human exposure, but the debate on accepta-ble levels in children continues. Lead will bediscussed in detail in chapter 10.

Chapter 2----introduction ● 47

Table 2-2-SeIected Major neurotoxicity Incidents

Year(s) Location Substance Comments400 B.C.1930s

1930s1932

19371946

1950s

1950s1950s

1950s-1970s

1956

1956

1956-1977

19591960

196419681969

1971

1971

1973

1974-1975

1976

1977

1979-1980

1980s

1981

1985

1987

RomeUnited States(Southeast)EuropeUnited States(California)

South Africa—

Japan(Minamata)FranceMorocco

United States

—

Turkey

Japan

MoroccoIraq

JapanJapanJapan

United States

Iraq

United States(Ohio)United States(Hopewell, VA)United States(Texas)United States(California)United States(Lancaster, TX)United States

Spain

United Statesand Canada

Canada

leadTOCP

Apiol (w/TOCP)thallium

TOCPtetraethyl lead

mercury

organotinmanganese

AETT

endrin

HCB

clioquinol

TOCPmercury

mercuryPCBsn-hexane

hexachlorophene

mercury

MnBK

chlordecone(Kepone)Ieptophos(Phosvel)dichloropropene(Telone II)BHMH(Lucel-7)MPTP

toxic oil

aldicarb

domoic acid

Hippocrates recognizes lead toxicity in the mining industry (5)Compound often added to lubricating oils contaminates “Ginger-Jake,” an

alcoholic beverage; more than 5,000 paralyzed, 20,000 to 100,000 affected (1)Abortion-inducing drug containing TOCP causes 60 cases of neuropathy (1 )Barley laced with thallium sulfate, used as a rodenticide, is stolen and used to

make tortillas; 13 family members hospitalized with neurological symptoms;6 deaths(1)

60 South Africans develop paralysis after using contaminated cooking oil (1)More than 25 individuals suffer neurological effects after cleaning gasoline

tanks (4)Hundreds ingest fish and shellfish contaminated with mercury from chemical plant;

121 poisoned, 46 deaths, many infants with serious nervous system damage (1 )Contamination of Stallinon with triethyltin results in more than 100 deaths (1)150 ore miners suffer chronic manganese intoxication involving severe

neurobehavioral problems (1)Component of fragrances found to be neurotoxic; withdrawn from market in

1978; human health effects unknown (1)49 persons become ill after eating bakery foods prepared from flour contami-

nated with the insecticide endrin; convulsions resulted in some instances (5)Hexachlorobenzene, a seed grain fungicide, leads to poisoning of 3,000 to

4,000; 10 percent mortality rate (3)Drug used to treat travelers’ diarrhea found to cause neuropathy; as many as

10,000 affected over two decades (1)Cooking oil contaminated with lubricating oil affects some 10,000 individuals (1)Mercury used as fungicide to treat seed grain used in bread; more than 1,000

people affected (6)Methylmercury affects 646(1 ,6)Polychlorinated biphenyls leaked into rice oil, 1,665 people affected (9)93 cases of neuropathy occur following exposure to n-hexane, used to make

vinyl sandals (1)After years of bathing infants in 3 percent hexachlorophene, the disinfectant is

found to be toxic to the nervous system and other systems (5)Mercury used as fungicide to treat seed grain is used in bread; more than 5,000

severe poisonings, 450 hospital deaths, effects on many infants exposedprenatally not documented (3,6)

Fabric production plant employees exposed to solvent; more than 80 workerssuffer polyneuropathy, 180 have less severe effects (1)

Chemical plant employees exposed to insecticide; more than 20 suffer severeneurological problems, more than 40 have less severe problems (1)

At least 9 employees suffer serious neurological problems following exposureto insecticide during manufacturing process(1)

24 individuals hospitalized after exposure to pesticide Telone following trafficaccident (1 O)

Seven employees at plastic bathtub manufacturing plant experience seriousneurological problems following exposure to BHMH (8)

impurity in synthesis of illicit drug found to cause symptoms identical to those ofParkinson’s disease (11 )

20,000 persons poisoned by toxic substance in oil, resulting in more than 500deaths; many suffer severe neuropathy (2)

More than 1,000 individuals in California and other Western States and BritishColumbia experience neuromuscular and cardiac problems following inges-tion of melons contaminated with the pesticide aldicarb (7)

Ingestion of mussels contaminated with domoic acid causes 129 illnesses and 2deaths. Symptoms include memory loss, disorientation, and seizures (12)

SOURCES: (1) P.S. Spencer and H.H. Schaumburg, Experirnerrfa/ and C/inica/ I’Veurofoxmry (Balttmore, MD: Wilhams & Wilkins, 1980); (2) H. Altenkirch et al., “Theneurotoxicologlcal Aspects of the Toxic Oil Syndrome (TOS) in Spare,” Toxkmbgy 49:25-34, 1968; (3) B. Weiss and T.W. Clarkson, “Toxic ChemicalDisasters and the Implications of Bhopal for Technology Transfer,” Mi/bank Ouartedy 64:216-240, 1986; (4) D.A.K. Cassells and E.C. Dodds, “Tetra-ethylLead Poisoning,” British Medica/ Journal 2:681, 1946; (5) CD. Klaassen, M.O. Amdur, and J. DouII (eds.), Casaret? and DOUWS Toxicology (New York, NY:Macmillan Publishing Co., 1986); (6) World Health Organization, Principles and Methods for the Assessment of neurotoxicity Assoc/aWd With Exposure toChemica/s, Environmental Health Criteria 60 (Geneva: 1986); (7) Morbidity and Mortalny Weekly Report, “Aldicarb Food Poisoning From ContaminatedMelons< alifornia,” Journa/ of American the Medica/ Association 256:1 75-176, 1986; (8) J.M. Horan et al., “Neurologlc Dysfunction From Exposure to2-+-Butulazo-2-Hydroxy -5-Methylhexane (BHMH). A New Occupational Neuropathy,” American Journal of Public Health 75:513-517, 1985; (9) G.G. Goetz,“Pesticides and Other Environmental Toxins, ” Neurotoxins m C/inica/ Pract/ce (New York, NY’ Spectrum Publications, Inc., 1985), pp. 107-131; (10) U.S.Public Health Service, Centers for Disease Control, Morbldlty and Mortality Weekly Report, “Acute and Possible Long-Term Effects of 1,3-dlchloropropene-California,” Feb. 17, 1978, pp. 50, 55; (11) I.J Kopln and S.P. Maukey, “MPTP Toxlclty” Implications for Research In Parkinson’s Disease,” Annual Revmwof Neuroscience 11 :81 -96, 1988; (12) J.M. Hungerford and M.M. Wekell, “Control Measures In Shellfish and Flnfish Industries: USA, ” Bothell, VA, U S. FDA,m press.


Mercury compounds are potent neurotoxic sub-stances and have caused a number of humanpoisonings worldwide. Common symptoms of expo-sure include lack of coordination, speech impair-ment, and vision problems, In the mid-1950s, achemical plant near Minamata Bay, Japan, dis-charged methylmercury, a highly toxic organic formof mercury, into the bay as part of waste sludge (17).Fish and shellfish became contaminated and wereconsumed by local inhabitants, resulting in anepidemic of mercury poisoning and severe neurotox-icological and developmental effects. Mercury usedas a fungicide in treating seed grain was the cause ofa very serious epidemic in Iraq in 1971, resulting inmore than 450 deaths (57) (see box 2-A).

Manganese is required in the diet in trace quanti-ties but is highly toxic when relatively large amountsare inhaled. Hundreds, perhaps thousands, of minersin several countries have suffered from ‘manganesemadness, ’ a disorder characterized by hallucina-tions, unusual behavior, emotional instability, and

numerous neurological problems (43). Other metals,including aluminum, cadmium, and thallium, areneurotoxic in varying degrees. It is particularlychallenging to limit public exposure to metalsbecause they occur naturally in the environment.

Industrial Chemicals

Thousands of chemicals are produced by industry,and new substances are constantly entering themarketplace. Organic solvents are a class of indus-trial chemicals that have the potential for significanthuman exposure. This is due in large part to theirvolatility; that is, in the presence of air they changerapidly from liquids to gases, which may be readilyinhaled. Their fat volubility and other chemicalproperties make many solvents neurotoxic in vary-ing degrees. Exposures may be accidental, as oftenoccurs in the industrial or household setting, ordeliberate, as in glue-sniffing, a common form ofinhalant abuse. Many solvents, including ethers,hydrocarbons, ketones, alcohols, and combinations

Photo credit: W. Eugene Smith end Aileen Smith

A child victimized by mercury poisoning during the Minamata Bay, Japan, incident in the 1950s is bathed by his mother.This is one of the most dramatic poisoning incidents involving a neurotoxic substance.

Chapter 2-Introduction . 49

Box 2-A—Mass Mercury Poisoning in Iraq, 1971

Wheat is believed to have been domesticated first in the fields of the Fertile Crescent, an area extending fromthe Persian Gulf to the Palestinian coast, including much of what is now Iraq. Following a major drought in 1971that ruined the wheat harvest of this region, the Iraqi government decided to switch to a more resilient variety ofwheat from Mexico, known as Mexipak. The Iraqis requested that the wheat seed be treated with mercury to protectit from fungal infections. However, in placing the order, a single-letter typographical error was made in the nameof the fungicide, resulting in treatment of the grain with highly toxic methylmercury instead of the relativelyharmless form of organic mercury normally used.

In the fall of 1971, the largest commercial order of wheat in history (178,000 tons) was delivered to Iraq anddistributed throughout the country. In some areas the wheat arrived too late for planting and was used instead tomake bread. The sacks contained labels warning against consumption, but the labels were in Spanish. The grain hadalso been colored by a pink dye to indicate that it was poisonous, but the farmers were not aware of the significanceof the color. Some of the sacks still carried the original warning labels from the U.S. manufacturer, with the skulland crossbones poison designation; however, the Iraqi farmers were not familiar with this symbol.

The mercury-treated grain was consumed by thousands of Iraqis over a period of a few weeks. Indeed, the pinkcolor of the bread was thought to be attractive. Weeks later, the effects of mercury poisoning began to appear. Atfirst the symptoms were a burning or prickling sensation of the skin and blurred vision. These symptoms werefollowed by uncoordinated muscular movements, blindness, deafness, coma, and in some cases death. Tragically,one village was not aware of the delayed effects of mercury poisoning and assumed that the traditional yellow wheatthey had just eaten was responsible for the poisoning. Their efforts to obtain the pink variety, which they had recentlyrun out of, were unfortunately successful. The estimated toll of the mass poisoning was 6,000 hospitalizations, 5,000severe poisonings, and 450 hospital deaths. Since many persons were not admitted to hospitals, the actual totals arenot known; however, the number of individuals significantly affected has been placed at more than 50,000 and thenumber of deaths at 5,000.

The effects on developing fetuses in mothers who ate the bread have not been fully documented, but subsequentanalyses indicate that the fetus may be more than 10 times as sensitive to mercury poisoning as the adult. Afterbirth,the exposed child may suffer seizures, abnormal reflexes, and delayed development. Severe cases involve cerebralpalsy. The extent and consequences of this tragedy still are not completely documented.

SOURCE: B. Weiss and T.W. Clarkson, “Toxic Chemical Disasters and the Implications of Bhopal for Technology Transfer, ” MilbankQuarterly 64:216-240, 1986.

of these, have caused neurological and behavioral often unaware of the permanent damage that thisproblems in the workplace. For example, in 1973,workers at a fabric production plant in the UnitedStates were discovered to have neuropathies, ordegeneration of nerve fibers. These workers hadbeen regularly exposed to methyl-n-butyl ketone(MnBK), a dye solvent and cleaning agent intro-duced to the plant the previous year (25). Subsequentlaboratory studies implicated MnBK as the causa-tive agent. neurotoxic solvents in the workplace willbe discussed further in a case study in chapter 10.

Solvents are commonly used in glues, cements,and paints. The fumes of toluene-based spray paints,various solvents, and modeling cements are some-times inhaled as intoxicants. Inhalant abuse, animportant public health problem (13,38,45), cancause severe degeneration and permanent loss ofnerve cells. About one in five high school studentshas tried inhalants. Unfortunately, young people are

type of substance abuse can cause (46). -

Pesticides

Pesticides are one of the most commonly encoun-tered classes of neurotoxic substances. In this report‘‘pesticide’ is used as a generic term and includesinsecticides (used to control insects), fungicides (forblight and mildew), rodenticides (for rodents such asrats, mice, and gophers), and herbicides (to controlweeds), among others. More than 1 billion pounds ofpesticides are used annually in the United Statesalone. Some 600 active pesticide ingredients used oncrops are registered with EPA. These active ingredi-ents are combined with so-called inert substances tomake thousands of different pesticide formulations.

The organophosphorous insecticides, which ac-count for about 40 percent of the pesticides regis-tered in the United States, have neurotoxic proper-

50 ● neurotoxicity; Identifying and Controlling Poisons of the Nervous System

ties (10), as do other classes of pesticides, includingthe carbamate and organochlorine insecticides. Be-cause of the biochemical similarities between theinsect and human nervous systems, insecticides canadversely affect humans as well, Organophospho-rous and carbamate insecticides inhibit acetylcholin-esterase, an enzyme responsible for inactivating theneurotransmitter acetylcholine (a common chemicalmessenger in the nervous system) after it has beenreleased by stimulation of a nerve cell. Conse-quently, these pesticides cause acetylcholine toaccumulate in the synapses (or points of contact)between nerves and muscles. This leads to overstim-ulation of many nerves, including those that controlmuscle movement, some organ systems, and thoughtand emotional processes. Indeed, it is this propertythat led to the development and use of organo-phosphorous compounds as “nerve gas” weapons.Acute human poisoning from organophosphorousinsecticides can cause muscle weakness, paralysis,disorientation, convulsions, and death. Of particularconcern are the delayed neurotoxic effects of someof the organophosphorous insecticides. Some ofthese compounds cause degeneration of nerve proc-esses in the limbs, leading to changes in sensation,muscular weakness, and lack of coordination (29).Because of this property, the EPA requires thatorganophosphorous insecticides undergo specialtesting for delayed neurotoxicity.

In the mid-1970s, the American public becameacutely aware of the threat to human health posed byneurotoxic substances when a number of workers ata chemical plant in Hopewell, Virginia, were ex-posed to the insecticide chlordecone (a chlorinatedhydrocarbon marketed as Kepone). A previouslyunidentified neurological disorder resulted, charac-terized by tremors, muscle weakness, slurred speech,lack of coordination, and other symptoms (24). Ofthe 62 verified cases, more than a third displayeddisabling neurological symptoms. The symptomsappeared from 5 days to 8 months after onset ofexposure to large amounts of the insecticide andremained in several of the workers for months aftercessation of exposure and closing of the plant (29).This incident illustrates the difficulty physiciansface in diagnosing poisoning episodes. Affectedworkers reported that the overt signs of poisoningwere preceded by a feeling of ‘‘nervousness, ’ asymptom that might not lead a physician to suspectexposure to a neurotoxic substance.

Because of their widespread use, pesticides aredispersed in low concentrations throughout theenvironment, including the Nation’s food and watersupplies. Between 1982 and 1985, the Food andDrug Administration (FDA) detected pesticide resi-dues in 48 percent of more than two dozen frequentlyconsumed fruits and vegetables (28). However,OTA recently found that FDA’s analytical methodsdetect only about one-half of the pesticides thatcontaminate fruits and vegetables (53). Use ofpesticides has been so widespread that measurablelevels are frequently found in human tissues. DDT,for example, was banned a number of years ago, yetnearly everyone born since the mid-1940s hasmeasurable levels of this pesticide or its metabolizesin their fatty tissues (29). Some scientists believethat the levels of the persistent pesticides present inhumans pose no risk; others think there is cause forconcern and that more research is needed to evaluatethe public health risk of chronic, low-level expo-sures. The possible effects on the developing nerv-ous system of chronic exposure to pesticides are ofparticular concern.

Exposure to agricultural pesticides is highestamong mixers, loaders, applicators, farmworkers,and farmers. Some 2 million seasonal and migrantfarmworkers harvest the Nation’s crops (9). Accu-rate statistics on the total number of these farmwork-ers who develop adverse health effects due topesticides are not available, but in California, wherephysicians are required by law to report suspectedcases of pesticide-related illnesses, 1,093 cases werereported in 1981. Of these, 613 cases were related toagricultural activities, and 235 involved field work-ers exposed to pesticide residues (60). Reportedcases seem to reflect only a fraction of the actualnumber, however (16). The issue of neurotoxicpesticide use in the agricultural setting is the subjectof a case study in chapter 10. Poisonings are aparticular problem in developing countries, wherethe misuse of pesticides is relatively common (seech. 9).

Therapeutic Drugs

Therapeutic drugs often alter the function, andless often the structure, of the nervous system.Generally, this alteration is desirable, as, for exam-ple, in the case of the tranquilizing effects of a drugto treat anxiety or the mood-lifting effects of a drugto treat depression. But such drugs can haveundesirable effects on the brain also. As mentioned

Chapter 2-Introduction ● 51

earlier, some drugs that effectively control thesymptoms of schizophrenia may also severely affectneuromuscular function. Drugs that are used to treatillnesses or health problems unassociated with thenervous system (e.g., some anticancer drugs) mayhave neurotoxic side-effects. Often, the adverseeffects of drugs are poorly documented or may goundetected.

Of particular concern are the effects of therapeuticdrugs on the developing fetus. Most prescriptiondrugs given to pregnant women have not been testedfor potential effects on the fetus, nor have over-the-counter drugs been evaluated for use during preg-nancy (14). Physicians normally exert particularcaution in prescribing drugs for pregnant women.

The Federal Food, Drug, and Cosmetic Actrequires that drugs be both safe and effective. Somepersons assert that FDA does not require adequateneurotoxicity testing of prescription drugs and thatneurotoxic concerns are not being adequately ad-dressed in the FDA review and regulatory process.Others suggest that FDA moves too slowly inapproving drugs and that regulations are overlyburdensome. However, FDA officials believe thatcurrent testing and evaluation procedures adequatelyaddress neurotoxicological concerns (58).

The reported adverse effects of drugs listed in thePhysicians Desk Reference (42) and similar publica-tions illustrate that many prescription drugs, espe-cially psychoactive drugs, have neurotoxic side-effects of varying significance. Some adverse effectsare an accepted consequence of drug therapy. Whena drug has been properly tested for neurotoxiceffects, doctor and patient can make informeddecisions about using it. However, inadequate test-ing for neurotoxicity exposes the public to unneces-sary risk. There is scientific disagreement regardingwhether or not the safety of food additives and drugscan be established in the absence of specificneurotoxicity testing.

Abused Drugs

In 1986, drug abuse in the United States led tomore than 119,000 emergency room visits and 4,138deaths (37). Many more cases go unreported. Asusers and their families and friends sometimesdiscover, substance abuse can permanently damagethe nervous system. In some cases, damage is sosevere as to cause personality changes, neurologicaldisease, mental illness, or death. Persons who abuse

Photo credit: John Boyle, Drug Enforcement Agency

drugs are often not aware of, or do not take seriously,the threat these substances pose to their health.

Although the adverse effects of drugs are oftenshort-lived, some effects can be prolonged orpermanent. MPTP, an impurity sometimes formedduring the illicit synthesis of an analog of the drugmeperidine, can cause irreversible brain damage andlong-term dysfunction characteristic of Parkinson’sdisease (18,20,21). LSD, a highly potent hallucino-gen, can seriously affect nervous system function(17). Other drugs may have more subtle neurotoxiceffects. The chemically sophisticated, illicit “de-signer drugs” can dramatically alter normal brainfunctions. MDMA, known on the street as “Adam’or ‘‘ecstasy, ’ is a synthetic drug that causeseuphoria and hallucinations. It also causes confu-sion, depression, severe anxiety, blurred vision, andparanoia (3,33). Some of these effects may occurweeks after taking the drug. It was recently discov-ered that MDMA, at relatively high doses, causesselective degeneration of brain cells producing theneurotransmitter serotonin (4). Figure 2-1 illustratesthe degeneration of nerve fibers in a region of the


monkey’s cerebral cortex involved in the perceptionof touch and position sense. Similar degeneration isseen in most areas of the cortex. Until it becameillegal, MDMA was occasionally used as an adjunctto psychotherapy because of the belief that itremoved barriers to communication between doctorand patient.

Phencyclidine (PCP) is another major abuseddrug. In 1984, it was responsible for 11,000 hospitalemergency room visits and more than 225 deaths.Chronic use of PCP leads to depression, speechdifficulties, and memory loss (32,36).

Cocaine (known as ‘crack’ in its smokable form)is currently the most frequently abused street drug inthe United States. More than 22 million Americanshave used cocaine at some time in their lives (34). In1986, approximately 25,000 high school seniorsreported that they had used cocaine in the past yearand were unable to stop using it (35). Cocaine blocksreabsorption of the neurotransmitter dopamine intonerve cells. Feelings of euphoria are thought to bedue to excess dopamine in the synapses betweencells. Large concentrations of dopamine causechanges in nerve cells, making them less responsiveto normal levels of the transmitter. Consequently,when individuals stop using the drug they experi-ence depression and want to take more to feel“normal.” They are then caught in the addictioncycle (35). Recently, it was reported that cocaine useby pregnant women alters the development of thebrains of fetuses and infants (59). “Cocaine babies’are a tragic consequence of drug abuse by pregnantwomen (see box 2-B).

Food Additives

Food additives serve a variety of purposes, suchas to prolong shelf-life or to improve flavor, andhundreds of them are used during the preparation,manufacture, and marketing of foods. The use ofthese substances is regulated by FDA, which main-tains a list of additives that are generally recognizedas safe and may be used without specific approval.All other food additives must be approved prior touse. However, few additives have undergone neuro-toxicity testing. In 1984, the NAS reported that 73percent of the food additives it examined had notbeen tested for neurobehavioral toxicity (30). Al-though animal testing of food additives is requiredunder the Federal Food, Drug, and Cosmetic Act toevaluate their safety, studies in humans are not

Figure 2-1-neurotoxic Effect of MDMA onSerotonin Nerve Fibers in the Cerebral Cortex

of the Monkey

A. Control

B. MDMA

Repeated administration of MDMA (5mg/kg, 8 doses) to aCynomolgus monkey produced degeneration of most serotoninnerve fibers in this region of the cortex, which is involved in theperception of touch and position sense. Similar toxic effects areseen in most areas of the cerebral cortex.SOURCE: M.A. Wilson and M.E. Molliver, Department of Neuroscience,

Johns Hopkins University School of Medicine.

required. Approval of drugs, however, does requirehuman testing. Many observers believe that foodadditives should come under the same scrutiny asdrugs, particularly because many of them are regu-larly ingested by millions of people. The foodadditive approval process is examined in a casestudy in appendix A.

Cosmetics

Some 3,400 chemicals are used as cosmetics orcosmetic ingredients in U.S. products (30). The

Chapter 2-Introduction ● 53

Box 2-B-Cocaine and the Developing FetusWhen a pregnant women abuses a psychoactive drug, she alters not only the activity of her own nervous

system, but that of her unborn child as well. Depending on the abused substance, the frequency of use, the dose,and other factors, the mother’s quest for a temporary high can lead to permanent damage of the rapidly developingfetal nervous system. According to a recent survey by the National Association for Perinatal Addiction Researchand Education (NAPARE), each year as many as 375,000 infants may be adversely affected by substance abuse.Maternal substance abuse is frequently not recognized by health-care professionals during pregnancy.Consequently, prevention and treatment programs are often too late. According to the National Institute on DrugAbuse, approximately 6 million women of childbearing age (15 to 44) use illicit drugs, about 44 percent have triedmarijuana, and 14 percent have used cocaine at least once.

A recent study of 50 women who used cocaine during pregnancy revealed a 31 percent incidence of pretermdelivery, a 25 percent incidence of low birthweight, and a 15 percent incidence of sudden infant death syndrome.These types of parameters are easy to quantify. The biochemical and neurobehavioral effects are more difficult todocument, but they are just as real. Early research indicates that cocaine babies suffer abnormal development of thenervous system, impaired motor skills and reflexes, seizures, and abnormal electrical activity in the brain.

Cocaine is so addictive that it can suppress one of the most powerful human drives-maternal care. As onepregnant crack addict put it: “The lowest point is when I left my children in a park for like 3 or 4 days. I had leftmy kids with a girl that I know and told her. . . ‘watch them . . . I’ll be back’ and I didn’t come back. So that waslike—when I finally came down off of that high. I realized that I needed help. ” Sick and abandoned children ofcocaine mothers have placed a heavy burden on a number of the Nation’s hospitals. During a l-week period at onehospital, one in five black infants and one in ten white infants were born on cocaine, Taxpayers usually end uppaying the health-care bill—a bill that can easily exceed $100,000 per infant.

SOURCES: National Association for Perinatal Addiction Research and Education, news release, Aug. 28, 1988; J.H. Khalsa, “Epidemiologyof Maternal Drug Abuse and Its Health Consequences: Recent Finding,’ National Institute on Drug Abuse, in preparation; ‘CocaineMothers: Suffer the Children,” West 57th Street, CBS, July 15, 1989.

Courtesy of Dr. Emmalee S. Bandstra, M. D., Division of Neonatology, University of Miami/Jackson Memorial Medical Center


neurobehavioral toxicity of only a small percentageof these has been reviewed. Indeed, the NationalAcademy of Sciences evaluated a representativesample of cosmetics in 1984 (focusing on publiclyavailable documents) and found that none hadundergone adequate testing to identify potentialneurobehavioral effects (30).

The consequences of inadequate toxicity testingare illustrated by the AETT incident. In 1955, AETT(acetylethyl tetramethyl tetralin) was introducedinto fragrances; years later it was found to causedegeneration of neurons in the brains of rats andmarked behavioral changes in rats, including irrita-bility and aggressiveness. In 1978, it was voluntarilywithdrawn from use by the fragrance industry. Itseffects on humans through two decades of use willprobably never be known (50).

FDA lacks the authority to require premarkettesting of cosmetics. The agency may initiate aninvestigation, however, if a basis is presented fordoubting a particular product’s safety. The regula-tion of cosmetics is discussed further in chapter 7.

TOXIC SUBSTANCES ANDNEUROLOGICAL AND

PSYCHIATRIC DISORDERSConcerns about the effects of neurotoxic sub-

stances on public health have increased recentlybecause of new evidence that some neurological orpsychiatric disorders may be caused or exacerbatedby toxic agents in the environment. A noted case inpoint is Parkinson’s disease. Researchers recentlydiscovered that exposure to small amounts of thetoxic substance MPTP can cause Parkinson-likesymptoms (20). Exposure to small quantities over aperiod of days to a few weeks leads to the muscleweakness and rigidity that is characteristic ofParkinson’s disease.

Because of this finding, the possibility that toxicchemicals might be causative agents in some casesof Parkinson’s disease is being actively consideredby researchers. Some recent findings support thishypothesis. For example, it has been reported that incases in which Parkinson’s disease afflicts severalmembers of a family, the onset of the disease tendsto cluster in time (5,21). Normally, if a disorder hasa purely genetic basis, onset of symptoms occurs atsimilar ages, not at similar times. Evidence thatParkinson’s disease does not occur more frequently

in identical than fraternal twins also argues againsta hereditary determinant of the disorder (18). Arecent epidemiological study revealed that between1962 and 1984, U.S. mortality rates for Parkinson’sdisease substantially increased in individuals overthe age of 75 (figure 2-2). Environmental factorsappear to have played a significant role in theincrease (23). The relative roles of hereditary andenvironmental factors in triggering Parkinson’sdisease remain to be determined.

Evidence for a substantial increase in the inci-dence of motor neuron disease (MND), primarilyamyotrophic lateral sclerosis (ALS), or LouGehrig’s disease, in the United States has alsorecently been reported (22). This disease is charac-terized by the progressive degeneration of certainnerve cells that control muscular movement. MNDis a relatively rare disease, and its cause has eludedresearchers for more than a century. Recent dataindicate that between 1962 and 1984, the MNDmortality rate for white men and women in older agegroups rose substantially (figure 2-3). The increaseis thought to be largely due to environmental factors(22).

Naturally occurring toxic substances can alsoaffect the nervous system. An unusual combinationof the neurodegenerative disorders ALS, Parkin-son’s disease, and Alzheimer’s disease endemic toGuam (known as Guam ALS-Parkinson’s dementia)puzzled investigators for many years because of thecorrelation between incidence of the disease andpreference for traditional foods. During food short-ages, residents of the island ate flour made from thefalse sago palm, a member of the neurotoxic cycadfamily. The cycad contains one or more naturallyoccurring toxic substances that appear to cause aneuromuscular disease in cattle and trigger slowdegeneration of neurons (49), As old age approachesand natural brain cell death accelerates, the effects ofthe degeneration become apparent and the neurolog-ical symptoms appear, This possible link between anaturally occurring compound and a neurodegenera-tive disease has stimulated the search for other toxicsubstances that may trigger related neurological andpsychiatric disorders. This work and that of othersled to the hypothesis that Alzheimer’s disease,Parkinson’s disease, and ALS could be due in part todamage to specific regions of the central nervoussystem caused by environmental agents and that thedamage may not become apparent until severaldecades after exposure (6). Aluminum and silicon,

Chapter 2-Production ● 5 5

Figure 2-2—Average Annual Parkinson’s DiseaseMortality in the United States, White Males

Rate per 100,000 population60 !-

I

50I

40

30

20 & 6

10 9

00 10 21 4 2o-–

~ 50 50-54 55-59 60-64 65-69 70-74 75-79 80-04 85*Age

@ Between 1962-1964 _ Between 1980-1984

SOURCE: Adapted from D.E. Lilienfeld et al., “Two Decades of IncreasingMortality From Parkinson’s Disease Among United StatesElderly,” Archives of Neurology, in press.

Figure 2-3-Average Annual Motor Neuron Disease*Mortality in the United States, White Males

Rate per 100,000 population

‘2~

10

8

6 54

4 3 32 2

20 0 1 1 1 1

8

c 40 40-4445-4950-5455-59 60-6465-6970-74 75-7980-84 85*Age

@ Between 1962-1964 _ Between 7980-1984

● Most motor neuron disease is diagnosed as amyotrophic lateral sclerosis(ALS), or Lou Gehrig’s disease.

SOURCE: Adapted from D.E. Lilienfeld, et al., “lncreasing Mortality FromMotor neuron Disease in the United States During the Past TwoDecades,” Lancet, Apr. 1, 1989, vol. 1, pp. 710-713.

for example, have been hypothesized to be causativeagents in Alzheimer’s disease; however, numerousother possible causes have been proposed, and nolink between a toxic chemical and the disease hasbeen conclusively demonstrated (52).

Several other foods contain known neurotoxicsubstances and can be responsible for severe neuro-logical disorders. The drought-resistant grass peacauses lathyrism, a disease characterized by weak-

ness in the legs and spasticity and resulting fromdegeneration of the spinal cord. The disease has beenknown since ancient times and has been responsiblefor several epidemics in Europe, Asia, and Africa(48,50). Studies currently under way indicate thatthe prevalence of lathyrism in an Ethiopian popula-tion that consumes the grass pea is 0.6 to 2.9 percent,an unusually high incidence for a neurodegenerativedisease. Similarly, a large segment of the Africanpopulation regularly eats a species of cassava(Manihot esculenta) that also damages the nervoussystem and causes irreversible spasticity (47). Cas-sava (manioc), one of many cyanide-releasing food-stuffs in the human diet, is found with increasingfrequency in U.S. supermarkets.

Understanding the relationship between toxicsubstances and biochemical and physiological neu-rological disease requires concerted epidemiologi-cal analyses. The extent to which toxic substancescontribute to major neurological and psychiatricdisorders is not known. Considerable research isneeded to define the role of neurotoxic substances ascausative agents.

IDENTIFYING neurotoxicSUBSTANCES

Controlling neurotoxic substances is a two-stepprocess. The first step is to identify existing sub-stances that adversely affect the nervous system andtake action to minimize human exposure to them.The second step is to identify new neurotoxicsubstances being generated by industry and takeaction either to prevent the manufacture of those thatcause serious neurotoxic effects or limit the releaseof the substances into the environment and henceprevent human exposure to them. Testing is the keyto both objectives; however, as indicated earlier,relatively few substances are evaluated specificallyfor neurotoxicity. There are numerous examples ofneurotoxic substances that have entered the market-place because of failure to conduct sufficient tests.

A classic example of testing inadequacy is BHMH(Lucel-7), a catalyst used in the manufacture ofreinforced plastics such as bathtubs. The substancehad only been used for a few weeks at a plant inLancaster, Texas, before workers began experienc-ing neurological symptoms ranging from dizzinessand muscle weakness to visual disturbances andmemory loss. Two years later, several workers werestill experiencing some of these symptoms. Prelimi-


nary animal studies suggested that, BHMH wasneurotoxic, however regulatory action had not beentaken (15). Animal studies conducted after theexposure demonstrated that rats experienced adverseeffects similar to those seen in humans. BHMHmight not have been marketed had appropriateneurotoxicological tests been conducted and had thedata been properly analyzed and reported.

An important consideration in controlling toxicsubstances is the need for efficient, economical, andscientifically sound tests to identify substances thatshould be regulated. Numerous tests are currentlyavailable to evaluate neurotoxicity. A number ofthese tests are described in detail in chapter 5. At thepresent time, animal tests are an essential componentof neurotoxicological evaluations.

In vitro testing, based on tissue and cell culture, isalso useful in evaluating the neurotoxic potential ofchemicals (12). Two likely advantages are that manysubstances can be screened in a relatively shortperiod of time and that costs may be considerablyless than the costs associated with animal tests (51).In vitro tests may someday prove to be useful as arapid toxicity screening tool; however, further testdevelopment is necessary. Like all tests, in vitro testshave inherent limitations. For example, they areprobably of little use in identifying behavioraleffects because such evaluations require the intactnervous system. Also, testing drugs or other chemi-cals in vitro makes it difficult to evaluate activemetabolizes that may form or accumulate followingadministration to the intact animal.

REGULATING neurotoxicSUBSTANCES

Regulatory agencies are responsible for limitingpublic exposure to toxic chemicals through pro-grams mandated by Congress. Because of thediversity of toxic substances, numerous laws are inplace to control their production, use, and disposal.These laws are administered by a variety of Federalagencies, but primarily by EPA, FDA, and theoccupational Safety and Health Administration.

New and existing industrial chemicals are regu-lated under the Toxic Substances Control Act.Pesticides are controlled by the Federal Insecticide,Fungicide, and Rodenticide Act, and exposure totoxic substances in the workplace is regulated by theOccupational Safety and Health Act. In addition, the

Federal Food, Drug, and Cosmetic Act regulatesfood additives, drugs, and cosmetics. Although theselaws address most toxic substances, more than adozen other acts focus on less prevalent but equallyimportant substances. While neurotoxicity is oftennot explicitly mentioned in laws regulating toxicsubstances, it is implicit in general toxicity concerns.

Regulating toxic substances on the basis of anysingle endpoint such as carcinogenicity may notadequately protect the public health. Effects onorgan systems and other toxicities may pose an equalor greater threat than carcinogenicity itself. Lead, forexample, is both neurotoxic and carcinogenic; how-ever, the neurotoxic concerns have far outweighedthe carcinogenic concerns in decisionmaking. Com-plete characterization of the risk posed by exposureto toxic substances should include an evaluation ofboth carcinogenic and noncarcinogenic risk, includ-ing the potential for neurotoxicity. The Federalframework for regulating toxic substances in gen-eral, including neurotoxic substances, is described indetail in chapter 7.

ECONOMIC CONSIDERATIONSAlthough it is expensive to evaluate any chemical

for its potential toxic effects, these costs may besmall relative to the costs associated with develop-ment of a new product, care of injured persons,workers’ compensation, or litigation resulting frominjury. Furthermore, the costs to society of publicexposure to toxic substances, measured in terms ofmedical care and lost productivity, are potentiallyvery high.

Society must weigh carefully the positive healthand economic impacts of use of hazardous chemicalsagainst the negative health and economic conse-quences of human exposure to substances whosetoxicity has not been adequately evaluated. Ifindustry is required to do additional testing, regula-tory agencies should ensure that the tests areappropriate and cost-effective. Chapter 8 focuses onthe challenge of balancing economic costs andbenefits.

INTERNATIONAL CONCERNSneurotoxicity is an international as well as

national problem. Of particular concern to manypersons is the export of neurotoxic substances fromthe United States to other nations. Tens of thousandsof tons of pesticides, for example, are exported each

Chapter 2-Introduction . 57

year by U.S. manufacturers, even though the use ofsome of these substances is banned or severelyrestricted in the United States. Critics of this policyraise questions regarding the ethics of a wealthy,industrialized nation profiting from the export ofsuch substances to developing nations that may nothave the resources to ensure protection of the public.In what has been called the ‘circle of poison,” foodsimported into the United States sometimes containresidues of exported pesticides that are unregistered,restricted, or banned for U.S. use (55).

In 1979, a Federal Interagency Hazardous Sub-stances Export Policy Task Force prepared guide-lines governing the export of pesticides, drugs, andother materials. Its recommendations led to anExecutive Order on Federal Policy RegardingBanned or Significantly Restricted Substances. Theorder was signed by President Jimmy Carter inJanuary 1981, several days before the end of histerm, but it was revoked by President Ronald Reaganshortly thereafter. Consequently, policy regardingthe export of banned and restricted hazardoussubstances, whether pesticides, foods, or othermaterials, remains a topic of debate. These and otherinternational issues are discussed in more detail inchapter 9.

1.

2.

3.

4.

5.

6.

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Learning Disabilities, ” Learning Disabilities andPrenatal Risk, M. Lewis (cd.) (Urbana, IL: Univer-sity of Illinois Press, 1986), p. 3.Horan, J. M., Kurt, TL., Landrigan, P., et al., “Neu-rologic Dysfunction From Exposure to 2-+-Butyluo-2-Hydroxy-5-Methylhexane (BHMH): A New Occu-pational Neuropathy, ” American Journal of PublicHealth 75:513-517, 1985.Kahn, E., “Pesticide-Related Illness in CaliforniaFarm Workers, ” Journal of Occupational Medicine18:693-696, 1976.Klaassen, C. D., Amdur, M. O., and Doull, J. (eds.),Casarett and Doull’s Toxicology (New York, NY:Macmillan, 1986).Kopin, I.J., and Markey, S.P., “MDTP ToxicityImplication for Research in Parkinson’s Disease, ”Annual Reviews in Neuroscience 11:81-96, 1988.Kusserow, R. P., “Medicare Drug Utilization Re-view, ” Office of Inspector General Report (Wash-ington, DC: U.S. Department of Health and HumanServices, 1989).Langston, J. W., Ballard, P., Tetrud, J. W., et al.,‘‘Chronic Parkinsonism in Humans Due to a Productof Meperidine-Analog Synthesis, Science 219:979-980, 1983.Levin, R., ‘‘More Clues to the Cause of Parkinson’sDisease,” Science 7:978, 1987.Lilienfeld, D. E., Chan, E., Ehland, J., et al,, ‘Increas-ing Mortality From Motor Neuron Disease in theUnited States During the Past Two Decades, ”Lancet, vol. 1, pp. 710-713, Apr. 1, 1989.

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Chapter 3

Fundamentals of neurotoxicology

‘ ‘The upsurge of interest in recent years in academia, industry, and government on the effects of toxicchemicals on the nervous system has created a new discipline of neurotoxicology.”

Peter S. Spencer, Ph.D.Herbert H. Schaumburg, Ph.D.

Experimental and Clinical neurotoxicology, 1980

". . . the recognition that a chemical component in street heroin [causes] Parkinson’s disease or [a]

Parkinsonian disease or [a] Parkinsonian state comes like a lightning bolt to the medical community. . . . Nowsuddenly, with this new awareness, the neurological community is beginning to ask questions about otherdisorders, such as Lou Gehrig’s disease, Alzheimer’s disease. Could this possibly be the result of chemicalexposure?

Bernard Weiss, Ph.D.Testimony before the House Committee on Science and Technology

October 8, 1985

<< . . . this is not a situation where we get depressed and anxious first and then developed these symptoms inour mind. This is a situation where these symptoms came along from exposure to fumes and chemicals andthen we got severely depressed and anxious. ’

Aerospace WorkerTestimony before the Senate Committee on Environment and Public Works

July 15, 1989

CONTENTSPage

OVERVIEW OF TOXICOLOGICAL PRINCIPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Absorption, Distribution, Biotransformation, and Excretion . . . . . . . . . . . . . . . . . . . . . . . .Interaction of Multiple Toxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ... ..,...,+

THE NERVOUS SYSTEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Development and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

EFFECTS OF TOXIC SUBSTANCES ON THE NERVOUS SYSTEM . . . . . . . . . . . . . . .Structural Changes . . . . . . . . . . . . . . . . . . . . . . . . . . .,,.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Functional Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Behavioral Effects .+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Susceptibility to neurotoxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CLASSES OF neurotoxic SUBSTANCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ActionsActionsActionsActionsActionsFurther

on the Neuronal Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .on Neuronal Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .on Glial Cells and Myelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .on the Neurotransmitter System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .on Blood Vessels Supplying the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . .Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63646465676767697070717272747474767676

BoxesBox Page3-A. The Ginger-Jake Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693-B. The Endangered Hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .713-C. MPTP and Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

3-1. The Fundamental Structure of the Nerve Cell. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3-2. Chemical Communication at the Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .+...

6566

Chapter 3

Fundamentals of neurotoxicology

Toxicology is concerned with the adverse effectsof natural or synthetic chemicals on the biochemical,physiological, and behavioral processes of livingorganisms. Because of the large number of chemi-cals in commerce and the wide variety of effects theymay cause, toxicology is a broad science andtoxicologists tend to specialize in one or more areasof the field. Biochemical toxicologists study theeffects of toxic chemicals at the molecular andcellular levels. Regulatory toxicologists evaluate therisks posed by these substances and recommendactions that can be taken to reduce human exposureand environmental contamination. Clinical toxicol-ogists examine the effects of drugs and toxicchemicals on human health and develop treatmentsto mitigate adverse effects. Behavioral toxicologistsare concerned with the effects of toxic substances onanimal and human behavior. Environmental toxicol-ogists address the effects of pollutants on plants andanimals, including humans (10).

neurotoxicology is concerned with the adverseeffects of chemicals on the nervous system. Re-search in this field involves examining the modes bywhich neurotoxic substances enter the body, theeffects of these substances on the various compo-nents of the nervous system, the biochemical andphysiological mechanisms by which these effectsoccur, the prevention of damage to the nervoussystem, and the treatment of neurological andpsychiatric disorders associated with exposure totoxic substances. Although scientists have madetremendous progress in understanding the nervoussystem, there is still much to learn about its functionunder both normal and abnormal circumstances.

OVERVIEW OFTOXICOLOGICAL

PRINCIPLES

In order for a toxic substance to cause adversehealth effects, it, or its metabolic products, mustenter the body and reach the target organ(s) at asufficient concentration and for a sufficient length oftime to produce a biological response. Chemicalsdiffer in toxicity, with some being toxic in verysmall quantities and others having little effect at

even very high doses. This relationship betweenexposure to a toxic substance and the extent of injuryor illness resulting from it is called the “dose-response” relationship. In addition to dose, othercritical variables determining toxicity are the prop-erties of the chemical (e.g., its volubility), the meansof exposure (through the lungs, stomach, or skin),the health and age of the exposed individual, and thesusceptibility of the target organ or tissues (10).

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64 ● neurotoxic@: Identifying and Controlling Poisons of the Nervous System

Absorption, Distribution, Biotransformation,and Excretion

Toxic substances normally enter the body throughthe lungs (inhalation), the skin (absorption), or thegastrointestinal tract (ingestion). In the industrialsetting, most exposures occur through inhalation orabsorption. After the substance enters the blood-stream, it is partitioned into body tissues, where itmay act on target organs or tissues. For variousreasons, including insolubility, some substances arenot distributed through the body. Ultimately, toxicsubstances are eliminated from the bloodstreamthrough accumulation in various sites in the bodyand through biotransformation and excretion.

Sites of accumulation of toxic substances mayormay not be the primary sites of toxic action. Carbonmonoxide, for example, reaches its highest concen-tration in red blood cells, where it competes success-fully with oxygen for binding sites in hemoglobin;it then causes widespread brain damage when thesered blood cells fail to supply an adequate amount ofoxygen to the brain. Lead, a potent neurotoxicsubstance, is found in highest concentrations in bonebut exerts its most serious effects on the brain. Theliver and kidney are major sites of accumulation oftoxic substances, probably because of their largeblood capacities and their roles in eliminating toxicsubstances from the body. Lipophilic toxic chemi-cals (i.e., chemicals soluble in fat-like materials; alsotermed hydrophobic) tend to accumulate in lipid-rich areas such as body fat. The brain may beparticularly vulnerable to these toxic substancessince 50 percent of the dry weight of the brain islipid, compared to 6 to 20 percent of other organs ofthe body (5).

The body has a number of ways to detoxifyforeign substances. The liver is the principal organinvolved in detoxification, but other organs such asthe kidney, the intestine, and the lung also playmajor roles. In fact, nearly every tissue tested hassome capacity for detoxification; these capacities,however, are often limited to particular types ofcompounds. Adverse effects may occur when thequantity of the substance ingested overwhelmsdetoxification mechanisms, when an injury or illnesshas compromised the body’s capabilities for detoxi-fication, or when no mechanism is available tomodify or remove the particular substance.

Before excretion, a substance may undergo bio-transformation, the biochemical process by which itis converted into new chemical compounds whichare often more easily excreted. This process usuallychanges lipophilic compounds to compounds whichare more hydrophilic (water soluble) and thereforemore easily excreted. Although biotransformationnormally aids in the detoxification of substances, itsometimes results in compounds that are more toxic.Therefore, when analyzing neurotoxic substancesand the health risks they pose, it is important toremember that the compound originally ingested orabsorbed by an organism may not be the toxicsubstance that eventually acts on the nervous sys-tem.

Excretion of toxic chemicals from the body occursthrough a variety of routes. Many substances areremoved by the kidney and excreted through theurine. The liver is effective in detoxifying andremoving substances that enter the body through thegastrointestinal tract. Some toxic substances, such aslead and mercury, are excreted from the liver into thebile and then into the small intestine, bypassing theblood and the kidneys (10).

Toxic substances are more easily removed fromthe body if they are hydrophilic or if they can bebiotransformed into a more hydrophilic compound.Lipophilic toxic substances are removed from thebody through a number of mechanisms; theseinclude excretion in feces and bile, excretion ofwater-soluble metabolizes in the urine, expirationinto the air, and excretion through the skin.

Interaction of Multiple Toxic Substances

The health effects of toxic substances are fre-quently examined with the assumption of a singlechemical acting alone on a particular organ or typeof tissue. Such an analysis has limitations, however.In some cases, an individual may be exposed tomultiple chemicals that act on different organs andtissue types, and one cannot assume that the effect ofthese substances combined is the same as thecombined effects of separate exposures. Chemicalinteractions may take place between substances.Sometimes the effects are additive (i.e., the com-bined effects are equal to the sum of the effects ofeach of the substances individually); at other times,the effects may be synergistic (i.e., the combinedadverse effects exceed the sum of the individualeffects).

Chapter .3-Fundamentals of neurotoxicology . 65

A substance that is not toxic may increase thetoxicity of another substance through a processcalled potentiation. More rarely, two toxic chemi-cals may result in no adverse effect when presenttogether, a phenomenon called antagonism. Syner-gism, potentiation, and antagonism must be takeninto account when examining exposure to complexmixtures of toxic substances such as those found incontaminated drinking water, smoke from an indus-trial fire, and fumes from a hazardous waste site (10).

THE NERVOUS SYSTEMThe fundamental unit of the nervous system is the

nerve cell, or neuron (figure 3-l). While neuronshave many of the same structures found in every cellof the body, they are unique in that they have axonsand dendrites, extensions of the neuron along whichnerve impulses travel, and in that they synthesize

and secrete neurotransmitters, specialized chemicalmessengers that interact with receptors of otherneurons in the communication process.

Certain nerve cells are specialized to respond toparticular stimuli. For example, chemoreceptors inthe mouth and nose send information about taste andsmell to the brain. Cutaneous receptors in the skinare involved in the sensation of heat, cold, and touch.Similarly, the rods and cones of the eye sense light.

Glial cells appear to perform functions whichsupport neurons-i. e., supplying nutrition, struc-tural support, and insulation. Certain glial cells, forexample, produce myelin, a fatty substance thatcovers the axons of many neurons throughout thebody and acts as insulation.

Electrical information in the form of nerveimpulses travels along the axons and dendrites of

n Figure 3-l—The Fundamental Structure of the Nerve Cell

Cell body

A.

SOURCE: Office of Technology Assessment, 1990. ‘

“Ites


neurons. The impulses are generated by a rapidlychanging flow of charged ions, primarily sodiumand potassium, through channels in the nerve cellmembrane. The insulating myelin sheath surround-ing many nerves allows the electrical impulses(action potentials) to travel farther and faster thanthey otherwise could. Impulses generally travelaway from the cell body of the neuron along axonsand interact with the dendrites of other neurons. Thepoint of interaction between adjacent nerve cells iscalled the synapse (figure 3-2). Here, neurotransmit-ters stored in vesicles in the axon terminal arereleased by electrical impulses, travel across thesynaptic cleft, and bind to receptors on adjacentnerve cells, triggering biochemical events that leadto electrical excitation or inhibition. Informationmay also be transmitted from nerves to musclefibers; in this case the point of interaction is calledthe neuromuscular junction.

Neurotransmitters are chemical messengers thatcan be subdivided into two categories: the classicalneurotransmitters and the neuropeptides. Classicalneurotransmitters include serotonin, dopamine, ace-tylcholine, and norepinephrine; the neuropeptidesinclude endorphin, enkephalin, substance P, andvasopressin. Classical neurotransmitters are typi-cally secreted by one neuron into the synaptic cleft,where they interact with receptors on the surface ofthe adjacent cell. Neuropeptides, on the other hand,may act over long distances, traveling through thebloodstream to receptors on other nerve cells or inother tissues. Binding of a transmitter to a receptortriggers a series of biochemical events that ulti-mately affect the electrical activity, or excitability,of the neuron. Depending on the type of transmitterreleased and the type of receptors, the effect of thechemical interaction is either to inhibit or tostimulate the electrical activity of the adjacent cell.When multiple neurons impinge on a single neuron,that neuron integrates the inputs, resulting in a netexcitation or inhibition.

The nervous system is anatomically separatedinto two major divisions: the central nervous systemand the peripheral nervous system. The centralnervous system encompasses the brain and spinalcord, while the peripheral nervous system encom-passes the nerves that travel to and from the spinalcord, sense organs, glands, blood vessels, andmuscles.

Figure 3-2-Chemical Communication at the Synapse

Synapse

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Neurotransmttter .. .vesicles

IAxonterminal I

Synapticcleft

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The brain is composed of between 10 billion and100 billion cells organized into vast networks ofinteracting axons and dendrites which comprise onthe order of 1015 connections (17). The brain andspinal cord control vital functions of the body(including vision, hearing, speech, learning, mem-ory, and muscular movements) through these com-plex networks and through a wide variety ofneurotransmitters.

Information from sensory receptors is sent to thespinal cord and brain, where it is translated andintegrated with other information. Sometimes thesensory information leads to muscular movement—for example, if one touches a hot stove. This reflexcircuit involves both sensory neurons, which sensethe heat and send the information to the spinal cord,and motor neurons, which send instructions to themuscles.

Most of the central nervous system is partiallyprotected by the blood-brain barrier, a layer oftightly juxtaposed cells in blood vessel walls thatallow some substances to pass from blood to neuraltissue while keeping others out. This selectivebarrier protects much of the nervous system fromsubstances that are either not necessary for meta-bolic functions or that may be damaging. Smallercompounds and compounds that are soluble in lipidstend to cross the barrier more easily, while largercompounds and substances which are soluble inwater may be kept out. In addition, some compounds

Chapter 3-Fundamentals of neurotoxicology ● 67

cross the barrier with the help of carrier proteinswhich bind specifically to them. Drugs intended toact directly on the nervous system must therefore bedesigned in such a way as to pass through theblood-brain barrier into the brain. Most tranquiliz-ers, narcotics, and anesthetics readily traverse thebarrier.

Development and Aging

The first signs of the nervous system are exhibitedaround the 10th to 14th day of fetal development,when a flat sheet of around 125,000 cells forms fromthe outer layer of the ball of undifferentiatedembryonic cells. The sheet then rolls into a tube,called the neural tube, which will eventually developinto the spinal cord and brain. Over the next 2months these cells multiply, migrate, and begindifferentiating into specific types of neurons andglia. The mechanism by which the undifferentiatedembryo develops is unknown; however, embryolo-gists believe that the cells’ chemical environmentsplay large roles in these determinations.

At approximately the 20th week, the neuronsbegin to extend axons and dendrites, initiatingdevelopment of the nervous system’s complexnetwork of synaptic contacts. The nervous system isnot fully developed until sometime during infancy.However, small modifications in the network doappear to take place even in the adult nervous system(7).

The nervous system undergoes major changeswith aging. At the tissue and cellular level, the agingprocess results in nerve cell loss, neurofibrillarytangles (abnormal accumulation of certain filamen-tous proteins), and neuritic plaques (abnormal clus-ters of proteins and other substances near synapses).Neurons have a very limited capacity to regenerate;thus, as cells die, the complex neuronal circuitry ofthe brain becomes impaired. Aging is also accompa-nied by alterations in neurotransmitter concentrationand the enzymes involved in the synthesis of thesetransmitters. Some neurons gradually lose theirinsulating myelin sheath, slowing conduction ofelectrical impulses along the axons.

Some-components of the nervous system appearto age differently than others. In a healthy person, forexample, intellectual abilities such as memory,vocabulary retention, and comprehension seem to bemaintained at least until the mid-70s, while motorskills, coordination, and sensory functions gradually

become impaired (15). Specific areas of the brainmay age at different rates. The locus ceruleus and thesubstantial nigra, two discrete areas of the brain,undergo a period of cell loss between the ages of 30and 50, with the decline in cell number slowingthereafter (9). Between the ages of 20 and 80, thenumber of cells in the cerebral cortex may bereduced by half. In contrast, the Purkinje cells of thecerebellum decline in a linear fashion throughoutlife, while other clusters of cells are maintained atthe same levels regardless of age.

EFFECTS OF TOXIC SUBSTANCESON THE NERVOUS SYSTEM

Structural Changes

Toxic substances can alter both the structure andthe function of cells. Structural alterations includechanges in the morphology of the cell and thesubcellular structures within it, and destruction ofgroups of cells. The long axons of some neurons, theinability of neurons to regenerate, and the nervoussystem’s dependency on a delicate electrochemicalbalance for the proper communication of informa-tion make the system especially vulnerable to theeffects of toxic chemicals.

When a toxic substance enters the human body, itcan affect the biochemistry and physiology ofneurons and glia in a variety of ways. The cells mayswell, their internal contents may become moreacidic, and biochemical processes such as proteinsynthesis and neurotransmitter secretion may beinhibited. Often these changes result from anoxia—i.e., oxygen deprivation. Neurons require relativelylarge quantities of oxygen because of their highmetabolic rate and are therefore more vulnerablethan other cells to anoxia.

At the morphological level, toxic substances seemto act selectively on the various components of thenervous system, damaging the neuronal bodies(neuropathy), axons (axonopathy), and myelinsheaths (myelinopathy). A common type of struc-tural change induced by toxic substances on axonsis central-peripheral distal axonopathy (CPDA).Degeneration of this type usually begins at the endof the axon and proceeds toward the cell body, henceit is often referred to as the “dying-back” process.Some organophosphorous insecticides can causethis type of damage after a single exposure; how-ever, for the majority of chemicals producing this


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effect, continuous or prolonged intermittent expo-sure is necessary. Thousands of people were para-lyzed during Prohibition after ingesting a popularalcohol substitute contaminated with an organo-phosphorous chemical (see box 3-A).

Toxic substances often cause a slow degenerationof the nerve cell body or axon that may result inpermanent neuronal damage. Acute carbon mon-oxide poisoning, for example, can produce a de-layed, progressive deterioration of portions of thenervous system that may lead to psychosis and deathover a period of weeks (8).

Functional Changes

Toxic chemicals can induce functional changesthat involve modifications of motor and sensoryactivities, emotional states, and integrative capabili-ties such as learning and memory. Numerous sen-sory systems can be adversely affected, includingsight, hearing, and touch and pain sensation. Theseeffects may be caused by destruction of the myelinsheath that surrounds neurons (a process known asdemyelination), damage to the neuron itself, or

damage to the neurotransmitter system. Sensorychanges are often reported as numbness or a tinglingsensation. Methyl mercury is one chemical that isextremely toxic to the visual, sensory, and motorsystems. Several episodes of large-scale humanintoxication by this organic heavy metal have beendescribed (3). In recent years, tests have beendeveloped to detect sensory changes, particularly invisual and auditory functions resulting from expo-sure to toxic substances.

Organophosphorous and carbamate insecticidescan induce functional changes by inhibiting ace-tylcholinesterase, an enzyme that breaks down theneurotransmitter acetylcholine. The functionalchangesinclude hyperactivity, neuromuscular paralysis, weak-ness, vomiting, diarrhea, and dizziness, with moresevere cases exhibiting convulsions, coma, or death.The onset and duration of symptoms depend on theinherent toxicity of the insecticide, the dose, theroute of exposure, and preexisting health conditions.Some organophosphorous pesticides can producedelayed and persistent neuropathy by damagingneurons in the spinal cord and peripheral nervous

Box 3-A—The Ginger-Jake Syndrome

During Prohibition, contamination of a popular ginger extract with triorthocresyl phosphate led to an epidemicof partial paralysis that came to be known as the Ginger-Jake syndrome. The case serves as a dramatic example ofthe neurotoxic potential of organophosphorous substances.

Extract from the Jamaica ginger had been used in the United States since the 1860s as a medicinal tonic. Atypical preparation contained 70 to 80 percent alcohol by weight and reputedly aided in digestion, preventedrespiratory infections, and promoted menstrual flow. Nicknamed ‘‘Jake," the tonic became especially popular inthe early 1900s in areas where local legislation outlawed the sale of alcoholic beverages.

During Prohibition, the legal sale of ginger extract was limited to a “fluidextract” which contained 5 gramsof ginger per cubic centimeter of alcohol (usually ethanol). Since the high concentration of ginger yielded a solutiontoo irritating to drink, the requirement was supposed to confine its use to medicinal purposes. Department ofAgriculture agents would occasionally check for the appropriate ginger content by boiling off the alcohol andweighing the solid residue. However, bootleggers soon saw the possibility of dissolving small amounts of gingerinto alcohol and substituting adulterants, such as molasses or castor oil, for the remaining required solid content.The result was a potable alcohol source that could be sold at bargain prices.

In 1930, perhaps in response to an increase in the price of castor oil, one bootlegger tried Lyndol, aheat-resistant oily material used in lacquers and varnishes, as an adulterant. When consumed, the triorthocresylphosphate in Lyndol caused axonal degeneration in neurons of the central and peripheral nervous systems.Depending on the severity of the case, symptoms ranged from temporary numbness and tingling in the extremitiesto permanent partial paralysis. Estimates vary widely, but between 20,000 and 100,000 people were permanentlyaffected before all the poisonous shipments were seized.

SOURCES: M.B. Abou-Doniaand D.M. Lapadula, “Mechanisms of Organophosphorus Ester-Induced Delayed neurotoxicity: Type I and TypeII, ” Annuuf Review of Pharmacology and Toxicology 30:405440, 1990; S.D. Davis and R.J. Richardson, “OrganophosphorusCompounds, ” Experimental and Cfinical Neurofoxicofogy, P.S. Spencer and H.H. Schaumburg (eds.) (Baltimore, MD: Williams& Wilkins, 1980); J.P. Morgan, “The Jamaica Ginger Paralysis,” Journal of the American Medical Associatwn 248; 1864-1867,1982; J.P. Morgan, City University of New York, personal communication, Jan. 4, 1990.


system; in these cases, the resulting muscle weak-ness may progress to paralysis (4, 26).

Motor and sensory functions are closely linkedwithin the nervous system. Body movements, forexample, involve complex feedback interactionsbetween motor and sensory neurons to allowsmooth, controlled movements. Consequently, dam-age to sensory systems can indirectly affect certainmotor functions. Some toxic substances affect motorneurons directly; others damage both sensory andmotor neurons (a condition termed mixed neuropa-thy). Neurophysiological tests are available to moni-tor the conduction velocity of impulses along nerveaxons, and various neurological tests can be used todetect muscle weakness and lack of control ofmuscular movements.

Toxic substances often affect the higher functionsof the nervous system such as learning, memory, andmood. Exposure to inorganic lead can lead to mentalretardation in children; at lower levels of exposure,however, it may manifest itself as a shortenedattention span or a learning disability (16, 23).Various tests are available to detect impairment ofthese processes, some of which are described inchapter 5.

Behavioral Effects

Behavioral changes may be the first indications ofdamage to the nervous system. An individualexposed to a toxic substance may initially experi-ence vague feelings of anxiety or nervousness.These feelings may progress to depression, diffi-culty in sleeping, memory loss (see box 3-B),confusion, loss of appetite, or speech impairment. Insevere cases, a person may exhibit bizarre behavior,delirium, hallucinations, convulsions, or even death.Often, behavioral toxicological testing can detect animpairment for which investigators have not yetfound a physiological or biochemical mechanism.

Exposure to neurotoxic chemicals during preg-nancy may not produce obvious symptoms ofbehavioral toxicity until long after the exposure hasceased. This phenomenon has given rise to the fieldof behavioral teratology (18). An issue of particularconcern to neurotoxicologists is the latency of someneurotoxic effects. One explanation for latent, or“silent,” damage is that at younger ages the brainmay be able to compensate for some adverse effects.With age, this ability to compensate diminishes, andthe damage inflicted early in life may become

apparent (19, 25). It has been proposed that exposureto toxic substances may trigger biochemical eventsthat may later contribute to the cause of certainneurological diseases such as Parkinson’s disease,amyotrophic lateral sclerosis (ALS, or Lou Gehrig’sdisease), or Alzheimer’s disease. This hypothesis,sometimes referred to as the environmental hypothe-sis, has recently been the subject of increasedinterest following the MPTP incident (see box 3-C)and the Guam-ALS episode (19). (See ch. 2).

Susceptibility to neurotoxic Substances

Everyone is susceptible to the adverse effects ofneurotoxic substances, but individuals in certain agegroups and persons with certain health problemsmay be particularly at risk. The developing nervoussystem is especially vulnerable to certain toxicsubstances. Its cells are actively growing, dividing,migrating, and making synaptic connections, and theblood-brain barrier is not yet fully developed.During the first weeks of prenatal development,toxic substances may interrupt closure of the neuraltube, leading to such birth defects as spina bifida (adefect in which the vertebral column is exposed) andanencephaly (the absence of all or part of the brain).During later development, the risks of exposure havediminished for many components of the nervoussystem; however, the cerebrum and cerebellum,major portions of the brain responsible for functionssuch as sight and movement, remain particularlyvulnerable (15, 22).

Factors such as dose of the toxic substance andnutritional deficiencies in the mother also influencethe extent of damage. Ethanol (alcohol), cocaine,antibiotics, and steroids, for example, can all ad-versely affect the fetal nervous system (18). Sincefew drugs have been adequately evaluated for effectson the developing fetus, physicians are advised toexert special care in prescribing drugs to pregnantwomen.

As the structure and function of the nervoussystem decline with age, individuals become moresusceptible to the effects of many neurotoxic sub-stances. Adverse effects that might have beenmasked at a younger age by a vital, healthy nervoussystem may become apparent. Those suffering fromneurological disorders are at greater risk becausetoxic chemicals may exacerbate existing problems.Persons suffering from multiple sclerosis or neu-romuscular disorders, for example, are vulnerable

Chapter 3-Fundamentals of neurotoxicology . 71

Box 3-B—The Endangered HippocampusDeep inside the brain is a crescent-shaped structure that acts as a switching and information storage center. The

hippocampus, as it is called, is a site of convergence of many neural pathways and is in a strategic position tomodulate chemical information as it is transferred from one region of the brain to another, It is a major componentof the limbic system, which, along with the hypothalamus and amygdala, is involved in the control of emotion andmotivation. In recent years, evidence has mounted that the hippocampus is important if not critical, to learning andmemory processes. These processes are significantly impaired if the hippocampus or certain nerve pathwaysentering it or leaving it are destroyed.

Learning and memory are often adversely affected by toxic substances, and some researched believe that thehippocampus is an important target site of these substances. A number of toxic chemicals preferentially affect thehippocampus, including many metals, some abused drugs, and certain viruses (including those responsible forrabies and AIDS). The hippocampus is also adversely affected in neurodegenerative disorders such as Alzheimer’sdisease and in Down’s syndrome.

Many of the cells of the hippocampus appear to use the excitatory amino acids glutamate and aspartate asneurotransmitters, Under normal circumstances the synthesis, storage, and release of these transmitters is delicatelybalanced. However, adverse conditions associated with trauma, stroke, or exposure to toxic chemicals and drugsmay upset this balance, sometimes leading to an event known as excitotoxicity. This is a process by whichexcitatory neurotransmitters released from neurons flood neighboring cells and weaken their membranes, leadingto cell death. The mechanism of this cascade of events is being examined closely in the case of glutamate becausethe characteristics of the receptor that binds this transmitter are beginning to be understood. Recently, it wasdiscovered that the drug PCP blocks glutamate receptors and that other compounds that effectively block thisreceptor are virtually identical to PCP.

There is much to learn about the transmitter systems in the hippocampus and the mechanisms by which toxicsubstances alter these systems. Clues to how some aspects of learning and memory are altered by toxic substancesmay ultimately be found in the biochemical machinery of this region of the brain.

SOURCES: S. Blakeslee, ‘Pervasive Chemical, Crucial to the Body, Is Indicted as an Agent in Brain Damage,” New York Times, Nov. 29, 1988;TJ. Walsh and D.F. Emerich, “The Hippocampus as a Common Target of neurotoxic Agents,” Toxicology 49:137-140, 1988.

because the neural targets of these diseases are the the liver (15). This problem is especially relevant forsame as those of many neurotoxic substances.Persons suffering from mental disorders may also bemore susceptible to neurotoxic substances becauseof possible augmentation of their symptoms. Toxicchemicals can cause or exacerbate anxiety, depres-sion, mania, and psychosis. Most adverse effects areshort-term and reversible; however, long-term ef-fects, including permanent damage to mental health,can occur.

Diseases involving organs such as the kidney orliver can indirectly affect the nervous system. Thebuild-up of waste products in the bloodstream due tokidney failure or diabetes, for example, can causeadverse effects on nervous tissue similar to thosecaused by environmental exposure to toxic chemi-cals.

Malnourished individuals are generally at greaterrisk of harm from neurotoxic substances than areindividuals with adequate diets. A person with athiamine (vitamin Bl) deficiency, for example, ismore susceptible to the toxic effects of ethanol on

developing nations-that face regular food shortages.

CLASSES OF neurotoxicSUBSTANCES

neurotoxic substances can be categorized accord-ing to the structural or functional changes theycause. The following categorization, which groupsneurotoxic substances according to where theyappear to act, is a summary of a scheme developedby Spencer and Schaumburg (20). The schemeincludes the following targets: neurons, glial cellsand myelin, the neurotransmitter system, and bloodvessels supplying the nervous system.

Some adverse effects may not be included in thisapproach. For example, neurotoxic substances mayalso affect cells of the immune system, which can inturn influence nervous system function at any ofthese neural sites. Interactions between the immuneand nervous systems have become the subject of

72 ● neurotoxiciV: Identifying and Controlling Poisons of the Nervous System

Box 3-C-MPTP and Parkinson’s Disease

In recent years, the hypothesis that Parkinson’s disease and other neurological disorders might be triggered byenvironmental factors has become more widely accepted. Although toxic substances have long been consideredpossible contributors to the cause of some disorders of the nervous system, the MPTP incident has focused moreattention on this environmental hypothesis.

MPTP is the abbreviation for l-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine, a compound that can be createdduring the production of synthetic heroin. Remarkably, in just 5 to 15 days, this highly neurotoxic substance caninduce a syndrome virtually identical to Parkinson’s disease—a disease that usually occurs late in life and developsslowly over a period of years. Both Parkinson’s disease and the- MPTP-induced syndrome are characterized bytremors and lack of muscular control that stem from degeneration of neurons in the substantial nigra, a region deepin the central area of the brain. Neurons in the substantial nigra synthesize and secrete the neurotransmitter dopamine,hence Parkinson’s patients are treated with levodopa, a precursor of this neurotransmitter.

The discovery of the link between MPTP and Parkinson’s disease has dramatically changed the nature ofresearch on this disease. Much work has focused on MPP+, a metabolize of MPTP that is responsible for the adverseeffects on the brain. Recently, researchers discovered that a monoamine oxidase inhibitor, a type of drug sometimesused to treat depression, blocks the conversion of MPTP to MPP+. Other researchers have shown that themonoamine oxidase inhibitor Deprenyl, administered to Parkinson’s patients in combination with levodopa,reduces the symptoms of the disease and extends their lives. It was found that Deprenyl slows the rate ofdegeneration of neurons in the substantial nigra, perhaps making it useful in the treatment of Parkinson’s disease.

The MPTP story illustrates how a neurotoxic substance might cause or contribute to the development ofneurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. Therelative contributions of environmental and genetic factors to the causes of these diseases are not understood andare the subject of considerable research and debate within the scientific community. Although the extent to whicha neurotoxic substance contributes to the cause of Parkinson’s disease is unclear, the MPTP story serves as anexample of how neurotoxicological research can lead to a better understanding of the causes of neurological diseaseand ways to treat it.

SOURCES: LJ. Kopin and S.P. Markey, “MPTP Toxicity: Implications for Research in Parkinson’s Disease,’ Annuul Review of Neuroscience11:81-96, 1988; J.W. Langston, P. Batlard, J.W. Tetrud, et al., “Chronic Parkinsonism in Humans Due to a Product ofMeperidine-Analog Synthesis, ” Science 219:979-980, 1983; R. Lewin, “Big First Scored With Nerve Diseases,” Science245:467468, 1989.

considerable interest in recent years, leading to a causing numbness in the face, neck, and limbs. Thisnew field of research known as neuroimmunology.

Actions on the Neuronal Membrane

As described earlier, the neuron consists of thecell body and the dendrites and axons projectingfrom it. The neuronal membrane contains a complexsystem of pumps, receptors, and channels throughwhich charged molecules (ions such as sodium,calcium, and potassium) travel into and out of thecell. Toxic substances may act on any of thesecomponents. Determining the mechanism of actionof neurotoxic substances often requires researchersto investigate possible adverse effects on a variety ofreceptors and channels.

Naturally occurring toxic substances such astetrodotoxin (from the puffer fish) and saxitoxin(from the marine alga responsible for paralyticshellfish poisoning) block ion channels, initially

is followed by difficulty in speaking and swallowingand by an inability to coordinate muscular move-ments. In severe cases, respiratory paralysis mayresult.

Toxic substances can also act to increase the flowof ions across the membrane, resulting in many ofthe same symptoms as those caused by the channelblockers. Scorpion toxin and the pesticide DDT, forexample, act by increasing the flow of sodium ions.Pyrethroid pesticides are an example of widely usedcommercial compounds that exert toxic effects inthis manner.

Actions on Neuronal Structures

Substances such as mercury and lead causedegeneration of the central nervous system. Intoxi-cation by organic mercury, particularly in children,can cause degeneration of neurons in the cerebellum


and can lead to tremors, difficulty in walking, visualimpairment, and even blindness. Lead adverselyaffects the cortex of the immature brain, causingirreversible mental retardation in young children(23).

The peripheral nervous system is particularlyvulnerable to the effects of toxic substances becauseit lies outside the central nervous system which ispartially protected by the blood-brain barrier. Theantitumor agent doxorubicin, for example, causesdegeneration of both central and peripheral nerveaxons (21).

Degeneration of the axon is one of the mostfrequently encountered neurotoxic effects. Manychemicals and drugs will cause axonopathy but willnot affect the cell body. In most cases, repeated orchronic exposure is required before adverse effectsoccur. The precise mechanisms by which axonaldegeneration occurs are not understood. Someresearch suggests that toxic substances block the

Photo credit: U.S. Environmental Protection Agency

transport of substances between the cell body andregions of the axon.

Often, degeneration begins at or near the end ofthe axon and proceeds toward the cell body. Asnoted earlier, this type of pathological effect is calledcentral-peripheral distal axonopathy (CPDA). Anafflicted individual may experience loss of sensationin the hands and feet or muscular weakness. In somecases, the effects gradually worsen, and the loss ofsensation progressively ascends to the limbs asshorter nerves become affected. With time andremoval from exposure, recovery is often possible.

Numerous toxic substances cause CPDA, includ-ing such industrial chemicals as carbon disulfide(discussed further in ch. 10), hexane, acrylamide,and Lucel-7 (discussed in ch. 2). Drugs that causethis axonopathy include thalidomide (whose othertragic side-effects on the developing fetus have beenwell documented) and vincristine, a drug used totreat cancer. Alcohol abuse, some organophosphor-ous pesticides, and natural toxins present in buck-


thorn (from the fruit of the shrub Karwinskiahumboldtiana) also adversely affect the nervoussystem in this manner.

A less common form of axonal degeneration,central-distal axonopathy, is characterized by ad-verse effects on the spinal cord but not on theperipheral nervous system. Some 10,000 casesoccurred in Japan between 1956 and 1972, when thedrug clioquinol was considered a safe and effectivenonprescription treatment for diarrhea caused by anamoeba. Affected individuals experienced abdomi-nal discomfort, numbness in the feet, weakness inthe legs, blurred vision, and, in cases where largeamounts of the drug were consumed, encephalitis(inflammation of the brain).

The most serious form of neurotoxicity involvesthe complete loss of nerve cells. Sensory nerve cellsmay be lost in patients treated with megavitamindoses of vitamin B6; hippocampal neurons undergodegeneration with trimethyltin poisoning; motornerve cells are affected in cycad toxicity, which hasbeen linked tentatively to Guam-ALS-Parkinsonismdementia (19).

Actions on Glial Cells and Myelin

A large number of neurotoxic substances cancause degeneration of glia1 cells and the myelin thatthese cells produce. Diphtheria toxin, for example,interferes with the cell bodies of myelin-producingglial cells. Hexachlorophene interferes with theenergy-producing mitochondria within glial cells.Perhexilline maleate, a drug used to treat the chestpain of angina pectoris, sometimes causes degenera-tion of myelin and leads to numbness in the handsand feet and muscle weakness.

Actions on the Neurotransmitter System

Other toxic substances may affect the neurotrans-mitter systems of neurons. The nicotine in cigarettesand some insecticides, for example, mimic theeffects of the neurotransmitter acetylcholine. Organ-ophosphorous compounds, carbamate insecticides,and nerve gases act by inhibiting acetylcholinesterase,the enzyme that inactivates the neurotransmitteracetylcholine. This results in a build-up of ace-tylcholine and can lead to loss of appetite, anxiety,muscle twitching, and paralysis.

Amphetamines stimulate the nervous system bycausing the release of the neurotransmitters norep-inephrine and dopamine from nerve cells. Cocaine

affects both the release and reuptake (the process bywhich neurotransmitters and their metabolizes arerecycled) of norepinephrine and dopamine. Bothamphetamines and cocaine can cause paranoia,hyperactivity, and aggression, as well as high bloodpressure and abnormal heart rhythms.

Some drugs act by altering the action of theneurotransmitter serotonin. LSD, a drug widelyabused in the United States, especially in the 1960s,is a potent hallucinogen. Although it is not knownprecisely how LSD functions, it does interfere withthe activity of the neurotransmitter serotonin. Mes-caline and psilocybin (from the hallucinogenicmushroom Psilocybes) act in a similar fashion.

Opium-related drugs such as morphine and heroinact at specific opioid receptors in the brain. Thesereceptors interact with the endogenous brain neu-ropeptides, such as the enkephalins and endorphins,which control the perception of pain and give rise tofeelings of euphoria. Consequently, drugs acting atopioid receptors cause sedation and euphoria andreduce pain. They also tend to slow the heart rate andmay cause nausea, convulsions, and slow breathingpatterns. They are highly addictive, leading to as yetunidentified changes in the structure and function ofthe nervous system. Researchers are actively seek-ing to understand the mechanisms by which addic-tion to opiates occurs. Withdrawal from this class ofdrugs leads to impaired vision, restlessness, andtremors.

A relatively recent phenomenon of increasingconcern to health-care workers is the addictedinfants born to women who use drugs such ascocaine. These infants suffer from a variety ofbehavioral abnormalities. Many of the symptoms ofwithdrawal seen in adults can also be seen in theseinfants immediately after birth (see box 2-B).

Actions on Blood Vessels Supplying theNervous System

The nervous system is supplied by an extensivesystem of blood vessels and capillaries. The brainneeds large quantities of oxygen and nutrients andrelies on an extensive circulatory system to supplyneeded substances and to remove toxic wasteproducts. Lead damages capillaries in the brain andleads to the swelling characteristic of encephalopa-thy. Other metals (e.g., cadmium, thallium, andmercury) and organotins (e.g., trimethyltin) cause

Chapter .3-Fundamentals of neurotoxicology ● 75

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rupturing of vessels that can result in encephalo-pathy as well.

Further Information

Neurobiology and toxicology are rapidly expand-ing scientific fields that cut across many disciplines.A brief chapter can only touch on some of thegeneral scientific principles underlying neurotoxi-cology, which lies at the intersection of these twofields. The interested reader may wish to consult anyof several textbooks or nontechnical books forfurther information.

SUMMARY AND CONCLUSIONSThe complexity of the nervous system has made

the field of neurotoxicology one of the mostdemanding disciplines in toxicology. In the lastdecade, neurotoxicologists have been able to differ-entiate the effects of many chemicals in terms ofwhere they act and the symptoms they produce, butin most cases they have not yet been able todetermine the mechanisms of action. Very fewsuspected neurotoxic chemicals have been evaluatedin the laboratory and even fewer have been testedthoroughly. These chemicals act at many levels ofthe nervous system and exert their effects in a varietyof ways, with consequences ranging from mildsensations of tingling in the extremities to severemental retardation, loss of sensory function, anddeath. The chemicals may be particularly toxic tosusceptible populations such as the unborn, theyoung, the sick, and the elderly. In order to safeguardhuman populations against the potentially damagingeffects of these chemicals, it is necessary to study theconsequences of prolonged low-level exposures aswell as the effects of neurotoxic chemicals onsensitive populations.

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Cherniak, M. G., “Organophosphorus Esters andPolyneuropathy,” Annals of Internal Medicine 104:264-266, 1986.Cooper, J.R., Bloom, F.E., and Roth, R.H., TheBiochemical Basis of Neuropharmacology (NewYork, NY: Oxford University Press, 1982).Davis, S. D., and Richardson, R.J., “Organophospho-rus Compounds, Experimental and Clinical Neuro-toxicology, P.S. Spencer and H.H. Schaumburg(eds.) (Baltimore, MD: Williams& Wilkins, 1980).Ferry, G., “The Nervous System: Getting WiredUp,” New Scientist, Inside Science 19:1-4, Mar. 4,1989.Ginsburg, M.D., “Carbon Monoxide,” Experimen-tal and Clinical neurotoxicology, P.S. Spencer andH.H. Schaumburg (eds.) (Baltimore, MD: Williams& Wilkins, 1980).Katzman, R., and Terry, R. (eds.), The Neurology ofAging (Philadelphia, PA: F.A. Davis, 1983).Klaassen, C,, “Principles of Toxicology” and “Dis-tribution, Excretion, and Absorption of Toxicants, ”Casarett and Doull’s Toxicology, C. Il. Kkiassen,M.O. Arndur, and J. Doull (eds.) (New York, NY:Macmillan, 1986).Kopin, I.J,, and Markey, S.P., “MPTP Toxicity:Implications for Research in Parkinson’s Disease,”Annual Review of Neuroscience 11:81-%, 1988.Langston, J. W., Ballard, P., Tetrud, J. W., et al.,“Chronic Parkinsonism in Humans Due to a Productof Meperidine-Analog Synthesis, ’ Science 219:979-980, 1983.bwin, R., ‘‘Big First Scored With Nerve Diseases,”Science 245:467-468, 1989.Morgan, J. P., “The Jamaica Ginger Paralysis,”Journal oftheAmericaniUe&”caL4ssociatwn 248:1864-1867, 1982.National Research Council, Drinking Water andHealth (Washington, DC: National Academy Press,1986).Needleman, H. L., “Epidemiological Studies,” Neu-robehavioral Toxicology, Z. Annau (cd.) (Baltimore,MD: Johns Hopkins University Press, 1986), pp.279-287.Restak, R. M., The Brain (New York, NY: BantamBooks, 1984).Riley, E.P., and Vorhees, C.V. (eds), Handbook ofBehavioral Teratology (New York, NY: PlenumPress, 1986).Spencer, P. S., Nunn, P. B., Hugon, J., et al., “GuamAmyotrophic Lateral Sclerosis-Parkinsonism-Demen-tia Linked to a Plant Excitant Neurotoxin, ” Science237:517-522, 1987.Spencer, P. S., and Schaumburg, H. H., “An Ex-panded Classification of neurotoxic Responses Basedon Cellular Targets of Chemical Agents, ” ActaNeurological Scandinavia 100:9- 19(suppl.), 1984.


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Spencer, P. S., and Schaurnburg, H.H. (eds.), Experi-mental and Clinical neurotoxicology (Baltimore,MD: Williams & Wilkins, 1980).Suzuki, K., “Special Vulnerabilities of the Develop- 24.ing Nervous System to Toxic Substances, ’ Experi-mental and Clinical neurotoxicology, P.S. Spencerand H.H. Schaumberg (eds.) (Baltimore, MD: Wil- 25.liams & Wilkins, 1980).U.S. Department of Health and Human Services,Public Health Service, Agency for Toxic Substances 26.and Disease Registry, The Nature and Extent of Lead

Poisoning in Children in the United States: A Reportto Congress (Atlanta, GA: Centers for DiseaseControl, 1988).Walsh, T.J., and Emerich, D.F., “The Hippocampusas a Common Target of neurotoxic Agents,” Toxi-cology 49:137-140, 1988.Weiss, B., “Neurobehavioral Toxicity as a Basis forRisk Assessment,” Trends in Pharmacological Sci-ences 9:59-62, 1988.Young, B. B., ‘‘neurotoxicity of Pesticides,’ Journulof Pesticide Reform 6:2, 1986.

Chapter 4


“There is increasing concern that basic research directed towards predicting, detecting, and understandingneurotoxicity is being neglected by government, industry, and academic researchers.

Committee on Science and TechnologyU.S. House of Representatives

September 16, 1986

“I would say that the methyl n-butyl ketone outbreak was the key episode in bringing attention to the fieldof behavioral toxicology. That signaled a shift in thinking about behavioral problems. Before Columbus,many of us thought, ‘Well, people who work with some chemicals might have trouble concentrating, or maybeeven some temporary or unimportant changes. After Columbus, we could see that even relatively safechemicals, in concentrations that pose no danger to other systems of the body, can bring serious andsometimes irreversible damage to the nervous system.

W. Kent Anger, Ph.D.Psychology Today

July 1982

“Much more work on mechanisms of chemical neurotoxicity will be required before structure-toxicologyconsiderations prove generally useful as a screen for neurotoxicity.

Peter Spencer, Ph.D.“Testimony before the House Committee on Science and Technology

October 8.1985

CONTENTSPage

FEDERAL RESEARCH ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Environmental Protection Agency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81National Institutes of Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84Alcohol, Drug Abuse, and Mental Health Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 88Food and Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88Agency for Toxic Substances and Disease Registry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89Department of Defense . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Department of Energy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Department of Agriculture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92National Aeronautics and Space Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

ACADEMIC RESEARCH ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92Factors Influencing Academic Research Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92Cooperative Agreements Between Government and Academia ..,..... . . . . . . . . . . . . . . 94

INDUSTRIAL RESEARCH ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Pesticide Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Pharmaceutical Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Consumer Product Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Specialty and Commodity Chemical Industries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

INTERACTIONS AM0NG GOVERNMENT, ACADEMIA, AND INDUSTRY . . . . . . 96Industry and Government Consortia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96Industry Research Consortia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96Cooperation in Epidemiological Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96Charitable Organizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

EDUCATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Education of Research Scientists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Education of Health-Care Professionals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

FiguresFigure Page

4-1. Resources for EPA’s neurotoxicology Division . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834-2. Funding for NIOSH Research Grants... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

TableTable Page4-1. Federal Funding for civilian neurotoxicity-Relatec! Research . . . . . . . . . . . . . . . . . . . 81

Chapter 4


Increasing public concern about the effects oftoxic substances on the nervous system has led tosome expansion of research programs in govern-ment, academia, and industry in recent years. Evenso, the research programs are relatively small, andquestions are frequently raised as to whether they arecapable of addressing the threat that neurotoxicsubstances pose to public health. The style andpurpose of research differs in each of these settings,yet each makes important contributions. An optimalnational research program requires effective cooper-ation among researchers in all sectors and anappropriate balance of effort.

This chapter describes current programs in theUnited States and future needs for research into thecauses, extent, and consequences of exposure toneurotoxic substances. The first half of the chapterdescribes Federal research programs; the second halfaddresses research efforts under way in academiaand industry. State research programs are notdescribed in this report.

FEDERAL RESEARCHACTIVITIES

Federal research related to neurotoxic substancesis conducted primarily at the National Institutes ofHealth (NIH), the Alcohol, Drug Abuse, and MentalHealth Administration (ADAMHA), and EPA. Lim-ited research programs are under way at the Foodand Drug Administration (FDA), the Centers forDisease Control (CDC), the Department of Energy,the Department of Agriculture, and other agencies.As indicated in table 4-1, total Federal funding forneurotoxicology -related research (excluding researchrelated to nicotine and smoking, alcohol and alco-holism, and radiation) is $67 million. The bulk ofthis funding (89 percent) is through ADAMHA andNIH and tends to focus on the toxicity of drugs andthe biochemical mechanisms underlying neurologi-cal and psychiatric disorders. A number of otherFederal agencies and organizations provide limitedfunding for research related to neurotoxicity as well.Given the threat that neurotoxic substances poseto public health and the lack of knowledge of themechanisms by which these substances exertadverse effects, OTA found that, in general,Federal research programs are not adequatelyaddressing neurotoxicity concerns.


The principal research component of EPA is theneurotoxicology Division (NTD) within the HealthEffects Research Laboratory at Research TrianglePark, North Carolina. This division was organized in1978 and has gradually grown into an effectiveinterdisciplinary research program. A committee ofEPA’s Science Advisory Board recently reviewedNTD’s program and described it as “the leadingFederal neurotoxicology research organization” (30).NTD research programs range from development ofmethods to evaluate the neurotoxicity of chemicalsto testing of specific substances and determining themechanisms by which toxic substances adverselyaffect nervous system structure and function.

The NTD is divided into three branches: theNeurophysiology and Neuropathology Branch, theBehavior and Neurochemistry Branch, and theSystems Development Branch, which provides engi-neering and technical support services to the firsttwo. Recently, the Science Advisory Board reviewcommittee recommended that consideration be givento developing a branch to focus on cellular andmolecular toxicology (30)0

EPA has developed a multidisciplinary programto examine how toxic substances adversely affectthe nervous system. The overall program strategystresses the development of test methods and ap-proaches for identifying and characterizing neuro-toxicity and for predicting risk to humans. Studiesconducted to evaluate the cellular and molecular

Table 4-l-Federal Funding for Civilianneurotoxicity-Reiated Research

Agency Researcha ($ millions)

National Institutes of Healthb . . . . . . 32.6Alcohol, Drug Abuse, and Mental

Health Administrationc . . . . . . . . . . 26.6Environmental Protection Agency. . . 3.9National Institute for Occupational

Safety and Health . . . . . . . . . . . . . 0.7Food and Drug Administration . . . . . 1.8Department of Energyd . . . . . . . . . . . 0.5Department of Agriculture . . . . . . . . . 0.4

Total . . . . . . . . . . . . . . . . . . . . . . . . 66.5aTotalS are b~ed primarily on fiscal year 1988 data.bExcludes research related to nicotine and smoking.cExcludes research related to alcohol and alcoholism.dExclu&S research related to radiation.


-81-

82 . neurotoxicity: Identifying and Controlling Poisons of the Nervous System

basis for chemically induced functional changes inthe central and peripheral nervous systems aredesigned so that effects on laboratory animals can beextrapolated to humans.

Behavioral research is aimed at evaluating auto-nomic, sensory, motor, and cognitive functions;developing measures to screen chemicals for neuro-toxic potential; and evaluating specific behavioralprocesses that are disrupted by exposure to toxicsubstances (12). Research to determine the utility ofshort-term behavioral tests for measuring neurotoxiceffects helps EPA regulatory program offices in thedevelopment of test guidelines. Long-term researchgoals include the development of animal models thatcan be used to predict behavioral toxicity in humans.

Cellular and molecular research focuses on locat-ing biochemical and anatomical sites of toxicant-induced changes in the nervous system. This in-cludes developing biochemical markers to identifythe targets of toxic substances within the nervoussystem and performing morphological studies todetermine the structural consequences of exposureto neurotoxic substances. NTD’s long-term goals areto develop cellular and molecular approaches thatimprove neurotoxicity testing and provide a betterunderstanding of the neurobiological basis for riskassessment.

The neurophysiology component of the researchprogram is aimed at attaining a better understandingof how physiological processes are disrupted byneurotoxic chemicals. A primary focus is the elec-trophy biological evaluation of sensory systems,which allows for direct measurement of nervoussystem activity. Where possible, the program usesmethods that have direct counterparts in humanresearch, in order to make extrapolation easier (9).

EPA regulatory program offices need more meth-ods of evaluating neurotoxicity, largely because ofthe general requirements of the Federal Insecticide,Fungicide, and Rodenticide Act (FIFRA) and theToxic Substances Control Act (TSCA) (see ch. 7).When EPA requires industry to conduct neurotox-icity testing under TSCA, it must specify the typesof tests required and the data it expects from them.At times, industry may request permission to deviatefrom EPA guidelines (e.g., in the case of test ruledevelopment under TSCA), but these alternative testmethods must be evaluated by the Agency. NTDprovides much of the technical expertise necessaryto support EPA program offices in this regard.

NTD is actively developing and validating twomajor neurotoxicity screening tests: the functionalobservational battery and automated testing ofmotor activity (see ch. 5). These tests are validatedby evaluating how well they confirm the neurotox-icity of known, representative toxic substances. Inthis way, profiles can be developed for classes ofneurotoxic chemicals.

Other approaches to neurotoxicity testing are alsobeing developed. Electrophysiological approachesare being refined to enable investigators to monitorthe excitability of individual nerve cells or groups ofnerve cells or regions of the brain. Behavioral testsare being developed to assess the effects of toxicsubstances on memory, learning, and muscularcoordination. In addition, methods are being devisedto evaluate the effects of toxic substances on thedeveloping nervous system. A variety of molecularand cellular approaches are being developed todetermine the effects of toxic substances on variousproteins in nerve cells (including enzymes) and onseveral biochemical processes, including the trans-port of substances along the axons of nerves. Testsdesigned to evaluate exposures at toxic waste sitesand at chemical spills are also being developed andrefined:

Because EPA’s neurotoxicology Division is theprincipal Federal intramural research organization inthe environmental neurotoxicology field, and be-cause resource information on the program has beenavailable since its inception, OTA analyzed thefunding of this program in some detail. The totalnumber of principal investigators (including somepostdoctoral fellows and on-site contractors) fell to23 in fiscal year 1988, down from 25 in fiscal years1986 and 1987 (figure 4-1A). Funds for on-sitecontract support remained constant over these yearsat $1.7 million, up from $0.9 million in 1984 (figure4-l B). Funds for outside contracts and cooperativeagreements have fluctuated considerably (figure4-lC). Budget stability has been a continuingadministrative problem. According to the EPAScience Advisory Board committee’s analysis, fundsfor NTD are frequently cut with little prior notice,impeding in particular the development of long-range plans. As indicated in figure 4-lD, NTD’ssupplies and equipment budget has dropped precipi-tously in recent years. In 1985, NTD allocated$23,500 in supplies and equipment to each principalinvestigator. In 1988, only $8,100 could be allocated(figure 4-lE). In its recent review, the Science

Chapter 4-Research and Education Programs . 83

Figure 4-l-Resources for EPA’s neurotoxicoiogy Division

A. Total Principal Investigators

Thousands of dollars

28

24

20

16

12

8

4

0

25 2523

11

14

22

17

1980 1981 1982 1983 1984 1985 1986 1987 1988

C. R&D Funds: Outside Contractsand Cooperative Agreements

Thousands of dollars8 0 0 T – — — -— — – - — — ‘ -

o > - — ~ ‘ - - - ‘ T

— , – — . — , —— i

1979 1980 1981 1982 1963 1984 1965 1986 1987 1988

B. R&D Funds: On-site Support Contracts

Thousands of dollars2,000 1 I

1,800

1,600

1,400

1,200

1,000

600

600

400I

~,

2001

,-/ /

() < -. , — - J—T I ‘T –, — — —

1979 1980 1981 1982 1983 1984 1985 1986 1987 1986

D. Funds: Supplies and Equipment

Thousands of dollars600

500

400

300

200

100

0

—

470

369

270234

187

1984 1985 1986 1987 1988

E. Supplies and Equipment per Principal Investigator

Thousands of dollars30 ~ - –

25 { 23.5

15i

101

5

16.8

9.410.8

1984 1985 1986 1987

SOURCE: Based on R. Dyer, U.S. Environmental Protection Agency, personal communication,

1968

19aa



Advisory Board committee described NTD’ssupply budget as “totally inadequate” and con-cluded that “important research is not carriedout” because of budgetary restrictions (30).

EPA has rarely funded extramural grants in theneurotoxicology field. A substantial grants programin this area would be a valuable adjunct to itsintramural program.

In recognition of the need to expand its researchprograms in the neurotoxicology area, EPA recentlysubmitted to the Office of Management and Budget(OMB) a request to expand its research budget by$1.5 million. Approximately $1.0 million was re-quested for the development of in vitro neurotoxi-

cology tests; another $0.5 million was requested toexamine adverse effects associated with cholinest-erase inhibition and the utility of cholinesteraseinhibition as a biomarker for exposure. HoweverOMB allowed no funding for either research effort.In vitro test development is often cited as ahigh-priority research need because of the require-ment to rapidly screen toxic chemicals and to try tominimize the use of animals in research. A technicalEPA panel recently recommended that the agencyinitiate studies to examine the relationship betweencholinesterase inhibition and other adverse effectson the nervous system.

National Institutes of Health

Approximately 250 neurotoxicology -related re-search projects were funded by NIH in fiscal year1988 (29). Most were funded through competitivegrants to investigators in public and private institu-tions; the rest were conducted at NIH itself. About80 percent of the neurotoxicology -related research(based on fiscal year 1988 expenditures) is fundedthrough or conducted at the National Institute ofNeurological and Communicative Disorders andStroke (NINCDS) and at the National Institute ofEnvironmental Health Sciences (NIEHS) in Re-search Triangle Park, North Carolina. (NIEHS is theonly NH-I institute not located in Bethesda, MD.)Individual research projects averaged about $120,000.NIH expenditures on neurotoxicology -related re-search (excluding projects at the National CancerInstitute related to nicotine and cigarette smoking)totaled approximately $33 million. This is 0.5percent of the total $6.5 billion ND-I research budget(44). In comparison, NIH spends approximately $1.5billion on cancer research (44), which accounts forabout 23 percent of the total research budget.

OTA found that NIH supports few programs in thefield of neuroepidemiology. NIH supports a rela-tively large number of research projects designed toelucidate how toxic substances influence the nerv-ous system but devotes few resources to projectsexamining the extent to which these substancescontribute to human neurological disorders. Al-though the latter studies are often expensive andtime-consuming, they are critical to understandingthe extent to which toxic substances adversely affectpublic health and in determining the direction andscope of regulatory programs.

Chapter 4-Research and Education Programs ● 85

National Institute of Neurological andCommunicative Disorders and Strokel

In fiscal year 1988, NINCDS funded 71 researchprojects related to neurotoxicity. All but three ofthese were extramural grants to investigators atpublic and private institutions. Research sponsoredby NINCDS covers abroad range of problems, fromthe level of the gene, to the cell, to the wholeorganism. Much of the work focuses on the mecha-nisms by which toxic substances adversely affect thenervous system: for example, how the flow of ionsthrough membrane channels is altered by toxicsubstances, how these substances cause degenera-tion of nerves, how they alter other biochemicalcomponents of the nerve cell, and how toxicsubstances cause or contribute to neurological disor-ders. Several projects focused on how the chemicalMPTP affects the nervous system and how it inducessymptoms of Parkinson’s disease. Other projectsexamined how therapeutic drugs influence the struc-ture and function of the nervous system. Forexample, drugs used in cancer chemotherapy mayadversely affect the nervous system. It is importantto understand how and when this occurs in order tohelp maximize effects on cancerous cells andminimize damage to healthy cells.

Three intramural projects are under way atNINCDS laboratories. The largest was funded atmore than $400,000 and is examining how cellsderived from the brain of mammals perceive andrespond to signals in their environment. A secondproject is examining the neurological and behavioraleffects of MPTP on the monkey, and the third isdevoted to the mechanism by which nerves lose theirmyelin sheaths.

National Institute of EnvironmentalHealth Sciences

NIEHS conducts and supports research related tothe effects on human health of chemical, physical,and biological agents in the environment. NIEHShas an extensive extramural program, and it spon-sored more than 80 grants related to the neurotoxic-ity of environmental contaminants and other sub-stances in fiscal year 1988. The NIEHS extramuralgrants program is the largest source of Federalfunds for research grants in the environmental

neurotoxicology field. Funding for these projectsamounted to nearly $12 million. NIEHS also re-ceived nearly $900,000 from EPA’s Superfundprogram (through an interagency agreement) tosupport four extramural projects. In addition, NIEHSfunded three neurotoxicology-related contracts to-taling $755,000. The extramural projects focused ona broad range of neurotoxic substances, includingmetals, pesticides, solvents, natural toxins, PCBs,and other industrial chemicals. NIEHS also fundedgrants to several academic institutions.

Until 1987, an intramural Laboratory of Behav-ioral and Neurological Toxicology existed withinNIEHS. Following a management change, the labo-ratory’s emphasis shifted to basic neuroscienceresearch (specifically, molecular and cellular neuro-biology) and its name was changed to the Laboratoryof Molecular and Integrative Neuroscience (LMIN).This laboratory comprises three sections and severalsmaller working groups, only one of which, theNeurobehavioral Section, focuses primarily on envi-ronmental neurotoxicology problems. (The neuro-toxicologist who headed that section left the Insti-tute in 1989.) An OTA analysis of fiscal year 1988research projects found that many LMIN researchprojects in the neuroscience were only generallyrelated to toxicology. Of the $3 million expended onintramural research in the neuroscience, OTAfound that only about one-fourth was devoted tostudies in which neurotoxicology was the primaryfocus. Hence, OTA found that, with the exception ofthe Neurobehavioral Section of LMIN, there is littledistinction between intramural basic neuroscienceresearch programs at NIEHS and those at other NIHand ADAMHA institutes. This has lead to a promi-nent intramural research gap at NIH in the environ-mental neurotoxicology field.

National Toxicology Program

The National Toxicology Program (NTP) wasestablished in 1978 by the Secretary of the Depart-ment of Health and Human Services (DHHS) tocoordinate DHHS activities related to the testing oftoxic chemicals. The program was initiated todevelop information about the toxicity of selectedchemicals, to test selected chemicals for toxicity, todevelop and validate tests and protocols, and to setpriorities for testing needs and communicate results

1~ ]ate 1988, the Nation~ kstitute of Neurolo@c~ and Communicative Disorders and Stroke became the National Institute of Nwdogicd

Disorders and Stroke (NINDS), and the National Institute on Deafness and Other Communication Disorders (NIDCD) was formed. Since OTA’s analysiswas based on fiscal year 1988 programs, this discussion will refer to NINCDS programs.


to government agencies, the scientific community,and the public. NTP coordinates toxicology-relatedprograms within the NIEHS, the National Institutefor Occupational Safety and Health (NIOSH), andthe U.S. Food and Drug Administration’s (FDA)National Center for Toxicological Research (NCTR).NTP is administered by the Director of NIEHS.Program activities are overseen by an executivecommittee made up of the senior administrators ofFederal health research and regulatory agencies. Thequality of technical research programs is ensured byan independent Board of Scientific Counselors.After receiving nominations from participating Fed-eral agencies and other public and private organiza-tions, NTP selects chemicals to be tested. Testing isthen performed by outside organizations throughcontract arrangements. Federal regulatory agencieshave rarely requested neurotoxicity studies by NTP.From 1982 to 1988, only one substance had beennominated for neurotoxicity by the multiagencynominating committee (16). Consequently, NTP hassponsored little extramural neurotoxicology researchas of fiscal year 1988. One of the few projects fundedby NTP resulted in development of an automatedassessment of behavior in the home cage (13,14).Intramurally, NTP has developed a neurobehavioraltest battery to be used as part of its analysis of targetorgan toxicity. This battery will be used in a tieredtesting approach to determine whether more special-ized testing is necessary (43).

Within NIEHS, NTP is located under the Divisionof Toxicology Research and Testing. The division iscomposed of four branches: Carcinogenesis andToxicologic Evaluation, Cellular and Genetic Toxi-cology, Chemical Pathology, and Systemic Toxicol-ogy. Toxicological concerns focus on carcinogensand mutagens (and to a limited degree on terato-gens). NTP also evaluates the toxic effects ofenvironmental agents on organ systems, includingthe nervous system. When health hazards are identi-fied by NTP, additional studies characterizing thehazard are often undertaken by researchers in othergovernment agencies, industry, and academia (16).Although the Division of Toxicology Researchand Testing at NIEHS is the primary toxicologi-cal testing organization within the Federal Govern-ment, in 1988 it employed no neurotoxicologists.As of 1989, expert in-house scientific advice wasprovided through periodic consultation with thechief of the Neurobehavioral Section of LMIN. NTPis presently restructuring its program to address

neurotoxicological concerns more effectively. Rep-resentatives of the NTP agencies participating inresearch efforts are preparing cooperative programplans to address neurotoxicologica.1 concerns specif-ically (16).

National Cancer Institute

The National Cancer Institute sponsored eightneurotoxicity-related projects in fiscal year 1988.Half of them focused on the adverse effects of cancerchemotherapy agents on the nervous system. Theother four examined such problems as the inductionof brain tumors by neurotoxic agents and thetreatment of pain caused by cancer. Althoughsmoking and nicotine are not included in this report,it should be noted that the Institute sponsored 64projects related to smoking and nicotine addiction.Total funding for these 64 projects was in excess of$26 million in fiscal year 1988.

National Institute on Aging

The National Institute on Aging (NIA) sponsored10 neurotoxicology -related research grants in fiscalyear 1988. Several of these projects examine thepossible role of metals in causing Alzheimer’sdisease; recent work has suggested that aluminummay contribute to the development of the structuralchanges in the brain that are characteristic of thisdisease. Other projects analyze age-related changesin the concentrations of excitatory amino acids(aspartate and glutamate) and the reduction in brainglutamate receptors seen in individuals with Alz-heimer’s disease, Two projects focus on MPTP, theaging process, and induction of Parkinson’s disease-like symptoms. NIA is particularly interested in thequestion of why certain populations of nerve cellsare particularly vulnerable to neurodegenerativediseases. Because the mechanism of cell death maybe similar in different diseases, NIA is encouragingresearch into the molecular events underlying celldeath (28). A 1988 workshop, sponsored by NIA,examined issues related to the susceptibility of theaging nervous system to infections and toxic sub-stances.

The NIA has two intramural projects underway toexamine the influence of toxic metals on agingprocesses and their possible role in the onset ofdementia. The distribution of metals in the brain isbeing examined, as are the factors controlling thetransport of metals across the blood-brain barrier.

Chapter Research and Education Programs ● 87

In 1988, NIA sponsored a small workshop on theepidemiology of pesticide exposure and cognitivedisorders in aging migrant and seasonal farmwork-ers. The effects on the human nervous system oflong-term, low-level exposure to neurotoxic agricul-tural pesticides and herbicides are not known. Theworkship assessed the feasibility of using seasonaland migrant farmworkers, resident farmers, andothers as research subjects in epidemiological stud-ies.

National Institute of Child Health andHuman Development

The National Institute of Child Health and HumanDevelopment sponsored 11 research projects relatedto neurotoxicity in children in fiscal year 1988, withfunding totaling approximately $1.2 million. Six ofthese projects focus on lead, which adversely affectsthe developing nervous system (see ch. 10). Two ofthe projects analyzed the effects of drugs used totreat epilepsy on the fetuses of mothers who musttake these drugs. There is evidence that valproicacid, a drug widely used to treat epilepsy, adverselyaffects the nervous system of the developing fetus.The effects of valproic acid and phenytoin (anotherantiseizure drug) on the development of the nervoussystem of rhesus monkeys are being examined.

Another project is evaluating the effects of dietshigh in sugar or the artificial sweetener aspartame, orboth, on the behavior and mental development ofchildren. Other projects are examining mechanismsby which acrylamide, alcohol, and other substancesaffect the developing brain.

Division of Research Resources

The Division of Research Resources funded atotal of 47 neurotoxicity-related research projects atvarious private and public research institutions.Projects focused on a broad range of toxic sub-stances, including lead, pesticides, chemotherapyagents, ethanol, mercury, MPTP, and natural ven-oms and toxins. Total funding for these projects infiscal year 1988 was $788,000.

Other NIH Institutes and Organizations

The National Institute of Allergy and InfectiousDiseases (NIAID), National Institute of GeneralMedical Sciences (NIGMS), National Heart, Lung,and Blood Institute (NHLBI), National Center forNursing Research, Fogerty International Center(FIC), and National Institute of Dental Research

Photo credit: John O’Donoghue

This photograph illustrates the swelling of axons (darkareas) that can occur following exposure to a neurotoxic

substance, in this case, 2,5-hexanedione.

sponsored several projects concerned with neurotox-icity. These include projects investigating the ac-tions of a paralytic toxin from a snail (NIGMS), theadverse effects of an antibiotic on hearing (NIGMS),how bacteria degrade and avoid the effects oforganophosphates (NIGMS), the possible neuro-toxic effects of drugs used to treat Herpes virusinfections (NIAID), the side-effects of drugs used totreat high blood pressure (NHLBI), and the effects ofantipsychotic drugs on brain dopamine receptors(FIC).National Library of Medicine

The National Library of Medicine (NLM) sup-ports toxicological research by maintaining auto-mated toxicology databanks and providing informa-tion services. The Toxicology Information Programwas established in 1967 in response to a recommen-dation made by the President’s Science AdvisoryCommittee that efforts to handle toxicologicalinformation be enhanced. The NLM maintainsseveral computerized, interactive retrieval services,including Toxline, Toxnet, and Chemline. Toxlineprovides information on the toxicological effects ofdrugs and chemicals. Toxnet contains informationon potentially toxic or hazardous substances. Chem-line is a chemical dictionary providing chemicalnames, synonyms, registry numbers, molecular for-mulas, and related information.



ADAMHA is composed of the National Instituteon Alcohol Abuse and Alcoholism (NIAAA), theNational Institute on Drug Abuse (NIDA), and theNational Institute of Mental Health (NIMH). Asindicated in chapter 2, OTA is excluding research onalcohol and alcoholism from this assessment; conse-quently, research programs at NIAAA will not bedescribed. Both NIDA and NIMH have extensiveresearch programs to examine the neurotoxic effectsof drugs (NIDA) and the influence of neurotoxicsubstances on mental health (NIMH).

National Institute on Drug Abuse

NIDA sponsors a large research program relatedto the neurotoxicity of abused drugs. In fiscal year1988, it funded 110 neurotoxicity-related grants.Total extramural funding was $15.5 million, orapproximately $140,000 per grant. The extramuralprogram addresses a broad range of issues from avariety of perspectives, including biochemical, phar-macological, pathological, and behavioral studies(14) and supports studies on all abused drugs. In1988, it spent $1.5 million on in vitro studies of theneuropathological effects of drugs and on theneurotoxicity of designer drugs, cocaine, and in-haled solvents. An interagency agreement withNCTR supported studies of marijuana neurotoxicity(11).

Intramural research at NIDA is conducted at theAddiction Research Center in Baltimore, Maryland.Scientists at the center are examining the adverseeffects of drugs such as MDMA (’ ‘ecstasy’ and therelated drug fenfluramine, cocaine, and THC, theactive component of marijuana. The center’s neuro-toxicology-related research is conducted primarilyin its neurobiology laboratory, but projects are alsobeing carried out in its molecular pharmacology,preclinical pharmacology, neuropharmacology, neu-roendocrinology, immunology, and cognitive sci-ences laboratories. Through an interagency agree-ment, FDA has provided the Addiction ResearchCenter with funding to develop and validate method-ologies for assessing the neurotoxicity of variousdrugs currently prescribed or under consideration fortreatment of neuropsychiatric disorders. The centerhas been asked by the Drug Enforcement Adminis-tration to assess the neurotoxicity of some sub-stances that are currently under consideration for

regulatory scheduling (8). Funding for intramuralneurotoxicity-related research in fiscal year 1989was approximately $256,000 (8).

National Institute of Mental Health

A sizable portion of NIMH’s research effort isdevoted to neurotoxicity-related concerns. In fiscalyear 1988, it funded 65 extramural grants totaling$8.6 million (excluding alcohol-related research), anaverage of some $132,000 per grant. These grantssupported research into such issues as the mecha-nisms by which psychoactive drugs influence nerv-ous system function, ways of minimizing the ad-verse effects of psychoactive drugs, and the contri-bution of toxic substances to neuropsychiatric disor-ders (14).

NIMH spent $2.2 million on eight major intramu-ral research programs related to neurotoxicity. Theseprograms are examining how toxic substances influ-ence behavior and memory, how toxic substancesmay contribute to such diseases as Parkinson’sdisease and dementia, the mechanisms by whichtoxic substances disrupt biochemical processes withinnerve cells, and methods of detecting toxic sub-stances in the brain (14).


FDA’s primary responsibility is to protect “thehealth of the Nation against impure and unsafefoods, drugs and cosmetics, and other potentialhazards” (27). neurotoxicity research at FDA islimited in size and scope. A small research program(within one laboratory) exists in the Center for FoodSafety and Applied Nutrition (CFSAN), but there isno significant research program in the Center forDrug Evaluation and Research. Several intramuralresearch projects related to developmental neurotox-icology and one extramural project are underway atthe National Center for Toxicological Research.

Center for Food Safety and Applied Nutrition

The General and Molecular Toxicology Branch ofCFSAN conducts toxicological research related tofood and nutrition and examines approaches toassessing health risks posed by food additives. TheNeurobehavioral Toxicology Team (NBT), one offive teams within this branch, conducts neurotoxi-cological studies in this area. With the recentdeparture of a principal investigator, NBT currentlyconsists of only the team leader, one laboratorybiologist, and several laboratory assistants.


In recent years, FDA has interacted closely withEPA’s Health Effects Research Laboratory, and forsome time FDA has transferred funds to EPA as partof an interagency agreement (37,38). NBT is cur-rently examining how altered ratios of carbohydratesto proteins affect brain function and how toxicchemicals are distributed in the brain. The team isalso developing dog and miniature swine modelsystems that may eventually prove useful in predict-ing the effects of toxic substances on the humannervous system. Efforts are being made to assess thereliability and sensitivity of the model through acollaborative effort with investigators at NIMH.

The FDA is sponsoring three extramural projectsrelated to aspartame and the influence of dietaryamino acids on brain function (see app. A). Onecontractor is examining how changes in the relativeconcentrations of dietary amino acids affect thefunction of transmitters and receptors at neuronalsynapses. Under an interagency agreement withFDA, NIEHS is determining whether an alteredamino acid balance affects neuronal excitability orinduces behavioral changes, or both, in adult anddeveloping animals. FDA also has an interagencyagreement with the Federal Aviation Administrationto conduct clinical studies of the effects of aspartameon cognitive functions (39).

National Center for Toxicological Research

Located in Jefferson, Arkansas, NCTR conductstoxicology research programs that:

. . . study the biological effects of potentially toxicchemical substances found in the” environment,emphasizing the determination of the health effectsresulting from the long-term, low-level exposure totoxicants and the basic biological processes forchemical toxicants in animal organisms; developsimproved methodologies and test protocols forevaluating the safety of chemical toxicants and thedata that will facilitate the extrapolation of toxico-logical data from laboratory animals to man; anddevelops Center programs under the National Toxi-cology Program (27).

neurotoxicity-related research at NCTR currentlyfocuses on developmental issues. NCTR is wellqualified to carry out investigations of toxicologicalproblems. Expertise is available in the areas ofneurochemistry, neuropathology, neuropharmacol-ogy, behavioral pharmacology, primatology, devel-opmental neurotoxicology, and nutritional influenceon neurotoxicity.

Approximately one-third of the intramural re-search conducted within NCTR’s Division of Repro-ductive and Developmental Toxicology is devotedto developmental neurotoxicology and related is-sues. The approximately $1.3 million intramuralneurotoxicology effort includes seven to eight full-time scientists, seven to eight laboratory technicians,and two to three graduate students (32).

From fiscal year 1983 to 1988 NCTR conducteda study of the effects on primates of chronicexposure to marijuana. This project was not fundedby FDA, but through an interagency agreement withNIDA. Cumulative fiscal year 1983 to 1987 fundingwas $1.8 million. The project was then extended for1 year (through fiscal year 1988) at $748,000.

NCTR has the facilities, equipment, and person-nel to expand interdisciplinary research in neurotox-icity and to conduct research related to therapeuticdrugs and food additives, but it is currently con-strained by lack of funds. NCTR recently decided toconsider establishing a formal neurotoxicology unit.

Agency for Toxic Substances andDisease Registry

The Agency for Toxic Substances and DiseaseRegistry (ATSDR) is responsible under the Compre-hensive Environmental Response, Compensation,and Liability Act of 1980 (CERCLA, or Superfund)and the Superfund Amendments and Reauthoriza-tion Act of 1986 to carry out applied research onhealth effects of exposure to hazardous substances.

Hazardous waste sites contain solvents, pesti-cides, and metals, all of which are known to beneurotoxic. These chemicals have been releasedfrom waste sites into the air, soil, and waterhowever, it is not known what neurotoxic effects, ifany, will be caused by long-term exposure to thesechemicals in the environment. The neurotoxic ef-fects on sensitive and vulnerable populations, forexample, pregnant women, young children, and theelderly, are also not understood.

ATSDR is required by statute to compile a list ofthe 200 most toxic substances found at Superfundsites. This list contains hazardous substances knownto cause neurotoxic effects (e.g., toluene and others).ATSDR is also required to fill in any significant gapsin data on adverse health effects associated withexposure to these chemicals. For many of thesechemicals, little is known about their neurotoxic


effects. ATSDR is collecting information on theneurotoxicity of these substances for disseminationto the public (4).

Another way that citizens may come into contactwith solvents, pesticides, and metals is when one ormore of these chemicals is spilled during transport.The acute and chronic neurotoxic effects in rescueworkers and others who respond to spills and incitizens who do not have the time, knowledge, orability to evacuate an area are not known. Thesesituations can be serious because frequently there isa large concentration of the chemical in one location,the incident occurs suddenly, and the populationsexposed may not know how to minimize adverseeffects (4). Although ATSDR does not conduct orsponsor laboratory research in this area, it recentlysupported the National Academy of Sciences studyneurotoxicology and Models for Assessing Risk, andwas a cosponsor of the Third International Sympo-sium on Neurobehavioral Methods in Occupationaland Environmental Health.

National Institute for Occupational Safetyand Health

NIOSH has identified neurotoxic disorders as oneof the 10 leading occupational problems in theUnited States. NIOSH funds intramural and extra-mural activities designed to implement a program toidentify, characterize, and control exposure to neuro-toxic agents.

Intramural activities include an extensive surveil-lance program directed toward identification of awide range of possible endpoints that may include,but are not restricted to or focused exclusively on,neurotoxic agents. These activities include thedevelopment of a database describing exposuresfrom an extensive sampling of workplaces through-out the Nation, in order to identify patterns of use ofknown neurotoxicants, and a health hazard evalua-tion program that responds to requests for workplaceassessments throughout the Nation (and which hasidentified cases of neurotoxic exposure in the past).

The identification and characterization of neuro-toxic agents are conducted through both the intramu-ral and extramural programs. Current intramuralresearch includes the evaluation of possible long-latency effects of chronic exposure to ethylene andpropylene oxide in primates and the effects of acuteexposures to aliphatic carbons on motor activity andphysiology of rodents. A human study is also being

designed to evaluate the impact of exercise onexposure to combinations of chemicals. Effects ofexposure will be assessed by means of behavioralmeasures and will be correlated with pharmacologi-cal information. A study of workers exposed topesticides is in the early stages of development.

The primary thrust of NIOSH’s intramural pro-gram is methods assessment. The Institute is partici-pating in the National Health and Nutrition Survey,in which approximately 6,000 people from aroundthe Nation will be given three tests from theNeurobehavioral Evaluation System (NES) in orderto develop baseline data for future evaluations ofexposure to neurotoxic chemicals. Similarly, NIOSHis one of three organizations conducting the interna-tional, cross-cultural assessment of the Neurobehav-ioral Core Test Battery (NCTB) recommended bythe World Health Organization. The NCTB assess-ment has been conducted jointly with an evaluationof the NES. In this study, people in different ageranges were administered both batteries, thus pro-viding information on the effects of participant ageand means of administration. The NES is adminis-tered by a computer, and the NCTB is administeredby a psychologist or other suitably trained profes-sional (6).

Funding for that portion of the intramural programdirected exclusively at assessing neurotoxic disor-ders includes nine full-time-equivalent staff (includ-ing four persons with Ph.D.s) and $90,000 for thefour projects currently funded.

Funding for neurotoxicology-related grants makesup a small portion of the total NIOSH extramuralbudget. In 1989, that total was $6.1 million, with$0.2 million (6), or less than 4 percent, devoted toneurotoxicology -related research. Since 1985, fund-ing for neurotoxicology -related grants has declined,reflecting in part a decline in NIOSH’s total extra-mural grants budget (figure 4-2). The current NIOSHbudget has approximately half the buying power itdid in 1980, due to inflation and budget cuts (47).NIOSH extramural grant programs are clearly weakin the neurotoxicology area.

Center for Environmental Health

Toxicology research at the Center for Environ-mental Health (CEH) in Atlanta, Georgia, is con-ducted under two divisions. The Division of Envi-ronmental Hazards and Health Effects is responsiblefor design, implementation, and analysis of expo-


Figure 4-2—Funding for NIOSH Research Grants

~ Millions of dollars-

LAll NIOSH grants7 (current dollars)

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2 grants (current dollars)

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1980 1981 1982 1983 1984 1985 1986 1987 1988 1989

‘Based on the Biomedical Research and Development Price Index


sure assessments and epidemiological studies. TheDivision of Environmental Health Laboratory Serv-ices develops and standardizes laboratory methods.

CEH is designing sensitive laboratory tests toassess the impact of toxic chemicals on publichealth. A major objective of its program is todevelop tests that will enable investigators toevaluate toxic substances under a variety of biologi-cal conditions. Another major objective is to con-duct tests at sites of environmental hazards todetermine the threat to human health.

CEH conducts epidemiological investigations ofhuman exposure to environmental hazards, includ-ing man-made and naturally occurring toxic sub-stances, and determines the health effects resultingfrom exposure. It also provides emergency responseto environmental disasters.

Department of Defense

The Department of Defense conducts and sup-ports research related to neurotoxicity, much ofwhich is relevant to the toxicity of chemical warfareagents. Defense-related neurotoxicology researchprograms were not evaluated by OTA for this report.

Department of Energy

The Department of Energy (DOE) supported onlytwo research projects related to neurotoxicologythrough grants to public institutions in fiscal year1988. Total funding of these projects was $487,000

(46). The first project examined the effects ofenvironmental agents (as well as endogenoushormones and neurotransmitters) on cultured braincells, A major goal of the project was to analyze thesensitivity of three major types of brain cells toenvironmental agents and to identify chemicals thatinfluence the survival, proliferation, and differentia-tion of these cells.

The second project focused on the biologicaleffects of magnetic fields. This type of non-ionizingradiation emanates from magnetic resonance imag-ing devices used in medicine and to a lesser extentfrom high-voltage power lines. There is considera-ble debate as to whether magnetic fields in thevicinity of high-voltage power lines adversely affectthe nervous system. In this project, researchers haveused several techniques to examine a series ofphysiological parameters, including possible effectson vision and other nervous system functions.

The Department of Energy Organization Act of1977 mandates that DOE carry out the planning,coordination, support, and management of a bal-anced and comprehensive energy research anddevelopment program. The Act requires that DOEadvance the goals of restoring, protecting, andenhancing environmental quality and assuring pub-lic health and safety (Public Law 93-577, Title 42).

For several years, DOE supported applied re-search on the neurotoxicological and behavioraleffects of chemicals. Recently, however, it changedthe focus of some of its research programs fromenergy-related issues to fundamental biologicalquestions, for example, sequencing the humangenome. This shift in direction appears to have ledto reductions in applied toxicological research,including work in the neurobehavioral field.

DOE research programs are currently not ade-quately addressing neurotoxicological concerns. DOEcould be conducting neurotoxicological researchinto the health effects of energy-related processesand products including lead and lead substitutes ingasoline, methanol, and other fuels, and heavymetals used in nuclear and nonnuclear processes. Itcould be examining the effects of combustionproducts on the nervous system, and it could beworking with Federal agencies and other public andprivate organizations to develop new and bettertoxicological tests to evaluate these effects.

20-812 - 90 - 3 : QL 3


Department of Agriculture

The U.S. Department of Agriculture (USDA)supports a small number of extramural researchprojects related to neurotoxicology. These projectsare administered through the Cooperative StateResearch Service and fall into four major categories:

1. USDA competitive research grants,2. special grants to State Agricultural Experiment

Station scientists,3. animal health funds, and4. Hatch Act funds (34).

In fiscal year 1988, USDA supported 25 researchprojects related to neurotoxicology, nearly all ofthem involving insecticides and their metabolizes.Total funding for these projects was $422,000. Mostof the research was supported by Hatch Act funds;the remainder was supported by special grants,animal health funds, and competitive grants. USDAresearch efforts span a wide range of objectives,from molecular biology and biochemistry, to structure-activity relationships, monitoring of agricultureworkers, and the development of poisoning anti-dotes (21,33).

National Aeronautics and SpaceAdministration

Toxicology research within the National Aero-nautics and Space Administration (NASA) is con-ducted in the Biomedical Laboratories at theJohnson Space Flight Center in Houston, Texas.Space flight involves prolonged confinement in anartificial atmosphere with an array of equipment andmaterials. The Biomedical Laboratories evaluatespacecraft equipment and materials to ensure thatflight crews are not exposed to harmful levels oftoxic substances.

In the last several years, NASA has evaluated theneurobehavioral effects of many potentially toxicsubstances, including polyurethane thermal decom-position products, bromothifluoromethane, and vari-ous fire-extinguishing agents. In 1988, NASA com-pleted a study of continuous low-dose exposure toHalon 1301, the active component in fire extinguish-ers in the space shuttle cabin.

NASA has established maximum allowable con-centrations (MACs) of atmospheric contaminants inmanned spacecraft for missions of up to 7 days.These criteria are used in the development of allmaterials that will be used in space vehicles to

ensure a nontoxic cabin atmosphere. In 1981, MACswere established or revised for some 200 chemicalsthat might be used in spacecraft.

ACADEMIC RESEARCHACTIVITIES

Research interest in the neuroscience has in-creased rapidly in the last decade, as evidenced bygrowth in the membership of the Society forNeuroscience. The neurobehavioral sciences havemade major advances in recent years, and societycan continue to expect new and important discover-ies that will not only improve understanding of thebrain and behavior, but also make substantialcontributions to public health. In the last decade,neurobehavioral toxicology has become an increas-ingly active field. Scientific papers are published inan array of journals, including two specialty journals(Neurotoxicology and Neurotoxicology and Teratol-ogy). A neurotoxicology specialty section has beenorganized within the Society of Toxicology, and twosmall scientific societies have been formed, theBehavioral Toxicology Society and the BehavioralTeratology Society. Behavioral scientists and neu-roscientist have been appointed to the editorialreview boards of the journals of the Society ofToxicology and participate in the peer reviewprocess of the extramural grants programs sponsoredby NIH, ADAMHA, and EPA (48). However,despite recent advances, U.S. neurotoxicology re-search programs are small relative to the threatneurotoxic substances pose to public health.

Factors Influencing Academic ResearchDirections

Neurotoxicology will continue to benefit from therapid advances being made in understanding thestructure and function of the nervous system. Withthe tools of modern molecular biology and pharma-cology, investigators are mapping and redefining thebrain itself. As researchers learn more about thebrain and its molecular components, they gaininsights into how chemicals can alter nervoussystem structure and function. The detailed study ofsimple neuronal systems in invertebrates or in tissueculture can aid in understanding the mechanisms bywhich chemicals exert their effects in mammals;such studies should assist in screening for neurotox-icity. Improved understanding of the behavioraldeterminants of chemical actions will assist in theconstruction of test systems that will facilitate both

Chapter Research and Education Programs . 93


the detection and characterization of toxic effects.Increased efforts in academia, as well as in industryand government, are necessary in order to movebeyond basic research and to apply basic knowledgeto the development and validation of neurotoxicitytests.

The challenge in the years ahead will be to fosterbasic research and to persuade investigators andstudents that the field of neurotoxicology offerssubstantial opportunities for increasing our under-standing of the structure and function of the nervoussystem. The neuroscience could provide novel andbeneficial approaches to many important occupa-tional and environmental health problems. Theseinclude identifying subtle neurological and psychi-atric disorders occurring in exposed populations;

exploring why some individuals appear to be partic-ularly sensitive to chemicals; and developing prepa-rations targeted at health problems associated withsingle chemicals, industries, occupations, modes oftransportation, sources of energy, urban environ-ments, and dietary habits. If occupational andenvironmental chemicals do play a key role incausing neurodegenerative disorders, for example,Parkinson’s disease and Alzheimer’s disease, pre-vention becomes an important goal.

The contributions of colleges, universities, andresearch institutes to neurotoxicology depend oncontinued grant support for research and graduateeducation. Neurotoxicology research and trainingtake place in many university and medical centercontexts, for example, departments of pharmacol-ogy, toxicology, pathology, psychology, neurology,psychiatry, anatomy, obstetrics and gynecology,ophthalmology, pediatrics, epidemiology, and occu-pational, environmental, preventive, and communitymedicine. There are only a few laboratories orinstitutes around the country that focus on neurotox-icology. There are no broadly based centers ordepartments of neurotoxicology. Thus, there are fewenvironments in academia where neurotoxicology orbehavioral toxicology is a major focus. As in anyacademic research environment, the spatial, finan-cial, and personnel resources available, as well as theprofessional advancement and remuneration of theinvestigator, depend on the perceived merits of theresearch and on the interest and goodwill of theresearcher’s colleagues (48).

What leads an investigator to study a particularneurotoxic substance? In many cases, a chemical isof interest not because of its impact on human health,but because of its usefulness as a tool to studynervous system structure or function. Such studiesprovide necessary information about the substrateson which chemicals exert their effects and themechanisms by which the effects occur. Knowingthe mechanism of action of a toxic substance notonly advances our knowledge, but aids in predictingwhat other chemicals will have similar effects. Inother cases, a neurotoxic substance is selected forstudy because it has produced human injuries thathave been well described or, if the compound hasinjured only a few people, because the injuriesproduced a severe impairment, repeatable in ani-mals, that is of interest to the investigator, a fundingagency, or public interest organization. There is alsoacademic interest in understanding the possible role

94 ● Neurotoxicity: Identfying and Controlling Poisons of the Nervous System

of toxic chemicals in triggering neurodegenerativediseases.

Universities see basic research as one of theirprincipal missions; routine toxicity evaluations arenot usually considered to be an appropriate use ofuniversity resources or faculty time. There is littleinterest in studying either proprietary products orchemicals about which little or nothing is knownunless the study offers insight into the mechanismsby which related chemicals exert known effects.

Funding pressures play a substantial role in aninvestigator’s choice of research project. Two fac-tors are at work: 1) the difficulty of finding asponsoring agency, and 2) the short duration oftypical grant awards. Neurotoxicology, like otheremerging areas of toxicology, is a discipline thatgenerates relatively small numbers of grant applica-tions. Consequently, for the most part, there are noinitial review groups, that is, expert committeesappointed by Federal agencies to review the meritsof neurotoxicology grant proposals. A study sectioncharged with reviewing occupational or environ-mental health problems may understand the conse-quences of human exposure to a compound but notbe able to review adequately the scientific methodsof a research proposal or to balance its merit andrelevance against those of other studies. If theproposal is forwarded to a study section that iscompetent to review the techniques involved, it maystill face difficulties. A proposal deemed an appro-priate application of existing techniques to an“applied” problem would not fare well in competi-tion with a proposal that advances “basic” knowl-edge. One funding strategy that has been productiveis to integrate neurotoxicity studies with a larger,multidisciplinary center or program project. Ingeneral, the success of any grant application dependslargely on both accurate identification of the fundingagency and specific tailoring of the proposal to theinitial review group (48).

Funding usually extends for 3 to 5 years and takesthe form of an individual grantor a multidisciplinaryprogram project or center grant. Progress, as meas-ured by publications, is necessary to maintain aresearch career. In order to achieve results rapidly,investigators are frequently drawn to compoundsthat produce easily recognized and reproducibleeffects after exposing animals for brief periods.Experiments involving agents that require inhalationexposure or chronic administration are more costly

and require more effort, hence the number of journalarticles produced at the end of the project is- .correspondingly reduced.

Cooperative Agreements BetweenGovernment and Academia

Government agencies sometimes channel intra-mural funds to ‘investigators in universities orresearch institutes. These negotiated agreementstend to focus on projects of mutual interest andusually address specific problems. They have theadvantage of permitting questions to be examinedmore rapidly and at less expense than would bepossible intramurally. As a means of supportingextramural research programs, however, they havedrawbacks: they often do not benefit from theintense scrutiny of the peer review process, and theytend to devalue research that does not produce dataand conclusions in the short term. In times of tightbudgets, this pattern of funding is the frost to be cut,because it is usually derived from the resourcesavailable to support intramural programs.

INDUSTRIAL RESEARCHACTIVITIES

Industrial research falls into several categoriesand is funded by several mechanisms:

1. internal basic and applied research,2. research conducted in contract laboratories,3. research conducted through consortia,4. contract research through universities, and5. research grants for universities.

Toxicity evaluations conducted as part of internalapplied research are necessary to develop safe andeffective products, to protect employees, to protectthe environment, and to control cost liability.Research programs vary considerably, depending onthe types of products manufactured and economicconsiderations.

Pesticide Industry

The search for new pesticides begins with screen-ing tests, which are designed to provoke a particularbiological response. The toxicity profiles developedfrom screening tests may be considered to beproprietary information, because disclosure of themcould give the competition information useful forproduct development. There are, however, methods


of giving outside experts data without compromis-ing trade secrets.

Industry is willing to perform tests to obtain ormaintain product registration, but it is cautious aboutdevoting funds to the development of test protocolsthat might not satisfy regulatory authorities. Govern-ment and academic scientists may suggest testingstrategies that they judge to be appropriate but mayfind it difficult to defend a specific testing scheme ifthere is an inadequate history of testing for the classof compounds in question or the extent of the publichealth hazard and possible economic impacts onsociety are difficult to predict (48).

Pharmaceutical Industry

Drug development begins with screening anddevelopment of structure-activity relationships. Acuteand subchronic toxicity information emerges earlyin the process, but characterization of chronictoxicity usually develops more slowly. The quest forbiological activity has produced some compoundsthat reach the market, but most are importantresearch tools for the neuroscience and have noclinical utility or are too toxic to be used clinically.

Pharmaceutical industry research on toxic sub-stances is directed largely toward therapy for centralnervous system impairments and the development ofanimal models for screening drugs to ameliorate thesigns and symptoms of nervous system damage.Examples of such injuries include oxygen starva-tion, MPTP-induced Parkinsonism, seizures in-duced by convulsant drugs, and brain injuriesproduced by excitotoxins (chemicals that produce somuch activity in localized areas of the brain that thecells there die). The pharmaceutical industry alsoevaluates compounds in behaviorally normal ani-mals and in the offspring of mothers exposed to toxicsubstances. It has promoted the development of avariety of neurotoxicity tests. The research contribu-tions of the pharmaceutical industry emerge as aproduct nears approval. However, as is true in othersectors, much information generated by industry isnever made public, even though it may be importantin other contexts (48).

Consumer Product Industry

Information about the toxicity of consumer prod-ucts typically emerges from premarket testing,human exposures, accidental ingestions by consum-ers, or in response to regulatory demand. Manufac-

turers of consumer products frequently maintainvigorous product development research teams. Theirwork sometimes produces serendipitous findings ofwider interest, but it seldom sheds light on thepossible neurotoxicity of their products.

Little information on the neurotoxicity of con-sumer products has been generated as a result ofthese recommendations. The laws administered bythe Consumer Product Safety Commission (CPSC)permit the agency to require some toxicity evalua-tions as part of compliance with labeling andpackaging regulations (15 U.S.C. 1261—FederalHazardous Substances Act). For several years CPSChas encouraged regulated groups to develop volun-tary standards. One such group is the art suppliesindustry, which developed recommendations forminimizing injuries through product labeling. (Somematerials used by artists have neurotoxic potential.)Labeling standards may, in turn, prompt manufac-turers to reformulate products in order to minimizetoxicity and the need for warnings at the point ofpurchase. These recommendations were recentlygiven the force of law in the Art Materials LabelingAct (Public Law 100-695).

Specialty and Commodity Chemical Industries

Chemical companies have a mixed record withrespect to minimizing the adverse effects of chemi-cals on the health of their workers. Like otherindustries, however, they have no interest in market-ing chemical products that may become substantialliabilities. Some companies rely on developinginformation of such high quality that it defines thestate of the science—this is no doubt the best defenseof a successful and prestigious corporation. Toachieve this end, good scientists must be recruitedand maintained as vigorous members of a corporateteam. A good example is the publication by scien-tists at one major U.S. corporation of a series ofhigh-quality papers describing the role of diketonesin causing peripheral neuropathy (20). Unfortu-nately, less well capitalized companies cannot affordto invest in research of this kind, instead testingsolely to comply with regulatory requirements.Commodity chemicals are produced by a number ofdifferent companies, so it is generally not in theinterest of any one company to assume responsibil-ity for evaluating the adverse health effects of aparticular substance. The companies that manufac-ture and distribute such chemicals could be com-pelled to address the chemical’s toxicity under


TSCA, or they could avoid such regulation bysupporting a testing program under the auspices ofa trade association.

INTERACTIONS AMONGGOVERNMENT, ACADEMIA,

AND INDUSTRY

Industry and Government Consortia

Industry and government consortia devoted toenvironmental health are rare. One such consortiumis the Health Effects Institute (HEI), an independent,nonprofit corporation ‘‘organized and operated tostudy the health effects of emissions from motorvehicles . . .’ (18). HEI serves as a potential modelfor other consortia. The institute makes no regula-tory or social policy recommendations; its goal is

, “simply to gain acceptance by all parties of the datathat may be. necessary for future regulations” (34).It has joined together the regulator and the regulatedindustry in mutual support of research activitiestargeted at joint concerns, and it does so by derivingfunding jointly from EPA and the automobileindustry.

The institute has recognized the importance of theeffects of automobile emissions on the nervoussystem and on the quality of life in general. It hasconducted a review of the topic (48) and hassolicited research proposals in this area, The HEImodel is a promising one for circumstances in whichhealth concerns are generic and in which proprietaryand competitive interests do not interfere withindustry’s participation.

Industry Research Consortia

The Chemical Industry Institute of Toxicology(CIIT) is a research institute funded by a consortiumof chemical companies to study commodity chemi-cals of concern to members. CIIT has achieved areputation for conducting excellent toxicologicalresearch targeted at a broad range of problems andhas generated considerable goodwill in the process.Interest in neurotoxicity issues has recently beenevidenced in the publications of the institute. How-ever, in the absence of a significant new initiative,the contributions of this organization to knowledgeof neurobehavioral effects may be limited.

CIIT could serve as a model for other industrieswith common interests, particularly industries meet-ing similar regulatory challenges. The pesticide

industry as a group makes proprietary products, andit is unlikely that a group of competitors would bewilling to share the cost of generating informationabout a single member’s profit-making product. Thecompanies are bound together by a common desireto be regulated appropriately and efficiently, how-ever, and they could benefit from a joint researchprogram that would help advance the state of the artin toxicology and risk assessment. This wouldinclude advances in the development of in vitrotesting, the extrapolation of data from rodents toprimates, the validation of screening approachestailored to the needs of the pesticide industry, andthe detailed characterization of identified toxicitiesand their mechanisms of actions, an importantcontribution to the risk assessment process.

Other industries with profitable products arechallenged periodically by a rule-making activity orjudicial finding requiring them to provide toxicityinformation. Such organizations might find it intheir interest also to be part of a larger, standingorganization with a governance structure that en-sures that its research and testing of products are ofthe highest quality.

Cooperation in Epidemiological Investigations

Since individuals working in the chemical indus-try almost invariably experience higher levels ofexposure to chemicals than do other groups insociety, they are at greater risk of suffering theadverse effects of exposure to toxic substances.Thus, workers also serve as a sentinel population forthe detection of neurotoxic disorders that occur inthe general population. Often, workers are the firstto identify adverse effects and bring them to theattention of their doctors. Epidemiological studiescan be initiated by a number of organizations, butthey are most often conducted by the CDC, ATSDR,and State health authorities. CERCLA and TSCArequire manufacturers to collect and keep informa-tion regarding exposure and effects on health.Unions can play an important role in obtainingcooperation and in ensuring compliance with theseefforts.

Unions can also help stimulate research activitiespertinent to the health of their members. The UnitedAuto Workers recently established jointly adminis-tered research programs with Ford, General Motors,and Chrysler in which studies of neurobehavioral

Chapter 4-Research and Education Programs . 97

toxicity were identified as a priority. The fundingwas directed predominantly at human studies (26,49).

Charitable Organizations

The Third World Medical Research Foundation isa small, U.S.-based, nonprofit organization thatencourages university and other biomedical scien-tists worldwide to find innovative solutions to toxic,nutritional, and other disorders of importance todeveloping countries. Working with university andNIH scientists, it was able to demonstrate theassociation of African cases of spasticity withinfection by the HTLV-1 virus and to disprove aproposed causal association with methylmercury.More recently, it has focused on promoting thedevelopment of non-neurotoxic strains of the grasspea to prevent the spastic disease lathyrism and togenerate safe, drought-resistant food and animalfeed for drought-stricken areas of Africa and Asia.

EDUCATION

Education of Research Scientists

A significant portion of current knowledge aboutthe effects of neurotoxic substances comes frombasic research and the application of that research toenvironmental health problems. Yet many observersbelieve that there are too few scientists adequatelytrained in both neuroscience and toxicology. Asdiscussed earlier in this chapter, research trainingexists in a variety of universities and medicalcenters, but there are few places in academia whereneurotoxicology is a major focus.

The National Institute of Environmental HealthSciences awards grants to educational institutionsfor the training of environmental toxicologists.These grants support approximately 200 doctoralstudents in 24 universities. Only about half theschools offer intensive training in any aspect ofneurotoxicology. Few institutions have comprehen-sive academic programs with adequate faculties toundertake a substantial research program. Since ittakes about 5 years for a graduate student to earn adoctorate, fewer than 40 students supported by thesetraining grants finish their degrees each year. Onlysome 10 to 15 students graduate from strongprograms in neurotoxicology in the United Stateseach year. While this does not mean that positionsdemanding an education in neurotoxicology willnecessarily go unfilled—there are many other,usually small, programs that award the doctorate but

do not have training grants-it does mean that theprimary Federal program targeted to the Nation’smanpower needs in toxicology can make only asmall contribution in the area of neurotoxicology(23).

The NIEHS institutional training grants alsosupport about 80 postdoctoral trainees, and another5 students receive fellowships directly though individ-ual training grants. Of course, many of these traineescome from predoctoral training programs in toxicol-ogy and thus represent no net gain in numbers. Sincepostdoctoral training takes a minimum of 2 yearsand only a fraction of the trainees stay in the field ofneurotoxicology, this source yields only a smallnumber of fully trained neurotoxicologists per year(23).

The American Board of Toxicology (ABT) certi-fies professionals in general toxicology. The certifi-cation examination includes neurotoxicology andclinical toxicology. More than 90 percent of theABT-certified toxicologists possess a doctorate andhave more than 3 years of professional experience.Questions about neurotoxicology and clinical toxi-cology are a routine part of the examination,including questions on the neurotoxicity of pesti-cides, the behavioral effects of metals, and neuro-toxic drugs. Certification is for 5 years, and recertifi-cation includes continuing education and practice intoxicology (5).

Education of Health-Care Professionals

Much of the illness resulting from exposure toneurotoxic substances occurs among workers. Often,neurotoxic chemicals are first identified because ofthe occupational illness they have caused. Increasedresearch and testing are needed so that harmfulchemicals can be identified and worker exposurelimited. Prevention of occupational illness is achallenging undertaking and involves identifyinghazards, controlling hazards at the source, monitor-ing workers, and educating, training, and dissemi-nating information to all persons involved. Thesetopics have been addressed in a previous OTA report(45) and will not be covered in detail in this section.Instead, this discussion will be limited to thepotential role that better education of health-careprofessionals might play.

Physicians, nurses, and industrial hygienists de-liver most health care to workers who have beenexposed to toxic substances in the workplace. The


number of professionals trained in the area ofoccupational health is not adequate to meet publichealth needs in the United States.

Physicians

A large percentage of physicians who provideoccupational health services are employed by indus-try, yet many workers have no source of occupa-tional health services and must rely on their familyphysicians. Family physicians are rarely trained inoccupational medicine and thus are less likely toobtain histories of occupational exposure.

General training in occupational medicine duringmedical school is not extensive. Two surveys ofmedical schools, one conducted in 1977-78 (24) andthe other in 1982-83 (25), found that the proportionof medical schools offering courses in occupationalhealth in the preclinical years increased from 50percent at the time of the first survey to 66 percentat the time of the second. The proportion of schoolsrequiring that students take such courses increasedfrom 30 percent to 54 percent. However, in thoseschools that required coursework in occupationalhealth, there was a median curriculum time of only4 hours over 4 years. A survey conducted by theAssociation of American Medical Colleges foundthat 70 percent of medical schools offer clinicalelectives in occupational medicine or environmentalhealth. However, of the students responding to thesurvey (65 percent), only 1 percent actually took theoffered elective (42).

Residency programs in primary care specialties—namely, family and general practice, pediatrics,internal medicine, obstetrics and gynecology, andpsychiatry-rarely include training in occupationalmedicine. However, organizations such as the Amer-ican College of Occupational Medicine, whosemembers are board-certified in occupational medi-cine, sponsor conferences and seminars to educateprimary care and other physicians about occupa-tional health issues (19).

Occupational medicine is one of the areas inwhich physicians specializing in preventive medi-cine can choose to be certified. The Institute ofMedicine recently emphasized the need for a greaternumber of physicians specializing in occupationalmedicine. In 1987, there were 25 residency pro-grams with 118 residents (0.1 percent of the totalnumber of residents that year) (7). Between 1955 andApril 1989, the American Board of Preventive

Medicine certified 1,378 physicians in occupationalmedicine. The number of those physicians no longerpracticing is not known (17). The requirements forboard certification include 1 year of postgraduatetraining in preventive medicine; 1 year of residencyin occupational health; 1 year of training, research,teaching, or practice of occupational medicine; andthe completion of a master’s degree in public health.The requirements are somewhat different for physi-cians who graduated from medical school beforeJanuary 1984 (40).

Some effort to encourage medical students toenter the field of occupational medicine is beingmade. The American College of Occupational Medi-cine has a scholarship fund for medical students andresidents interested in occupational medicine (41).Also, there is a mechanism under current law bywhich Congress could encourage the training ofphysicians in occupational health. Public Law 100-607 (sec. 613) states that:

The Secretary [of the Department of Health andHuman Services] may make grants to and enter intocontracts with schools of medicine, osteopathy, andpublic health to meet the costs of projects (A) to planand develop new residency training programs and tomaintain or improve existing residency trainingprograms in preventive medicine; and (B) to providefinancial assistance to residency trainees enrolled insuch programs.

Advocates of expanded training programs in occu-pational medicine note that the current language inthe law says “may” and that changing the wordingto “shall” would strengthen the law.

Nurses

Nurses provide a crucial aspect of care for workersexposed to toxic substances in the workplace.Indeed, they constitute the largest group of healthprofessionals in the workplace-approximately 24,000in 1980 (10). Occupational health nursing synthe-sizes principles from several disciplines in the healthsciences, including, but not limited to, nursing,medicine, safety, industrial hygiene, toxicology,administration, and public health epidemiology.Activities focus on promotion, protection, mainte-nance, and restoration of health. The occupationalhealth nurse is primarily concerned with the preven-tive approach to health care, which includes earlydetection of disease, health teaching, and counseling(2).


The American Board of Occupational HealthNurses is the only board that certifies nurses inoccupational health. It has certified over 45,000nurses since 1973 and estimates that 2,800 of themare still practicing (36). Certification requires apassing score on a national examination. Eligibilityfor the examination entails 5 years of experience inthe specialty and a satisfactory record of formal andcontinuing education in designated subjects (3).

University-based baccalaureate programs in nurs-ing provide courses and clinical experience incommunity and public health nursing and adulthealth that are basic to the practice of occupationalhealth nursing. Specialty education in occupationalhealth at the master’s degree level is offered inseveral schools of nursing and public health. Al-though programs differ in their course requirements,most include adult health, elements of workplaceexposures, epidemiology, toxicology, biostatistics,and opportunities for field work. Some programsprovide education in neurotoxicology through courses,clinical experiences, and reviews of research (l).Doctoral-level education for nurses in occupationalhealth has been offered for the past 10 years, andgraduates are employed in the private sector as wellas by governmental agencies and universities.

Federally supported programs for occupationalhealth nurses have provided significant resourcesand continue to encourage training in this field.Since 1977, graduate-level academic programs havebeen funded as one component of the interdiscipli-nary Educational Resource Centers. These regionalcenters were developed under the OccupationalSafety and Health Act of 1970 in response to theneed for an adequate supply of trained professionalsin occupational health (l).

The American Association of OccupationalHealth Nurses is the professional organization thatrepresents registered nurses engaged in that spe-cialty as practitioners, managers, consultants, andeducators. The association develops standards ofpractice, monitors legislation related to occupationaland environmental health, sponsors continuing edu-cation, and publishes a journal (l).

Industrial Hygienists

The role of the industrial hygienist is to recognizeand reduce occupational health hazards in theworkplace. Industrial hygienists thus attempt toanticipate, recognize, evaluate, and control those

environmental factors or stresses stemming from theworkplace that cause sickness, discomfort, or ineffi-ciency among workers or members of the commu-nity (31). Industrial hygienists examine the overallsafety of the working environment and recommendplant improvements. Part of their duty is to collectsamples of dust, gases, liquids, vapors, and rawmaterials and determine the extent of worker expo-sure. For example, an industrial hygienist mightsample the air inhaled by an employee working withorganic solvents throughout an 8-hour shift (manyorganic solvents have potential or known neurotoxicproperties, see ch. 10).

Most industrial hygienists have a bachelor’sdegree in engineering, physical science, biologicalscience, or natural science, and some also obtain amaster’s degree in industrial hygiene. There are twolevels of industrial hygienists, certified and uncerti-fied. To become certified, one must complete abaccalaureate degree in the sciences or engineering,have 5 years of practical industrial hygiene experi-ence, and pass a 2-day written examination given bythe American Board of Industrial Hygiene. Hygien-ists may seek certification in the general field ofindustrial hygiene, or they may specialize in anumber of areas, one of which is toxicology.Currently, there are approximately 4,000 certifiedindustrial hygienists in the United States (35). Thosehygienists who are uncertified rely on their skills,training, and experience but are not required to meetany minimum standards established by a govern-mental or professional organization (22).

The American Industrial Hygiene Association isa nonprofit professional society for persons practic-ing industrial hygiene in industry, government,labor, academic institutions, and independent organ-izations. The association, composed of some 7,400members, publishes a journal and sponsors continu-ing education courses in industrial hygiene (15).

NIOSH Educational Resource Centers

Many of the professional organizations for toxi-cology, occupational medicine, occupational nurs-ing, and occupational hygiene offer conferences andseminars as continuing education. The FederalGovernment also plays a role, through NIOSH’sEducational Resource Centers, mentioned earlier.There are 14 centers located within universitiesthroughout the United States. The centers conductboth ongoing research projects and programs offer-ing academic degrees and continuing education. The


four main areas on which they focus are industrialhygiene, occupational medicine, occupationalhealth nursing, and occupational safety. Courses areoffered in toxicology and to a limited extent inneurotoxicology (1,47).

NIOSH also offers some in-house courses. Noneof these focuses on toxicology or neurotoxicologyspecifically, but some address the broader issues ofoccupational health and industrial hygiene.

SUMMARY AND CONCLUSIONSFederal research related to neurotoxic substances

is conducted primarily at the National Institutes ofHealth; the Alcohol, Drug Abuse, and Mental HealthAdministration; and the Environmental ProtectionAgency. Limited research programs are under wayat the Food and Drug Administration, the Centers forDisease Control, the Department of Defense, theDepartment of Energy, the Department of Veterans’Affairs, the Department of Agriculture, and theNational Aeronautics and Space Administration.Total Federal funding for neurotoxicology -relatedresearch (excluding research related to alcoholismand cigarette smoking) is $56.8 million. The bulk ofthis funding (85.2 percent) is through NIH andADAMHA and tends to focus on the toxicity ofdrugs and the biochemical mechanisms underlyingneurological and psychiatric disorders. A number ofother Federal agencies and organizations providelimited funding for neurotoxicological research.

Research related to environmental neurotoxicol-ogy is confined primarily to the intramural programat EPA and the extramural program at the NationalInstitute of Environmental Health Sciences withinNIH.

The extent of academic research related to neuro-toxicology is strongly dependent on the availabilityof grant support from the Federal Government.Academic research in neurotoxicology is supportedalmost exclusively by NIH and ADAMHA. Mostextramural research funded by NIH is through theNational Institute of Neurological Disorders andStroke and the National Institute of EnvironmentalHealth Sciences, although several other Instituteshave substantial programs. ADAMHA funds re-search through the National Institute on Drug Abuseand the National Institute of Mental Health.

EPA has a relatively large intramural neurotoxi-cology research program that has been limited in

recent years by lack of funding for supplies andequipment. EPA has a small extramural grantsprogram that has rarely funded neurotoxicology-related projects. Traditionally, Federal agencieshave supported both intramural and extramuralefforts to ensure a balanced, comprehensive, andcost-effective program.

FDA funds several research projects related toneurotoxicology, primarily through its intramuralresearch programs. The National Center for Toxico-logical Research is conducting a number of intramu-ra1 research projects related primarily to develop-mental neurotoxicology. The Center for Food Safetyand Applied Nutrition has a small in-house programand is supporting three extramural research projects.

Within CDC, the National Institute for Occupa-tional Safety and Health has small intramural andextramural programs devoted to the identificationand control of neurotoxic substances in theworkplace. CDC’s Center for Environmental Healthand Injury Control conducts epidemiological inves-tigations of human exposure to environmental haz-ards.

Industry undertakes neurotoxicology-related re-search through several mechanisms, including in-house scientists, contract laboratories, consortia,contracts with universities, and grants to universi-ties. Toxicity evaluations conducted as part ofinternal applied research are necessary to developsafe and effective products, to protect employees, toprotect the environment, and to control liabilitycosts. Research programs vary considerably, depend-ing on the types of products manufactured andvarious economic considerations. Industry and gov-ernment consortia, such as the Health EffectsInstitute, which studies the health effects of emis-sions from motor vehicles, are useful in bringing theregulated and the regulator together to supportresearch projects of mutual interest.

The education of research scientists in neurotoxi-cology is limited, in part, by inadequate Federalsupport for training programs. Part of the difficultyin obtaining funding is due to the nature of neurotoxi-cology—the intersection of neuroscience and toxi-cology. Few academic departments devote signifi-cant resources to neurotoxicology, and few majorFederal organizations devote their primary efforts toit. The National Institute of Environmental HealthSciences supports training in the neurotoxicology

Chapter Research and Education Programs ● 101

field; however, funding limitations allow for supportof only a relatively small number of trainees.

Millions of American workers are exposed toneurotoxic substances in the workplace, but illnessstemming from these exposures often goes unde-tected and untreated. The subtlety of neurotoxicresponses is one reason for this situation; forexample, complaints of headache and nervousnessare often ascribed to other causes. Another reason isthe lack of adequately trained health-care profes-sionals to diagnose and treat neurotoxic disorders.Medical schools, in general, devote little of theircurricula to occupational health issues. After medi-cal school, physicians may undertake residencytraining in occupational medicine, but in 1987 onlyabout 1 in every 1,000 residents was specializing inoccupational medicine. Nurses are also needed in theoccupational health field to provide emergencyservices, monitor employee health, and providecounseling and referral to physicians. Industrialhygienists are needed to evaluate and control healthhazards in the workplace.


2.

3.

4.

5.

6.

7.

8.

9.

10,

11.

Agnew, J., Johns Hopkins University, personalcommunication, June 21, 1989.American Association of Occupational Health Nurses,“Standards of Practice, ” American Association ofOccupational Health Nurses Journal 36:162-165,1988.American Board of Occupational Health Nurses,Certification Program (Santa Monica, CA: 1988).Andrews, J. S., Agency for Toxic Substances andDisease Registry, personal communication, 1989.Bean, J. R., U.S. Department of Energy, personalcommunication, 1989.Biersner, R., National Institute for OccupationalSafety and Health, personal communication, 1989.Crowley, A. E., and Etzel, S.1., “Graduate MedicalEducation in the United States, ” Journal of theAmerican Medical Association 260: 1093-1101,1988.de Souza, E.R., Addiction Research Center, NationalInstitute on Drug Abuse, personal communication,1989.Dyer, R., U.S. Environmental Protection Agency,personal communication, 1988.Ebert, F., “The Occupational Health Nurse,” Occu-pational Medicine: Principles and Practical Appli-cations, LaZenz (cd.) (Chicago, IL: Year BookMedical Publishers, 1988).Erinoff, L., National Institute on Drug Abuse, per-sonal communication, June 1989.

12.

13.

14.

15.

16.

17.

18.

Evans, H. L., Institute of Environmental Medicine,New York University, personal communication, July1989.Evans, H. L., “Behaviors in the Home Cage RevealToxicity: Recent Findings and Proposals for theFuture,” Journal of the American College of Toxicol-ogy 8:35-51, 1989.Gause, E., Alcohol, Drug Abuse, and Mental HealthAdministration, personal communication, Apr. 25,1989.Gerbec, L., Administrative Assistant for MemberServices, American Industrial Hygiene Association,personal communication, Apr. 6, 1989.Griesemer, R. A., National Institute of EnvironmentalHealth Sciences, personaI communication, June 8,1989.Griest, J., Administrative Assistant, American Boardof Preventive Medicine, personal communication,Apr. 6, 1989.Health Effects Institute, 2987 Annual Report (Camb-ridge, MA: 1988).

19. Imbus, H. R., “Is Occupational Medicine a Spe-cialty?” American Journal of Industrial Medicine14:109-1 16, 1988.

20. Krasavage, W. J., O’Donoghue, J. L., DiVincenzo,G. D., et al., “The Relative Neurotoxicity of Methyln-Butyl Ketone and Its Metabolizes, ” Toxicologyand Applied Pharmacology 52:433-441, 1980.

21. Kunde, M. L., U.S. Department of Agriculture, per-sonal communication, Sept. 14, 1989.

22. Landrigan, P. J., and Markowitz, S. B., OccupationalDisease in New York State: Proposal for a StatewideNetwork of Occupational Disease Diagnosis andPrevention Centers: Report to the New York StateLegislature (New York, NY: Department of Cornrnu-nity Medicine, Mount Sinai School of Medicine ofthe City University of New York, 1987).

23. Laties, V., University of Rochester, School of Medi-cine, personal communication, 1989.

24. kVY, B. S., ‘‘The Teaching of Occupational Health inAmerican Medical Schools,” Journal of MedicalEducation 55:18-22, 1980.

25. kVY, B. S., ‘‘The Teaching of Occupational Health inAmerican Medical Schools: Five-Year Follow-Up ofan Initial Survey,” American Journal of PublicHealth 75:79-80, 1985.

26. Mirer, F., United Auto Workers, personal communic-ation, Jan. 10, 1990.

27. National Archives and Records Administration, Of-fice of the Federal Register, U.S. Government h4an-ual 1988/89 (Washington, DC: U.S. GovernmentPrinting Office, 1988).

28. National Institute on Aging, Neuroscience and Neu-ropsychology of Aging Program, Aging and Neuro-toxins, correspondence to OTA, June 1989.


29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

National Institutes of Health, Associate Director forScience Policy and Legislation, correspondence toOTA, November 1989.Nelson, N., Griesemer, R. A,, and McMillan, D., letterto Ue M, Thomas, Adrninistrator, U.S. Environ-mental Protection Agency, Sept. 9, 1988.Olishifski, J.B. (cd.), Fundamentals of IndustrialHygiene (Chicago, IL: National Safety Council,1983).Paule, M. G., National Center for ToxicologicalResearch, personal communication, July 17, 1989.Ragsdale, N.N., U.S. Department of Agriculture,personal communication, June 15, 1989.Ruckelshaus, W. D., speech before the World Indus-try Conference on Environmental Management, Nov.14, 1984.Snow, B., Administrative Assistan~ American Boardof Industrial Hygiene, personal communication, May1, 1989.Snyder, M., Executive Director, American Board ofOccupational Health Nurses, personal communicat-ion, Apr. 7, 1989.Sobotka, T., U.S. Department of Health and HumanServices, Food and Drug Administration, Center forFood Safety and Applied Nutrition, personal commu-nication, Sept. 15, 1987.Sobotka, T., U.S. Department of Health and HumanServices, Food and Drug Administration, Center forFood Safety and Applied Nutritio~ personal communica-tion, Jan. 27, 1989,Sobotka, T., U.S. Department of Health and HumanServices, Food and Drug Administration, Center forFood Safety and Applied Nutrition, personal commu-nication, May 30, 1989.“Special Report: Establishing Eligibility for Exami-nation in the Specialty of Occupational Medicine, ’Journal of Occupational h4edicine 28:303-305, 1986.

41.

42.

43.

44.

45.

46.

47.

48.

49.

Strasser, A. L., ‘Occupational Medicine Matures intoDiverse, Specialized Field,” Occupational Healthand Safety Special, sec. 52, April 1988.Swanson, A., Association of American MedicalColleges, personal communication, Feb. 7, 1989.Tilson, H. A., “Animal Neurobehavioral Test BatteryUsed in NTP Assessments,” paper presented at theThird International Symposium on NeurobehavioralMethods in Occupational and Environmental Health,Washington, DC, Dec. 12-13, 1988.U.S. Congress, House of Representatives, Commit-tee on Appropriations, Subcornrnittee on the Depart-ments of Labor, Health and Human Services, Educa-tion, and Related Agencies, Appropriations for 1990,hearings Mar. 21 through Apr. 3, 1989 (Washington,DC: U.S. Government Printing Office, 1989).U.S. Congress, Office of Technology Assessment,Preventing Illness and Injury in the Workplace,OTA-H-256 (Washington, DC: U.S. GovernmentPrinting Office, April 1985),U.S. Department of Energy, OffIce of Energy Re-search, Office of Health and Environmental Re-search, correspondence to OTA, Nov. 29, 1988.U.S. Department of Health and Human Services,Public Health Service, Centers for Disease Control,National Institute for Occupational Safety andHealth, Projects of the National Institute for Occupa-tional Safety and Health (Cincinnati, OH: 1988).Wood, R., “Neurotoxicity Research-Current Activ-ities and Future Directions, ’ paper prepared for theOffice of Technology Assessment, November 1988.‘‘Worker Participation in Health and Safety: LessonsFrom Joint Programs of the American AutomobileIndustry,” presentation to the American IndustrialHygiene Conference, San Francisco, CA, May 16,1988.

Chapter 5


“Over the last 10 to 15 years, cancer had dominated the discussion of occupational standards and it continuesto remain terribly important. At the same time, information on neurotoxins has increased. The notion ofchronic and subclinical neurotoxicity has developed. Although these things are progressive and don’t occurovernight, you’ll see more attention paid to neurotoxicity in the years ahead. ”

Philip LandriganOccupational Hazards 49:36, 1987

“The reasons for inadequate neurobehavioral testing of chemicals. . relate to economic factors and politicaldecisions, not to inadequacies of the test methods. ”

Donald McMillanOccupational Hazards 49:37, 1987

‘‘We need to know a lot more about how toxicity is expressed in behavior. We need to be able to recommendtests for chemicals before they move into the marketplace. This is why we need more of what NIOSH is doing.As it is, we are still using workers as part of an early-warning system. ”

Ronald WoodPsychology Today, July 1982, p. 30

CONTENTSPage

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .., .., ,. .. .. .. ”. .”- C” ”” ””O.C”ANIMAL TOXICITY TESTS . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .., .. .. ... .”. ””””.””

Designing Useful Tests . . . . . . . . . . . . . . . . . . . . .. .................++.” ... ”+”....””””Evaluating Chemicals for Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . .. .........+.””.Types of Animal Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...”....”...””..+Animal Testing Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,+.+~~”.~..”’o.o+woo

ALTERNATIVES TO ANIMAL TESTS . . . . . . . . . . . . .. .. .. .. .. .. .. ... +.. ...+.... ...In Vitro Neurotoxicity Test Development . . . . . . . . . . . . . . . . . . .. .. .. .. ....+.... ..+..Applications of In Vitro Techniques to Neurotoxicity Testing .. .. .. .. ..+. . . . . . . . . .Advantages and Limitations of In Vitro Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

HUMAN TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . o..Overview of Human Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Human Exposure Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. .....+... “..Legal and Ethical Considerations in Neurotoxicity Testing and Monitoring ... ....+.Prevention of Human Exposure to Neurotoxic Substances . . . . . . . . . . . . . . . . . . . . . . . . .

MONITORING OF TOXIC SUBSTANCES .. .. ., .. .. .. .. .~. ... ... .......+ . . . . . . .Specimen Banking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...Biological Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..”.+.’...Other Monitoring Programs . . . . . . . . . . . . . . . . . . .. .. .. .. .. .. . ... . .......+. .. ...+...

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

BoxesBox5-A. Tiered Animal Testing To Identify Adverse Neurobehavioral

Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5-B. Conducting the EPA Functional Observationa1 Battery . . . . .

. . . . . . . . . . . . . . . . . . . .

Effects of,.,.... . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .

5-C. Ethical Issues Associated With Chronic Exposure to a Neurotoxic Agent . . . . . . . .5-D. Neurotoxicants Released Into the Environment by Industry: The Toxics

Release Inventory Supplies New Evidence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

FiguresFigure5-1.5-2.

5-3.

The Effects of Toxic Substances on Motor Activity . . . . . . . . .Pattern Reversal Evoked Potential (PREP) and Flash Evoked

. . . . . . . . . . . . . .Potential (FEP)

After Treatment With Chlordimeform. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . +....Neurotoxic Substances Are Prominent Among the Toxics Release Inventory’sTop 25 Chemicals Emitted Into the Air in 1967 .. .. ... .. .....+... . . . . . . . . . . . . . .

TablesTable

105105106109110121121122123124125125128130130132132133134136137

Page

110112131

135

Page113

120

136

Page

5-l, Subject Factors Influencing Neurobehavioral Test Results . . . . . . . . . . . . . . . . . . . . . . 1265-2. Behavioral Test Battery for Toxicopsychological Studies Used at the

Institute of Occupational Health in Helsinki .. ..’..... . . . . . . . . . . . . . . . . . . . . . . . . . . . 1275-3. WHO Neurobehavioral Core Test Battery. . . . . . . . . . . . . . . . . . . .. . . .. . . . ....+.... 127

Chapter 5


INTRODUCTIONPeople are exposed to chemicals every day in the

course of eating, working, and recreation. Some ofthese chemicals are synthetic; others, whose proper-ties may be unknown, occur naturally in the environ-ment and in food. Modern society could not existwithout them. However, the same chemicals thatcontribute to our high standard of living may alsoproduce unanticipated and undesired effects. Regu-latory officials are concerned with weighing thebenefits of use against the risks of adverse healtheffects.

All substances, even water, can be toxic at a highenough level of ingestion. Determining the riskposed to human health by toxic substances requiresinformation about the potential hazard and about theexpected level of exposure, resulting in an estimateof the probability that a substance will produce harmunder certain conditions (see ch. 6) (105).

There are many approaches to testing for neuro-toxicity, and each has both advantages and limita-tions. Toxic substances can be evaluated throughwhole animal (in vivo) tests, tissue and cell culture(in vitro) tests, and tests on human subjects. Thelatter is the best means of predicting the effects ofpotentially toxic substances on human health. Thisapproach, however, is generally difficult, expensive,and in some circumstances unethical. Consequently,it is usually necessary to rely on animal or in vitrotests.

Most toxicity testing is performed on animals,usually mice and rats. Animals are used for severalreasons, one of which is that, biologically, theyresemble humans in many ways and can often serveas adequate models for toxicity studies. On the otherhand, it can be difficult to extrapolate the results ofanimal studies to humans. It is also important to keepin mind that the biochemical and physiologicalprocesses underlying human neurological and psy-chiatric problems are highly complex and oftencannot be modeled in any single system.

In vitro tests can be used to complement animaltests and reduce the number of animals used inroutine toxicity testing. In vitro testing may also beless expensive and less time-consuming. By under-standing the structure or function affected by a toxic

substance in vitro, it is sometimes possible to predictadverse effects in the whole animal. Like all testingstrategies, in vitro tests have limitations, includingthe inability to analyze behavioral effects such asloss of memory or irritability.

Some human toxicological data are derived fromaccidental exposures to industrial chemicals andsome from epidemiological studies. Prescriptiondrugs are tested on humans to determine safety andefficacy.

This chapter briefly describes some methods ofneurotoxicity testing and the advantages and limita-tions of each. The first section addresses animaltoxicity tests, including the types of neurotoxicitytests currently proposed for regulatory use by theU.S. Environmental Protection Agency (EPA). Thesecond section describes alternatives to animal tests,including in vitro approaches, and the third sectiondescribes human testing. Finally, approaches tomonitoring of toxic substances are briefly discussed.

ANIMAL TOXICITY TESTSIn designing animal tests and evaluating data,

appropriate weight is given to the following factorson a case-by-case basis, taking into account theseriousness of the hazard and the assumptionsneeded to estimate human health risks (105):

●

●

●

●

●

●

●

the relationship between dose and response;the effects at the molecular, cellular, organ,organ system, and whole organism levels;the reproducibility of the study results andpossible explanations for lack of reproducibil-ity;the effects of structurally similar substances onhumans or animals;any known metabolic differences between hu-mans and the test species that could affectresponse;statistical uncertainties and difficulties in ex-trapolating to a low dose; andother factors, such as sex, species differences,and route of administration.

An Office of Technology Assessment (OTA) report,Alternatives to Animal Use in Research, Testing,and Education, contains a detailed discussion of theuse of animals in research and associated ethical

-105-


concerns (105). The issues raised there will not bereaddressed in this report.

Toxicity testing should aim to obtain all the dataneeded for accurate risk assessment at the lowestpossible cost. Factors that influence cost include thenumber of appropriate test species, the nature of theparameters studied, the choice of test subjects, thecontrols required, and the skilled staff necessary toperform the studies. In addition, toxicity testingrequires a substantial investment in labor. Asidefrom the maintenance needs of the animals used,many observations are necessary. Acute studiesoften involve observations of behavior and appear-ance as well as histopathological observations.Subchronic and chronic studies require more de-tailed pathological studies as well as weekly clinicalexaminations of all the animals used in the studies(92). Testing costs will be discussed in more detailin chapter 8.

Designing Useful Tests

Animal tests are used to determine the functional,structural, and biochemical effects of toxic sub-stances. Experimental animal models have limita-tions, however, and the accuracy and reliability of aquantitative prediction of human toxicity depend ona number of conditions, such as choice of species,choice of tests, similarity of human and animalmetabolism, design of the experiment, and methodof extrapolation of animal data.

When designing animal toxicity tests, therefore, itis essential that the examiners clearly define theobjective of their study and understand how theresulting data will be used. Several questions shouldbe answered in advance: Will the data obtained fromthe animal tests be meaningful? Will the data beuseful in the risk assessment process? Can the databe extrapolated from animals to humans?

The World Health Organization (WHO) recentlysuggested several general objectives of neurotoxi-cology testing (123):

●

●

●

identify whether the nervous system is alteredby the toxic substance,characterize the nervous system alterationsassociated with exposure,ascertain whether the nervous system is theprimary target for the chemical, and

● determine dose- and time-effect relationshipsto establish no observed adverse effect levels(NOAELs).

The initial goal is to determine whether or not thenervous system is affected by a substance for whichno toxicological data exist. This often involvesscreening for neurotoxicity using tests that predictthe potential of a substance to produce adverseeffects. To be most effective, the tests should besimple, rapid, and economical to administer. Once achemical is known to produce a neurotoxic effect,further studies can be performed in order to charac-terize the nature and mechanism of the alterations.Screens are generally designed to explore theconsequences of exposure and to indicate whether ornot the nervous system is adversely affected.

Chemicals are unlikely to affect all major compo-nents of the nervous system at the doses tested;therefore, it is important to use a variety of tests thatmeasure different functional, morphological, orchemical alterations in order to maximize theprobability of detecting neurotoxicity. The methodsused may differ with the objective of the study, theage of the animal, and the species examined (123).

Potential neurotoxic risks are difficult to assessbecause of the complexity of the nervous system.Some of the problems in assessment are associatedwith the wide variations in response that can occur.Other problems are related to the examiner’s incom-plete understanding of what is being measured by agiven test. Therefore, no single test can be used toexamine the total functional capacity of the nervoussystem (123).

Animal Choice

In preliminary screening of known or suspectedtoxic substances, numerous economic factors influ-ence the design of the evaluation. It is useful if thereexist adequate anatomical, physiological, and toxi-cological databases on the species chosen for studyto allow meaningful interpretations of effects andappropriate hypotheses about mechanisms and sitesof action (123).

Most routine toxicity testing is carried out withonly one or two species. For example, cancerbioassays frequently involve the use of rats andmice, and the monkey may be used for identifyingthe effects of MPTP, a byproduct in the illicitsynthesis of a meperidine analog. Hens have beenused to evaluate the neurotoxic potential of organo-

Chapter 5-Testing and Monitoring ● 107

phosphorous pesticides. Most other neurotoxicityscreening studies use laboratory rats. Ideally, morethan one animal species should be tested—if only asingle species is tested, it is possible to conclude thathuman exposure is acceptable when in fact it is not.However, routine multispecies testing is a costly anddemanding enterprise. The facilities and servicesneeded for animal husbandry and the equipment andtechnical expertise needed to carry out the researchmake multispecies testing economically impracticalin many instances (59).

There are other variables besides species thatshould be considered. For example, the sex of thetest animal may influence results of the study. Sometoxic substances may have a greater adverse effecton females than males or vice versa. Consequently,EPA testing guidelines require both male and femalerats for neurotoxicity testing.

Another important factor is the age of the animal.The effects of a toxic substance may vary dramati-cally, depending on the stage of maturation of theanimal. For example, cell loss in the nervous systemdue to natural aging processes may predispose ananimal to the adverse effects of toxic substances.Most preliminary assessments are designed to pro-vide information on the population with the greatestpotential for exposure, namely, adults. However,aged populations or those undergoing rapid matura-tion are often especially vulnerable to environmentalexposures; thus, tests to assess the neurobehavioralfunctioning of these populations are necessary for acomplete evaluation.

The ideal tests are those that permit longitudinalassessment of animals of both sexes at any stage ofdevelopment (i.e., at young childhood, prepuberty,and adulthood) (67). Whenever possible, the choiceof animal model should take into account suchfactors as the differences in metabolism of sub-stances between species, genetic composition of thespecies, and the sensitivity of the test animals to thetoxic effects of the substances (50 FR 39458).

Dosing Regimen

Some compounds produce one kind of toxic effectfollowing a single exposure and other effects follow-ing prolonged or repeated exposure. In environmentaltoxicology, a major objective is the detection ofcumulative toxicity following continued (or inter-mittent) exposure. Thus, a multiple-dosing regimenis most commonly used. This is particularly impor-

tant in neurobehavioral testing, since both quantita-tive and qualitative changes in the response toenvironmental factors can occur with repeatedexposure, or at some later time following a singleexposure (67,123). Normally, assessments are madefor a period of time following termination of thedosing regimen, both to determine the reversibilityof any observed effects and to see if any new effectsappear (123).

Substances are administered in varying doses, thedose being a function of the concentration of thesubstance and the duration and frequency of expo-sure. Significant differences in response may occurwhen the same quantity of toxic material is admin-istered over different exposure periods. Acute expo-sure to substances may produce both immediate anddelayed toxic effects (such is the case for someorganophosphorous pesticides). These effects maydiffer from the effects following long-term expo-sure. Repeated exposure to certain solvents mayproduce immediate effects after each dosing as wellas delayed adverse effects from long-term exposure(47).

Acute toxic responses result when an animal issubjected to high concentrations of a substance overa short period of time. The acute response may besudden and severe, and usually lasts for a briefperiod of time; in some cases, however, it ispermanent. If the dose is sufficiently high, death mayresult. Lower doses (lower concentrations overlonger periods of time) may not immediately causedeath. As the dose decreases, the response isgenerally less severe and may take longer todevelop. In chronic exposures, clinically adverseeffects may take years to develop (47).

Route of Exposure

The most common routes by which toxic sub-stances enter the body are, in descending order,inhalation (through the lungs), oral (through inges-tion), and dermal (through the skin). Althoughsubstances generally produce the greatest effect andmost rapid response when given intravenously, thisis an unlikely route of entry except in the case ofdrug therapies or drug abuse. The manner in whicha potentially toxic agent enters the body caninfluence the time of onset, intensity, and duration ofthe toxic effects. The route of exposure may alsoinfluence the degree of toxicity and the organs mostseverely affected.


Exposure to toxic chemicals in the atmosphere isunavoidable unless devices are used to remove thecontaminants from the air before they enter therespiratory tract. In order for any contaminant toreach the alveoli of the lungs (where gas exchangetakes place), it must be either a gas or of a certainparticulate size (less than 10 microns in diameter) sothat it is not removed in the airway to the lungs. Theactual and potential’ hazards associated with expo-sure to toxic agents via inhalation are evident inindustrial workplaces and in urban areas withpolluted atmospheres (55,1 17).

Most episodes of acute toxicity result fromintentional or accidental ingestion of a chemical. Forinstance, a person may deliberately take an overdoseof a psychoactive drug. Poisonous mushrooms maybe accidentally ingested. Sufficiently large particlesof inhaled toxic matter may collect in the throat andbe swallowed.

The simplest route of exposure for humans andanimals is accidental or intentional contact of thechemical with the skin. The skin is the most readilyaccessible organ to all forms of foreign chemicals,yet it is also an efficient barrier to many toxicsubstances. Many substances can be absorbedthrough the skin, including substances in fragrances(AETT), antidandruff shampoos (zinc pyridinethion-ine), and solvents (methyl n-butyl ketone) that haveproven to be neurotoxic in humans or animals, orboth (3,44,47). The degree of absorption is influ-enced by the type of compound(s) involved and thecondition of the skin. For example, cuts or abrasionson the skin’s surface will allow the agent to bypassthe epidermis, the outer, protective layer of the skin.Once through the epidermis, the substance can easilypass into the circulatory system. Depending on theconcentration and duration of the exposure, somesubstances, solvents, for example, can easily passthrough the epidermis.

Extent and Duration of Exposure

The exposure of animals to chemicals is oftendivided into four categories: acute, subacute, sub-chronic, and chronic. Acute is defined as exposureto a chemical for less than 24 hours. The purposeof an acute test is to observe the evidence of toxicityafter administration of the compound and the degreeof lethality (55). While acute exposure usually refersto a single administration, repeated or continuousdoses may be given within a 24-hour period for somesubstances with limited acute toxicity. An example

is acute exposure by inhalation, which refers tocontinuous exposure for less than 24 hours. Re-peated exposures are divided into subacute, sub-chronic, and chronic categories. Subacute exposurerefers to repeated exposure to a chemical for 1month or less, subchronic exposure occurs typi-cally from 1 to 3 months, and chronic exposuresoccur for more than 3 months (47).

As mentioned earlier, the toxic effects followinga single exposure to a substance may be quitedifferent from those produced by repeated exposure.This may occur because of compensatory changeselicited by repeated administration or because ofcumulative effects of mechanisms different fromthose causing acute toxicity. For example, theprimary acute toxic effect of carbon disulfide isdepression of central nervous system activity; how-ever, repeated exposures can result in peripheralneuropathy or parkinsonism. Acute exposure torapidly absorbed substances is likely to produceimmediate toxic effects, but acute exposure can alsoproduce prolonged toxicity that may or may not besimilar to the toxic effects of chronic exposure.Likewise, chronic exposures may produce someimmediate effects after each administration in addi-tion to the chronic effects (47).

The extent of exposure is another important factorin the characterization of exposure parameters.Generally, but not always, fractionation of the dosereduces the effect. A single dose of a compound thatproduces an immediate, severe effect might produceless than half the effect when given in two equaldoses and no effect when given in 10 doses over aperiod of several hours or days. Chronic toxic effectsoccur if the compound accumulates in the organ-ism’s system, if it produces irreversible toxic effects,or if there is insufficient time for the system torecover from the toxic damage (47).

Other Considerations

Several additional factors are considered in de-signing neurotoxicological tests. One condition thatmay affect toxicity is the nutritional state of theanimal. Changes attributed to exposure to toxicantsmight be due to relatively nonspecific effects relatedto inhibition of growth or decreases in food or waterconsumption.

Another factor is the housing conditions of theexperimental animals. Sometimes animals arehoused individually in cages during toxicological

Chapter S--Testing and Monitoring ● 109

studies, an arrangement that may alter their respon-siveness to the test compounds. For example, achemical that causes depletion of the neurotransmit-ters norepinephrine and dopamine produces lessdepression of motor activity in isolated rats than ingrouped rats (125).

Temperature of the environment is anotherimportant factor. Normally, the response of ananimal to a toxic compound decreases as theenvironmental temperature is lowered, but the dura-tion of the overall response may be delayed. Also,some drugs are more toxic in certain environmentaltemperatures than in others. For example, com-pounds affecting the neurotransmitter acetylcholinemay produce significantly greater toxicity in a warmenvironment than in a colder one. Some substancesinhibit sweating. Eventually, the body temperaturebecomes elevated because the absence of perspira-tion prevents cooling (38). In such a case, toxiceffects may result from hyperthermia, not directlyfrom the effect of the substance on the nervoussystem.

Validation

Validation is a critical component of the testdevelopment process because it ensures that datagenerated as a result of testing will be useful inevaluating the health risk posed by a particularsubstance. The value of any toxicity test lies in itsability to measure the endpoint it is designed todetect. For neurotoxicity, the endpoints are adversechanges in the structure or function of the nervoussystem. General acceptance of a new toxicity testusually requires demonstration that the test isreliable, sensitive, and specific. For validation stud-ies, chemicals with known neurotoxic potential andthose known not to be neurotoxic are studied todetermine the ability of the test to distinguishbetween them. Because toxic substances can havemany different effects on the nervous system, knownneurotoxic substances with different effects on thenervous system are chosen for validation studies.Before test guidelines are proposed for national orinternational use, validation studies commonly in-clude a multilaboratory phase to test the reproduci-bility of the testing paradigm in different laborato-ries (58,81).

Evaluating Chemicals for Neurotoxicity

It is impossible to thoroughly examine the neuro-toxicity of each of the chemicals in commerce.

However, it


may be possible through a well-developed screening program to flag the substanceseither currently in use or recently introduced thathave neurotoxic potential. Screening is conducted toprovide an initial evaluation of the effects of varioussubstances on the nervous system. The results ofscreening may be used to reduce the number orquantity of hazardous substances in commerce or toaid in determining which additional studies shouldbe undertaken to further characterize their toxicolog-ical properties (67). An efficient screen shouldevaluate a variety of neurological effects rather thanjust one. Screens should also be sensitive, reproduc-ible, and capable of being administered rapidly(32,33),

Testing strategies often involve a tiered approach.Tiered testing involves a stepwise progression ofmore specific and sophisticated tests, beginningwith a general screen to determine if further testingis necessary. In the initial screen of the tiered testingapproach, the outcomes of acute studies are inter-preted. If acute effects are identified, then experi-ments involving repeated exposures are performedin the second tier. The third tier is composed ofdetailed studies of subtle effects or mechanisms oftoxicity. At each stage the examiner builds on thedata collected from the previous tier.


Typically, 5 to 10 animals of the same species andstrain are used in the tests. It is important to select theproper animal model initially because it is desirableto use the same model in subsequent tiers. Using thesame animal is more efficient, costs less, and allowsconsistent analysis of data. Some toxicity tests onlyrequire the acute dosing regimen, and it is notnecessary to conduct repeated dosages. Box 5-Aillustrates one example of a tiered testing approach.Other investigators have proposed slightly differentschemes (32-34,62).

As in vitro tests become available, tiered testingschemes may be modified to take advantage of bothwhole animal and tissue and cell culture testingapproaches. For example, a future scheme might callfor in vitro tests as a screen, followed by in vivo tests(32,37). In vitro tests will be described later in thischapter.

Types of Animal Tests

The EPA has taken the lead in devising neurotox-icity tests for use in regulatory programs. In 1985,the Agency devised a final rule on general toxicitytesting guidelines under the Toxic Substances Con-trol Act (50 FR 39398-39418). The guidelines are

dermal, inhalation, and oral exposure); subpart Cincludes testing procedures for subchronic dermal,inhalation, and oral exposure; and subpart D de-scribes testing procedures for chronic exposure.

General toxicological tests evaluate a broadspectrum of potential toxicological effects, includ-ing some effects on the nervous system; however,these tests are not designed to examine comprehen-sively the possible neurotoxic properties of chemi-cals. In 1985, EPA proposed specific guidelines forneurotoxicity testing (50 FR 39458-39470). EPAhas proposed guidelines for the functional observa-tional battery (FOB) and specific tests to analyzemotor activity, schedule-controlled operant behav-ior (SCOB), developmental neurotoxicity, neuropa-thology, and the effects of organophosphorouspesticides (1 12). When specific neurotoxicity test-ing is necessary, EPA currently plans to require theFOB, together with motor activity and neuropathol-ogy tests. At the present time, these three tests arereferred to by EPA as the core test battery. EPA’sOffice of Toxic Substances and Office of PesticidesPrograms are currently considering a requirement touse the core tests routinely in evaluating new and old

categorized into three subparts: subpart B describes chemicals and pesticide products. When appropri-the procedures for general toxicity testing (i.e., acute ate, other tests may also be required.

Box 5-A—Tiered Animal Testing To Identify Adverse Neurobehavioral Effects of Substances

Tiered testing is an efficient and cost-effective approach to evaluate the toxicity of chemicals. In the first tierof an experiment, the recommended strategy is to identify acute hazards of substances. The second tier is designedto characterize the toxicity in repeated exposure, and the third is used to undertake detailed studies of specialimpairments or of mechanisms of chemical injury. Each tier provides useful information for subsequent tiers.

First tier—Animals are exposed to the substance being evaluated. The exposure period is short and coversa wide range of concentrations. The investigator seeks to identify any evidence of mortality, morbidity, ormorphological changes. The experimenter also observes behavior. The first tier helps establish the parameters ofexposure that are appropriate for the second tier. It may also suggest mechanisms by which the effect is produced,which may assist in the design of more sensitive experiments in the third tier.

Second tier—Animals are repeatedly or continuously exposed to substances being evaluated. This tierprovides an opportunity to characterize delayed toxicity, to observe the development of tolerance, and tocharacterize the reversibility of adverse effects.

Third tier—At this stage, highly focused studies are performed to fully characterize toxicity, using methodsdictated by the nature of the system. This tier can identify subtle sensory or perceptual impairments, affectivedisorders, or cognitive and intellectual dysfunction. A detailed hazard characterization not only can facilitate theidentification of the most sensitive situation, but also may clarify the mechanism of action of the substance.

The above schemes may be modified in the future as in vitro tests become available.

SOURCES: A.M. Goldberg and J.M. Frazier, “Alternatives to Animals in Toxicity Testing,” Scientific American 261(2):24-30, 1989; R.W.Wood, American Psychological Association, testimony before the Neurotoxicity Subpanel of the FIFRA Science Advisory Panel,U.S. Environmental Protection Agency, Washington, DC, Oct. 15, 1987.

Chapter .5-Testing and Monitoring . 111

In August 1989, EPA sponsored a meeting of theFederal Insecticide, Fungicide, and Rodenticide Act(FIFRA) Scientific Advisory Panel to examinevarious issues related to proposed guidelines forneurotoxicity and mutagenicity testing under the Actand to review the classification of several selectedcompounds (54 FR 35387).

Unless otherwise specified, it is assumed that bothacute and subchronic testing will be conducted forboth FOB and motor activity. Although someexperts have recommended that neuropathologicalexaminations be conducted following acute expo-sures, at the present time EPA anticipates requiringsuch analysis only after repeated exposures. Theseneurotoxicity tests represent an initial approach toidentifying hazardous chemicals and are not specifi-cally designed to develop the data necessary forfull-scale risk assessments (101). (See ch. 6.)

The EPA core battery does not represent acomplete screening assessment of the nervous sys-tem. For example, it does not adequately assesscognitive function, neurophysiology, or neurochem-istry. Some neurotoxicologists have challenged theusefulness of the core battery, saying that it does notgo far enough. Nevertheless, EPA plans to requirejust the core battery, with the option of using morecomprehensive tests for selected compounds. Addi-tional tests that EPA might require in conjunctionwith or in place of the core battery include SCOB,developmental neurotoxicity, and neurotoxic est-erase assay (101).

Which tests are most appropriate for routine usein screening for neurotoxicity is the subject ofdisagreement in the scientific community. Somescientists believe that developmental and SCOBshould be part of the EPA core test battery becausethey measure different aspects of neurotoxicity thando the FOB, motor activity, and neuropathologytests. Others believe that the motor activity andSCOB tests should not be used as part of an initialscreen, because they may not be direct measures ofneurotoxicity. EPA believes that the initial screenshould include FOB, motor activity, and neuropa-thology assessments because these tests provideadequate initial measures of neurotoxicity andenable investigators to judge whether or not addi-tional (second tier) testing is necessary. Descriptionsof various neurotoxicity tests follow.

Functional Observational Battery

An FOB is a collection of noninvasive tests toevaluate sensory, motor, and autonomic dysfunctionin either animals exposed to substances or animalshaving endured direct damage to the nervous system(57). FOBS are generally used as screens to deter-mine which substances require additional testing.

EPA published a test guideline for an FOB in1985. The EPA guideline incorporates aspects oftests developed and used in industry and academia(32-34,42,79,80). The battery is designed to be usedin conjunction with general toxicity tests or neuropa-thological examinations, or both (50 FR 39458-39460). It serves as a screening tool (thus, it isconsidered a first tier test), indicating which sub-stances should be further characterized using secondtier methods. It is not intended to provide an overallevaluation of neurotoxicity. EPA is currently refin-ing and validating its FOB.

The EPA test battery is administered to femaleand male rats, usually 10 per dose group per sex.Three doses of the test substances are used, withdoses chosen so that the highest dose producesobvious signs of toxicity. The doses are selected onthe basis of values from previous literature andexperiments in order to ensure the detection ofneurobehavioral effects (69,70). The observer is notaware of the dose identification. The observerrecords each response subjectively, using estab-lished rating scores. After all data are collected, theyare entered into a computer, summarized, andanalyzed using statistical methods (17,68-70). Box5-B summarizes the procedures for conducting theEPA FOB.

The FOB is advantageous because it can be easilyadministered and can provide some notion of thepossible functional changes produced by exposureto neurotoxic substances. It also allows evaluation ofthe dose-response and time course characteristics ofthe neurological and behavioral changes producedby exposure to a substance. Furthermore, the equip-ment used is relatively inexpensive, and the totaltime to complete an entire evaluation is short(68,69). Potential problems include difficulty indefining certain measures, a tendency toward sub-jective biases in assessing behavior (123), and theneed for trained observers.


Box 5-B-Conducting the EPA Functional Observational Battery

In conducting the EPA functional observational battery (FOB), the technician first observes and describes therat’s posture in the home cage, then closure of the rat’s eyelid and any convulsions or tremors that may be present.Next, the animal is picked up and rated for ease of handling and removal from the cage. The rat is observed andrated for signs, such as lacrimation and salivation, that the autonomic nervous system has been adversely affected.The rat is then placed on a cart top for 3 minutes, during which time the number of rears are counted and the gait,mobility, and level of arousal are rated. At the end of the 3 minutes, fecal and urine output are recorded.

Next, the technician rates the rat’s responses to several stimuli, such as the approach of a pencil, snap of a metalclicker, touch of the pencil on the rat’s rump, and pinch of the tail with forceps. Using a pen flashlight, the observertests the rat for pupil constriction in response to light. The righting reflex is then measured by the ability of the ratto flip over in midair and land on its feet. Using strain gauges, the rat’s forelimb and hindlimb grip strength aremeasured. The rat’s hind feet are painted, and the technician then holds the rat a few inches above the cart top anddrops it in order to measure landing foot splay. Finally, the rat’s weight and rectal temperature are recorded. Theentire procedure takes approximately 6 to 8 minutes per animal.

SOURCES: V, Moser, Director, NSJ Tedmology Services Corp., Research Triangle Park, NC, personal communication, Nov. 16, 1988; V.Moser, J. McCormick, J.P. Creason, et al., “Comparison of Chlordimeform and Carbaryl Using a Functional ObservationalBattery,” Fundamental and Applied Toxicology 11:189-206, 1988.

Photo credit: John O’Donoghue

One component of the functional observational battery(FOB) evaluates a rat’s response to an auditory stimulus.

Motor Activity

Motor activity is generally defined as any move-ment of the experimental animal, and it is most oftenevaluated after acute and subchronic exposures. Theacute motor activity test is used to examine changesin animal movement following the administration ofa range of acute doses. This test can also be used todetermine the potential of a substance for producingacute neurotoxicity, and it may be used as a screento evaluate certain classes of substances for neuro-toxicity. The subchronic motor activity test is used

to determine whether repeated dosing with sus-pected chemicals results in changes in activity, Thistest may be used to determine a substance’s potentialfor producing subchronic neurotoxicity (50 FR39460) (60). There is disagreement as to whethermotor activity is a primary indicator of neurotoxic-ity. For example, the primary action of a toxicantmay be at some site other than the nervous system;the changes in motor activity maybe secondary, thatis, a result of the primary effect.

Proposed EPA guidelines require that the testsubstance be administered in different amounts togroups of animals. Levels of exposure that result insignificant changes in motor activity are comparedto levels that produce toxic effects not originating inthe central nervous system (50 FR 39460). Observa-tion measurements may be either quantitative orqualitative. The quantitative approach measures thefrequency, duration, and sequencing of variousmotor components of behavior. The qualitativeapproach is used to gather data on the presence orabsence of certain components of activity (90).

The use of observational methods to detect subtlechanges in behavior has limitations. Many man-hours are required to obtain and evaluate the data.Some studies also require more than one observer.Because of possible subjective influences on datacollection, a great deal of technical knowledge isrequired to ensure reliability. Finally, subject-observer interaction is an important consideration.

Chapter 5—Testing and Monitoring ● 113

For example, the presence of the observer maymodify the animal’s behavior (90).

The techniques of observational analysis haveincluded videotape recordings and computerizedpattern recognition. In most cases, videotaping hasminimized the problem of subject-observer interac-tion and has provided a permanent record ofbehavior which can be used for standardizingobservations. The computer techniques have allevi-ated the problems of subjectivity (subject-observerinteraction and subjective bias) and laborious data-collection procedures (90).

Some of the automated techniques that have beendeveloped for motor activity testing include photo-cell devices, mechanical devices, field detectors, andtouch plates. Photocell devices provide direct meas-ures of motor activity in which beams of lighttraverse a cage and collide with photoreceptors. Thistechnique involves placing the rat in a figure-8 mazeand recording any movement of the experimentalanimal that interrupts the beam of light. The numberof beam interruptions is counted and recorded by acomputer for a l-hour time period (60,68). Thefigure-8 maze is only one of a variety of chambersused for motor activity examinations. For example,another device commonly employed for assessingmotor activity is the Motron Electronic MobilityMeter, which differs from the figure-8 maze becauseof its rectangular shape and the density and arrange-ments of the photodetectors that are used to recordmotor activity (60). Automated motor activity meas-ures may be used to generate dose-response data.This is typically done by placing rats in a plexiglassbox, Two video cameras monitor the animal’sbehavior, and the video signals are transferred tocomputers in order to identify common patterns inmovement and behavioral classification of the data(71).

Toxic substances may have a variety of effects onmotor activity. To generate the data illustrated infigure 5-1, motor activity was measured for 1 hourin a group of rats in a figure-8 maze after administra-tion of a toxic substance or placebo (P). The numbersrepresent motor activity units for the entire hour.Group FLT received the pesticide fenvalerate, whichdepressed activity. Group TPT received the pesti-cide triphenyltin, which had no effect on activity.Group TDM received the pesticide triadimeform,which stimulated activity, Experiments are ordinar-ily conducted with many doses of a toxic substance

Figure 5-l—The Effects of Toxic Substanceson Motor Activity

Motor activity units500 475

400-

300- 280 II

200-

100-

235

P FLT P TPT P TDMSubstance

P , Placebo FLT = Fenvalerate TPT . Triphenyltin TDM = Triad tmeform

SOURCES: K.M. Crofton and L.W. Reiter, “The Effects of Type I and IIPyrethrolds on Motor Actiwty and the Acoustic Startle Re-sponse in the Rat,” Fundamental and A#ied Toxicology10:624-634, 1988; K,M. Crofton, V.M. Boncek, and R.C.MacPhail, “Evidence for Monoaminergic Involvement in Tri-adlmefon-induced Hyperactivity ,“ Psychopharmaco/ogy97 :326-330, 1989; S, Padilla, R,C. MacPhail, and L.W. Reiter,“Neurotoxic Potential of Pesticides: Age-related Effects ofPesticides to Youth in Agriculture,” U.S. Environmental Pro-tection Agency report, Health Effects Research Laboratory,1985.

to determine how motor activity changes with levelof exposure (59).

Motor activities recorded with mechanical de-vices involve a vertical or horizontal displacementof the chamber in response to the animal’s motions.Some of the mechanical devices used includestabilimeters and running wheels. Stabilimetersrecord the movement of the animal when it causesthe chamber floor to be displaced from its restingposition. Running wheels are designed so that thewheel is positioned on a horizontal axle and theanimal’s running causes the device to rotate. Run-ning wheels have been used in behavioral toxicologyfor over three-quarters of a century to study theeffects of food deprivation, water deprivation, es-trus, lesions of the central nervous system, andlocomotor activity (90).

Field detectors are used to record the disturbancesthat an animal creates in moving within a test cage.Touch plates measure motor activity by recordingcontacts of the animal with sections of the chamberfloor (90).


There are many advantages of motor activity tests.These include the availability of automated testequipment, ease of testing, and objectivity of data(60). Additional factors include obtaining reproduci-ble data that are sensitive to the effects of acuteexposure to various toxic substances. These methodsdo not require any special training or surgicalpreparations prior to testing.

Several organizations, including the NationalAcademy of Sciences, the World Health Organiza-tion, and the Federation of American Societies forExperimental Biology, have recommended thatmotor activity testing be included in evaluating thetoxicity of potential and known neurotoxic sub-stances (30,64,74,123). However, further testing isusually needed to provide more specific informationon the adverse health effects of the test substance.Furthermore, the data collected may not provideinformation on the origin of the problem or indicatewhat subsequent tests should be administered (64).There is general agreement within the scientificcommunity that questions remain concerning thespecificity of motor activity measures. For example,sickness resulting from chemical exposure is notalways associated with changes in motor activity(60).

Photo credit: V Moser and R.C. MacPhail

The figure-8 maze is used to evaluate changes in motoractivity after exposure to neurotoxic substances.

Photo credit: Julia Davis, NSI Technology Services Corp.,Research Triangle Park, NC

The electron microscope is a useful tool in examining nervetissue damaged by toxic substances.

Neuropathology

Neuropathology is the third component of theEPA core test battery (50 FR 39461). The neuropa-thological examination is designed to develop dataon structural and functional changes in the nervoussystem as a result of exposure to toxic substances.EPA’s guidelines recommend procedures to detectpathological alterations produced by neurotoxicsubstances. Morphological examination of animalsexposed to neurotoxic substances helps to distin-guish between pharmacological and structural typesof adverse effects, describes the relative frequencyand severity of the lesions, establishes the locationof structural changes in the central nervous system,serves as a basis for relating particular classes ofcompounds to particular kinds of damage, andreveals the cellular components that have beendamaged. Additional neuropathological techniquesare currently in use to determine NOAELs and toexamine the effects of toxic substances on thenervous system (48,100).

There is general agreement that neuropathologicalstudies should be conducted in parallel with otherneurotoxicity tests. Neuropathological evaluationsmay be performed following acute, subchronic, and

Chapter S-Testing and Monitoring ● 115

chronic exposures to toxic substances (50 FR39461).

Developmental Neurotoxicology

Developmental neurotoxicology (behavioral ter-atology), an emerging discipline within the toxico-logical sciences, is concerned with behavioral andrelated effects in the offspring of parents exposed toneurotoxic substances prior to conception, duringgestation, during lactation, or any combination ofthese times (45). Research efforts are under way tounderstand the basic principles of behavioral neuro-toxicity, the biological mechanisms involved, andthe appropriate methods for testing and obtainingdata to be used by regulatory agencies in settingstandards (45). In recent years, major advances havebeen made in methods for detecting the adversebehavioral effects of toxic substances on the devel-oping organism. In 1979, the National Center forToxicological Research (NCTR) developed a bat-tery of tests to be used for the CollaborativeBehavioral Teratology Study. NCTR served as thepilot test facility for conducting the study, and fiveother laboratories were involved in evaluating astandard protocol. The study was designed to assessthe reliability of the test methods used and to detectthe sensitivity of each (1,14,45,114,115).

Regulatory efforts in behavioral teratology beganin 1975, when Great Britain and Japan producedguidelines for testing pharmaceutical substances. In1983, the European Economic Community devel-oped similar guidelines. WHO proposed draft test-ing guidelines for drugs and other substances in1986 (45). That same year, EPA proposed testingguidelines for several glycol ethers (51 FR 17883;51 FR 27880). A final test rule for diethylene glycolbutyl ethers (53 FR 5932) was set in 1988 and fortriethylene glycol monomethyl ethers (54 FR 13472)in 1989. These were the first testing guidelinesdirectly related to developmental neurotoxicity to bepromulgated by a U.S. regulatory agency.

Developmental neurotoxicity tests are used tocharacterize various aspects of damage to thedeveloping nervous system, including adverse struc-tural and functional changes. This informationserves as a basis for relating particular classes ofcompounds to particular kinds of damage; it can thenbe used to predict what classes of compounds maybe neurotoxic. Developmental neurotoxicity testsare also used in determining the magnitude ofdamage resulting from particular exposure levels,

and they aid in establishing NOAELs (51 FR17890). The guidelines for glycol ethers consist ofevaluations of morbidity and mortality, growth andphysical development, neurological and physicalabnormalities, auditory startle habituation, learningand memory, developmental locomotor activity, andneuropathology. Recently, a consent order for thetesting of 1,1,1 -trichloroethane was published (54FR 34991); it includes developmental neurotoxicitytesting.

In 1987, FIFRA’s Science Advisory Panel ap-proved the development of a generic testing guide-line for developmental neurotoxicity testing (alongwith a guideline for adult neurotoxicity testing).Generic guidelines have also recently been proposedfor developmental and adult neurotoxicity testing ofpesticides. These tests are designed to determine theeffects of maternal exposure to pesticides on thenervous systems of offspring. The proposed generictest guidelines require administration of the testsubstance to several groups of pregnant animalsduring gestation and lactation. Selected offspring arethen tested for neurotoxicity. This evaluation isdesigned to detect any effects on growth anddevelopment, gross neurological effects, or behav-ioral abnormalities. These guidelines will be re-quired for the testing of pesticides on a case-by-casebasis. Testing may be required for substances thatcause central nervous system malformations, sub-stances already known to be neurotoxic in adults,hormonally active substances, and substances thatare structurally related to known neurotoxicants(46).

In April 1989, a workshop on the comparability ofhuman and animal developmental neurotoxicity wassponsored by EPA and the National Institute onDrug Abuse to evaluate and compare the effects ofknown neurotoxic substances on the developingnervous system. The workshop focused initially onseveral agents known to adversely effect humans,including selected abused substances (primarilymethadone and cocaine), alcohol, lead, polychlori-nated biphenyls, diphenylhydantoin, methyl mer-cury, and X-irradiation. It is possible to makequalitative comparisons of effects across species,especially when major categories of function arecompared. Making quantitative comparisons in datais more difficult (46).

Based on this information, work groups thenfocused on the underlying basis for comparability of


effects across species, the appropriateness of currenttesting approaches, alternative approaches to riskassessment, and the considerations (triggers) thatshould be used in determining when to requiretesting. Participants agreed that the support forcross-species comparability was great enough that areliable effect (including permanent and transienteffects) should be considered a potentially adverseeffect in humans. Also, developmental effects, in thepresence or absence of maternal toxicity, should beconsidered adverse. Since no single category offunction was found to be routinely the most sensi-tive, it was agreed that a battery of functions shouldbe included in any developmental neurotoxicitytesting screen. Although limitations were identified,workshop participants felt that a reference doseshould be established to identify a level below whichno increase in developmental neurotoxicity is ex-pected, An abbreviated test battery was proposed forscreening purposes. Whether to use this abbreviatedbattery or a full-scale testing protocol may dependon the type of information already available. Forexample, a substance that causes central nervoussystem malformations should be thoroughly evalu-ated for developmental neurotoxicity, whereas asubstance that is structurally related to knownneurotoxic substances might be tested first using theabbreviated battery (46).

EPA has published risk assessment guidelines fordevelopmental toxicity (51 FR 34028) and hasrecently proposed amendments to these guidelines(54 FR 9386). Developmental neurotoxicity datamay aid in evaluating the long-term consequences ofadverse effects discovered at the time of birth and therelationship of the behaviorally effective dose to thetoxic dose. These data may also aid in identifyingeffects that should be monitored in exposed popula-tions (45). EPA is currently developing guidelinesfor the use of data on adult and developmentalneurotoxicity in risk assessments.

Schedule-Controlled Operant Behavior

Changes in behavior are a useful indicator ofexposure to neurotoxic substances because behaviorinvolves the integration of motor, sensory, andhigher order nervous system activities (102). Regu-latory officials increasingly recognize behavioralchange as an important endpoint of neurotoxicity.Several organizations, including the National Acad-emy of Sciences and WHO, have recommended thatoperant behavior testing be included in evaluations

Photo credit: D. Cory-Slechta

Schedule-controlled operant behavior (SCOB) tests areused to evaluate a rat’s learned behavior in

scheduled intervals.

of potential and known neurotoxic substances (74,75,123). Operant behavior refers to “behavior that ismaintained by its own consequences’ (50). Schedule-controlled operant behavior refers to reinforcing ananimal’s response to stimuli according to an explicitschedule, thereby producing orderly patterns ofbehavior (50).

There are several reasons why operant behaviortests may be useful. Operant behavior is critical foradaptation and long-term survival of animals. Testsof this kind allow reliable and quantitative examina-tion of the effects of substances on behavior, and theextensive literature on operant behavior provides aconceptual framework for analysis of effects. Fi-nally, operant conditioning allows the researcher totailor the behavior to the needs of the experiment(98). Disadvantages of using this type of test includethe cost of equipment and of data acquisition andanalysis systems, the time involved in traininganimals to certain schedules, and the difficulties ininterpreting the toxicological significance of someof the subtle endpoints used as indices of operantperformance.

In 1985, EPA established guidelines for evaluat-ing the effects of toxic substances on simple learningprocesses using SCOB tests. SCOB evaluates theeffects of acute and chronic exposures on the rate


and pattern of responses under schedules of rein-forcement (50 FR 39465). Following testing forbehavioral effects, additional tests may be neces-sary. Operant behavior studies may be used inconjunction with neuropathological examinations.

EPA’s approach to operant behavior testing in-volves placing the animal in an apparatus containinga lever and a device to deliver a reinforcer, such asmilk. One method is to train the animal under afixed-ratio reinforcement schedule, in which a fixednumber of presses on the lever is followed by areward of milk. For example, if one rewards ananimal for exactly each third lever press that itmakes, the ratio between responses (lever presses)and reward is fixed (50,68). Animals may also betrained under variable-ratio reinforcement sched-ules. In other words, the technician varies theschedules so that sometimes the third responseyields milk, sometimes the seventh, and sometimesthe hundredth. The animal never knows when thenext reward is coming (50). These schedules ofreinforcement may be used to generate moderateresponse rates that may increase or decrease as afunction of exposure to toxic substances (50 FR39466). Several kinds of SCOB tests are currentlyused in industry (49,50,89,102).

A variety of other testing schemes are commonlyused to examine behavior. These include tests todetermine the effects of neurotoxic substances onmotor coordination, tremor, sensory processes, re-flexes, and learning and memory (23,27,29,49,66,102).There is some disagreement in the scientific commu-nity as to the optimal approach for evaluatingoperant behavior.

Biochemical Markers

Various biochemical markers have been used toassess the effects of toxic substances on adult anddeveloping nervous systems. EPA recently devel-oped a proposed guideline for the assessment ofdevelopmental neurotoxicity using a glial fibrillaryacidic protein (GFAP) radioimmunoassay (77). GFAPsare proteins located in the glia, the non-neuronsatellite cells of the central nervous system. Whenglial cells are damaged by toxic substances, theysubstantially increase production of GFAP. Theproposed test is designed to develop data on changesin the amount of GFAP in the developing nervoussystem after postnatal exposure to a toxic substance.Such an assay is a useful adjunct to developmentalneuropathological examinations (76,77), Assays of

A. Control

B. Rat exposed to trimethyltin.Photo credit: J.P. O’Callaghan, U.S. Environmental Protection Agency

Trimethyltin increases levels of glial fibrillary acidic protein(GFAP) in astrocytes of the rat brain, a sign of nervous

system damage.

proteins in neurons and glia can be used to detect andcharacterize specific responses and alterations inbrain development due to toxic substances. Whilenot designed to uncover basic mechanisms underly-ing specific neurotoxic effects, this approach can aidin defining neurochemical mechanisms underlyingaltered brain development (78).

Specialized Tests for OrganophosphorousPesticides

.

Exposure to some organophosphorous pesticidesproduces delayed effects, including weakness oflimbs and improper function of certain motor


neurons. Evidence of toxicity first appears approxi-mately 2 to 3 weeks after initial exposure. In 1985,EPA established guidelines for neurotoxic esteraseassay for organophosphates (50 FR 39463). Theseguidelines describe the procedure for measuring theinhibition of an enzyme known as neurotoxicesterase (NTE) in the brain or spinal cord of hensexposed to organophosphorous substances (50 FR39463). This assay is intended to serve as an adjunctto behavioral and pathological examinations of hensand is not intended to replace in vivo tests.

EPA also established guidelines in 1985 for a testof acute delayed neurotoxicity of organophosphor-ous substances (50 FR 39466-39467). This testinvolves administering a single dose of these sub-stances orally to adult hens and observing them forsymptoms such as gait changes, lack of coordina-tion, and paralysis. The animals are observed dailyfor approximately 3 weeks until effects are deter-mined. All signs of toxicity are recorded, as well asthe duration and extent of exposure. In addition, thehens are evaluated for motor ability at least twice aweek, with various tests. If neurotoxic effects are notseen immediately, the dosage may be repeated andthe observation period extended (50 FR 39466-39467). Later, pathological examinations are alsoconducted on the animals.

Subchronic delayed neurotoxicity refers to aprolonged lack of coordination resulting from re-peated exposure to a toxic substance over a limitedperiod of time. In 1985, EPA established guidelinesfor a test of subchronic delayed neurotoxicity oforganophosphorous substances (50 FR 39467). Thistest involves administering these substances orallyto hens for approximately 3 months. It is usuallyconducted after obtaining information from acutetests. Evaluators observe the hens daily for suchindicators as gait changes, lack of coordination, andparalysis. Following the observation period, path-ological tests of selected neural tissues are con-ducted using perfusion techniques and microscopicevaluations. In addition to providing information onthe possible health effects of repeated exposures toorganophosphorous substances, this test may pro-vide information on dose-response, thus aiding indetermining an estimate of a no-effect level.

Neurophysiology Techniques

Neurophysiological tests for assessing the healtheffects of potential and known neurotoxic sub-stances are usually adopted by neurotoxicologists

from testing techniques used in the basic neuros-ciences. These tests are designed to provide specifictypes of information, and the technique or set oftechniques chosen for a given application willdepend on the nature of the scientific issues underinvestigation (9).

In general, neurophysiological testing techniquesdepend on the electrical properties of nerve cellmembranes. The firing of a single neuron involvesthe movement of electrically charged ions across themembrane. This movement of charged particlescreates electrical potentials which can be measured.The measured potentials, in turn, reflect the func-tioning of the neuron or neurons that generated them.Neuronal potentials are usually measured by placingelectrodes on or near the neural tissue of interest. Inmany cases where the neural tissue is not directlyavailable, such as the human brain, the electrodescan be placed at remote sites for detection ofelectrical activity which is conducted through thecranial tissues. The electrical signals recorded fromthe electrodes are typically amplified, filtered, andpassed on to a data acquisition device such as acomputer (9).

It is convenient to categorize electrophysiologicaltesting techniques by the size of the recordingelectrodes used. These range from a few microns toseveral millimeters. The former, termed "microelec -trodes," can be used to penetrate cell membranesand measure the function of single neural cells orparts of cells, such as membrane ion channels orsynaptic endings. Moving up in size, “multiunitelectrodes” can be placed in the vicinity of severalcells and can measure the activity of each neuron ina cluster of neurons simultaneously. Still larger‘‘macroelectrodes’ can measure the summed activ-ity of many neurons, possibly thousands of cells.With macroelectrodes, the activity of individualcells is no longer detectable; instead, the activity ofneural systems can be monitored (9). Neurophysiol-ogical tests may be used to study neural functioneither in vitro or in vivo, and they can measurespontaneously emitted neural responses or thoseevoked in response to some type of stimulation (9).

For neurotoxicological applications, microelec-trode techniques and in vitro procedures are usefulfor investigating mechanisms of action of knownneurotoxic substances because of the specificity ofthe techniques. For investigating the potential neu-rotoxicity of compounds with unknown properties,

Chapter .5--Testing and Monitoring . 119

in vivo macroelectrode procedures are more usefulbecause of their generality. One set of macroelec-trode techniques, sensory evoked potentials (EPs), isbeing developed by EPA for potential use inneurotoxicology testing paradigms. This approachhas been endorsed by several industrial organiza-tions (9).

Sensory evoked potentials can be used to identifywhich of the sensory systems in the nervous systemare affected by neurotoxic substances and to provideinformation about the nature of these changes. Inaddition, sensory systems are model systems forstudying ‘generic’ dysfunctions, since they includeall the components of other systems but can bestudied relatively noninvasively. Evoked potentialsare essentially electrical signals that are generatedby the nervous system in response to a stimulus.Using neurophysiological techniques, these signalscan be measured and recorded. Various types ofevoked potential techniques are currently in use,including brainstem auditory evoked responses,flash evoked potentials, pattern reversal evokedpotentials, and somatosensory evoked potentials(25,56,61).

The electroencephalograph (EEG) records spon-taneous, ongoing electrical activity in the brain(activity that, unlike EPs, is not associated withpresentation of a stimulus). Electrodes are surgicallyimplanted in a rat’s skull or pasted onto a human’sscalp. The electric potential differences between theelectrodes are measured and the changes in thepotential difference are recorded. EEGs can providea detailed record of electrical activity at several brainsites, allowing investigators to identify generalregions of the brain that may be adversely affectedby acute or long-term exposure to known or potentialneurotoxic substances. However, EEG data can bedifficult to interpret, and the technique provideslimited information on the mechanisms of action oftoxic substances (4,43,97). The limitations of EEGsspurred the innovation of methods for measuringevoked potentials.

Brainstem auditory evoked responses (BAERs)can be used to detect specific losses in the auditorysystem and thus to determine specific regions of therat’s nervous system that have been damaged (25).This approach has been used to assess the effects onhearing of various solvents, such as toluene (56,61,82,83,88).

Photo credit: Julia Davis, NSI Technology Services Corp.,Research Triangle Park, NC

Experimental neurophysiologist examines a visual evokedpotential recorded from a subject watching the

checkerboard stimulus seen at right.

Visual evoked potentials, which include flashevoked potentials (FEPs) and pattern reversalevoked potentials (PREPs), are used to evaluate theeffects of toxic substances on those components ofthe nervous system responsible for vision (25,61).The visual system is vulnerable to neurotoxicsubstances, and acute and chronic exposure to suchsubstances can lead to damage of the retina and thenerve cells in various areas of the brain that processthe information received from the retina. Visualevoked potentials have been used to assess theeffects of various heavy metals, pesticides, andsolvents on visual function in rats. Potentials can begenerated using stimuli ranging from diffuse lightflashes to complex patterns of shapes and colors(25,61,83).

FEPs in rats are altered by exposure to manyheavy metals, pesticides, and solvents. One tech-nique for using FEPs in neurotoxicological studiesinvolves flashing a strobe light of high intensity(turning on and off an intense stimulus) at the testspecies followed by observing and analyzing theeffects on the visual system. One common techniqueinvolves placing the rat in a chamber surroundedwith mirrors on three walls and on the fourth wall astrobe light which flashes at various intensity levels.Stimulus intensity, pupil diameter, and level of light


adaptation are the major parameters of concern inrecording FEPs (4,25,56,61,82,97). Following FEPexaminations, a neuropathological examination maybe conducted to identify any retinal or brain lesions(damage or loss of retinal cells) caused by exposureto the toxic substance.

PREPs are used in the diagnosis of optic neuritis,multiple sclerosis, and other illnesses that affect thevisual system in humans. Visual evoked potentialscan be created by changing a pattern of bright anddark areas on a screen in front of an animal withoutaltering the overall level of illumination. Patterns forPREP testing are generated by reversing the checkson a checkerboard display (black for white and viceversa) or the bars in a horizontal or verticalarrangement. One drawback of this technique is thatit is difficult to ensure that animals focus on thepatterns, especially without training (4,25,56,61 ,82,83,97). On the other hand, PREPs can be recorded inawake rats without concern for the focal point. Whenthe stimulus is in the rat’s visual field, the eyes willbe in focus (10).

Figure 5-2 indicates the results of testing thechemical chlordimeform on the rat visual system. Asthe dosage of the toxic substance is increased (fromO to 40 micrograms per kilogram), the amplitude(size) of the PREPs increases (note, e.g., the distancefrom points N1 to Pi), but the amplitude of the FEPsis unchanged. The chlordimeform enhances theresponse to high-contrast, but not to low-contrast,stimuli (12).

Somatosensory evoked potentials (SEPs) arecommonly used to determine the effects of bothpotential and known toxic substances on the nervoussystem. The somatosensory nerves are the longestcells in the body, extending from the limbs to thehead. In testing, an electric current is applied to thesensory nerve of particular interest and the SEPs aremeasured. Responses can be examined at manypoints along the nerve. This approach has been usedto study the effects of acrylamide (4,25,26,56,61 ,82)and sulfuryl fluoride on the rat’s somatosensorysystem (63).

Figure 5-2-Pattern Reversal Evoked Potential (PREP) and Flash Evoked Potential (FEP)After Treatment With Chlordimeform

A. Pattern reversal evoked potential B. Flash evoked potential

NI N1 N2N3 N2 N3

N1 N2

o PIP3

PI

N1 N3 N1OYx N2

F5 P1

60c-aC/Ys

gN1 N1

N1oalE 15~~ P1-!=c)

P2 P2

N3N1 N1

40

-1P1

25u V

+[50 msec P2 50 msec

SOURCE W Boyes and R S Dyer, “Chlordimeform Produces Profound, SeIective, and Transient Changes in VisualEvoked Potentials of Hooded Rats,” Experimenta/ Neurology 86434-447, 1984


SEPs have been used extensively in neurotoxicol-ogical studies because they provide rapid, effective,and quantifiable methods for testing sensory func-tions (including the visual, auditory, and somatosen-sory systems). Another advantage is ease in survey-ing the entire sensory pathway to the brain. How-ever, the equipment associated with this technique isexpensive, and special training is often required tooperate it. Another limitation is that, due to the largevariability among rats, many must be tested to obtainstatistically reliable results.

Animal Testing Issues

How Well Are Animal Test ResultsExtrapolated to Humans?

An important goal of toxicology is to increase thecapability of predicting human responses fromanimal toxicity tests and to understand the causes ofinterspecies differences in susceptibility to toxicsubstances. The greatest difficulty in extrapolatinganimal data to humans is the difference in responsesbetween humans and animals to toxic substances.Humans may be more sensitive to certain substancesthan animals and vice versa. In addition, since thehuman population is more heterogeneous than anyanimal species, the range of doses producing aneffect on humans maybe larger than that for animals(122).

Sex, age, health, nutritional state, and geneticmakeup may affect an animal’s response to toxicsubstances and must be considered when selectingan animal model. Also, similarity between animaland human metabolism is an important considera-tion because it may influence the final determinationof whether a chemical will be therapeutic or toxic,will be stored or excreted, or will cause acute orchronic effects in humans (65).

When the risks of toxic substances are beingassessed, the potential exposure of humans is acritical consideration. Toxicological data on experi-mental animals should be applied to the situationsand routes of exposure that are likely to occur forhumans. For example, data collected from the oraladministration of a substance to animals have lessrelevance to a situation in which humans areexposed by inhalation. In addition, an evaluatorshould be cautious when applying data obtained onyoung, healthy animals to a human population thatis diseased, malnourished, or diverse in its geneticmakeup. The data that are to be evaluated to


determine a potential risk should be obtained fromanimal models that are as similar to humans aspossible (65). When assessing functional effects, themeasures taken in animals should relate to thefunctions that are at risk in humans. Thus, if humancomplaints are confusion, memory loss, or irritabil-ity, the animal data should be addressed, to theextent possible, to changes in these functions.

ALTERNATIVES TO ANIMAL TESTSSome individuals argue that more animals are

used for testing than are needed and that changes inexperimental design or improved methods of dataanalysis could reduce the number of animals used.Alternatives to animal tests, such as in vitro tests,


serve the same fundamental purpose as wholeanimal tests: to establish the toxicological propertiesof a chemical in order to protect and improve humanhealth and the environment. In vitro approaches useanimal, human, or plant cells, tissues, or explantsmaintained in a nutritive medium for use as a modelsystem in toxicity testing.

Concern about the use of animals in testing seemsto be accelerating at the same time as concern aboutproduct and drug safety. However, the need for moreexperimental animals is an incentive for the devel-opment of new techniques, especially faster and lessexpensive ones (105). While Federal regulatoryagencies currently rely on animal tests to predicthuman toxicity, in vitro alternatives are likely toplay an increasingly important role in future toxico-logical evaluations.

In vitro tests are often used to complement animaltests and reduce the number of animals being usedfor routine toxicity testing. Methods for integratingin vitro tests into routine toxicity testing are neces-sary to enhance understanding of the neurotoxicpotential of toxic substances (37).

Toxicologists have identified three major reasonsfor developing in vitro techniques: scientific-academic, economic, and humane. There are manyscientific-academic reasons for developing in vitromethods. There are more than 60,000 chemicals inEPA’s inventory of toxic substances and thousandsmore chemical formulations, many of which havenot been tested for toxicity. Current testing methodsare time-consuming; for example, it might take from3 months to 2 years to complete a battery of chronicstudies. With the enormous number of substancesthat have not been tested and with new substancescontinually entering commerce, rapid, inexpensivemethods are needed for screening.

In vitro testing is already of critical importance inacademic scientific research. This approach is oftenemployed to determine the mechanism of action oftoxic agents because in vitro systems are lesscomplicated and can be manipulated easily. Tissueculture methodologies have advanced rapidly, andnew equipment and facilities will ensure continuedprogress (36). It has been estimated that more than$70 million has been spent in the United States overthe past decade to develop in vitro testing (37). Thereare numerous opportunities to apply the knowledgethat has been gained in basic research to thedevelopment of methods of toxicity testing.

The cost of in vivo research and testing isincreasing. In vitro approaches are generally moreeconomical, being both less expensive and lesstime-consuming. In addition, they are also morehumane because they reduce animal use and mini-mize animal suffering (36).

In Vitro Neurotoxicity Test Development

Interest in using in vitro testing approaches toassess neurotoxicity has increased considerably inrecent years. In 1980, a symposium on the use oftissue culture in toxicology, held in Sosterberg,Holland, focused on the potential application of invitro approaches to the study of neurotoxic sub-stances. Participants emphasized the need for im-proved methodologies and increased awareness inthe regulatory community of the utility of in vitrotechniques. Since that time, efforts to develop invitro tests have advanced rapidly (36,37,103).

In vitro tests do have some limitations. Theycannot mimic the complex biochemical and physio-logical interactions that take place in vivo. Also, thesupply of normal human cells available for toxico-logical testing is currently limited. In order forhuman cells to be used routinely for toxicity testing,some method of making them more readily availablemust be devised. In addition, not all human cell typescan be cultured (103).

A number of companies in the United States arecurrently developing in vitro toxicological tests. Forcompetitive reasons, industry initiatives are gener-ally not made public. Consequently, they will not beaddressed in this report.

The Food and Drug Administration (FDA), theNational Institutes of Health (NIH), the ConsumerProduct Safety Commission (CPSC), and EPA areexamining potential in vitro testing approaches(116). In particular, the National Toxicology Pro-gram of the Department of Health and HumanServices is evaluating in vitro systems and has askedfor proposals on alternative test development (1 16).The CPSC is attempting to make greater use ofexisting chemical, biological, and human data inorder to avoid animal tests, to reduce the number ofanimals used in tests, and to modify existingmethods so as to reduce pain and suffering (95). EPAhas also taken action to reduce the use of animals intoxicity research and testing.


Photograph by J.C. Owicki and K.M. Kereso

Photomicrograph of living cells in the wells of chambersthat allow monitoring of changes in cellular metabolism

following exposure to toxic substances.

Numerous in vitro techniques are currently in use.Tissue culture involves maintaining or growingorgans, tissues, or cells in vitro for more than 24hours. Tissue culture can be further subdivided intocell culture and organ culture (22,105).

Tissue Culture

Many tissues from humans and animals can besuccessfully maintained and studied in culture.Roux originally used tissue culture in 1885 tomaintain chick embryos outside the egg (99).Nervous tissue was among the first tissues to becultured. In 1907, R.G. Harrison developed a methodfor maintaining frog neural tissues in vitro for weeks(40). In the 1930s, advances were made in definingthe media required for maintaining cells and tissuesin culture, and by the 1950s, tissues could becultured in entirely synthetic media. At the sametime, scientists became aware of the importance ofadding antibiotics to culture systems. Before antibi-otics, bacterial growth interfered with the develop-ing cells, and all work had to be done in asepticconditions. It is now standard procedure to inhibitbacterial growth with antibiotics (99,105).

Pure cultures of cells and mixtures of cells havedifferent properties. These differences may be usedto study various aspects of cell activity, such asdifferentiation. In this process, one can distinguishbetween cells that have a capacity to form other cells(undifferentiated cells), and cells that have reachedtheir final stage of development and will not undergoany further change (differentiated cells) (21,99).

In cell cultures, the colony consists of a mass ofdifferentiated or undifferentiated cells, and individ-ual cell types are not easily identified. However,where a number of different kinds of cells aregrowing together, such as in organ cultures, the cellsretain their normal function and differentiated form;thus, the different types of cells are easy to identify(99). Tissues can be kept alive outside the livinganimal for months or years in cell cultures; however,whole organs can be sustained in cultures for only afew days to a few weeks.

Assessing toxicity using tissue culture approachesgenerally involves adding a test substance to theculture, observing the viability of the cells, andidentifying any structural or functional changes.

Applications of In Vitro Techniques toNeurotoxicity Testing

Various types of in vitro techniques are beingdeveloped to evaluate the effects of potential andknown neurotoxic substances. These approaches canbe grouped into three general categories: primarycultures, cell lines, and cloned cells.

Primary Cultures

Primary culture refers to the removal and mainte-nance of cells, tissues, and organs in vitro. Embryoculture, for example, has proven to be very useful inneurotoxicological studies. Recently, the ChemicalIndustry Institute of Toxicology (CIIT) in ResearchTriangle Park, North Carolina, developed a rodentfetal cell culture system for in vitro testing. Thisapproach involves removing certain regions of thebrain from mouse embryos and culturing them in achemically defined environment. After the culture isexposed to various known and potential neurotoxicsubstances, the tissues and cells can be examined formorphological and biochemical changes (20). Thistechnique is useful because neuronal tissues undergonormal or near-normal development, and cellularand tissue interactions can be analyzed.


CIIT scientists are using a class of substancesknown as monohalomethanes to validate this testsystem. Animal and human exposure to monoha-lomethanes may result in a variety of neurologicalsymptoms, such as tremors, lack of coordination,epileptic seizures, and coma. The results from invitro studies using monohalomethanes are comparedwith documented animal studies to determine corre-lations between in vitro and in vivo methods.Development of a database to compare results fromin vitro and whole animal studies, human studies,and epidemiological studies may aid in validatingthis system (20). A similar embryo culture approachwas used successfully by others to demonstrate thatethyl alcohol can retard the growth and differentia-tion of fetal tissues (13).

Retinal neurons may also be employed toevaluate the effects of toxic substances on thenervous system. This approach involves dispersionand culture of retinal cells removed from chickembryos. Culture methods have recently been im-proved, allowing growth of low-density, clump, andflat cell-free cultures of chick embryo neurons.These cultures can be used to analyze the effects oftoxic substances on cell differentiation using time-lapse video recordings. In addition, various biologi-cal techniques may be used to define and character-ize observed effects (2).

Techniques for culturing neonatal mouse retinalneurons and photoreceptors have also been devel-oped recently. Cells from the retinas of 2-day-oldmice can be cultured in serum-free, completelychemically defined environments. They serve asuseful models for evaluating the survival anddifferentiation of photoreceptor cells, which arecritical to visual processes (87).

A “monolayer” culture system has been devel-oped to allow the survival and differentiation ofchick embryo retinal neurons and photoreceptorswithout contamination. Photoreceptor cells can bepurified with kainic acid and B-bungarotoxin, which,when added to the culture medium, destroy manyretinal neurons without affecting the photoreceptors(86). The technique of selectively destroying cells isa recognized means of cell separation in tissueculture. Once purified photoreceptors are available,the effects of various toxic substances can bedetermined without the complicating factors intro-duced by multiple cell types.

Muscle cells can also be cultured, allowinginvestigators to analyze the effects of toxic sub-stances on the neuromuscular system. Culturedmuscle cells from rats and chicks have been used inelectrophysiological studies to examine the sensitiv-ity of acetylcholine receptors. Toxic substances havealso been used to aid in characterizing the structureand function of acetylcholine receptors (91). Thistype of system could be adapted to assess the effectsof toxic substances on the neuromuscular junction.

Another useful testing method involves organo-typic cultures, cultures that preserve the connec-tions and spatial relationships between neurons andglia (126). One such culture used in neurotoxicitystudies is of the ganglion (a collection of nerve cellsexternal to the brain or spinal cord) (96). In addition,the mouse embryo spinal cord has been used to studythe effects of various neurotoxic substances, includ-ing organophosphorous pesticides (35). Organo-typic cultures have also been used to examine themechanisms of action of a wide range of neurotoxicsubstances, including such metals as mercury andthallium and such organic compounds as chloro-quine (a drug used to treat rheumatic fever) and2,5-hexanediol, a metabolize of n-hexane (126).

Explant cultures are also useful in evaluatingneurotoxicity. They involve placing a small piece ofnerve tissue in a culture medium and maintaining itfor several weeks or months at a time. Explants havebeen used to evaluate the effects of chemicals on themyelin sheath surrounding nerve cells and on thesynaptic connections between these cells (96).

Cell Lines

Cell lines take advantage of the immortal proper-ties of certain types of malignant nervous systemcells. For example, the neuroblastoma C-1300 andthe rat glioma C-6 cell lines have been used inneurochemical and morphological studies for evalu-ating the effects of a variety of neurotoxic substances(22,35). One group of investigators recently fusedrat retinal cells with mouse neuroblastoma cells tocreate a hybrid cell line that proved to be very usefulin evaluating the neurotoxic effects of the aminoacid glutamate and related compounds (73). Celllines are especially useful because a large quantity ofsingle cell types are available for biochemicalanalysis, the cells can be easily examined micro-scopically, and electrophysiological evaluations maybe undertaken (96).

Chapter .5-Testing and Monitoring ● 125

Advantages and Limitations ofIn Vitro Testing

In vitro tests are advantageous for several reasons.They involve simpler procedures and consequentlytake less time to complete than animal tests. Forexample, technicians can conduct morphological,biochemical, and physiological studies on the samepreparation (93). Furthermore, cultures can be trans-ferred from one region of the country to another,allowing evaluation of the same culture in variouslaboratories specializing in particular tests. Culturescan be made of human cells, hence the difficulty ofspecies variation and of extrapolation of data isminimized. Substances may be studied in isolation,and responses by selected cell populations can beexamined. Also, the cellular environment can becontrolled through modification of the concentrationand nature of specific nutrients, which is difficultusing animals (21,99,20).

On the other hand, in vitro tests normally do notaccount for the route of exposure to a substance, itsdistribution throughout the body, or its completemetabolism. Also, because in vitro systems gener-ally do not duplicate the neural circuitry of the entireanimal, toxic endpoints (e.g., behavioral changes,motor disorders, sensory and perceptual disorders,and lack of coordination) may be difficult to define(93). Other concerns are that substances added to theculture to keep it viable (e.g., antibiotics) mightinteract with the tested substance, that cell lines ofcancerous cells may respond to toxic substancesdifferently than normal cells, and that it may not bepossible to perform chronic toxicity studies due tothe relatively short lifespan of many cultures (celllines using immortal cells are a possible exception).Nevertheless, all test systems have limitations, andthere is general agreement that the many advantagesof in vitro testing present a strong incentive forcontinued development and increased utilization(21,99,20).

HUMAN TESTINGMillions of U.S. workers are exposed full- or

part-time to general toxic or neurotoxic substances(3). Nearly 400,000 cases of occupational diseasesare recognized annually (111). Preventing the ad-verse health effects of chemicals is largely depend-ent on understanding the toxicological properties ofnew and existing chemicals. Various standardizedhuman tests are available to assess the adverse

effects of toxic substances on the nervous system;however, because of the ethical issues inherent inperforming some human tests and the difficulty ofobtaining trained staff and expensive equipment,there have been relatively few human studiesconducted (24).

Overview of Human Tests

Human testing may occur in response to occupa-tional, environmental, or laboratory exposures. Themethods used to assess the toxicity of substancesvary from one setting to another, since someapproaches are appropriate in one situation but notin others. For example, when determining earlysymptoms of chronic exposure, subjects exposedoccupationally are better test groups than groupsexposed environmentally. On the other hand, incertain epidemiological studies, subjects exposedenvironmentally may be helpful because of the largediversity of individuals and wide range of ages (74).

In the occupational setting, workers are oftenexposed unintentionally to toxic substances. In thegeneral environment, exposure groups may includeindividuals and families living near sources ofindustrial pollution, people living in large industrialcities where they are exposed to vehicle exhaust andfuel additives, and farmers and agricultural workersexposed to pesticides in the field (74). Epidemiol-ogical studies of these individuals are required todetermine the extent to which neurotoxic substancesare affecting human health.

Neurobehavioral Tests

Neurobehavioral tests can provide objective eval-uations of nervous system and neurobehavioralfunctions. Test methods have been utilized both inevaluation of groups of workers exposed to sub-stances and in laboratory examinations of individu-als suspected of having occupational illnesses. In theevaluation of a group of workers, neurobehavioraltests are used to assess exposure-effect relationshipsand, in some cases, to serve as guides for establish-ing standards for workplace exposures. In thelaboratory setting, neurobehavioral methods areuseful in quantifying the degree of functionaldisability and in making a diagnosis (44).

Several considerations are involved in the selec-tion of testing techniques to determine the effects ofneurotoxic substances on workers’ health. It is veryimportant to consider the purpose of the examina-


tion. For example, the study may be designed toidentify effects on individual workers who areexposed or on a population of workers exposed as agroup. Furthermore, the frequency and duration ofexposure must be determined: a study of acuteeffects may require tests measuring different func-tions and properties than a study of chronic effects.Finally, in some tests a certain time period mustelapse before effects become apparent (44,67).Researched most commonly select tests that areknown to measure functions affected by severalneurotoxic substances; provide a complete analysisof nervous system effects, ranging from reflexes tocomplex behaviors; are known to measure one ormore well-defined functions, whether psychologicalor neurophysiological; and are cost-effective interms of the information they provide (44,67).

Neurobehavioral test results are influenced bymany factors. These can be divided into threegeneral classes: subject, examiner, and environ-mental. Subject factors include the individual’s age,sex, education, socioeconomic status, health anddrug history, and motivation. Table 5-1 summarizesthe subject factors influencing neurobehavioral testresults. Examiner factors are another importantconsideration. In order to ensure the cooperation ofsubjects and to maximize the reliability of the data,

Table S-l-Subject Factors InfluencingNeurobehavioral Test Results

Age: The performance on neurobehavioral tests varies with age.When comparing exposed groups, subjects should bematched by age as closely as possible.

Sex: There are biological and social differences that must beconsidered when designing tests that include male and femaleworkers.

Years of school education: Amount of education also influencesthe performance on neurobehavioral tests.

Socioeconomic status: Socioeconomic status includes a combi-nation of educational, cultural, and occupational factors thatmay affect test results. This factor takes into account the yearsof school education, regular income, and special occupationaltraining.

Health and drug history: Any disease that affects neurologicalfunctions will affect neurobehavioral studies. Some of thesediseases include epilepsy, diabetes, and arthritis. If anindividual has any of these health problems, the evaluator maywant to exclude the individual from the study. Drugs must alsobe considered. Psychoactive drugs, in particular, can alterperformance on the study. In addition, certain consumed foodsand beverages may alter the individual’s alertness andperformance. These include coffee, colas, and chocolate, allof which contain caffeine.

Motivation: The attitude of the participants must also be takeninto account.

SOURCE: B.L. Johnson (cd.), Prevention of Neurotoxic Illness in WorkingPopulations (New York, NY: John Wiley& Sons, 1987).

it is important to establish a good working relation-ship between examiner and participants. It is alsoimportant that a well-trained examiner speak andinteract with all subjects in a consistent and stand-ardized manner (44). Environmental factors thatinfluence neurobehavioral studies include the testsurroundings, subject-experimenter interaction, andseason of the year.

Finland’s Institute of Occupational HealthApproach

During the 1950s, the first neurotoxicity testbattery for occupational exposure was developed atFinland’s Institute of Occupational Health (FIOH).The battery was designed to study the effects ofvarious substances, especially solvents, on workers.The 14 neurobehavioral tests listed in table 5-2 aretypical methods used at FIOH to evaluate effects onintelligence, short- and long-term memory, learningability, perception, motor performance, and person-ality. The battery is now used routinely in Finland(39).

Psychological testing is usually conducted at theInstitute, although sometimes it is conducted at anindustrial facility. The tests are usually performed onan individual basis. Before the tests are adminis-tered, the patient is interviewed. The tests arepresented in a fixed order, as indicated in table 5-2.The examination takes 1 to 3 hours, depending onthe tests used and the time available(39).

World Health Organization’sRecommended Approach

During a meeting cosponsored by

for- interviews

WHO and theNational Institute for Occupational Safety andHealth in 1983, neurotoxicologists recommended acore set of tests, known as the Neurobehavioral CoreTest Battery, that could be used in screening forneurotoxic effects. This test battery is particularlyuseful in developing countries or in places wherethere are limitations in the setting or the literacy ofthe test population (3).

Table 5-3 lists the tests used in this battery. Theywere chosen to allow development of uniform,consistent data from a variety of occupations andneurotoxic exposure situations (3). Most of the coretests require the use of paper and pencil in order tominimize the need for mechanical instruments (aconcern for developing countries). These tests gen-erally require minimal training to administer; how-

Chapter 5-Testing and Monitoring . 127

Table 5-2-Behavioral Test Battery forToxicopsychological Studies Used at the

Institute of Occupational Health in Helsinki

Test method+Test descriptionWechsler Adult Intelligence:

-determining similarities between items;measures verbal ability

-determining synonyms of words;measures general intelligence and verbal ability

—reproducing patterns of design using blocks;measures visual ability

-determining the missing parts of pictures;measures perception

—associating symbols and digits;measures memory and speed

—recalling digits in series;measures verbal memory

Wechsler Memory Scale:–logical memory, visual reproduction, and associative learning

Benton Visual Retention Test:—recalling and reproducing figures;

tests memory and visual retention abilityKuhnburg Figure Matching Test:

—recalling various figures on cards;measures speed and memory

Bourdon Wiersma Vigilance Test:—strike over all groups of 4 dots as printed on the test sheet

(50 rows); each row contains 25 groups of 3,4, or 5 dots;performed as accurately and quickly as possible;measures speed and perception

Figure Identification:—identifying figures; measures speed and perception

Symmetry Drawing Test:-drawing the other symmetric half of figures;

measures perception and motor speed

● Santa Ana Dexterity Test:—test for manual dexterity; hand-eye coordination;

measures the ability to perform skillful movements with handsand arms

Flnger Tapping Test:—taps a counter with thumb rapidly;

measures motor speed

Reaction Time:—reactions of hands or feet from visual and auditory signals;

measures simple reaction time to respond to stimulus

MIra Test:-draw simple, straight, and broken lines without seeing the paper

and pencil;measures psychomotor behavior and psychomotor ability

Rorschach Inkblot Test:—variables: adaptability, emotionality, spontaneity v. inhibition,

rational self-control, originality of the perception;measures personality, nonintellectual personality disturbances,changes in mood, readiness for affective reactions

Eysenck Personality Inventory:—measures two dimensions of personality: neuroticism and extro-

version-introversion

Questionnaire:—measures changes in mood, emotionality, and subjective well-

being; two forms used: 1) measures sleep disturbances, fatigue,neurotoxic behavior; and 2) measures disturbances in control ofmood, emotions, attention, fatigue

SOURCE: H. Hanninen and K. Lindstrom, Behavioral Test Battery forToxicopsychological Studies Used at the Institute of Occupa-tional Health in Helsinki (Helsinki: Institute of OccupationalHealth, 1979), pp. 1-58.

Table 5-3—WHO Neurobehavioral Core Test Battery

Functional domain Core test

Motor speed, motorsteadiness

Attention, response speed

Perceptual-motor speed

Manual dexterity

Visual perception,memory

Auditory memory

Aiming (Pursuit Aiming ii):assess the control and precision ofhand movements; individual is re-quired to follow a pattern of smallcircles, placing a dot in each circlearound the pattern; subject’s scoreis the number of taps in the circlewithin 1 minuteSimple reaction time; see table 5-2for descriptionWechsler Adult Inteiiigence Scale:a sheet contains a list of numbersthat are associated with certain sim-ple symbols and a list of randomdigits with blank spaces below them;subject asked to write correct sym-bols in blank spaces as fast aspossibleSanta Aria: see table 5-2 for de-scriptionBenton Visual Retention: see table5-2 for descriptionWechsler Adult intelligence Scale:recall digits in series forwards andbackwards immediately after hear-ing them

SOURCE: B.L. Johnson, (cd.), Prevention of Neurotoxic Illness in WorkingPopulations (New York, NY: John Wiley & -Sons, 1987).

ever, the reaction time test requires the use of anelectrical instrument that necessitates some training.The total amount of time necessary to complete thecore test battery is approximately 45 minutes (44).

Computer-Based Testing

Computer-based neurobehavioral tests have re-cently been developed in response to the need forstandardized testing methods that objectively andefficiently collect data on various neurotoxic effectsseen in exposed workers. Computer testing has beenused to study acute exposures of workers in labora-tory (experimental) studies and to study chroniceffects on workers in epidemiological studies. Somecomputer-based tests are reliable for conductingcomparative studies of workers, but methods appro-priate for clinical studies have not been developed(52).

The most extensively used computer-based testbattery is the Neurobehavioral Evaluation System.The tests selected analyze a broad range of centralnervous system functions, including psychomotorperformance, memory, perceptual ability, vocabu-lary ability, and mood (53,7).

Various computer-based tests have been devel-oped for epidemiological applications, including the


MicroTox System (27); Swedish Performance Eval-uation System (41); Milan Automated Neurobehav-ioral System, a computer implementation of many ofthe tests in the WHO Neurobehavioral Core TestBattery (15); and the Cognitive Scanner, developedin Denmark (51).

Computerized techniques have several advan-tages and limitations. Some of the primary advan-tages are reproducibility of testing conditions, easeof scoring, immediate reporting of results to thesubjects, and storage of data in the computer’smemory for future use. In addition, highly trainedstaff are not required (52,7). The limitations of thesetechniques center on the cost and availability ofequipment. In addition, computer techniques usuallyemphasize speed of response; thus, other behavioralresponses may not be adequately measured.

Neurophysiological Techniques

As is the case for animal testing, a variety ofneurophysiological techniques can be used to assessthe health effects of potential and known neurotoxicsubstances on humans. Many of the same techniquesused in animal studies can be employed for evaluat-ing worker exposure to various neurotoxic sub-stances. These include the sensory evoked poten-tials, electromyograph, and electroneurograph. Sen-sory evoked potentials include brainstem auditoryevoked responses, flash evoked potentials, patternreversal evoked potentials, and somatosensory evokedpotentials. Most of these techniques have beensummarized earlier in this chapter; they will not bereaddressed here. (See the section on neurophysiol-ogical techniques of animal testing.) EPA summa-rized several situations in which analysis of sensoryevoked potentials would be useful (82), includingdetermining the sensory effects of injured workerswho are unconscious, immobile, or unable to re-spond verbally; sensory testing of workers claimingcompensation when malingering is suspected; sen-sory testing of workers whose complaints do notcorrespond to clinically significant deficits in rou-tine clinical examination; distinguishing peripheralfrom central nervous system damage in sensorypathways; and monitoring of workers chronicallyexposed to chemicals known to be neurotoxic.

Electromyography (EMG) and electroneuro-graphy (ENG) are established testing techniqueswell-suited to studies of various neuromusculardisorders. They are also often used in clinicalexaminations in neurology, orthopedics, and neuro-

surgery. EMG records electrical activities using aneedle electrode inserted into the muscle. Research-ers note several characteristics, including electricalactivity in the muscle when the needle is inserted,electrical activity of the resting muscle, and electri-cal activity of motor conduction velocity duringvoluntary muscle contraction (43). ENG measuresthe electrical signals generated by the nerves. Theelectromyograph has not been used extensively forevaluating the health effects of neurotoxic sub-stances on test animals, because few toxicologistsare trained in EMG procedures. Interpretation of theresults requires special training, and it can bedifficult to control the degree of muscle contractionin test animals (97,43).

Human Exposure Studies

Information collected in human neurotoxicitystudies may have several important uses, including:

providing indications of toxic effects that canserve as early warnings of chronic diseaseprocesses;testing the adequacy of existing or proposedexposure limits;identifying human performance capacities thatmay be impaired by short-term exposure totoxic chemicals; andproviding data on the neurotoxic effects ofexposure to more than one chemical or otherworkplace conditions (e.g., physical agents,work level, drugs) that may interact to modifythe neurotoxicity of single substances (44).

Fundamental components of this type of study arecontrolled exposure to the substances being studied,methods for estimating the body burden of thesubstances, appropriate tests and experimental de-sign to reflect the neurobehavioral response of thesubjects to the substance, and control groups orcontrol conditions. However, human exposure stud-ies are among the most difficult and expensivecontrolled laboratory experiments to conduct. Be-cause humans have complex personalities, eachindividual brings to the experiment several attributesthat may be difficult for an investigator to control.Such variables include age, sex, education, motiva-tion, and work history (24).

Human studies typically require more examiner-subject interaction than other types of tests. A certainamount of controlled and consistent interaction isnecessary to reduce the anxiety caused by the test


situation. Several factors may affect the interaction,including the presence of more than one examiner,and the personality, experience, and sex of theexaminer. Interaction effects occur when subjectsare tested in groups in large exposure chambers. Theresults of a study may change if the subjects aretested in groups of two or more rather than singly, ingroups of both sexes rather than one sex, or in groupsin which the subjects are friends rather than strangers(24).

Selection of Study Populations

The success of any human toxicity test depends ona well-designed study that has a clearly definedpurpose. Two major reasons for conducting a studyin the industrial setting are: 1) an awareness that agroup of people collectively has similar healthcomplaints and that a potential occupational healthproblem exists, or 2) a potential hazard has beenidentified and more information is needed to definethe extent of the hazard. When undertaking humanstudies, it is important to select a well-defined group.If the purpose of the study is a potential healthproblem, the study population may have beenidentified by a formal complaint from an individualor company to a Federal agency. Usually, the sourceof the complaint appears to be limited to a work siteor a plant. In this circumstance, a preliminaryscreening questionnaire may be conducted to deter-mine the study group (125).

Steps in Conducting Workplace Research

There are several fundamental steps in conductinga workplace research study, and there are severalsignificant dangers to be avoided. The identificationof a suitable work group is the first, difficult step.The evaluator should consider the willingness of acompany to allow worker participation. Prior tobeginning the test, the evaluator must seek out thecompanies involved and convince them of the valueof the test in order to ensure participation. Mostemployees will cooperate as long as they areconvinced that data on them will be kept confidential(3).

Testing conditions are determined by the industryinvolved and past experience with the test selection.Testing sites are usually clinics, hospitals, laborato-ries, and conference centers. It is standard practice todescribe the purpose and the benefit of the study totest subjects, what unpleasant tests they will encoun-ter, who is responsible for the study, and whom to

contact if they have questions or experience difficul-ties. They should also be informed that they maywithdraw from the study at any time if they feel thatit is unsatisfactory in any way (3).

Records should be kept on file for each researchproject. They should contain information on theday-to-day decisions regarding the study and anyunusual events that take place. In addition, thereshould be a comprehensive report containing infor-mation on worker characteristics such as age, sex,race, and education; the number of years that theworker has been at his or her profession; themeasurements or pattern of exposure over the years;the methods used to obtain the measurements;complete descriptions of all tests; descriptions ofstatistical tests used; and any adverse effects anddiseases that were determined (3).

Epidemiological Studies

Epidemiological studies play a very importantrole in evaluating the effects of neurotoxic sub-stances on workers and in developing strategies forthe prevention of occupational diseases affecting thenervous system (44). The advantage of such studiesover animal testing is that they provide directevidence of effects on human health. However,human studies are difficult to conduct and evaluate.One limitation is that if the exposure results only inacute effects, epidemiological studies must be per-formed shortly after exposure occurred.

Another limitation is the complex relationshipthat exists between toxic exposures and humandisease. Humans vary greatly not only in theirexposure to substances, but also in their physiologi-cal response to exposure. Despite these difficulties,extensive techniques for evaluating data from humanstudies have been developed. Epidemiology hasproved to be a reliable means of evaluating qualita-tive and quantitative relationships between exposureto toxic substances and human disease (16). Becauseepidemiological studies generally identify correla-tions between exposures and effects, it is oftennecessary to undertake animal studies to identifycause and effect relationships.

Occupational epidemiology is the study of thedistribution of a disease among a working popula-tion and the factors that influence this distribution.This field attempts to identify relationships betweendiseases and occupational exposures to chemicals.The value of such epidemiological studies is in-


creased when they are used with toxicologicalstudies on humans or animals. They are important inidentifying possible associations that can be testedin laboratory environments. Furthermore, they canbe used to evaluate human health risks suggested bylaboratory exposures (16).

Legal and Ethical Considerations inNeurotoxicity Testing and Monitoring

Deliberate exposure of humans to neurotoxicsubstances in the course of research calls for all ofthe basic protections afforded research subjectsunder existing Federal law. Department of Healthand Human Services regulations require institutionsperforming research on human subjects to create anduse Institutional Review Boards to check proposedprojects for compliance with regulations if thoseprojects are funded by the Department or itsconstituent agencies (45 CFR 46.103(b)). Althoughthese regulations are legally binding only on institu-tions receiving Federal funds, they are usuallyconsidered minimum standards for other institutionsand research situations as well.

After there has been an appropriate evaluation ofthe value, scientific merit, probability of generatingknowledge, and risk-benefit ratio of a proposedstudy, subjects can be selected and their consentsolicited. Federal law requires that specific informa-tion be disclosed before valid consent can beobtained. Under Federal regulations (45 CFR 46.116)and some State statutes, all reasonably foreseeablerisks and discomforts that subjects might experiencemust be disclosed.

Risk information is not the only type of informa-tion that requires greater elaboration in the researchsetting. Federal law also mandates disclosure re-garding the nature and purpose of the research;anticipated length of the subject’s participation inthe study; procedures to be followed; identificationof experimental procedures; benefits that may rea-sonably be expected to accrue to the subject or othersfrom the study; steps to be taken, if any, to maintainconfidentiality of records identifying participants;whether compensation and treatment are availablefor injury arising from a study where more thanminimal risk is involved; and who should becontacted if subjects have questions regarding theresearch or their rights, as well as the contact personin the event of research-related injury (45 CFR46.1 16(a)).

Workplace exposures to neurotoxic substancesmay be accidental or nonaccidental. The primaryethical obligation in the case of an accidentalexposure to a neurotoxic substance is prevention.Box 5-C illustrates the important ethical issues thatarise from chronic workplace exposure to neurotoxicsubstances such as mercury, A continuing issue inboth types of workplace exposure is whether it isappropriate to notify workers about past exposuresto hazardous substances, including neurotoxic sub-stances. Many persons believe that groups of work-ers who have been exposed to hazardous substancesin the past should be informed of this wheneverpossible. However, the possibility that some work-ers will be mistakenly identified and informed has tobe weighed against the value of a retrospectivenotice procedure.

Prevention of Human Exposure toNeurotoxic Substances

Some of the disorders caused by neurotoxicsubstances can require extensive therapy and medi-cal care. In addition, a significant number of thesemay be irreversible if exposure levels are high. Theseverity of these effects is an excellent reason forimplementing methods of preventing exposure toneurotoxic substances.

Several approaches are used. One method is toincrease awareness of the effects of neurotoxicsubstances through educational programs (6). Theseprograms are designed to educate supervisors andworkers about the signs and symptoms associatedwith exposure to certain toxic substances in theworkplace. Managers may reduce risk of exposure tosubstances by substituting a less hazardous sub-stance for the substance of concern, using adequateengineering controls, developing improved workingconditions, and providing proper protective equip-ment, such as respirators, gloves, eye shields, andboots (6,125).

All occupational safety and health programsshould be directed toward recognizing and prevent-ing problems early. This includes communicationamong Federal agencies, manufacturers, and usersof potentially neurotoxic substances.

Medical controls are another important aspect ofan exposure prevention program. The extent of thecontrols will depend on the hazards and seriousnessof the risks involved. Preemployment physicalexaminations, including detailed histories of previ-

Chapter S--Testing and Monitoring . 131

Box 5-C—Ethical Issues Associated With Chronic Exposure to a Neurotoxic Agent

One example of an occupational exposure to a neurotoxic agent is the case of workers assigned the task ofrecovering mercury from old or broken thermometers.

On October 16, 1986, two executives and a supervisor of the Pymm Thermometer Company were indicted oncharges of assault for allegedly endangering the lives of workers by knowingly and continually exposing them tomercury, conspiracy for hiding the existence of a cellar workshop from the Occupational Safety and HealthAdministration (OSHA) inspectors, and falsifying records in an attempt to conceal the cellar operation. Accordingto the brief filed on behalf of the workers:

Already aware of the dangerous conditions on their main manufacturing floor, defendants created andmaintained even worse conditions in a cellar mercury-reclamation operation. In order to salvage some of the valuablemercury that was being wasted in its main manufacturing process, Pymm constructed a crushing machine that groundup broken and defective thermometers, spewing mercury-laden dust into the face of the machine operator. Themachine was housed in a windowless, underventilated cellar, where defendants stored boxes leaking mercury fromthe broken and faulty thermometers to be processed (85).

One worker who was employed in this area for approximately 11 months suffered permanent brain damagefrom mercury poisoning (85). Exposure to mercury can cause tremors, headaches, and nausea, and more severe casesof mercury poisoning have been linked to brain damage, kidney disease, loss of vision and hearing, and motorimpairment. Humans can absorb mercury by inhaling the vapors in the air. Mercury passes from the lungs into thebloodstream, which transports and deposits it first in the brain and then in other parts of the body, including thespinal cord and peripheral nervous system. Once in the body, mercury binds to proteins in the central nervoussystem. As long as mercury circulates and remains in the body’s soft tissue, some of it can be returned to blood andplasma, to be extracted and excreted through the kidneys and intestines. In this way, the body rids itself of abouthalf of one day’s intake over a period of 40 to 70 days. When, however, a person takes in mercury faster than it becan excreted, the body begins to store mercury in bones and teeth (47). OSHA’s limit for exposure during an 8-hourday is 0.1 milligram per cubic meter of air.

Chronic exposure of workers to a known neurotoxic agent like mercury raises ethical arguments about theduties of employers not to knowingly inflict harm on workers, the use of coercion in exposure to neurotoxic agents,the right of an employee to know that he or she is working in a harmful area, and the right of the employee toexperience the full benefit of Federal efforts to ensure a safe workplace through OSHA inspectors and accuraterecord keeping. The employers in a case such as this could make an ethical argument that the greatest good for thegreatest number entails recovery of mercury, but they are not ethically or legally free to pursue this objective whenit clearly inflicts a known hazard on workers. The ethical dilemma in a case such as this would be an arguable ethicalright of the worker to assume the risks of exposure to a known neurotoxic agent, such as mercury, in order to pursuesome other value, such as increased pay. In order to explore whether the worker would have such a right it wouldbe necessary to ensure that the worker was freely and knowingly opting to take such a risk. In addition, it wouldbe important that the individual not impose unnecessary risk on others, for example, by exposing family membersto mercury by bringing it home on work clothes. In the Pymm case, it is alleged that when the workers asked aboutany possible dangers of working with mercury, the employer lied and provided no training, protective clothing, orother safety equipment (85). Although the company officers were convicted by the jury on the assault charges, thetrial court judge overturned the verdict. The State appealed to the appellate division of the Supreme Court of theState of New York. The case is continuing.

SOURCES: C.D. Klaassen, M.O. Amdur, and J. Doull (eds.), Casarett and Doull’s Toxicology (New York, NY: Macmillan, 1986); People ofthe State of New York v. William Pymm, Edward A. Pymm, Pym Thermometer, Inc., and Pak Glass Machinery Corp., Brief for theAppellant, Mar. 21, 1988.

ous exposures to substances and relevant preexisting the effectiveness of engineering controls. Symptomsconditions, are often very useful. Such examinations of a high level of exposure to a substance in a-groupcan identify persons who are likely to be susceptible of workers may indicate a failure that must beto specific toxic substances. In addition, they allow corrected. Consequently, more stringent engineeringthe occupational physician to take necessary steps to controls may be implemented to improve the work-limit employee exposure to certain hazards. Routine ing environment. A variety of engineering controlsmedical examinations also aid in monitoring the may be used to minimize exposure to neurotoxiceffectiveness of worker safety programs and verify substances. Because OTA described these in detail


in a previous report (104), they will not be addressedhere.

MONITORING OF TOXICSUBSTANCES

Numerous methods are currently being used tomonitor exposure to and adverse health effects oftoxic substances, including substances that mayaffect the nervous system. These methods includespecimen banking (long-term storage of biologicalspecimens for toxicological analysis), monitoring ofanimal tissues (e.g., marine mammal tissues andmussel tissues), and biological monitoring. Monitor-ing studies are used to develop baseline data, todetermine whether and to what extent humans andother organisms are exposed, and to assess exposuretrends. The following discussion summarizes someof the current domestic and international monitoringprograms.

Specimen Banking

Domestic and International ProgramsTo Monitor Toxic Substances

The purpose of specimen banking programs is totrack the concentrations of contaminants in tissuesover time. Data from programs of this kind are veryuseful to public health and regulatory officials, whomust ensure that human exposure to toxic substancesis limited. These data are also critical to epidemio-logical and other scientific investigations designedto link adverse health effects with particular toxicsubstances. Human tissue monitoring was firstundertaken in the Federal Republic of Germany andthe United States. Other countries now have plans tocollect and store human tissues, including Canada,Japan, and Sweden. In 1980 and 1981, the WestGerman Specimen Banking Program began collect-ing and storing human specimens at the Universityof Munster and at the central bank at the AtomicResearch Center in Julich (54). Three types ofhuman material were collected: whole blood, adi-pose tissue (fat tissue), and liver tissue. Biologicalspecimens from terrestrial, freshwater, and marineenvironments were also collected (54).

In 1973, EPA, in collaboration with the NationalBureau of Standards (NBS),l proposed the estab-lishment of a National Environmental SpecimenBank, a systematic approach to specimen banking

and monitoring for effects of toxic substances. Since1975, EPA and NBS have been involved in research-related programs for specimen sampling, analysis,and storage (118,120,1 19). Furthermore, in 1975,the Federal Republic of Germany and EPA agreed tocooperate in general activities of specimen banking(120). A workshop was sponsored by EPA and NBSin 1976 to design a pilot National EnvironmentalSpecimen Bank program and to evaluate the long-term storage of samples. The primary goals of thisprogram are the collection, processing, storage, andanalysis of specimens (120).

In addition, EPA has established two monitoringprograms to assess exposure to pesticides and toidentify changes in exposure levels. The first pro-gram analyzes pesticides in urine and blood serum;the second monitors and stores adipose tissue (54).

From 1976 to 1980, the National Center forHealth Statistics (NCHS) sponsored the NationalHealth and Nutritional Examination Survey II(NHANES II) to establish base-line data on publicexposure to various classes of pesticides, includingthe organophosphate, carbamate, chlorophenoxy,and organochlorine classes (54,72). Researchers setout to obtain health and nutritional information byconducting direct physical examinations and tests(including blood, serum, and urine specimens) forpesticide exposure in the general population invarious regions of the United States. The programhas provided estimates of the total prevalence ofselected illnesses, impairments of health and nutri-tional status, and the distribution of many conditionsin the population by sex, age, income levels, race,and region (72). Technicians have developed sys-tematic methods of collecting, analyzing, and inter-preting the data for the studies in order to detectpotentially toxic substances. In addition, from 1982to 1984, the Hispanic Health and Nutrition Examina-tion Survey (HHANES) was conducted by NCHS toprovide data on the health and nutritional status ofthe Hispanic population of the United States (31).

In 1985, NCHS began planning NHANES III (asurvey to be conducted between 1988 to 1994) toassess nutrition status, osteoporosis (abnormal de-crease in density and loss of calcium in the bone),arthritis, lung disease, heart disease, diabetes, AIDS,kidney disease, growth and development of children,and health and disability of older citizens (54,109).

lIn 1988, the National Bureau of Standards became a component of the National Institute of Standards and Technology.


Currently, all data are collected by computerizedmethods in mobile examination centers, whichincreases the quality and availability of the data foranalysis.

The current goals of NHANES III include exam-ining the national prevalence of various diseases andrisk factors, documenting and investigating reasonsfor trends, understanding disease etiology, andinvestigating the natural history of selected diseases(109),

Another type of program was established by EPAsome years ago to monitor toxic substances inhuman adipose tissue. In 1970, the Agency initiatedand sponsored a National Human Adipose TissueSurvey to determine incidence, levels, and otherindicators of exposure to pesticides in the generalpopulation of the United States (54). This programmonitors the levels of various pesticides in adiposetissue collected from cadavers during autopsies (54).

WHO is conducting a multinational specimenbanking program for human tissues. Specimensfrom the heart, brachial artery, aorta, and diaphragmof cadavers are being evaluated. This program isdesigned to compare exposure to trace metals withthe development of cardiovascular diseases (54).Additional human monitoring programs include aserum program conducted by the Centers for DiseaseControl and collection of preserved human tissues informaldehyde at the EPA Pesticide Research Labo-ratory (54)0

Monitoring of Nonhuman Tissues

In 1987, the Alaskan Marine Mammal TissueArchival Project was established by the MineralsManagement Service to collect and store Alaskanmarine mammal tissues in order to monitor toxicsubstances. To reach this goal, three objectives wereset: to collect marine mammal tissues that aresuitable for determining levels of organic andinorganic substances; to transport and archive tis-sues in a condition that is ideal for long-term storageand analysis; and to determine the most appropriatecollection protocols for long-term storage of marinemammal tissues (8,1 11).

In 1984, the National Oceanic and AtmosphericAdministration within the U.S. Department of Com-merce conducted studies through its National Statusand Trends Program for Marine Environment Qual-ity to determine the environmental quality of thecoastal and estuarine regions of the United States.

The objectives of this program are to determineconcentrations of substances in biological tissuesand sediments and to examine and record changes inthese concentrations. Since 1984 and 1986, respec-tively, samples have been collected at approximately50 benthic surveillance sites and 150 Mussel Watchsites. Benthic (bottom-dwelling) fishes are collectedat the Benthic Surveillance sites and their livers areremoved and stored for further chemical evaluation.At the Mussel Watch sites, molluscs are collected forchemical analysis. Commonly assayed substancesinclude polyaromatic hydrocarbons, polychlorinatedbiphenyls, pesticides, and the elements arsenic,cadmium, chromium, lead, mercury, silver, and tin(106,107,108).

Biological Monitoring

Monitoring programs are designed to observe,measure, and judge on a continuous basis thepotential health effects of substances and makeproper decisions on the adequacy of control meas-ures. Monitoring is more than just sampling the airwhere workers are being exposed or conductingmedical examinations of workers. It is an entireseries of activities that are undertaken to makeproper judgments on the protective controls neededor the adequacy of the control measures in place, orboth. One approach commonly used in occupationalhealth is biological monitoring. This makes itpossible to determine both the occurrence of expo-sure and the presence of particular substance(s) inbody fluids (i.e., blood or urine) or organs in orderto evaluate health risk (5).

Biological monitoring programs are designed todetect the presence in the body of substances fromall routes of exposure. The appropriate frequency ofmonitoring may be influenced by several factors,including intensity and duration of exposure andtoxicity of the substances. Monitoring is generallydone more often when the toxic substances beingevaluated are expected to produce irreversible changes.

One limitation of biological monitoring is that itis sometimes difficult to establish whether exposureto toxic substances is responsible for observedchanges in the biological parameters. Individuals areoften exposed to several substances simultaneously,and one must consider whether a different substanceor a combination of substances caused the observedtoxic effects. Variability in individual responsesmay be another limitation to monitoring. Multiple


factors may cause variability in response amongworkers exposed to the same substance. Thus, it maybe difficult to determine the normal response for agiven individual (5).

Internationally, the Global Environment Moni-toring System created a biological monitoring sys-tem to evaluate the health risks from exposure tolead, cadmium, and pesticides. The study of leadexposures was conducted between 1979 and 1981and involved 10 countries. In 1984, a follow-upstudy was conducted in four countries. Bloodsamples from volunteers were taken and analyzedfor lead and cadmium content. In 1981, a study ofselected organochlorine pesticides, including DDTand PCBs in human milk, was conducted in 10countries to assess the population’s exposure tothese substances (124).

Other Monitoring Programs

As part of the Federal Emergency Planning andCommunity Right-to-Know Act of 1986, EPA was


required to generate a database on toxic substancesreleased into the environment from industrial sitesthroughout the country. Commonly known as theToxics Release Inventory (TRI), the database con-tains information on approximately 328 toxic sub-stances (see box 5-D). Results of the inventoryindicate that in 1987, approximately 18 billionpounds of toxic substances were released directlyinto the air, surface waters, land, or undergroundinjection wells in the United States. In addition, 4.6billion pounds were transported offsite for disposalor treatment. TRI will enable regulatory and publichealth officials, researchers, and the public tomonitor what quantities of particular chemicals arebeing released from sites around the country. Thefirst data were published in 1989, and the inventorywill be updated annually. The database pertains onlyto manufacturing industries; Federal facilities arenot accounted for (94,1 13). Figure 5-3 illustrates theneurotoxic substances among the TRI’s top 25chemicals emitted into the air.

Chapter 5-Testing and Monitoring . 135

Box 5-D-Neurotoxicants Released Into the Environment by Industry:The Toxics Release Inventory Supplies New Evidence

Until recently, regulators had no comprehensive answer to a basic question underlying toxic substancesregulation: What amounts of toxic substances are we actually dealing within the United States? Despite dozens ofdatabases devoted to toxic chemical regulation, such as data on air pollution permits, surface water dischargescontrolled under Federal water pollution control regulations, and hazardous wastes regulated under the ResourceConservation and Recovery Act, no single compendium contained estimates of the overall amounts of chemicalsreleased into the environment. The Toxics Release Inventory, which grew out of reporting requirements mandatedin the 1986 Superfund amendments (Superfund Amendments and Reauthorization Act sec. 313), provides apreliminary answer—at least for the 327 chemicals covered by the statute that are discharged into air or water ordumped on land by manufacturers in 20 specified industries.

Inventory data show, for example, that manufacturing facilities emitted significant amounts of neurotoxicantsto the air in 1987. Overall, facilities released 2.6 billion pounds of the 327 toxic chemicals on the Inventory list.A brief review of the scientific literature reveals that 17 of the top 25 chemicals, accounting for 1.8 billionpounds (77 percent) of the total for the top 25, have documented neurotoxic effects ranging from narcoticeffects (drowsiness or fatigue) to more permanent and debilitating effects, such as hearing impairment andblindness. Of these 17 neurotoxicants, only benzene, which is a known human carcinogen, has been regulatedas a hazardous pollutant under the Clean Air Act. The neurotoxic effects of two additional chemicals-l,l,l -trichloroethane and glycol ethers, which account for another 189 million pounds (8 percent) of the top 25-are beinginvestigated under the Toxic Substances Control Act section 4 test rules. In sum, manufacturers released a total ofnearly 2 billion pounds of potential or known neurotoxicants (85 percent of the top 25) in 1987. Figures on 1988releases, which will become available in 1990, should give some indication as to whether emissions of theseneurotoxicants are increasing or decreasing.

The Inventory data do not cover many sources of toxic chemicals in the environment, notably consumerproducts and agricultural chemicals, nor do they address the chemical releases and exposures in the occupationalsetting. Furthermore, the data do not reveal the amounts to which people are actually exposed (chemicals may breakdown or be transported rapidly through the environment after being released, or they may accumulate in theenvironment) or the probable risks from exposure. The Inventory data do, however, suggest that significant amountsof identified neurotoxicants are finding their way out of factories and into the environment; these releases areplausible candidates for further study or control.

SOURCES: U.S. Environmental Protection Agency, Office of Pesticides and Toxic Substances, The Toxics Release Inventory: A NationalPerspective, 1987, EPA 560/4-89-006 (Washington, DC: 1989); W.K. Anger and B.L. Johnson, “Chemicals Affecting Behavior,”Neurotoxicity of lndustrial and Commercial Chemicals, vol. 1, J.L. O’Donoghue (cd.) (Boca Raton, FL: CRC Press, 1985), pp.51-148.

A wide variety of additional monitoring programs assayed for were less than 1 percent of acceptablehas been undertaken by several Federal agencies.For example, in 1978, the U.S. Department ofAgriculture (USDA) and the Human NutritionInformation Service devised a survey called theNationwide Food Consumption Survey to measurethe food and nutrient content of the U.S. diet, thedollar value of food used in the average U.S.household, and food and nutrient intakes of individ-uals at home and away from home. In addition, since1965, FDA has conducted a survey known as theTotal Diet Study to collect and analyze diet samplesfrom retail markets to assess concentrations ofmetals, pesticide residues, and other substancescommonly found in the diet. In 1987, FDA analyzed936 food samples in the diets of U.S. consumers andfound that the levels of intake of the pesticides

levels set by WHO and the United Nation’s Foodand Agriculture Organization (110). Also, the Na-tional Residue Program is conducted by USDA toevaluate pesticide residue levels and other poten-tially hazardous substances present in meat andpoultry. In 1984, EPA’s Office of Pesticide Pro-grams developed a Tolerance Assessment System inorder to estimate potential human exposure topesticides in the diet and analyze the risks that couldresult from exposure (31).

The Agency for Toxic Substances and DiseaseRegistry of the Department of Health and HumanServices recently set up a registry of personsexposed to toxic substances at hazardous waste sitesand at emergency chemical spills. The registry will


Figure 5-3-Neurotoxic Substances Are Prominent Among the Toxics Release Inventory’s Top 25Chemicals Emitted Into the Air in 1987

Millions of pounds350 I

IListed as a neurotoxic substance by

_ A n g e r a n d J ohnson (1985), orsubject to TSCA Sect ion 4 test ruIefor neurotoxic S Ub s t a n c e s

O N o t I i s ted as a neurotoxic substsance

AM TO ME AC 1T MK XY CD DI CH AO) ET F R HA TR PR GE NA TE ST BE Ml CL CS SA

AM - A m m o n l a MK - MethYI E t hv I Ke lone F R - F reon 113 ST - St y rene- -

TO - To I u e n e X V - Xy I e n~ ( m I xi d Isomers ) H A - H yd rOC h I Or iC AC I d b t - Benzene

ME - Me thano l CD - Car bon Dlsu I t i d e T R - Tr Ich Ioroel hy Ie ne M I - Met hyl Isobu t y I KetoneDI - Dlch Ioromet h a n e P R - Propylene

AC - Ace toneCL - Ch Iorofor m

CH - Ch I or IneIT - 1,1, l-Tr 1-

G E - G I YCOI EthersAO - A I u m I n u m Ox I d e

CS - Car bonyl Su I f IdeNA - N - BU t y I A lcoho l SA - Su I f u r i c Ac, d

chloroethane ET - E thy lene T E - Te 1 rac h I o ro e t h y I e ne

SOURCES: Data obtained from W.K. Anger and B.L, Johnson, “Chemicals Affecting Behavior,” Neurotoxicity of industrial andCommercial Chemicals, vol. 1, J.L. O’Donoghue (ad.) (Boca Raton, FL: CRC Press, 1985), tables 1 and 2, pp. 70-141;TSCA sec.4,52FR31445; TSCA seC. 4,53 FR 5932; 54 FR 13470; 54 FR 13473; U.S. Environmental Protection Agency,Office of Pesticides and Toxic Substances, The Toxics Release Inventory: A National Perspective, 1987, EPA560/4-89-006 (Washington, DC: 1989).

provide information needed by researchers to assessthe long-term health effects of both low-levelchronic exposures and high-level acute exposures(108).

SUMMARY AND CONCLUSIONSThe adverse effects of toxic substances on the

nervous system may be evaluated through threecategories of toxicological tests: whole animal,tissue and cell culture, and human subjects. Eachapproach has both advantages and limitations, and inpractice combinations of these tests may be used ina complete toxicological evaluation. The best meansof predicting human health effects is to evaluate theeffects of potentially toxic substances directly onhuman subjects. However, this approach is difficultand frequently presents ethical dilemmas. Conse-quently, it is often necessary to rely on animal testsin making predictions of human health effects. Insome cases, in vitro tests can be used to detect theneurotoxic potential of toxic substances. As more in

vitro testing techniques become available and arevalidated, they will be useful in initial screening, ascomplements to various animal tests, or both.

Several industrial and Federal organizations havedeveloped animal tests to evaluate the effects ofknown and potential neurotoxic substances. Inindustry, various testing approaches are currently inuse and protocols are continually being revised andimproved. In the Federal arena, EPA has developedguidelines under the Federal Insecticide, Fungicide,and Rodenticide Act and the Toxic SubstancesControl Act specifically for determining neurotoxicproperties of toxic substances. The guidelines arecomposed of a core set of tests consisting of thefunctional observational battery (a series of testsdesigned to screen rapidly for neurotoxic potential),tests of motor activity, and neuropathological exam-inations. For regulatory purposes, EPA plans toutilize the core tests and supplement them withadditional neurotoxicity tests when appropriate.These may include schedule-controlled operant


behavior, neurotoxic esterase assay for organo-phosphorous substances, acute and subchronic de-layed neurotoxicity of organophosphorous sub-stances, and developmental examinations. Neuro-physiological evaluations are also used in identify-ing neurotoxic substances and in evaluating theiradverse effects; however, EPA currently has notdeveloped guidelines for using these tests in regula-tory activities.

Several human tests are in use to determine theneurotoxic potential of suspected and known toxicsubstances. These include neurobehavioral evalua-tions and various neurophysiological tests. In addi-tion, computerized techniques are rapidly advancingto aid in studies of neurotoxicity.

Monitoring of toxic substances is critical becauseit enables investigators to systematically trace toxicpollutants and their sources that are contaminatingthe air, land, and water. Monitoring programsinclude human and animal specimen banking, bio-logical monitoring, and related efforts. Toxicitymonitoring programs now under way in Federalagencies address neurotoxicological concerns invarying degrees. However, much more could bedone in this area.

Until recently, Federal agencies have devotedlittle attention to neurotoxicity testing. EPA is theleader in developing test guidelines to evaluateneurotoxicity. The regulatory programs of otheragencies would benefit from joint test development,and more active involvement of industry and acade-mia in test development and validation programswould help ensure the optimal design of neurotoxic-ity tests for general use in regulatory programs,

EPA is continuing to examine the testing guide-lines already produced to determine whether a widerrange of tests is needed to evaluate the neurotoxicproperties of toxic substances, For example, theschedule-controlled operant behavior and devel-opmental tests provide additional information aboutcertain effects that cannot be determined by theFOB, motor activity, and neuropathology examina-tions.

The Federal Government is encouraging thedevelopment of in vitro neurotoxicological tests. Asthese tests become available, testing schemes maybe modified to take advantage of both in vivo and invitro approaches. Finally, monitoring programsunder way at various organizations and Federal

agencies would benefit by giving greater attention tosubstances with neurotoxic potential and by incor-porating a wider range of neurological and behav-ioral

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Chapter 6

Assessing and Managing Risk

‘The alternative to not performing risk assessment is to adopt a policy of either reducing all potentially toxicemissions to the greatest degree technology allows or banning all substances for which there is any evidenceof harmful effect, a policy that no technological society could long survive. ”

William D. RuckelshausIssues in Science and Technology

Spring 1985

“Risk assessment has become a central focus of environmental policy in the past couple years. In part, thisis a matter of fashion. But it also arises from the real need to compare the relative importance of the vastnumber of environmental threats, because it has become obvious that not all threats can receive maximumattention.’

William K. ReillyThe Conservation Foundation

1985

“Over the past decade increasingly sophisticated methods have been developed to identify health hazards andassess risks quantitatively. But society has yet to agree on the most critical step in risk management:identifying risk goals and translating them into practical regulations. Does society seek to eliminate all risks,eliminate all nontrivial risks, all significant risks, or only those risks that are not outweighed by benefits?”

Daniel Byrd and Lester B. LaveIssues in Science and Technology

Summer 1987

RISK ASSESSMENT .Hazard Identification

CONTENTSPage

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Dose-Response Assessment . .. .. ..+. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... .+....Exposure Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Risk Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

RISK MANAGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .RISK ASSESSMENT AND NEUROTOXIC SUBSTANCES . . . . . . . . . . . . . . . . . . . . . . .

Examples of Regulatory Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Limitations occurrent Approaches, ...,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

147147147148148149150150151154156

BoxBox Page6-A. Individual v. Social Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

FiguresFigure Page

6-1. The Relationship Between Risk Assessment and Risk Management . . . . . . . . . . . . . .6-2. Hypothetical Placement of a No Observed Effect Level (NOEL) and

No Observed Adverse Effect Level (NOAEL) for a Single Chemical on aDose-Response Curve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6-3. Use of Safety Factors in Deriving preference Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . .6-4. Postulated Decline in Brain Functional Capacity With Age and Exposureto

Neurotoxic

Table

Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...:..... . . . . . . . . .

Table

145

148149

152

Page6-1. Estimated Risk of Death to an Individual From Various Human-Caused and

Natural Accidents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

Chapter 6

Assessing and Managing Risk

Risk assessment is the analytical process bywhich the nature and magnitude of risks are identi-fied. Risk, as it pertains to the health effects of toxicsubstances, is the probability of injury, disease, ordeath for individuals or populations undertakingcertain activities or exposed to hazardous sub-stances. It is sometimes expressed numerically (e.g.,1 in 1 million); however, quantification is not alwayspossible, and risk may sometimes be expressed inqualitative terms such as high, medium, or low risk.

Risk management, a process guided by riskassessment, and by political, social, ethical, eco-nomic, and technological factors as well, involvesdeveloping and evaluating possible regulatory ac-tions and choosing among them (15). The fourcomponents of risk assessment and the process ofrisk management are summarized in figure 6-1 andare discussed in more detail below. In practice, riskassessment and risk management frequently overlapand become difficult to distinguish (27). This ispartly because definitions such as “adverse,’ “harm-ful,” and “toxic” involve both scientific and socialjudgments.

Some degree of risk is associated with almostevery aspect of modern living. For example, travel-

ing in an automobile involves a risk of accidentaldeath of 1 in 4,000, a relatively high risk. In contrast,the risk of being killed by lightning is 1 in 2 million.Whether a risk is acceptable or not depends on manyfactors, including benefits. Defining acceptable riskis the task not only of scientists and regulatoryofficials, but of society in general. Everyone evalu-ates risks on a daily basis and makes individualchoices depending on experience and numerousother factors. At times, one’s perception of risk maynot be entirely logical. For example, some people arereluctant to travel by air, even though the risk ofdeath associated with automobile travel is 25 timesgreater (table 6-1) (13). People tend to overestimatethe number of deaths from rare, dramatic risks and

Table 6-l-Estimated Risk of Death to an individualFrom Various Human-Caused and Natural Accidents

Accident Risk

Automobile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 4,000Drowning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 30,000Air travel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 100,000Lightning . . . . . . . . . . . . . . . . . . . . . . . . . . ........1 in 2.000.000SOURCE: C.D. Klaassen, “Principles of Toxicology,” Casarett and Doull’s

Toxicology, C.D. Klaassen, M.O. Amdur, and J. Doull (ads.)(New York, NY: Macmillan, 1986).

Figure 6-l-The Relationship Between Risk Assessment and Risk Management

Research Risk Assessment Risk Management

Laboratory and fieldobservation of adversehealth effects andexposures to particularagents

-F

II Field measurements, ~ ! t ExDosure assessment I=tm

\

>

/

I

;

/I

I

7Risk characterization(What is the es t ima ted ~incidence of the adverse I

effect in a given Ipopulation?) I

I I II Development ofI regulatory options

II I

I

Evaluation of publichealth, economic,social, politicalconsequences ofregulatory options

i Agency decisionsand actions

SOURCE: National Research Council, Risk Assessment in the Federal Government: Managing the Process (Washington, DC: National Academy Press,1983).

-145-

146 ● Neurotoxicity: ldentifying and Controlling Poisons of the Nervous System

underestimate the number from common, undramaticcauses (6). For example, public perception of theannual death rates from floods or tornadoes aretypically overestimated, while the risk from smok-ing or drinking alcoholic beverages is typicallyunderestimated (6).

Risk assessment practices are the subject ofongoing debate within the regulatory and scientificcommunities, and in the last two decades strategiesfor regulating toxic substances have changed con-siderably. In the early 1970s, environmental legisla-tion focused on regulating a relatively small numberof pollutants of known toxicity. Today, concern isfocused on thousands of toxic substances, for manyof which little information is available. Conse-quently, regulatory strategies have changed. Thischange has been forced in part by improved methodsof detecting toxic substances in the environment,improved capability of identifying the adverseeffects of those substances, and difficulty in deter-mining threshold levels below which no adverseeffects occur. A major question facing both regula-tors and the public is how much risk is acceptable.A wide variety of views has been expressed on thetopic of acceptable risk (4,6). A risk of death of lessthan 1 in 100,000 (10-5) to 1 in 1 million (10 -6) issometimes considered an acceptable risk for expo-sure to a chemical (13).

Policies regarding risk assessment have beencontroversial. Some people believe that Federalagencies overestimate risk by making overly conser-vative assumptions in developing risk assessments.Others feel that risk assessment practices do not takeinto account the complex interactions of multiplepollutants that often occur in the environment. Stillothers point out that risk assessments focus primar-ily on adverse effects on human health and devotelittle attention to other organisms and the environ-ment in general. Critics of established risk assess-ment procedures believe that too little attention isbeing paid to the potential effects of toxic substanceson children, infants, and the unborn, and efforts toaddress these concerns are under way at regulatoryagencies. Regardless of the various viewpoints, riskassessment has become an integral component ofregulatory strategies, and it is important to appreci-ate the scientific issues underlying this process inorder to understand how toxic substances are con-trolled (6).

illustrated by: Ray Driver

In this chapter, the basic principles of riskassessment as they relate to the neurotoxicity ofindustrial chemicals are described. The risks posedby pharmaceuticals, for example, are typicallyevaluated through other approaches. The Environ-mental Protection Agency (EPA) has actively pur-sued regulatory strategies based on risk assessment(17), and the National Research Council (NRC) ofthe National Academy of Sciences has examined theissue of evaluating the risk posed by neurotoxic

Chapter 6-Assessing and Managing Risk ● 147

substances. The reader may wish to refer to the NRCreport for further information on this subject (16).

RISK ASSESSMENTA complete risk assessment comprises four steps:

hazard identification, dose-response assessment,exposure assessment, and risk characterization (15).Each of these is discussed in the sections that follow.

Hazard Identification

Hazard identification involves gathering and eval-uating toxicity data on the types of injury or diseasethat may be produced by a substance and on theconditions of exposure under which the injury ordisease may be produced. Toxicity data typicallyderive from epidemiological and experimental ani-mal studies. Hazard identification involves judg-ments about the quality and relevance of these data.Of special importance is the question of whetherspecific toxic effects observed in one human popula-tion or in a particular experimental setting are likelyto be produced in populations for which such datahave not been or cannot be collected.

The most relevant toxicity data for identifyinghuman hazards are usually derived from studies inhumans. However, such information is often un-available or limited and can be obtained only afterhuman exposure has occurred. Consequently, it hasbecome common practice to rely on data fromanimal studies to assess the toxic properties ofchemicals. As discussed in chapter 5, a substantialbody of evidence indicates that results from animalstudies, with appropriate adjustments and qualifica-tions, can be used to infer human hazard (1 3). Thereare important exceptions to this generalization, butunless existing data on human toxicity convincinglycontradict a specific finding in animals, or there areother physiological reasons to consider certain typesof animal data irrelevant to humans, the assumptionis generally made that animal toxicity data can beused to identify potential human hazards (8).

The hazard identification section of a risk assess-ment report typically includes an evaluation of allavailable toxicity data to identify those adverseeffects that are best documented and those that aremost relevant to human health. In most cases, thetoxic effects causing greatest concern are thosethat are most severe, occur at lowest exposures,and persist after exposure ceases.

A complete hazard identification also includes adiscussion of the limitations of the available data.The absence of relevant data cannot, of course, betaken as evidence that a particular substance doesnot pose a hazard.

Dose-Response Assessment

In the second step of risk assessment, assessorsderive the quantitative relationship between expo-sure to a substance, usually expressed as a dose, andthe extent of toxic injury or disease. There may bemore than one relationship per substance, becauseseveral different kinds of responses may be elicited.

For any given chemical and exposure route, theseverity and frequency of an effect generally in-crease with dose. Because humans are typicallyexposed at lower doses than those used in toxicitystudies, it is necessary to extrapolate dose-responserelations. At present, there are differences betweendose-response extrapolations for noncarcinogenictypes of toxicity, such as neurotoxicity, and forcarcinogenicity. Noncarcinogenic effects are gener-ally assumed to occur only when a certain level ofexposure has been exceeded. This level is referred toas the threshold. It is frequently assumed that mostcarcinogens pose some risk at any level of exposure.However, the assumption that there is a threshold forall neurotoxic substances is questioned by somescientists (21).

The dose-response evaluation for noncarcinogensis derived from observations of a no observed effectlevel (NOEL) or no observed adverse effect level(NOAEL) in exposed people or experimental ani-mals (figure 6-2). The NOAEL or NOEL representsan approximate threshold for the group that has beenstudied. The NOEL is that dose at or below which nobiological effects of any type are noted (a determina-tion that is influenced by the sensitivity of analyticaltechniques), and the NOAEL is that dose at or belowwhich no harmful effects are seen. As noted earlier,definitions of “harmful” effects are influenced bysocial norms and values. If more than one effect isseen in animal tests, the effect occurring at thelowest dose in the most sensitive animal species andsex is generally used as the basis for estimating aNOEL or NOAEL. The NOAEL is most commonlyused in current neurotoxicological evaluations.

Experimental studies are often conducted usingrelatively high doses of a chemical to increase theprobability of observing effects in small groups of


Figure &2—Hypothetical Placement of a No ObservedEffect Level (NOEL) and No Observed Adverse Effect

Level (NOAEL) for a Single Chemical on aDose-Response Curve

Percent responding

I Ii Effects, but biological “

relevance unknown

Adverse effects

I

INOEL

DoseNOAEL


animals. Human exposures tend to be in low doses,where responses are not generally directly observa-ble. Therefore, in moving from laboratory exposuresto human exposures, it is usually necessary toextrapolate from high dose-responses to low dose-responses. Extrapolations are also necessary toadjust for differences between animals and humanswith regard to conditions of exposure and certainphysiological factors, such as size, lifespan, metabo-lism, brain maturation rate, and absorption. Adjust-ments are also made for variations in sensitivityamong individuals in a population (intraspeciesdifferences) (15). Some of these extrapolations andadjustments take the form of safety factors; these arediscussed in more detail in the risk characterizationsection of this chapter.

Exposure Assessment

The next step in risk assessment is determinationof the extent and nature of human exposure (includ-ing source, route, dose, and duration). An assess-ment of subgroups in the population expected toexperience unusual exposures is also appropriate(15).

Exposure can occur from many sources (e.g., soil,food, air, or water) and may enter the body by severalroutes, including ingestion, inhalation, or contact

with skin. It is important to note that an individualmay incur exposures from more than one source orroute. Determination of environmental concentra-tions and means of human exposure, route of entry,site of the exposed population, and uncertainties inexposure estimates are important factors in exposureassessment. The degree of exposure to some toxicsubstances is strongly influenced by occupation. Forexample, industrial workers may be exposed to highconcentrations of some chemicals that the publicmay encounter at much lower levels.

Duration refers to the period of time over whichindividuals are exposed. An acute exposure isgenerally a single exposure that occurs over a shortperiod of time. An exposure is considered chronicwhen it occurs over extended periods of time or asubstantial portion of a person’s lifetime (see ch. 5).Exposures of intermediate duration are called sub-chronic. Chronic and subchronic exposures may beepisodic (occurring at various intervals) or continu-ous (occurring over extended periods).

The pattern of exposure-the dose, duration,frequency, and route—is an important determinantof risk. Other concerns include knowledge of theage, sex, health status, and presence or absence ofother environmental exposures for a given popula-tion. Obtaining such information requires a compre-hensive monitoring program; however, data of thiskind for a given toxic substance are often notavailable.

Risk Characterization

The final step of risk assessment combines theresults of hazard identification, dose-response as-sessment, and exposure assessment to produce acharacterization of risk. The NOAEL (or, lessfrequently, the NOEL) derived in the assessment ofdose-response is divided by a safety factor, oruncertainty factor, yielding what is called thereference dose (RfD) (2). At the present time, riskcharacterization for noncarcinogenic forms oftoxicity, including neurotoxicity, is based on theNOAEL (or NOEL) safety factor approach. TheRfD (also called the acceptable daily intake)l is usedto characterize risk. If human exposure is consis-tently below the RfD, risk assessors assume there islittle health risk. If exposures exceed the RfD, it isassumed a significant risk exists. Generally, no


attempt is made to describe the magnitude of therisk.

Three safety factors are commonly used to de-velop an RfD. The NOAEL or NOEL is divided by10 when epidemiological or human experimentaldata are used to predict human risk. This safetyfactor is applied in order to protect sensitivemembers of the population when data have beenobtained from average, healthy persons. Anotherfactor of 10 is applied to the NOAEL or NOEL whenextrapolating from animals to humans. To developa chronic RfD when only subchronic animal studiesare available, another factor of 10 is added, for a totalsafety factor of 1,000. Sometimes a factor is addedfor an incomplete database. The magnitude of thesafety factor employed can vary from chemical tochemical. Scientific judgment may be exercised inevaluating species differences, the nature and extentof human exposure, the types of toxic effects, and therelative doses at which toxicity occurs in test species(see, e.g., 51 FR 34040). The application of safetyfactors is diagramed in figure 6-3.

A variation on the safety factor approach is themargin of safety (MOS), or margin of exposure(MOE). This involves dividing the NOAEL (orNOEL) by the current, desired, or most feasiblehuman exposure level. This margin is sometimescompared with the safety factors mentioned above inorder to judge its adequacy. Risk assessors generallyemploy the MOS approach to make judgments aboutthe safety of existing or proposed exposure levels.They use the safety factor approach in circumstanceswhere guidelines or regulations specify maximumallowable or safe exposure limits (3).

For substances that produce carcinogenic effects,the NOAEL (or NOEL) safety factor approach is notused. Instead, various extrapolation models areapplied to develop estimates of risk (typically, theprobability of developing cancer over a lifetime)associated with various levels of exposure. There islittle scientific literature on the application of thistype of extrapolation to noncarcinogenic effects.

Currently, cancer risks and RfDs are expressednumerically, but these quantitative figures may bequalified with factors such as the strength of theevidence of toxicity on which the risk or RfD isbased. The uncertainties and assumptions inherent inany risk assessment should also be stated. Thisinformation is as essential as the quantitative de-

Figure 6-3-Use of Safety Factors in Deriving aReference Dose

Animal Dose-Response Data

1NOEL or NOAEL

1Divide by 10

(for short- to long-term extrapolation)

1Divide by 10

(for animal to human extrapolation)

iDivide by 10

(for homogeneous to heterogeneous population extrapolation)

1Reference dose (RfD)

(or acceptable daily intake, ADI)


scription of risk associated with exposure to a toxicsubstance.

RISK MANAGEMENTThe purpose of risk management is to determine

whether an assessed risk should be reduced and toidentify the degree of risk reduction that is appropri-ate to a given situation. Risk management dependson information derived from the risk assessment, butit may also depend on political, social, ethical,economic, and technological factors. NRC hasrecommended that regulatory agencies take steps toestablish and maintain a clear conceptual distinctionbetween risk assessment and risk management (15).Different risk management approaches are taken bydifferent regulatory agencies, depending largely onthe kind of exposure being evaluated and theagency’s statutory authority. The three most com-mon risk management approaches mandated by thevarious environmental and public health laws arerisk only, risk balancing (risk-benefit), and techno-logical control (25), Public perceptions may alsoinfluence risk management decisions.

A regulatory decision using the risk only approachtakes into account only the level of risk that isconsidered necessary to protect public health. How-ever, the risk balancing approach may consider


social, economic, and technological factors as well.This approach involves developing a consensusamong interest groups and making trade-offs for thepublic well-being. The third risk management ap-proach, technological control, involves reducingrisk by applying the best available, most feasibletechnologies.

RISK ASSESSMENT ANDNEUROTOXIC SUBSTANCES

The risk assessment approaches outlined abovehave been discussed extensively in various Federaland State regulations and guidance documents (see,e.g., 51 FR 33992-34003; 50 FR 10372-10442) (5),as well as in the scientific literature (50 FR10372-10442) (15). Practical applications of thesemethods of risk assessment can be found in hundredsof regulations promulgated by EPA, the Food andDrug Administration, the Occupational Safety andHealth Administration (OSHA), and the ConsumerProduct Safety Commission, as well as in thescientific literature. A representative sampling of thelatter, and references to many more assessments, canbe found in the National Academy of Sciences’series Drinking Water and Health (8 volumesthrough 1988). While legitimate scientific differ-ences exist regarding many issues in risk assess-ment, particularly those concerning extrapolation,consensus exists regarding the need for some type ofanalysis of the risk posed by toxic substances.Differences in approaches to risk assessment canresult in different conclusions with respect to thedegree of risk posed by a toxic substance and howmuch of society’s resources should be used toaddress toxicological concerns.

To date, most risk assessments have been devotedto carcinogenic substances. As mentioned above,some basis has been found for development ofexplicit descriptions of noncarcinogenic risk, andmost of the guidance documents mentioned abovedeal with this issue. There is some discussion ofnoncarcinogenic effects in the Drinking Water andHealth series cited above, in EPA’s Toxic Sub-stances Control Act Test Guidelines (50 FR 39398-39418; 50 FR 39458-39470), and in various docu-ments issued by the World Health Organization (28).EPA’s “Guidelines for the Health Assessment ofSuspected Developmental Toxicants,” issued in1986 (51 FR 34040), were the first noncancer riskassessment guidelines produced.

Risk assessment strategies were originally devel-oped for evaluating carcinogens, which have oftenbeen viewed as exerting “all-or-none” effects(although this view is changing for some carcino-gens). Neurotoxic substances differ from carcino-gens in that adverse effects are strongly dependenton dose—severe effects may result from exposure tolarge concentrations of a substance, but little effectmay result from exposure to low concentrations.Also, cancer is a relatively well-defined, discreteendpoint. Neurotoxicity may result in multipleendpoints (e.g., seizures, memory loss, hearing loss),thus complicating risk assessment strategies. Inmost of these cases, and in many specific regulatoryapplications, the RfD approach to risk characteriza-tion (or its equivalent in occupational settings) isaccepted.

Examples of Regulatory Approaches

Federal regulatory agencies have not developeduniform risk assessment approaches to neurotoxicsubstances, although EPA has been particularlyactive in developing risk assessment guidelines (1 2).To illustrate how various agencies have used riskassessment, one may focus on four widely recog-nized neurotoxic substances: lead, ethyl-p-nitro-phenyl phosphonothionate (EPN, an organophos-phorous pesticide), acrylamide (a chemical oftenused because of its ability to polymerize), andn-hexane (a commonly used industrial solvent) (9).Each of these substances is representative of a majorcategory of environmental exposure: lead (generalexposure), EPN (pesticide), and acrylamide andn-hexane (occupational exposures).

Two of the four chemicals examined, EPN andn-hexane, are regulated primarily on the basis ofneurotoxic concerns. Risk assessments for the twofocus on histopathologica1 analyses, as opposed toexaminations of functional effects. Lead is regulatedbecause of its neurotoxic properties, especiallyprenatally and in early life, and its effects on theblood-forming system. Acrylamide is regulatedbecause of both its carcinogenic and its neurotoxicpotentials (box 7-E).

The methodological approaches used by EPA (forlead and EPN) and OSHA (for acrylamide andn-hexane) were generally the same. In identifyinghazards, the agencies placed greatest reliance onhuman data, when they were available, but alsorelied on animal data. Principal emphasis was placed

Chapter 6--Assessing and Managing Risk ● 151

Photo credit: National Arhives, EPA Documerica Collection

on identifying NOAELs and determining the appro-priate margin of exposure for humans.

In determining the bases for the occupationalstandards, OSHA adopted the American Conferenceof Governmental Industrial Hygienists’ (ACGIH)threshold limit values (TLVs) for the n-hexane andacrylamide standards. ACGIH documented its deri-vation of each TLV (l), but the relationshipsbetween the TLVs and the underlying documenta-tion were not explicitly stated. EPA’s standards werestated more clearly.

A detailed evaluation of the risk assessmentinformation used in the development of the stan-dards for lead, EPN, acrylamide, and n-hexaneconfirmed that the safety factor approach has beenused for neurotoxicity risk assessment in diversecircumstances. The safety factor approach (based ona NOAEL) is commonly used in the U.S. pharma-

ceutical industry, where neurotoxic effects some-times limit the dose (10).

To date, there have been few instances in whichneurotoxicity was the principal basis for regulation.There are perhaps three reasons for this. First,toxicity tests currently used by regulatory agenciesare generally not specifically designed to identifyneurotoxic agents. Histopathological analyses mayidentify some neurotoxic agents, but pathologicalanalyses alone are of limited use in identifyingadverse effects on the function of the nervous system(e.g., behavioral effects). Second, the risk assess-ment methodologies currently in use for carcino-genesis assume the absence of a threshold, whereasthose used for other toxic effects assume a threshold.The practical consequence of this dichotomoussystem is that whenever a toxic agent exhibits bothcarcinogenic and other-than-carcinogenic effects,concerns about the carcinogenic risks tend to over-ride concerns about other risks that may be associ-ated with the agent at low doses. As indicated earlier,however, these assumptions regarding thresholds forcarcinogenic and other toxic chemicals are thesubject of debate. Third, in some cases other,noncancer health effects may occur at lower levelsthan neurotoxic effects, and regulations may havebeen based on these concerns.

Concerns about carcinogenicity have dominateddiscussions about the risks posed by toxic sub-stances. However, the adverse effects on organs andorgan systems (the nervous system, liver, immunesystem, cardiovascular system, and so on) may posean equal or greater threat to public health. Conse-quently, it is important to devise risk assessmentstrategies to address noncancer health risks.

Limitations of Current Approaches

The nervous system is perhaps the most complexorgan system of the body. Consequently, evaluatingthe neurotoxic potential of environmental agents isa particular challenge. For example, testing for atoxic effect on one component of the nervous system(e.g., hearing) may or may not reveal a toxic effecton another component (e.g., vision); furthermore, aneffect on one nervous system function is notnecessarily predictive of an effect on another nerv-ous system function. Other factors that complicaterisk assessment of neurotoxic substances include theapparent reversibility of many neurotoxic effectsand the possibility of “silent,” or latent, adverse


effects, which become apparent only late in life (27)(see box 7-G).

An important difference between neurotoxicityand carcinogenicity is the extent to which the effectsare reversible. The endpoint of carcinogenicity isconsidered to be irreversible (although some personsargue that, strictly speaking, a “cure” would renderthe effect reversible), whereas the endpoints ofneurotoxicity may be either reversible or irreversi-ble, depending on the specific effect, the durationand frequency of exposure, and the toxicity of thesubstance (see box 7-G). Reversibility requires theintroduction of a new variable into the risk assess-ment equation. Consequently, it has been proposedthat it may be useful to specify a reversible effectlevel (27). Yet, determining whether or not an effectis truly reversible can be difficult. For example,exposure to a neurotoxic substance early in lifecould appear to give rise to a short-term, reversibleeffect, but later in life an irreversible effect (e.g., aneurological disease) could become apparent.

The age at which neurotoxic effects are evaluatedcan strongly influence the outcome of a risk analysis.For example, mice exposed to methylmercury dur-ing prenatal development may not exhibit adverseeffects until late in their lives (23). Similarly,humans exposed to a toxic substance early in lifemay not suffer adverse effects until decades later.With age, the functional capacity of the braindeclines significantly, and chronic exposure to someneurotoxic substances is thought to accelerate thisprocess (27). As indicated in the hypotheticalexample in figure 6-4, a small acceleration in the lossof functional capacity may, with time, have verysignificant effects. For example, in this model, thepostulated functional capacity of the brain that hasnot been chronically exposed to neurotoxic sub-stances through age 65 is more than 80 percent of thecapacity at age 65 (see figure 6-4, point A).However, even a modest acceleration of 0.5 percentper year results in a functional capacity of 65 percent(see point B), a more than 15-point reduction in thistheoretical example. As figure 6-4 suggests, anacceleration of 1.0 percent per year could result in alarge reduction in functional capacity over time.Hence, many scientists and regulatory officialsbelieve that risk analyses should consider adverseeffects over a range of ages and should take intoaccount possible latent effects (27). More research isneeded to understand the actual relationship be-

Figure 6-4-Postulated Decline in BrainFunctional Capacity With Age and Exposure

to Neurotoxic Substances

90.

\ ~ Normal decline wilh age80- -

70 \0.5% 0.1 %

1% Excess per year Excess per yearExcess per year #

60.25 35 45 55 65 75 85 95

Chronological age

The heavy line (top) shows the rate posited to occur without addedvariables. The lighter lines show accelerations of 0.1 percent, 0.5percent, and 1.0 percent annually, as might be produced bychronic exposure to neurotoxic substances.SOURCE: B. Weiss and W, Simon, “Quantitative Perspectives on the

Long-Term Toxicity of Methyl Mercury and Similar Poisons,”Behavioral Toxicology, B. Weiss and V. Laties (eds.) (New York,NY: Plenum Press, 1975).

tween decline in functional capacity and the impactof toxic substances on the nervous system.

Issues in Hazard Identification

Neurotoxicological assessment of environmentalagents is not uniform among Federal regulatoryagencies (1 1,20,24). Although hazard identificationthrough general toxicity testing (described inch. 5)can identify substances with obvious neurotoxicproperties, substances producing more subtle effectsare generally not detected. One exception is EPA’sOffice of Toxic Substances, which has included abattery of more sophisticated neurotoxicity tests inits regulatory requirements (see ch. 7). Until re-cently, however, EPA has not imposed these specifictest requirements on many substances.

As discussed in chapter 5, neurotoxicity tests (andtoxicity tests in general) should meet certain criteriasuch as sensitivity, specificity, and reproducibilitybefore being adopted for routine use in hazardidentification or dose-response assessment. Cur-rently, there is a consensus among scientists thatseveral neurotoxicological tests meet the necessarycriteria and could be used for routine testing ofpotentially neurotoxic substances (14,18,22). Aquestion that remains is precisely how EPA will usetest data in the regulatory decisionmaking process.


Issues in Dose-Response Assessment

Thresholds and the RfD Approach-Toxic agentsare conventionally classified into two groups: thosethat exert adverse effects only after a threshold doseis exceeded and those that theoretically increase riskat all doses greater than zero (no-threshold agents).This classification system, which has importantconsequences for risk assessment, has the practicaleffect of grouping all carcinogens into the no-threshold category and all other forms of toxicityinto the threshold category. As indicated earlier,there is uncertainty about whether all carcinogensbelong in the no-threshold group and all noncarcino-gens, including neurotoxic agents, belong in thethreshold group (19).

One consequence of this dichotomous system isthat different models for risk assessment are used forthe two groups. Typically, noncarcinogenic risk ismodeled under the assumption that risk declineswith dose and that the mathematical model thatdescribes this relationship applies even below theregion of observed effects. The model used forcarcinogens yields zero risk (zero probability ofdeveloping cancer) only when the dose becomeszero. On the other hand, the consequence of assum-ing a threshold model is the development of RfDs byapplying safety factors to NOELs or NOAELs.

NOAEL v. NOEL-The objective of using aNOAEL as opposed to a NOEL, as described above,is to establish a threshold dose such that no adverseeffect would be likely to occur at exposures at orbelow this dose. Implicit in the establishment of aNOAEL is the understanding that any effects thatoccur below this dose would have no knownbiological relevance, whereas effects occurring abovethis dose would be harmful. A NOEL, on the otherhand, reflects a dose below which no observableeffect of any type occurs. An effect might bemeasurable, yet not be deleterious to human health;in fact, the effect might be beneficial or might not bebiologically meaningful.

Due to limits in scientific understanding of thebiological relevance of measurable effects, regula-tory standards are often based on NOELs and notNOAELs. This reflects the intent to err on the sideof caution and to be overprotective rather thanunderprotective of public health. When regulatingpharmaceuticals, NOAELs are used because adverseeffects must be distinguished from positive pharma-

Photo credit: United Automobile, Aerospace, and AgriculturalImplement Workers of America-U4VPublic Relations Department

cological effects. Also, recent draft developmentaltoxicity testing guidelines (54 FR 13472; 53 FR5932; 51 FR 17890) are based on the NOAEL.Developmental testing is discussed in chapter 5.

Safety Factors—A safety factor, as describedabove, is generally applied to the NOEL or NOAELto estimate the RfD. However, the use of such factorscreates an uncertainty in itself. Safety factors aregenerally derived not from chemical-specific data,but from a priori estimations of the ranges ofvariation in extrapolations used to determine an RfD(from animals to humans and within the humanpopulation). The limited research done on the topicof safety factors needed to account for intraspeciesvariability indicates that the tenfold factor used forthis purpose tends to be more rather than lessprotective of a diverse human population (7,26).

What is unclear at the present time is the actualdegree of protection against toxic effects that isassociated with the RfD. It is likely that differentsafety factors are necessary for different chemicals;thus the RfD may be highly protective for oneneurotoxic substance (i.e., one associated with anextremely low risk) but insufficiently protective foranother.

154 ● Neurotoxicity: [dentifying and Controlling Poisons of the Nervous System

Issues in Risk Characterization

Uncertainty-An important component of riskcharacterization that often receives inadequate atten-tion is the delineation of uncertainties in the variousstages of the assessment. The greater the totaluncertainty, the less likely it is that the calculatedrisk represents the true risk. Every risk characteriza-tion should include a thorough discussion of all theuncertainties (50 FR 10372-10442, 51 FR 33992-34003).

There are uncertainties inherent in every riskassessment. Some are fundamental scientific ques-tions common to all risk assessments. Questions thatoften arise include:

. How useful are animals as predictors of humantoxicity?

. H OW well do responses at high doses predictresponses at low doses?

● What is the relative importance of individual v.social risk? (See box 6-A.)

These questions are often difficult to answer; indeed,at times they cannot be answered. In the meantime,assumptions must be made and mathematical andinterpretational conventions must be devised. Insome areas, such as high to low dose extrapolation,there is no consensus among scientists. Regulatoryagencies deal with such situations by adoptingscience policy assumptions (15). These assumptionstend to favor overstatement of risk, a practice thatagencies justify on public health grounds.

Other types of uncertainties arise because the dataavailable for any given risk assessment are incom-plete or imperfect. Examples of these kinds ofuncertainties include the following questions: Aretoxic responses resulting from different experimen-tal exposure routes comparable? What environ-mental concentrations of a contaminant are peopleactually exposed to? Is the toxic substance chemi-cally modified in the environment or metabolized inthe body to a more or less active form? Whatquantity of the chemical actually reaches and causesthe toxic effect in the target organ?

Assumptions must be made to fill these gaps ininformation. The risk assessor usually tries to beconservative by making a worst probable caseassumption. This results in a final risk number that,

although uncertain, is highly likely to overestimatethe true risk.

SUMMARY AND CONCLUSIONSToxicology and risk assessment have traditionally

dealt with effects that can be characterized byphysical changes, including morphological or bio-chemical abnormalities. Functional impairment ofthe organism, such as a chemically induced changein behavior, is now also considered a direct andmeasurable consequence of these types of abnormal-ities. The relationship between pathological changesand functional impairment needs to be furthercorrelated, however.

Determining the biological mechanisms underly-ing behavior is a frontier of basic research. Researchaimed at defining adverse effects at the cellular andsystems levels is being actively pursued in tandemwith the development of toxicity testing methods.Several tests already developed in the academic,regulatory, and private sectors can be used in routinepreliminary or secondary screening of neurotoxicsubstances. Regulatory agencies will most likelyadopt a tiered testing approach2 whenever specificneurotoxicity tests as well as general toxicity testsare required.

With respect to identifying neurotoxic hazardsand developing standardized methods of predictingthem, several approaches might be pursued simulta-neously. Research to improve the utility of structure-activity relationships in predicting neurotoxicity iscritically needed. Strong, continuing research pro-grams are needed to further refine and validateneurotoxicity tests. To guide the direction of thisresearch, specific epidemiological surveillance pro-grams could be developed to follow subpopulationsthat are exposed to high concentrations of neuro-toxic substances (e.g., certain occupational groups).Also, weight-of-evidence approaches for classifyingneurotoxic hazards, similar to EPA’s weight-of-evidence classification scheme for carcinogens,might help guide regulatory decisionmaking. EPAhas recently proposed such a scheme for neurotoxic-ity.

Further exploration of the scientific basis for thethreshold assumption now adopted for all noncarcin-ogens is needed. The desirability of adopting non-threshold dose-response relationships for some agents

Zne tle~ test~g approach is described iI’I ch. 5.

Chapter 6---Assessing and Managing Risk ● 155

Box 6-A—Individual v. Social Risks

Risk, particularly as it relates to carcinogenicity, is typically evaluated in the context of the individual,but evaluations of this kind may underestimate the overall risk to society. A useful example is levels of leadin children. A recent analysis of lead levels in newborns grouped concentrations of lead in the umbilical cordinto three categories: low (1.8 micrograms of lead per deciliter of blood, ug/dl), medium (6.5 ug/dl), and high(14.5 ug/dl). Even though children in the high exposure group fell just below the 15 ug/dl level consideredto be hazardous (according to the Centers for Disease Control), at age 2 these children score 8 percent lowerthan nonexposed children on a standard mental development index (the Mental Development Index of theBayley Scales of Infant Development).

Although individual children do not display adverse neurotoxic effects, the impacts on society can bevery significant. As shown in the figure below, a 5 percent reduction in the mean scores can result in asignificantly different distribution of IQ scores.

Probability Probability0.03- 0.03-

0.02- 0.02-

0.01- 0.01-

0,00 0.001 , I I 1 I 1 I I I I I I I ! I I I 1 (

50 70 90 110 130 150 50 70 90 110 130 150IQ Score IQ Score

Distributions of intelligence test scores. Left: standardized mean 100; standard deviation 15. Right: mean 95.

The graph on the left indicates a typical distribution, in which the mean IQ score is 100 (the standardizedaverage). In a population of 100 million, 2.3 million individuals would be expected to score above 130. Inthe distribution on the right, based on a mean score of 95, about 1 million individuals score above 130, areduction of 1.3 million individuals. Clearly, what may appear to be small differences in leadleve1-differences that are not apparent in individual evaluations-can translate into a major social problem,detectable only through statistical analysis of data from exposed and unexposed children.

SOURCE: Adapted from B. Weiss, ‘‘Neurobehavioral Toxicity as a Basis for Risk Assessment, ”Trends in Pharmacological Sciences9:59-62, 1988.

producing delayed, irreversible neurotoxic effects needed to identify relatively weak neurotoxic chem-might be considered. Alternative means of modeling icals that can cause adverse effects in humans afterdose-response relationships for neurotoxic agents low-level exposures over long periods of time.need to be investigated and developed into practical Facilitating and maintaining coordination amongtools. If the safety factor approach is to be main- researchers and scientists in the various regulatorytained, empirical verifications of its adequacy are programs will be crucial to ensure efficient anddesirable, not only for neurotoxic agents but for consistent integration of research findings intoother toxic agents as well. In addition, methods are regulatory decisionmaking.


1.

2.

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4.

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-7.

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12.

13.

14.

CHAPTER 6 REFERENCESAmerican Conference of Governmental IndustrialHygienists, Documentation of the Threshold LimitValues and Biological Exposure indices, Acrylamideand Hexane (Cincinnati, OH: 1986).Barnes, D. G., and Dourson, M., “Reference Dose(RfD): Description and Use in Health Assessments,”Regulatory Toxicology and Pharmacology 8:471-486, 1988.Bass, B. F., and Muir, W. R., Summary of FederalActions and Risk Assessment Methods Relating toNeurotoxicity, EPA Contract No. 68-02-4228 (Ar-lington, VA: Hampshire Research Associates, Inc.,1986).Byrd, D., and Lave, L., “Narrowing the Range: AFramework for Risk Regulators, ” Issues in Scienceand Technology (Summer) :92-100, 1987.California Department of Health Services, “A Policyfor Chemical Carcinogens: Guidelines on Risk As-sessment and Their Scientific Rationale, ” draftBerkeley, CA, 1984.Conservation Foundation, Risk Assessment and RiskControl (Washington, DC: 1985).Dourson, M. L., and Stara, J. F., “Regulatory Historyand Experimental Support of Uncertainty (Safety)Factors,” Regulatory Toxicology and Pharmacology3:238-244, 1983.ENVIRON Corp., Elements of Toxicology and Chem-ical Risk Assessment (Washington, DC: 1988).ENVIRON Corp., “Assessing Human Risks Posedby Neurotoxic Substances, ” prepared for the Officeof Technology Assessment, December 1988.Gad, S., Searle Research & Development, personalcommunication, May 23, 1989.Hampshire Research Associates, Inc., Expert Neuro-toxicity Assessment Report: Neurotoxicity Risk As-sessment Guidelines (Arlington, VA: 1985).Kimmel, C. A., “Regulatory Issues and Risk Assess-ment for Neurotoxicology, ” Neurotoxicology, Feb.27, 1989.Klaassen, C. D., “Principles of Toxicology,” Casa-rett and Doull’s Toxicology, C.D. Klaassen, M.O.Amdur, and J. Doull (eds.) (New York, NY: Macmil-lan, 1986), p. 25.McMillan, D. E., “Risk Assessment for Neurobehav-ioral Toxicity, ’ Environmental Health Perspectives76:155-161, 1987.

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National Research Council, Risk Assessment in theFederal Government: Managing the Process (Wash-ington, DC: National Academy Press, 1983).National Research Council, Neurotoxicology andModels for Assessing Risk (Washington, DC: Na-tional Academy Press, in preparation).Preuss, P. W., and Ehrlich, A. M., “The Environ-mental Protection Agency’s Risk Assessment Guide-lines,” JAPCA 37(7):784-791, 1987.Reiter, L. W., “Neurotoxicology in Regulation andRisk Assessment,” Developmental Pharmacologyand Therapeutics 10:354-368, 1987.Rodricks, J. V., Frankos, V., Turnbull, D., et al.,“Risk Assessment for Effects Other Than Cancer, ”Food Protection Technology, C.W. Felix (cd.) (Chel-sea, MI: Lewis Publishers, 1987).Sette, W. F., “Complexity of NeurotoxicologicalAssessment” Neurotoxicology and Teratology 9:411-416, 1989.Silbergeld, E.K., “Developing Formal Risk Assess-ment Methods for Neurotoxins, ” NeurobehavioralMethods in Occupational and Environmental Health(Washington, DC: Pan American Health Organiza-tion, 1988).Spencer, P. S., and Schaumburg, H.H. (eds.), Experi-mental and Clinical Neurotoxicology (Baltimore,MD: Williams & Wilkins, 1980).Spyker, J. M., Behavioral Toxicology, B. Weiss andV.G. Laties (eds.) (New York, NY: Plenum Press,1975), pp. 311-375.Tilson, H. A., “Symposium: Screening for Neurotox-icity: Principles and Practices, ” Journal of theAmerican College of Toxicology 8(1):13-17, 1989.U.S. Congress, General Accounting Office, HealthRisk Analysis: Technical Adequacy in Three SelectedCases, GAO/PEMD-87-14 (Washington, DC: 1987).Weil, C. S., “Statistics v. Safety Factors and Scien-tific Judgment in the Evaluation of Safety for Man, ”Toxicology and Applied Pharmacology 21:454-463,1972.Weiss, B., ‘‘Neurobehavioral Toxicity as a Basis forRisk Assessment, ” Trends in Pharmacological Sci-ences 9:59-62, 1988.World Health Organization, Principles and Methodsfor the Assessment of Neurotoxicity Associated WithExposure to Chemicals, Environmental Health Crite-ria 60 (Geneva: 1986).

Chapter 7

The Federal Regulatory Response

“The workplace should not be a test tube and company employees should not be guinea pigs. We cannottolerate stone-age protections for space-age dangers. ”

Senator Harry ReidCommittee on Environment and Public Works

March 6, 1989

“There are substances commonly used in the home that make our lives easier. We use these substances ingood faith, seldom questioning the fact that they could cause peripheral nerve or brain damage. Consumersrely on the Government’s and industries’ judgment on health dangers associated with the use of chemicalsand pesticides.

Representative Harold L. VolkmerCommittee on Science and Technology

October 8, 1989

“The industrial laboratory will always outpace the regulatory agency in providing substitutes for bannedchemicals, and some of those substitutes in field use may prove as troublesome as the ones they replace. ”

William D. RuckelshausIssues in Science and Technology

Spring 1985

CONTENTSPage

LICENSING AND REGISTRATION LEGISLATION AND REGULATIONS . . . . . . . 161Federal Food, Drug, and Cosmetic Act . +... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163Federal Insecticide, Fungicide, and Rodenticide Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168Toxic Substances Control Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

STANDARD-SETTING LEGISLATION AND REGULATIONS . . . . . . . . . . + . . . . . . . . 179Clean Air Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180Federal Water Pollution Control Act and Clean Water Act . . . . . . . . . . . . . . . . . . . . . . . . 182Safe Drinking Water Act . . . . . . . . . ● . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183Consumer Product Safety Act and Federal Hazardous Substances Act . . . . . . . . . . . . . 184Federal Mine Safety and Health Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185Occupational Safety and Health Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

CONTROL-ORIENTED LEGISLATION AND REGULATIONS . . . . . . . . . . . . . . . . . . 187Cornprehensive Environmental Response, Compensation, and Liability Act. . . . . . . . 187Controlled Substances Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 188Marine Protection, Research, and Sanctuaries Act.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188Lead-Based Paint Poisoning Prevention Act and Poison Prevention Packaging Act . 189Resource Conservation and Recovery Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

NEW INITIATIVES IN REGULATING NEUROTOXIC SUBSTANCES . . . . . . . . . . . 191Revision of EPA’s Neurotoxicity Test Guidelines for Pesticides . . . . . . . . . . . . . . . . . . . 191Revision of the FDA’s Red Book for Food and Color Additives . . . . . . . . . . . . . . . . . . 192Suggested Revisions of OECD Toxicity Testing Guidelines . . . . . . . . . . . . . . . . . . . . . . 194

CONSISTENCY OF FEDERAL REGULATION OF NEUROTOXIC SUBSTANCES . 194General Toxicological Considerations . . . +.. ....., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194Specific Neurotoxicological Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

ADEQUACY OF THE FEDERAL REGULATORY FRAMEWORK . . . . . . . . . . . . + . . . 201Measurements of Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201Expected and Detected Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201Monitoring Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204CHAPTER 7 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .205

BoxesBox Page7-A. Toxic Substances Laws Go To Court: The Judicial Role in Interpreting Legislative

Language and Regulatory Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . +.. 1627-B. Limitations of FDA’s Postmarked Monitoring System for Adverse Drug Reactions:

Halcion, A Case Study . . . . . . . . . . . . . . . . . . . . .., , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1697-C. Regulatory Requirements for Labeling: How Effective Are They? . . . . . . . . . . . . . . . 1727-D. Confidential Business Information Under TSCA: Does It Influence Regulatory

Effectiveness? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1767-E. Regulating for Neurotoxicity v. Other Toxic Effects: The Case of Acrylamide . . . 1787-F. The American Conference of Governmental Industrial Hygienists . . . . . . . . . . . . . . . 1867-G. Flexibility in Neurotoxicological Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1937-H. TSCA’s Premanufacture Notice Program: Is More Toxicity Testing Feasible? .,. 197

TablesTable Page7-1. Key Features of Federal Laws Regulating Toxic Substances . .......... .......+. 1607-2. Chemicals Subject to Neurotoxicity Evaluation Under Section 4 of TSCA . . . . . . . 179

Chapter 7

The Federal Regulatory Response

Over the years, Congress has enacted manystatutes that apply directly or indirectly to theregulation of neurotoxic substances. Some of thesestatutes are framed in broad terms to protect humanhealth in general; others address specific adversehealth effects, such as carcinogenicity, teratogen-icity, and in rare cases behavioral changes andneurotoxicity (25). Some statutes provide broadauthority for requiring that substances be tested forpotential toxic effects; others require the implement-ing agency to prove that substances may be harmfulbefore any regulatory action can be taken. Somestatutes call for absolute protection of health andsafety; others allow for balancing risks, costs, andbenefits.

Not surprisingly, Federal agencies have promul-gated equally diverse regulations. Some regulatoryprograms require substantial testing of chemicals toscreen for toxic effects; others are not empowered torequire any such testing. Some call for screeningsubstances before they are allowed to enter themarketplace; others are reactive, taking effect onlywhen evidence indicates that an existing chemicalcan, or does, cause harm.

Federal laws governing toxic substances can bedivided into three general categories:

1.

2.

3.

licensing and registration laws for new andexisting chemicals, which entail an explicitreview process and may include a requirementfor toxicity testing;standard-setting laws for chemicals used inspecific situations, under which regulatoryagencies determine recommended or requiredlimits on toxic substances in various environ-mental media (air, water, or soil) or emitted bya given source, or dictate appropriate labelingof products that contain toxic substances; andcontrol-oriented measures for dealing withchemicals, groups of chemicals, or chemicalprocesses that are explicitly identified in thelaws. 1

Distinctions among the three categories are notabsolute—there is more of a continuum than a

discrete grouping in the legislative language—butthis classification indicates the basic types ofapproaches that have been developed to protect thepublic and the environment from the adverse effectsof toxic substances. Table 7-1 presents key featuresof 18 Federal laws regulating the use of toxicsubstances (14).

The approach to regulation embodied in a statutelargely determines the Federal response. Licensingprograms are externally driven and must respond topetitions or applications from manufacturers or otheroutside parties; standard-setting and control-oriented programs may have to respond to deadlinesset by Congress (for control-oriented programs,however, these deadlines generally affect regulationof sites rather than specific chemicals). Applicationand notification procedures under the licensingstatutes require the regulatory agencies to reviewhowever many chemicals per year are submitted,whereas agencies charged with setting standards cancontrol the scheduling and priorities of review to agreater degree.

Although some of the standard-setting and control-oriented programs have the ability to pursue researchinto the adverse effects of chemical substances, it isthe licensing statutes that generally grant authorityto require that chemicals be tested for toxic effects.As a consequence of these and other differences,implementation of licensing statutes has tended to bemore active and, accordingly, more controversialthan that of standard-setting or control-orientedstatutes.

It is necessary to keep in mind that regulatoryactivities may be curtailed, expanded, or otherwiseaffected by various nonregulatory factors. Theappropriations process determines the resourcesavailable to an agency to carry out its regulatoryactivities. Oversight by the Office of Managementand Budget may require an agency to restrict ormodify regulatory implementation. Abundant litiga-tion challenging environmental laws and regulationshas created a large body of court decisions thatfurther interpret and clarify agencies’ regulatoryrights and responsibilities (see box 7-A); product

l~hers have clmsifi~ the regulatory response differently; one environmental law treatise, for example, suggests o~j’ two categofies+roductcontrols and pollution emission controls. The scheme proposed here is not definitive but is meant to emphasize how chemicals are singled out for attentionand review in the legislative and regulatory processes.

-159-


Table 7-l—Key Features of Federal Laws Regulating Toxic Substances

Regulatory authority Toxic substance orStatute (regulatory agency)a effect of concern Approach to risk

Part1-Licensing LawsFederal Food, Drug, and Control levels of added sub-

Cosmetic Act stances (FDA)

Control levels of natural com-ponents of food (FDA)

Control levels of environmentalcontaminants (FDA)

Set (EPA) and enforce (FDA,USDA) tolerances on pesti-cide residues for food andfeed crops

Regulate introduction of newdrugs and biologics (FDA)

Report on adverse reactions todrugs (FDA)

Label cosmetics (FDA)

Federal Insecticide, Fungicide, Register pesticides (EPA)and Rodenticide Act

Toxic Substances Control Act Require testing of existing chem-icals where data are inade-quate to assess risk (sec.4); prohibit introduction intocommerce of chemicals thatwill present an unreasona-ble risk (sec. 5); restrict orprevent production, use, ordisposal of existing chemi-cals that present unreason-able risk (sec. 6) (EPA)

Part II-Standard-Setting LawsClean Air Act

Federal Water PollutionControl Act; Clean WaterAct

Safe Drinking Water Act

Consumer Product Safety Act

Federal Hazardous SubstancesAct

Conduct research on air pollu-tion (EPA)

Set air quality standards; regu-late emissions of hazardousair pollutants; set standardsfor vehicle emissions, fuels,and fuel additives (EPA)

Set effluent standards for water;establish water quality cri-teria (EPA)

Set MCLs and MCLGs for pub-lic drinking water supplies(EPA)

Promulgate consumer productsafety standards (CPSC)

Ban hazardous substances forhousehold use (CPSC)

“any poisonous or deleterioussubstance which may ren-der it injurious to health”

“poisonous or deleterious . . .does not ordinarily render itinjurious to health”

“poisonous or deleterious . . .does not ordinarily render itinjurious to health”

“poisonous or deleterious . . .not generally recognized assafe for use . . . to theextent necessary to protectthe public health”

“substantial evidence that safeand effective”; no “immi-nent hazard to publichealth”

“any adverse experience ., .includes any side effect, in-jury, toxicity, or sensitivityreaction”

“poisonous or deleterious . . .may render it injurious”

“will not generally cause anyunreasonable risk to manor the environment”

“unreasonable risk of injury tohuman health or the environ-ment. . . including] carcino-genesis, mutagenesis, terato-genesis, behavioral disor-ders, cumulative or syner-gistic effects, and any othereffect. . .“

“adverse effects on health, in-cluding, but not limited to,behavioral physiological, tox-icological, and biochemicaleffects”

“endanger public health”

“identifiable effects on healthand welfare”

“may have an adverse effecton the health of persons”

“an unreasonable risk of in-jury”

“toxic. . . may cause substantialpersonal injury or substan-tial illness”

No explicit consideration of ben-efits

Balance risk against need forplentiful and affordable food

Balance risk against whetherrequired, unavoidable, or notmeasurable

Ensure adequate, wholesome,economical food supply; otherways pesticide affects con-sumers; usefulness

Balance risks against efficacyand need

Balance risks against drug ben-efits

No explicit consideration of ben-efits

Pesticide must not only be safeunder conditions of use, butalso effective

Risks posed by chemical mustbe balanced against bene-fits it provides (i.e., risk mustbe unreasonable)

NA

“Adequate margin of safety”

Water quality criteria do notconsider economic or tech-nological feasibility

MCLGs do not consider fea-sibility, but MCLs do

Balance risks against productutility, cost, and availability

“the public health and safetycan be adequately served”

Chapter 7—The Federal Regulatory Response ● 161

Table 7-l—Key Features of Federal Laws Regulating Toxic Substance-C o n t i n u e d

Regulatory authority Toxic substance orStatute (regulatory agency)a effect of concern Approach to riskFederal Mine Safety and Set standards for airborne con-

Health Act taminants in mines (MSHA)

Occupational Safety and Set standards for airborne con-Health Act taminants in the workplace

(OSHA)

Part III-Control-Oriented LawsComprehensive Environmental Fund cleanup of hazardous waste

Response, Compensation, sites; designate reportableand Liability Act; Superfund quantities for environmentalAmendments and Reauthor- release; report on communityization Act preparedness and release;

prepare toxicity profiles oncontaminants (EPA)

Controlled Substances Act Control drugs that have po-tential fo rabuse (USDJ, FDA)

Lead-Based Paint Poisoning Determine, if possible, a safePrevention Act level of lead in paint (CPSC)

Marine Protection, Research, Regulate ocean dumping (EPA)and Sanctuaries Act

Poison Prevention Promulgate standards for pack-Packaging Act aging substances that could

produce effects of concern(CPSC)

Resource Conservation and Regulate the handling of haz-Recovery Act ardous wastes; list hazard-

ous wastes on basis of constitu-ents (EPA)

“protection of Iife and preventionof injuries. . . material impair-ment of health or functionalcapacity”

“material impairment of healthor functional capacity”

“substantial danger to the pub-lic health or welfare”

“substantial and detrimental ef-fect”

Poisoning of children by lead-based paint

“adversely affect humanhealth, welfare or ameni-ties”

“serious personal injury or seri-ous illness”

“protect human health . . . seri-ous irreversible or inca-pacitating reversible illness

substantial present orpotential hazard”

Attain highest degree of healthand safety protection; latestavailable scientific data; fea-sibility; and experiencegained with health and safetylaws

Attain highest degree of healthand safety protection; latestavailable scientific data; fea-sibility; and experiencegained with health and safetylaws

Focus on highest-risk chem-icals

Define list of substances to becontrolled

Determine whether any safelevel could be establishedabove 0.06°/0

Consider appropriate alternativelocations

Determine degree and natureof hazard to children

Control handling to minimizerisks

aList of acronyms is given in app. F.


litigation may further modify the regulatory process.Furthermore, regulations may incorporate direct orindirect economic incentives in attempting to moti-vate industry to control pollutants (see ch. 9), addinganother dimension to regulatory implementation.Clearly, the regulatory processes described hereinare not rigidly circumscribed but are part of a largerregulatory dynamic (14).

LICENSING AND REGISTRATIONLEGISLATION AND

REGULATIONSThree statutes govern most aspects of the licens-

ing and registration of drugs, food additives, pesti-cides, and industrial chemicals: the Federal Food,Drug, and Cosmetic Act; the Federal Insecticide,

Fungicide, and Rodenticide Act; and the ToxicSubstances Control Act. All of these statutes requiresubmission of applications for use of, or notificationof intent to use, new chemical substances; they alsoauthorize reviews of previously registered chemi-cals. The review processes followed under these actshave

1.

2.

3.4.

four basic steps:

manufacturer’s submission of data;evaluation of data by the responsible regula-tory agency;requests for additional data (if necessary); andagency determination (which may or may notinvolve a formal rule-making procedure).

The extent to which neurotoxicity is addressed in theprocess varies among and within statutes according


Box 7-A—Toxic Substances Laws Go To Court: The Judicial Role in Interpreting LegislativeLanguage and Regulatory Implementation

The passage of a statute by Congress establishes overarching boundaries for regulatory implementation, buttranslating Congress’ goals, as stated in the legislative language, into regulatory action is by no means a simpleprocess. Environmental laws abound with general phrases calling for protection of “public health and theenvironment’ or for protection from ‘adverse effects’ some laws require that standards incorporate a‘ ‘marginof safety. ” The definition of these phrases often depends on the ever-changing forefront of scientific researchinto what levels of toxic substances may cause adverse effects—what, indeed, should be defined as an adverseeffect—and, based on the often uncertain conclusions of preliminary research, what constitutes a margin ofsafety. Congress leaves the interpretation of its mandates to the discretion of the Federal regulatory agencies.

Thus, regulatory agencies get the first opportunity to interpret what Congress meant, but their responses aremodified by many factors: the appropriations process; oversight by the Office of Management and Budget;requirements of the Administrative Procedures Act that the agency notify and obtain comments from the publicon any proposed regulations and that it respond to all significant comments; recommendations of scientific ortechnical advisory panels; recognition that standards and regulations may have a profound effect on productlitigation; and other internal and external pressures and requirements. It typically takes from 2 to 8 years for anagency to promulgate a rule, and the rule is then subject to further examination and interpretation through courtchallenges and interpretive rulings.

Administrative and procedural complexities have made environmental statutes the most frequently litigatedof all fields of administrative law (Grad, 1985). During litigation, courts must evaluate agencies’ interpretationsof congressional intent, and they must often evaluate the complex underlying technical issues as well—includingthe definitions of adverse effects or margins of safety. The judicial interpretation may have a considerable impacton how the legislative language can be interpreted and how the regulations can be implemented.

In at least one case, the Federal district courts have upheld the use of neurotoxic effects in the setting ofstandards. In 1980, the Lead Industries Association, Inc., brought suit against the Environmental ProtectionAgency (EPA), charging that the Administrator went beyond the scope of his authority in setting standards forlead under the Clean Air Act. EPA had issued a rule setting the primary national ambient air quality standardfor lead on the basis of its effects on the blood and on the nervous system (43 FR 46254). After considerablestudy, EPA had determined that lead’s effects on the nervous system begin to appear at the level of 50 microgramsof lead per deciliter of blood (ug/dl), that anemia and other effects appear at 40 ug/dl, and that identifiable changesin the blood (though not easily diagnosed through clinical examination) begin at 30 ug/dl. To provide an adequatemargin of safety, EPA set a target for the population of 15 ug/dl.

Among other arguments, the Lead Industries Association contended that the EPA’s rule was not adequatelysupported by the finding that neurotoxic effects begin to appear at 50 ug/dl and that basing the standard onsubclinical effects at 30 ug/dl went beyond the Agency’s statutory authority. The courts upheld EPA’s findingon neurotoxicity, stating that the record revealed ample support for the Administrator’s determination of whencentral nervous system effects begin to occur. The decision noted that it was not the function of the court ‘‘toresolve disagreement among the experts or to judge the merits of competing expert views. ’ (“ [C]hoice amongscientific test data is precisely the type of judgment that must be made by EPA, not this court. That evidence inthe record may also support other conclusions, even those that are inconsistent with the Administrator’s, doesnot prevent us from concluding that his decisions were rational and supported by the record. ’ The court furtherupheld EPA’s justification for the margin of safety, noting that the legislative history of the Clean Air Act showsthat margins of safety were considered essential for protecting against hazards that had not yet been identified.

Judicial interpretation is one of many factors influencing the implementation of regulations; as this caseshows, it may strengthen an agency’s regulatory decisions. As for neurotoxic effects, which have rarely beenexplicitly mentioned in statutes, the courts may play an important role in ensuring that they are considered inthe process of protecting public health and the environment.

SOURCES: F.P. Grad, “A Brief Account of the Beginnings of Modern Environmental Law,” Treatise on Environmental Law, sec. 1.01 (St.Paul, MN: Matthew Bender, 1985); “kid Industries Association, Inc. v, U.S. Environmental Protection Agency, ” FederalReporter (2d series) 647:1130-1189, 1980.


@, ‘ L - /


to the type of substance being reviewed and whetherit is a new or existing substance.2

Federal Food, Drug, and Cosmetic Act

The earliest Federal statute governing food safetywas the Food and Drugs Act of 1906 (19), whichprohibited the marketing or transport of “adulter-ated food,” that is, any food that contained “any

added poison or other added deleterious ingredientwhich may render such article injurious to health. ”The Federal Food, Drug, and Cosmetic Act (FFDCA)(21 U.S.C. 301-392),3 which replaced the originalAct in 1938, expanded controls to include naturallyoccurring as well as added toxic substances. How-ever, it did not delineate specific toxic effects. TheAct is based on a broad concept of safety as absenceof injury:

A food shall be deemed to be adulterated-if itbears or contains any poisons or deleterious sub-stances which may render it injurious to health; butin case the substance is not an added substance, suchfood shall not be considered adulterated under thisclause if the quantity of such substance in such fooddoes not ordinarily render it injurious to health . . .[sec. 402(a)(l)] [emphasis added].

Thus, added substances are governed by a stricterstandard than naturally occurring substances. Sinceits passage, FFDCA has been clarified and expandedby various amendments, but the language referringto toxic effects remains the same.

The Act grants the Food and Drug Administration(FDA) authority to regulate foods, drugs, andcosmetics in the following categories:

. food and general safety (sec. 402),

. environmental contaminants (sec. 406),

. pesticide residues (sec. 408),

. food additives (sec. 409),

. drugs and biologics (sec. 505),● cosmetics (sec. 601), and. color additives (sec. 706).

FDA can use this authority to require premarketsubmission of specific toxicity test data. It couldincorporate neurotoxicity tests in the guidelines forrecommended testing or require neurotoxicity test-ing during the application process if there isevidence of potential neurotoxic effects.

Environmental Contaminants of Food

FDA is authorized to regulate unavoidable con-taminants of raw agricultural commodities under”either the general food safety provisions (sec. 402)or the specific provisions of section 406, which callsfor FDA to:

2~e information in t~s section is draW pnm~]y from person~ comm~ica~ion wi~ offlci~s al the respective agenCieS.

3A11 Unitd States Code (U. S. C.) citations refer to the 1982 edition, unless otherwise noted.


. . . promulgate regulations limiting the quantitytherein or thereon to such extent as. . . [is] necessaryfor the protection of public health, and any quantityexceeding the limits so fixed shall also be deemedunsafe . . . (21 U.S.C. 346).

In setting the limits, FDA must consider whether thesubstance is required or unavoidable in the produc-tion or processing of the food item and the potentialeffects of the substance on health. Though notincluded in the statute, the extent to which thesubstance can be detected in foods is also consid-ered, since it would be impossible to enforce limitsthat could not be detected (19).

FDA asserts that it is not always appropriate to setformal tolerance levels for contaminants-e.g., whennew toxicity data are being developed for a sub-stance that previously had little or none (39 FR42745). In addition, the formal rule-making proce-dure demanded for setting tolerances is elaborateand time-consuming. Given these circumstances,FDA has chosen to rely primarily on a regulatoryoption not explicitly established by statute—that ofsetting informal tolerances, called action levels. An“action level is based on the same criteria as atolerance, except that an action level is temporaryuntil the appearance of more stable circumstancesmakes a formal tolerance appropriate” (39 FR42745 ).4 Action levels are not binding, nor do theyhave the legal force of tolerance levels, but they canbe used to “prohibit any detectable amount of thesubstance in food” (21 CFR part 109.4). Any foodthat contains more than the action level dictates maybe declared adulterated and be subject to furtherregulatory action.

In establishing either an action level or a toler-ance, FDA uses available information on healtheffects to determine a dosage at which risk ofexposure to a contaminant is acceptable. Once theaction level or tolerance is established, FDA maytake appropriate action to restrict food that does notmeet these standards.

Pesticide Residues

The 1954 amendments to FFDCA empoweredFDA to set and enforce standards for pesticideresidues on raw, unprocessed agricultural commodi-ties. More recent amendments bestowed the standard-

setting responsibility on the Administrator of theEnvironmental Protection Agency (EPA):

The Administrator [of EPA] shall promulgateregulations establishing tolerances with respect tothe use in or on raw agricultural commodities ofpoisonous or deleterious pesticide chemicals and ofpesticide chemicals which are not generally recog-nized . . . as safe for use, to the extent necessary toprotect the public health [sec. 408(b), 21 U.S.C.346a, 1976)].

Pesticides that are expected to become moreconcentrated during processing require separatetolerances. EPA may revoke or change tolerances ifnew evidence or further review indicates that achange is necessary (29).

The establishment of tolerances takes place con-currently with pesticide registration under the Fed-eral Insecticide, Fungicide, and Rodenticide Act,described below. The manufacturer petitions EPA toset a tolerance for the pesticide residue; the pesticidecannot be registered for use on a food or feed cropuntil a tolerance has been set or an exemptiongranted (48). The FFDCA specifies that a pesticidetolerance petition include “full reports of investiga-tions made with respect to the safety of the pesticidechemical” [sec. 408(d)(l)(C)], thus placing theburden of proof of the safety of a pesticide on themanufacturer.

Food and Color Additives

The Food Additives Amendment of 1954 (PublicLaw 85-929) sought to “prohibit the use in food ofadditives which have not been adequately tested toestablish their safety. ” The amendment initiated anapplication process for the approval of food addi-tives that, like the pesticide tolerance provisions,shifted the burden of proof from the FDA to theproducer.

Manufacturers must file a written petition beforea potential food additive can be approved for use.The petition must contain “scientific data adequateto support safety” (15) and “. . . full reports ofinvestigations made with respect to the safety for useof such additive, including full information as to themethods and controls used in conducting suchinvestigations’ [sec. 409(b)(2)(E)].

4RWent ~o~ ~h~lenge~, however, have ~e+u]t~ in ~ dwision rquifig ~A to subj~t propos~ action ]evels to public notification ad COIIIIWXlt;

FDA incorporated the decision in a proposed rule in April 1989 (54 FR 16128-30). It remains to be seen whether action levels will continue to offer astreamlined alternative to the setting of tolerances.


w

FDA decides whether, and in what amounts, afood additive may be used on the basis of the datasubmitted with the application. It has drawn itsinterpretation of safety from the legislative historyof the Act, which used the phrase “reasonablecertainty of no harm,” and has incorporated thatstandard into its regulations regarding toxicitytesting (15).

Color additives to food are regulated under theColor Additive Amendments of 1960. These regula-tions are essentially the same as those for foodadditives, including a process of premarketingapproval. In addition, color additives to drugs andcosmetics are regulated. A color additive may beapproved for general or restricted use if it is foundthat “it is suitable and may be safely employed”[sec. 706(b)(2)].

Petitions for approval of food and color additivesare handled by FDA’s Center for Food Safety and


Applied Nutrition (CFSAN). These include directfood additives (e.g., preservatives) and color addi-tives, as well as indirect additives, such as constitu-ents of packaging materials that might migrate intofood. Although the application process officiallybegins with submission of the petition and support-ing data, CFSAN may, and frequently does, holdinformal preapplication meetings with petitioners toclarify data needs.

Each application must contain all data relevant toassessing safety. The tests required are determinedon the basis of predicted exposure. For direct foodadditives, CFSAN test guidelines, known as the RedBook, list particular exposure levels and characteris-tics of chemical structure that require certain typesof tests (30). Most substances must be subjected tosubchronic studies in mammals as well as reproduc-tive tests. No specific neurotoxicity tests are re-quired, but the protocols do call for observation of


effects on animal behavior, so some prediction ofadult or developmental neurotoxicity, or both, maybe provided. The test requirements are negotiable,but the petitioner must present sufficient data toensure a reasonable certainty that no harm will resultfrom the use of the additive.

The Red Book is currently being revised, and thenew version may contain specific tests for neurotox-icity. The precise nature of these tests is still underreview. In order for FDA to impose any additionaltesting requirements, it must show that further testsare necessary.

Petitions must be reviewed within 90 days ofsubmission, although FFDCA permits extensions to180 days. Each petition is evaluated by seniorscientists from CFSAN’s Division of ToxicologicalReview and Evaluation. Most reviewers are generaltoxicologists; the division has had neurotoxicolo-gists directly involved in reviewing petitions in thepast, but few in 1988 or 1989. If the data indicateneurotoxic effects, the division may call on theNeurobehavioral Toxicology Team-neurotoxicol-ogists who are not generally members of the reviewteam-for further research. This team has beenasked to review three chemicals in the last 5 years;the total number of chemicals reviewed by CFSANduring that period is uncertain, but the centerannually reviews approximately 60 indirect foodadditives, 10 direct food additives, and 10 coloradditives.

If the toxicological data submitted with a petitionare insufficient for reaching a conclusion on whethera substance poses unreasonable risks, CFSAN nego-tiates with the petitioner to conduct additional tests.New data must be submitted within 180 days,although extensions may be given for reasonablecause. (Time spent on developing new data is notcounted in the time limit by which FDA must act onthe application, and if the necessity for new informa-tion is a result of the petitioner’s failure to submit alldata that were clearly required, the FDA may resetthe clock to day 1 when the additional data aresubmitted.)

If CFSAN determines, on the basis of toxicologi-cal data and potential exposure patterns, that asubstance may be harmful, the food or color additivepetition may be denied. Alternatively, FDA mayimpose limits on the amount of additives that will beallowed in foods. If the petition does not containenough evidence for CFSAN to make a determi-

a

nation on the safety of a substance, and if thepetitioner is unable or unwilling to develop thenecessary data, CFSAN requests that the petition bewithdrawn or the petition is denied approval.

To date, CFSAN has reviewed the neurotoxicpotential of a variety of direct food additives,indirect food additives, and color additives, includ-ing:

●

●

●

●

●

●

●

●

●

acrylamide (as a contaminant of polymer foodcontact surfaces),acrylonitrile (as a contaminant of polymer foodcontact surfaces),aspartame (artificial sweetener),chlorofluorocarbons (Freon 12),cyclamates (artificial sweeteners),erythrosin (FD&C Red No. 3),methyl chloride (as solvent for hop extract),methyl tin compounds (as stabilizers for plas-tics),organophosphites (antioxidants in food pack-aging):-di-tert-butylphenyl phosphite,--octadecyl phosphite, and—Tris phosphite.

As noted above, the Neurobehavioral ToxicologyTeam does not regularly participate in such reviews.

Drugs and Biologics

Drugs are regulated under various categories,including new drugs (for humans), biologics (bio-logical products such as vaccines), and animaldrugs. The statute requires submission of a new drugapplication (NDA) before a drug can be approved formarket. The NDA must contain “substantial evi-dence” that the drug is both safe and effective:

. . . evidence consisting of adequate and well-controlled investigations, including clinical investi-gations, by experts qualified by scientific trainingand experience to evaluate the effectiveness of thedrug involved, on the basis of which it could fairlyand responsibly be concluded by such experts thatthe drug will have the effect it purports or isrepresented to have under the conditions of useprescribed . . . [sec. 505(d)(7)].

This is generally considered to be the higheststandard for drug approval in the world.

The statute also provides that FDA shall notapprove a drug if it finds deficiencies in the safetytests conducted or if the test data indicate a lack of


safety. If clinical investigations “do not includeadequate tests by all methods reasonably applicableto show whether or not such drug is safe for useunder the conditions prescribed, recommended, orsuggested in the proposed labeling thereof or if“the results of such tests show that such drug isunsafe for use under such conditions or do not showthat such drug is safe for use under such conditions,’FDA is directed to refuse the application [sec. 505(d)(1) and (2)].

FDA may deny approval of a new drug on thefinding of “an imminent hazard to the publichealth” [sec. 505(e)]. If the application is approved,FDA specifies how the drug is to be packaged,labeled, and so on. New drugs that are identical topreviously approved drugs are subject to an abbrevi-ated application process.

Biologics, including “any virus, therapeutic serum,toxin, antitoxin, vaccine, blood, blood component,allergenic product, or analogous product” (42 U.S.C.262), are under the purview of a complex regulatorymechanism combining provisions of both FFDCAand the Public Health Service Act. Because they arealso defined as drugs, most biologics must be testedand approved by the same process FDA uses for newdrugs (29).

Animal drugs are approved under essentially thesame process as human drugs, with the additionalprovisos that FDA must consider “the probableconsumption of such drug and of any substanceformed in or on food because of the use of suchdrug’ and the ‘cumulative effect on manor animalof such drug” [WC. 512(d)(2)(A)].

FFDCA also requires reporting of adverse drugreactions, both during the application process [sec.505(i)] and after a drug has been approved [sec.505@]. “Adverse reactions” are defined by FDA as"

. . . any adverse experience associated with the useof a drug, whether or not considered drug-related,and includes any side-effect, injury, toxicity, orsensitivity reaction, or significant failure of expectedpharmacological action” (21 CFR 310.301). Thisrequirement for reporting adverse reactions could beused to gauge the effectiveness of the drug approvalprocess.

Applications for approval of new or investiga-tional prescription drugs are handled by FDA’sCenter for Drug Evaluation and Research; biologicalproducts are handled by the Center for Biologics

Evaluation and Research. The approval process fora new drug generally takes about 3 years, but it cantake up to 7 years. (The shortest approval time todate, for azidothymidine (AZT), used to treat AIDS,was 7 months.)

An NDA must contain data from all prior preclin-ical (animal) and clinical (human) studies. Clinicalstudies are conducted in three phases. Phase 1consists of short-term tests designed to elucidatehow the drug is metabolized in humans, to obtainbasic pharmacological and toxicological data inhumans, and, if possible, to find evidence that thedrug is effective in humans. Phase 2 tests are theinitial controlled clinical trials and studies of short-term side-effects. Phase 3 generally consists ofcontrolled and uncontrolled clinical trials in a largergroup of subjects. These trials are intended toprovide the additional information on safety andeffectiveness needed to determine the risk-benefitratio of the drug and to draft appropriate labeling.

All drugs that have not been previously tested inhumans, or for which additional clinical data arerequired before NDA submission, must submit aninvestigational new drug (IND) application beforethe sponsor can initiate clinical trials. New drugsthat have previously undergone clinical trials, suchas drugs that have been approved in other countries,may skip the IND application (if they have alreadybeen subjected to adequate, well-controlled clinicaltrials).

FDA has developed guidelines for the types ofnonclinical studies that are needed to supportapproval of different types of clinical trials. Theguidelines do not, for the most part, call for specifictests for toxic effects (the prevailing view at theCenter for Drug Evaluation and Research is thatrigid test guidelines rapidly become obsolete andmay lead to false assurance of the safety of a drug).Instead, the guidelines allow for considerable lati-tude in the selection of test protocol. The finalselection of test protocols requires that the petitionerconvince FDA that the data are adequate and thatFDA convince the petitioner that its requirementsare not unreasonable.

An IND is reviewed by a general toxicologist.Drugs that are not designed to cause neuropharma-cological effects are not necessarily reviewed sepa-rately for neurotoxicity, although behavioral effectsare evaluated in animal reproduction studies andneuropathology is conducted as part of the sub-


chronic studies required for the IND. A specificreview for neurotoxicity is initiated only if there iscause for suspicion. Outside experts may be calledin for such reviews through mechanisms such asstanding committees and special review committees.Drugs that are designed to act on the nervoussystem—i.e., neuroeffective substances—are re-viewed separately by neurotoxicology specialistsfrom the Division of Neuropharmacological DrugProducts of the Center for Drug Evaluation andResearch’s Office of Drug Evaluation I.

After the phase I tests have been concluded, theapplicant must conduct appropriate additional non-clinical toxicity tests. The data required hinge on theparticular clinical trial under consideration. A l-yearanimal study incorporating ophthalmological exam-inations and behavioral observations is required forall drugs. (For a drug to be prescribed to women ofchildbearing age, reproductive toxicity studies areroutinely conducted; the reproductive studies mayprovide some evidence regarding the potentialteratological effects of the drug.)

Positive evidence of toxic effects can lead totermination or modification of the clinical trials,depending on the nature of the evidence, the seventyof the effects, and the disease that the drug isintended to treat. If the animal data included in eitherthe IND application or NDA are inadequate, FDAwill issue a “clinical hold” order to delay furtherclinical testing until the appropriate preclinical dataare developed.

Postmarked monitoring of drugs occurs throughFDA’s spontaneous adverse report monitoring sys-tem. Any person observing an adverse reactionassociated with the use of a drug may submit a DrugExperience Report (form FDA-1639) directly toFDA or to the drug’s manufacturer, who, in turn, isrequired to report the information to FDA (21 CFR1989 ed. 314.80). About 90 percent of the adversereports FDA now receives are obtained throughmanufacturers and 10 percent through direct reports.Analysis of these reports constitutes FDA’s devicefor monitoring the adverse effects of prescriptiondrugs, including effects not noted during premarkettests or clinical trials. However, as described in box7-B, the system is limited in many respects.

No specific neurotoxicity tests are required fordrugs that are not expected to be neuroeffective.

Some FDA scientists believe that it is more appro-priate to conduct general preclinical toxicologicaltests than to focus on specific tests. FDA scientistsdo not appear to have reached a consensusregarding the validity of preclinical neurotoxicitytests as predictors of clinical effects. They arguethat it is difficult to design clinical trials that testspecifically for neurotoxic effects.

Cosmetics

Substances used in cosmetics are subject only tothe “may render it injurious” clause (sec. 601 ofFFDCA). FDA cannot require any toxicity testing. Itcan, however, require that any cosmetic product thathas not been adequately tested be packaged with awarning label stating that ‘the safety of this producthas not been determined” (21 CFR ed. 740.10).FDA has restricted or prohibited the use of fewerthan 20 ingredients on the finding that they were“poisonous or deleterious” (21 CFR ed. 700.11,21CFR ed. 250.220) (29).

Proposed Amendments

Among the proposed amendments to the FFDCAthat have been introduced during the 10lst Con-gress, the Food Safety Amendments of 1989 (identi-cal versions were introduced in the House andSenate as H.R. 1725 and S. 722, respectively) arepotentially relevant to toxic substances regulation. Akey provision of these bills is an attempt to define astandard of “negligible risk” that would apply topesticide residues on food without regard to balanc-ing costs and benefits. This definition would replacethe current approach, under which pesticide toler-ances for both raw commodities and processed foodsare set at a level to protect the public’s health unlessthe pesticide is a carcinogen, in which case nodetectable amount is allowed in processed foods.Hearings have been held on the bills, but neither hasbeen voted on by the full assembly.5 If passed, thenegligible risk provisions—and the absence ofauthority for cost-benefit analyses-could havefar-reaching consequences in the regulation ofpesticide residues.

Federal Insecticide, Fungicide, andRodenticide Act

FIFRA was enacted in 1947 to replace the 1910Federal Insecticide Act. FIFRA expanded the con-

5AS of February 1990.


Box 7-B—Limitations of FDA’s Postmarked Monitoring System for Adverse Drug Reactions:Halcion, A Case Study

Halcion, the most widely prescribed sleeping medication in the United States, was first approved for use in late1982 with a recommended usual adult dose of 0.25 to 0.50 mg. Its package insert included mentions of amnesia,confusion, agitation, and hallucinations as possible side-effects. Over the next few years, FDA’s adverse reactionmonitoring system recorded an excess of adverse reports for Halcion in comparison to other benzodiazepinehypnotics-even after correcting for market share of the drug. In 1987, as a result of the reports and the apparentdose-relatedness of some adverse effects, several labeling and marketing changes were made. The usual adult dosewas changed to 0.25 mg, two paragraphs mentioning the apparent dose-relatedness of some side-effects were addedto the package insert and a “Dear Doctor” letter was issued detailing the labeling changes. In early 1988, Upjohn,the manufacturer, discontinued the 0.50 mg tablet.

Following these changes, public concern about possible problems associated with Halcion use increased,largely because of a September 1988 article in California Magazine and a story on the ABC television program20/20 in February 1989. The number of adverse reports received, which was expected to decline as a result of thelabeling changes and Halcion’s status as an “older” drug (the number of adverse reports associated with a drugnormally decreases over time), rose. In September 1989, FDA convened an expert panel to review the reporting dataon Halcion and to discuss whether further changes should be made in the labeling or marketing of the drug.

Discussion at that meeting illustrates the difficulties of drawing conclusions from the spontaneous adversereporting process. In a comparison of adverse reports for Halcion (45 million prescriptions written since 1982) withadverse reports for Restoril (35 million prescriptions written since 1980), a drug prescribed to patients with similarsleeping problems, the following data were presented:

Total number of reports received by FDAAdverse event Halcion RestorilAmnestic events 267 4Hallucinations, paranoid behavior 241 12Confusion and delirium 304 17Hostility and intentional injury 48 2

Overall, an average of 38 adverse reports per million prescriptions was received for Halcion, while 7.5 adversereports per million prescriptions were received for Restoril.

These seemingly dramatic results, however, were tempered by myriad complicating variables, The influenceof publicity, differences in reporting rates by manufacturers, lack of dosage information in about one-half of theadverse reports for Halcion, and “new drug” v. ‘‘older drug’ effects all obscured the significance of differencesbetween the sets of data, The 4-week period following the 20/20 episode, for example, produced twice as manyadverse reports for Halcion as the 4-week period preceding the show. The FDA panel finally concurred that the datawere too unreliable to warrant action, except possibly in the case of amnesia.

The unreliable data generated by the postmarketing monitoring system now in place effectively limit FDAreview to premarket trials. Unexpected interactions with other medications or long-term side-effects may easily bemissed. This is particularly disturbing from the standpoint of neurotoxicity, since drugs not expected to haveneuropharmacological effects are not necessarily subjected to specific neurotoxicity testing. Changes which couldimprove the present system might include a requirement that all adverse report forms be sent directly to FDA aswell as a requirement that physicians submit reports for all ‘‘serious” adverse reactions observed.

Because of the inherent limitations in FDA’s drug approval and adverse reaction monitoring systems, it isimportant that physicians and patients be aware of the possible adverse effects of the medications they prescribeand consume. Drugs are approved for use under certain conditions and at certain doses, and complicating factorssuch as age, other medications, or illness may significantly alter the effects of these drugs. In most cases, the decisionto take any medication is a personal choice for the patient; an individual cannot make an informed decision withoutaccess to information about potential adverse effects.

SOURCES: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, PsychopharmacologicalDrugs Advisory Committee, Transcript of Proceedings, Thirty-First Meeting (Rockville, MD: September 1989); “When SleepBecomes a Nightmare,” 20/20, ABC, Feb. 17, 1989; Pharmaceutical Data Services, ‘‘Top 200 Drugs of 1989,’ American Druggist,in press.


sumer protection aspects of the earlier statute byinstituting a premarket registration procedure for allpesticides in interstate commerce. The 1972 amend-ments—the Federal Environmental Pesticide Con-trol Act (Public Law 92-516)—shifted the emphasisfrom consumer protection to the protection of publichealth and the environment (47). Amendments in1975 (Public Law 94-140), 1978 (Public Law95-396), 1980, and 1988 refined the regulatoryprocedures embodied in the legislation but main-tained the focus, namely, to govern pesticide use toprevent “unreasonable adverse effects. ” FIFRAuses a broad standard for adverse effects:

. . . any unreasonable risk to man or the environ-ment, taking into account the economic, social, andenvironmental costs and benefits of the use of anypesticide [sec. 2(bb)] [emphasis added].

The statute prohibits the sale or distribution of anypesticide in the United States unless it is registeredor exempt from registration under FIFRA. It givesEPA considerable authority to require submission ofdata, including neurotoxicity tests, as part of theregistration process for new and existing chemicals.The statute places the burden of proof of safety onthe manufacturer, although in the case of existingpesticides, EPA may have to go to considerablelengths to prove the inadequacy of data before it cancall for further data or regulatory action.

New Pesticide Registrations

FIFRA calls for premarket review and registrationof both new pesticides and pesticides with newactive ingredients.6 A pesticide may be registered ifEPA determines that, when considered with anyrestrictions on use:

●

●

●

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its composition is such as to warrant theproposed claim for it;its labeling and other material required to besubmitted comply with the requirements of theAct;it will perform its intended function withoutunreasonable adverse effects on the environ-ment; andwhen used in accordance with widespread andcommonly recognized practice, it will notgenerally cause unreasonable adverse effects

IthB

Photo credit: National Archives

on the environment [sec. 3(c)(5)] [emphasisadded].

The 1972 amendments enabled EPA to requirethat manufacturers submit whatever data EPA speci-fies for approval or continuation of the registration:

The Administrator shall publish guidelines speci-fying the kinds of information which will be requiredto support the registration of a pesticide . . . [sec.3(c)(2)(A)].

Applications for pesticide registration are submit-ted to EPA’s Office of Pesticide Programs (OPP).The applicant must demonstrate that anew pesticidewill be both safe and effective under the proposedconditions of use. In order to demonstrate efficacy,applicants must obtain an Experimental Use Permit(EUP) to conduct field studies. (An EUP application

bIne~ ~~~ents+me parts of tie ~sticide formulation not claimed to have any pesticidal activity-have not traditionally kn included in tieregistration process. EPA has recently begun to review and evatuate them, however. Although EPA believes that FIFRA provides the authority to requiretesting of inert ingredients of known toxicity, it is not clear how inert ingredients of unknown toxicity should be handled (l).


requires less extensive toxicity data than the regis-tration application, but the applicant must provideenough information to establish that the field testitself is safe.) EUPs are also obtained for new usesof a pesticide, such as application on a new crop. Ifthe pesticide is intended to be used on food or feedcrops, the applicant submits a petition for the settingof tolerances, which is done in tandem with theregistration process.

The toxicity data in each application are reviewedinitially by a toxicologist from OPP’s HazardEvaluation Division. The division has a neurotoxi-cologist on its staff who may be consulted ifnecessary, but the neurotoxicologist does not auto-matically participate in application reviews. Underdivision procedures, a single toxicologist is respon-sible for reviewing each application. The review isconducted in accordance with procedures codified inOPP’s Standard Evaluation Procedures or RiskAssessment Guidelines, or both. Limited neurotox-icity testing is required only for organophosphorouspesticides, but subchronic tests include a limitedevaluation of behavioral and pathological effects onthe nervous system.

If data provided with an application are deter-mined by EPA to be inadequate for a reasonableevaluation of potential hazards, the Agency willrequire additional toxicity testing. EPA may requiretests in addition to those specified in the testguidelines, if necessary, to clarify issues raised bythe data presented.

If OPP finds that a new pesticide presents anunreasonable risk of adverse effects, EPA may denythe registration altogether, restrict use of the pesti-cide to certain crops or to certain geographical areas,or require that it be applied under the supervision ofcertified applicators or that protective equipment beworn during application. In addition, EPA mayimpose specific labeling requirements (see box 7-C).

The FIFRA test guidelines (40 CFR ed. 158)contain very limited recommendations for neurotox-icity testing. At the present time, only organo-phosphates must be tested for neurotoxic effects, andthey are subject to just a single type of test—a hentest for delayed neuropathy (see ch. 5 for moreinformation on test procedures). Current guidelinesrequire limited neuropathological examinations andobservations for behavioral effects as part of acuteand subchronic toxicity studies. However, the testguidelines are now under revision, and new neuro-

toxicity test requirements are likely to be added (thedevelopment of new guidelines is described belowin the section on “new initiatives”). A review ofnew active ingredients registered in the past 5 fiscalyears revealed that out of 54 pesticides, including 20insecticides, only 3 were organophosphates.

Reregistration of Existing Pesticides

Because many pesticides were registered on thebasis of toxicity data that might now be consideredinadequate, EPA is reexamining the safety ofregistered pesticides. EPA may call for the registrantto develop new data for evaluating toxic effects ofthe pesticide. Section 3(c)(2)(B) of FIFRA states:

. . . If the Administrator determines that additionaldata are required to maintain in effect an existingregistration of a pesticide, the Administrator shallnotify all existing registrants.

In conjunction with the FIFRA reregistrationprocess, EPA is also mandated by FFDCA to settolerances for the maximum pesticide residuesallowed in or on various food and animal feed crops.EPA may periodically review previously set toler-ances, which are enforced by FDA and the U.S.Department of Agriculture (USDA) (48 FR 39499).As pesticides go through the reregistration process,EPA may decide that the tolerance levels need to bereassessed.

Reregistration of existing pesticides does notrequire the submission of applications or data.Rather, OPP initiates the process by reviewingavailable data from its internal files and, on rareoccasions, from the published literature. In the past,EPA has selected and scheduled reviews of chemi-cals with few restrictions, producing approximately25 registration standards (the document whichspecifies the conditions that a registrant must meetto maintain the registration of a pesticide) per year.The 1988 amendments to FIFRA mandated thatEPA review 600 active ingredients of existingpesticides by 1997 (i.e., more than 60 registrationstandards per year-a considerably faster rate thancurrent operating procedures have fostered). EPA,therefore, is developing procedures for conductingreregistration reviews more quickly and is determin-ing whether additional personnel will be required.

The evaluation process is similar to that for newchemicals and the test guidelines for re-registrationare the same as those for registration. OPP mayconsult with outside experts about what kinds of


Box 7-C—Regulatory Requirements for Labeling: How Effective Are They?Labeling requirements are a common regulatory tool for dealing with toxic but useful substances. Pesticides,

prescription and over-the-counter drugs, household substances, and all commercial poisons are subject to labelingprovisions incorporated in statutes such as the Federal Insecticide, Fungicide, and Rodenticide Act; the FederalFood, Drug, and Cosmetic Act; the Federal Hazardous Substances Act and the Consumer Product Safety Act.

Labels are intended to reduce the risks of exposure to, or harm from, toxic substances by alerting consumersto the dangers of a substance and providing instructions for its safe and proper use. When regulators make decisionscontingent on specific labeling requirements, they rely on at least three tacit assumptions: 1) that consumers willread the label; 2) that they will understand and believe it; and 3) that they will obey its instructions. Clearly, all threemust happen in order for labels to be effective in preventing dangerous exposures. But is it realistic to rely on labels?

Increasing evidence suggests that it is not. An Environmental Protection Agency (EPA) draft report on theeffectiveness of pesticide labeling finds several weaknesses in current schemes. The report which includes a surveyof representatives from the pesticide industry, State regulatory agencies, environmental organizations, andhousehold users, found that few people read an entire label and that many people may not even read the parts ofthe label that relate specifically to their intended use of the chemical. Labels maybe redundant and too technical;the information is often crowded and difficult to read; and the instructions may be vague or contradictory. (Forexample, the label on one rat poison instructed users to keep the poison away from wildlife.) Furthermore, thereare few guidelines on how to label for specific toxic effects, such as neurotoxicity, EPA concluded that many labelsare not well designed for their audiences and must be improved if they are to have any real effect.

What is the solution? EPA suggests measures such as greater use of hazard symbols, more readable and perhapsstandardized formats, and a uniform system of designating hazards so that consumers can recognize them moreeasily. EPA is developing criteria for the labeling of specific categories of toxic effects, including neurotoxicity;guidelines may be issued by early 1990.

Labeling requirements have often been central in product litigation cases. Court decisions have stressed theneed for labeling to protect humans from injury, and one State court ruled that even ‘‘compliance with Federallabeling requirements will not prevent the finding that the manufacturer had not fully disclosed the risks of aproduct” (Grad, 1985), It appears, then, that industry also stands to benefit by working with regulators to developadequate and effective labels.

SOURCES: U.S. Environmental Protection Agency, “Pesticide Label Utility Project Report, ” unpublished draft, April 1986; F.P. Grad,‘‘Pesticide Pollution-Labeling and Misbranding,’ Treatise on Environmental Law, sec. 8.03.4 (St. Paul, MN: Matthew Bender,1985).

additional data should be developed. If additional EPA has requested specific neurotoxicity test datadata are needed, EPA issues a data call-in, eitherthrough publication in the Federal Register or bysending letters to affected registrants. FIFRA grantsEPA the authority to request any additional data thatare determined to be necessary.

If EPA determines during the reregistration proc-ess that an existing pesticide ingredient may pose anunreasonable risk, the chemical may undergo aspecial review as described below. If registrants donot respond to the data call-in (as is generally thecase for pesticides that are no longer being manufac-tured), the registration is canceled. If, in the courseof reregistering a pesticide, EPA finds that it posesan unreasonable risk, the Agency may cancel orsuspend the chemical without initiating a specialreview.

in a number of cases. While the Agency’s databaseon registration standards does not enable investiga-tors to determine all chemicals for which neurotoxic-ity data call-ins have been issued, it does include adata call-in (under consideration) to evaluate nerv-ous system lesions that may be induced by thiocar-bamates and a developmental neurotoxicity studyprotocol on N, N-diethyl-m-toluamide (Deet), theactive ingredient in many mosquito repellents.

Active ingredients of existing pesticides undergospecial review if EPA finds that they may pose anunreasonable risk of adverse effects. The specialreview is a formal procedure; accordingly, a noticeof the initiation of the review and of each subsequentstep in the process must be published in the FederalRegister.


The review begins with an evaluation by EPAstaff similar to that conducted for the registration ofa new pesticide. In addition, EPA’s independentScience Advisory Panel examines each case, and theAgency seeks public comment as part of therule-making process. If a data call-in has not alreadybeen issued, EPA may issue one at this time. EPAcan request all data relevant to the question ofwhether a chemical poses unreasonable risks ofadverse effects.

If EPA determines that the risks of a pesticideoutweigh the benefits of its continued use, it maycancel or suspend registration of the pesticide orimpose restrictions on its registration. Registrationmay be suspended during the time it takes tocomplete the cancellation proceedings if EPA deter-mines that the risks of use during that time outweighthe benefits. A suspension may be appealed andpublic hearings requested. EPA may also issue anemergency suspension, which is immediate and


absolute and cannot be appealed. Other potentialrestrictions are the same as listed above for newpesticide registrations. Until 1988, EPA was re-quired to indemnify all manufacturers and consum-ers for any amounts of the pesticide they possessed,which made cancellation proceedings extremelycostly for pesticides that were being marketed insignificant quantities. Now, however, EPA mustreimburse only endusers (usually farmers).

About 14 special review decisions are made eachyear, one-third of which are final decisions to initiatespecial review. Five active ingredients are known tohave been reviewed for neurotoxicity. On furtherreview, three of these, dichlorvos, tributyl phosphoro-trithioate, and S, S, S-tributyl phosphorotrithioate,were returned to the registration process and two,acrylonitrile and EPN (phenylphosphonothioic acid,o-ethyl, o-p-nitrophenyl ester), were not (9). Regis-tration of acrylonitrile was voluntarily canceled;EPA imposed restrictions (protective clothing andnew labeling requirements) on the use of EPN(phenylphosphonothioic acid, o-ethyl, o-p-nitrophenylester), and subsequently all registrations were vol-untarily canceled. Aldicarb, which has well-documented neurotoxic effects, is subject to specialreview, but the principal focus of the special reviewis the potential of Aldicarb to contaminate ground-water. No chemical has undergone full specialreview for neurotoxicity.

Approximately 75 active pesticide ingredients areon EPA’s restricted use list (i.e., they may only beused under the supervision of a certified applicator),some of which are restricted because of concernabout their neurotoxic effects. While there arecertainly active ingredients whose use is restrictedbased on their neurotoxic effects (48 FR 39496),determining which ones was not feasible within thelimits of this survey.

Toxic Substances Control Act

The Toxic Substances Control Act (TSCA) (Pub-lic Law 94-469) was enacted in 1976 to “regulatecommerce and protect human health and the envi-ronment by requiring testing and necessary userestrictions on certain chemicals. ” Congress in-tended to create “adequate authority” to test andregulate chemicals in commerce that are not subjectto other statutes:

[A]dequate authority should exist to regulatechemical substances and mixtures which present an


unreasonable risk of injury to health or the environ-ment, and to take action with respect to chemicalsubstances and mixtures which are imminent haz-ards. . . [sec. l(b)(2)] [emphasis added].

TSCA defines several health and environmentaleffects of concern, including neurotoxic effects thatare exhibited as behavioral disorders:

The health and environmental effects for whichstandards for the development of test data may beprescribed include carcinogenesis, mutagenesis, ter-atogenesis, behavioral disorders, cumulative orsynergistic effects, and any other effect which maypresent an unreasonable risk of injury to health or theenvironment [sec. 4(b)(2)(A)] [emphasis added].

The statute, which is one of the most procedurallycomplex pieces of legislation in the area of humanhealth and the environment, sets forth a frameworkthat authorizes EPA to review the safety of existingchemicals, to receive premanufacture notices (PMNs)for new chemicals, to regulate hazardous substances,and to call for the reporting of data on health andenvironmental effects and substantial risks. EPAmay, in some cases, require that manufacturersconduct health and safety studies, but the burden of


proof is on the Agency to find that a chemicalsubstance or mixture may or will present an unrea-sonable risk to public health or the environment.

New Chemicals

TSCA requires manufacturers to notify EPA inadvance of the intended introduction into commerceof a new chemical (through PMNs) or the intendedmanufacture or processing of any chemical for asignificant new use. (The Act does not require PMNsfor the production of small quantities of chemicalsfor the purpose of research and development.)Submitters are required to present all test data thatindicate whether “the manufacture, processing,distribution in commerce, use, and disposal of thechemical substance or any combination of suchactivities will not represent an unreasonable risk ofinjury to health or the environment” [sec. 5(b)(2)(B)(i)].

EPA has 90 days (extendable under certaincircumstances to 180 days) to review the PMN. IfEPA determines that the chemical may present anunreasonable risk, it may prohibit or limit the use ofthe chemical in commerce until data are developedto permit a further evaluation of the chemical’seffects. If EPA decides that a substance “presents orwill present” an unreasonable risk, it may restrict orprohibit the production, use, or disposal of thesubstance.

The PMN contains data on a chemical’s identityand structure, proposed use, byproducts, and impuri-ties and is submitted to EPA’s Office of ToxicSubstances (OTS). Certain chemicals are also sub-ject to reporting under a significant new use rule(SNUR); EPA must be notified if such a chemical isto be used in a way that differs significantly fromthat proposed in the original PMN (usually becausethe evaluation of the PMN depended on a specificpattern of use).

Because TSCA does not require that manufactur-ers carry out any specific program of toxicity testingin order for new chemicals to be approved, PMNs arerarely submitted with toxicity data—fewer than 50percent of all PMNs and fewer than 65 percent ofPMNs for nonpolymers contain any toxicity data(5).PMNs that do include toxicity data generally pro-vide results from a minimal set of studies, perhapstwo or three acute tests and maybe a test for irritation(see ch. 5 for details on testing). The requirementfor manufacturers to submit all data in theirpossession may act as a disincentive to testing, in


that evidence of toxicity could lead EPA toconclude that there may bean unreasonable risk,whereas the absence of data will not do so.

Because the PMN generally provides few data,most evaluation is performed on the basis of thestructural analogues of the new chemical to existingchemicals and extrapolations from known propertiesof well-characterized chemical classes. Thus, thefirst stage of the PMN review is a computer-assistedsearch for structural analogues with known toxicity(or lack of toxicity). Senior OTS toxicologists withexpertise in various specialty fields then review thechemical’s potential toxicity. Their review is basedon the structure-activity relationships revealed bythe computer search and conducted by members ofthe review team. Until recently, neurotoxicologistswere not routinely present at the initial structure-activity meetings but were called on afterward ifconcerns about neurotoxicity were raised. Undercurrent OTS procedures, a neurotoxicologist ispresent at the initial structure-activity review and allappropriate meetings thereafter.

Unlike the public regulatory process for review-ing existing chemicals, the PMN process rarely callson reviewers outside of OTS. In addition, because ofthe high proportion of confidential business infor-mation that accompanies PMNs, little of the reviewprocess is open to the public (see box 7-D).

If toxicity is predicted on the basis of structuralanalogues, a chemical may be submitted to standardreview, a detailed examination that consumes muchof the time allotted for the PMN review. From fiscalyear 1984 through fiscal year 1987, approximately20 percent of the 6,120 PMN chemicals received adetailed review. Based on the standard review, EPAhas concluded that approximately 10 percent of allPMN chemicals may or will present unreasonablerisks of adverse effects on human health or theenvironment.

EPA cannot require additional toxicity data unlessit finds that a chemical mayor will present unreason-able risks. However, EPA can sometimes inducemanufacturers to develop the additional data thatEPA considers necessary by offering to suspend thePMN process in the meantime. In negotiating withmanufacturers, EPA may request tests listed in theguidelines for testing existing chemicals or addi-tional tests. If EPA finds that the chemical maypresent an unreasonable risk, it can halt the use of thechemical pending development of adequate data to

resolve the issue of risk. If EPA finds positiveevidence that a chemical presents or will presentunreasonable risks, it can ban or limit the use of thechemical.

A neurotoxicologist is present from the earlystages of a PMN review for all chemicals exceptpolymers, which, because of their low reactivity andlow potential for absorption, generally present lowertoxicity hazards and are thus evaluated separately.EPA has identified at least six classes of chemicals(acrylamide derivatives, acrylates, carbamates,phosphines and phosphates, pyridine derivatives,and imidazoles) that should alert reviewers to thepotential for neurotoxicity during the structure-activity review. Other chemicals likely to causeconcern include quaternary ammonium compounds,glycol ethers, and miscellaneous halogenated sol-vents. OTS is developing a more explicit set ofclassification criteria for neurotoxicity in order tostandardize the procedures; even so, EPA neurotoxi-cologists have expressed concern that accuratestructure-activity predictions may not be possiblewithout information on mechanisms of action,which is available for only a few classes ofchemicals (including quaternary ammonium, organ-ophosphate compounds, and some solvents).

Neurotoxicity concerns are one of the triggers forplacing a chemical into the standard review process.However, most chemicals identified as being poten-tially neurotoxic do not enter that process, for avariety of reasons, including lack of adequate data tosupport a case, lack of a strong structure-activityrelationship, data indicating that human exposurewould be minimal (or inadequate data on exposure),or lack of appreciation by individuals analyzing thedata of certain neurobehavioral effects.

Some 220 of the approximately 1,200 chemicals(out of 6,120 PMNs submitted) that underwentstandard review during fiscal years 1984 through1987 were identified as being potentially neurotoxic.However, neurotoxicity was not the basis for mostregulatory actions taken by EPA. EPA was not ableto provide precise information on the extent to whichconcerns about neurotoxicity did influence regula-tory decisionmaking, although such an analysis isnow pending (5,24).

Regulation of Existing Chemicals

Existing chemicals are regulated under severalsections of TSCA. Section 4 allows EPA to rule that


Box 7-D-Confidential Business Information Under TSCA: Does It InfluenceRegulatory Effectiveness?

In order to assess accurately the toxic risks posed by a chemical, a considerable amount of information mustbe reviewed, including the identity, properties, and intended uses of the chemical. Depending on the particularchemical and its application, some of this information may represent trade secrets that, if known to a competitor,would place the manufacturer or importer of a chemical at a competitive disadvantage.

The approach taken under the Toxic Substances Control Act (TSCA) toward the protection of trade secretshas been to allow nearly all information submitted to the Environmental Protection Agency (EPA) on apremanufacture notice (PMN) for a chemical to be claimed as confidential business information (CBI).Information covered by such a claim is divulged only to EPA employees who have been granted a special CBIclearance, primarily selected staff from and contractors for the Office of Toxic Substances (OTS). CBI may bereleased only if the Administrator determines that it is necessary to do so to protect against an unreasonable risk,and submitters must be given 30 days’ advance notice of CBI releases. EPA officials or officials of other Federalagencies may obtain access to needed CBI materials, but given the breadth of information covered by CBI claims,these officials are not in a position to know what CBI information in OTS files is relevant to the performanceof their duties.

The protection of CBI offered by TSCA is considerably greater than that offered by the confidentialityprovisions of some other laws. For example, under Title III of the Superfund Amendments and ReauthorizationAct, only the specific identity of a chemical covered by the reporting provisions of the Act can be claimed to beconfidential. Further, under TSCA, the burden of challenging CBI claims falls on EPA; PMN submitters are notrequired to substantiate CBI claims unless challenged.

Toxicity data per se cannot be claimed as CBI under TSCA, but much of the other information relevant toassessing toxic risks can be—including the identity of the chemical for which toxicity data are presented, itsphysical-chemical properties, and its intended uses. These provisions of TSCA present significant obstacles toeffective regulation, not only with respect to the PMN program, but also with respect to other regulatoryprograms, both inside and outside EPA. Three general types of obstacles can be identified: added administrativeburdens on OTS, interference with effective cooperation among regulatory programs, and prevention of publicoversight of the regulatory process.

Within the PMN program, CBI requirements have required OTS not only to maintain duplicate sets ofrecords (CBI and non-CBI), but also duplicate computer databases and even duplicate computers. Public interestgroups and other interested members of the public have no access to information that would allow them toquestioner to accept—EPA’s actions on PMNs, Neither can members of the public take any action forself-protection, as they are frequently kept from information regarding the identity of toxic chemicals or theproducts that might contain them. TSCA CBI provisions also pose a serious obstacle to the involvement ofregulatory, academic, and industrial scientists who could assist OTS in assessing the risks of PMN chemicals.

Because CBI has the capability to “contaminate” information systems (any document or informationsystem that contains CBI becomes CBI itself), the impediments to regulatory effectiveness posed by CBI havespread from the PMN program to programs dealing with other aspects of TSCA. Rule-making on asbestos is aparticularly egregious example, where much of EPA’s supporting analysis could not be made available for publicreview because it was based on CBI.

Persons involved in other regulatory programs, whether inside or outside of government, are not in aposition to obtain information that could make important differences in the implementation of regulations. AResource Conservation and Recovery Act permit writer in an EPA regional office, for example, will not haveaccess to information that might significantly influence decisions regarding the disposal of TSCA chemicals; andthe Consumer Product Safety Commission may not be made aware of information regarding chemicals inconsumer products.

Few persons would dispute the principle of protecting true trade secrets. There is good reason, however,to question whether the burden imposed by the liberal confidentiality provisions of TSCA on the government,the public, and even industry is justifiable. Industry has managed to adapt to the less protective provisions ofother laws, and alternative strategies for protecting proprietary information (e.g., patents) are available.


Chapter 7—The Federal Regulatory Response 177

chemicals or mixtures be tested for health andenvironmental effects if the Agency determines that:

(A)(i) the manufacture, distribution in commerce,processing, use, or disposal of a chemical substanceor mixture, or that any combination of such activi-ties, may present an unreasonable risk of injury tohealth or the environment (ii) there are insufficientdata and experience on which the effects of. . . suchactivities on health or the environment can reasona-bly be predicted, and (iii) testing of such substanceor mixture with respect to such effects is necessaryto develop such data; or (B)(i) a chemical substanceor mixture is or will be produced in substantialquantities, and (I) it enters or may reasonably beanticipated to enter the environment in substantialquantities or (II) there is or may be significant orsubstantial human exposure to such substance ormixture [sec. 4 (a)(l)].

If EPA can show that there is inadequate informa-tion on the effects of a compound and that testing isnecessary to obtain such information, it is requiredto write a test rule that defines what is to be testedand what particular tests are to be performed. OTShas developed guidelines that describe the generalprocedures for the conduct of toxicity tests (40 CFR796), although each test rule contains specificrequirements for the individual chemical involved.

In contrast to FIFRA, TSCA has mandated anexplicit means of identifying chemicals that must betested by EPA for their effects on health and theenvironment-namely, the Interagency Testing Com-mittee (ITC). The ITC is a multidisciplinary advi-sory panel composed of one member each fromEPA, the Occupational Safety and Health Adminis-tration, the Council on Environmental Quality, theNational Institute for Occupational Safety andHealth, the National Institute of EnvironmentalHealth Sciences, the National Cancer Institute, theNational Science Foundation, and the Department ofCommerce. ITC conducts an ongoing, independentreview of chemicals in commerce, based on recom-mendations from members as well as externalnominations, in order to select chemicals for testing.(ITC reviews data from the published literature andsolicits information from the public and frommanufacturers.) The committee recommends testingpriorities based on the finding that there are insuffi-cient data to assess the hazards posed by a substanceor the finding that potential human exposures aresignificant. (ITC has no overarching responsibility

to coordinate agency testing; it simply suggestshigh-priority chemicals for EPA to investigate.)

ITC publishes its findings in the Federal Registerand submits to EPA all data located on the sub-stance, as well as important gaps in data, by meansof a priority list which is updated every 6 months.The committee may indicate particular effects forwhich it believes that a substance should be tested,or it may simply point to high exposure and a generallack of data as justification for including a chemicalon the priority list.

Chemicals selected for review and testing aresubjected to an extensive evaluation by ITC mem-bers, experts called onto review documents, and anypersons who nominate chemicals for review. EPAthen conducts its internal review, which involves amultidisciplinary team, including neurotoxicolo-gists if indicated. The group may also requestassistance from EPA research personnel.

EPA examines the concerns raised by ITC anddecides whether or not to issue a test rule for asubstance. EPA is not limited to the issues raised byITC; it may decide that some concerns are unjusti-fied, or it may identify additional issues that werenot mentioned in ITC’s recommendations. The mainreasons for which EPA may decide not to test achemical are the determination that adequate data fora risk decision are available or that the chemical isno longer used in commerce. In three cases, EPA hasissued test rules on chemicals that were not nomi-nated by the ITC. If EPA decides to pursue testing,it may require tests on the basis of hazard concernsraised in the review or a high volume of production.EPA has developed guidelines for the types of teststhat may be required; these are published in the Codeof Federal Regulations (40 CFR 795; 40 CFR 798).

EPA can seek additional data under section 4 ofTSCA by negotiating a consent decree, which is alegally binding mutual agreement that industry willconduct specified tests and that EPA will not makeadditional requests. The process of negotiating aconsent decree can be faster and more efficient thanformal rule-making, and EPA generally prefers thisoption. In either case, the manufacturer must con-duct additional tests and submit the data to EPA ina timely manner. Once the test data have beendeveloped and submitted, section 6 of TSCA author-izes EPA to restrict or prohibit the production, use,and disposal of the substance if the data indicate anunreasonable risk.


Box 7-E—Regulating for Neurotoxicity v. Other Toxic Effects: The Case of Acrylamide

One of the first chemicals that the Interagency Testing Committee (ITC) considered, shortly after it beganoperations in 1977, was acrylamide, a chemical with a variety of commercial uses. Acrylamide was already knownto cause severe neurotoxic effects, but its ability to cause other chronic effects had not been well characterized. ITCnoted this state of research and recommended that acrylamide be tested for effects other than neurotoxicity. TheEnvironmental Protection Agency (EPA) had to decide whether the known neurotoxicity of this chemical wassufficient for regulatory purposes or whether additional data documenting its effects on health were necessary.

In its response to the ITC, EPA chose not to require testing of acrylamide, for two reasons. First, EPA believedthat acrylamide was so neurotoxic that regulatory restrictions would be imposed to the maximum degree possibleon the basis of known effects, and additional test information would be of little regulatory significance. Second, EPAnoted that a chemical company was already in the midst of performing a long-term bioassay for other effects, soif additional data were, in fact, necessary, they were already forthcoming.

When the chemical company in question learned that EPA was not going to require testing, it decided tosuspend its test for toxic effects other than neurotoxicity. EPA then had to decide whether neurotoxicity would beconsidered the driving effect or whether to impose new testing requirements. EPA retreated from its earlier positionthat the neurotoxicity data were sufficient and decided that data on other effects were needed. As a result, EPApersuaded the company to resume its testing and withheld assessments and final regulatory decisions pending thoseadditional data.

SOURCE: W.R. Muir, former director, Office of Toxic Substances, U.S. Environmental Protection Agency, and President, Hampshire ResearchAssociates, personal communication, 1988.

Neurotoxicity is one of the specific concerns that It may be necessary to examine other endpointsmay be identified by ITC in recommending that a for specific chemicals, depending on their structuresubstance be tested, in which case EPA mustrespond either by including a requirement forneurotoxicity testing in its test rule or by justifyingthe exclusion of neurotoxicity tests. In the 24 ITCreports to the EPA Administrator issued betweenOctober 1977 and May 1989, the ITC proposed 100chemicals or chemical classes7 for inclusion in theTSCA section 4 priority list for testing. Of theseproposals, one-third included an expression ofconcern regarding possible neurotoxicity (box 7-E).

Current EPA policy is to specify neurotoxicitytesting both when a chemical “may present anunreasonable risk” of neurotoxicity and when theremay be substantial human exposure. Under an ‘A’finding (an unreasonable risk finding), a core testbattery for neurotoxicity is recommended; the corebattery includes a functional observational battery(FOB), motor activity tests, and neuropathologicalevaluations. When appropriate, these tests can becombined with other toxicity studies. Unless other-wise specified, it is assumed that both acute andsubchronic testing will be conducted using the FOBand motor activity protocols, with neuropathologi-cal tests following subchronic exposures.

or the nature of existing data. Among the additionaltests specified in EPA guidelines are schedule-controlled operant behavior (SCOB), developmentalneurotoxicity, peripheral nerve function, and neuro-toxic esterase (NTE). For organophosphates andrelated compounds, study design would include a28-day repeated exposure period (e.g., 5 days perweek) and NTE, ataxia, and neuropathological tests.

Because of the wide variety of production levelsand exposure patterns among chemicals, EPA hasdeveloped a three-level approach to testing under a“B” finding (significant quantity finding). Testingof level 1 chemicals (low production, low exposure)generally includes the three core tests. FOB andneuropathology are considered a minimum require-ment, although a 28-day subchronic study may beused in place of the usual 90-day study. Fororganophosphorous compounds, acute NTE andacute delayed hen tests are required. For level 2chemicals (medium production and exposure, con-sumer exposure), the core battery is required; whenappropriate, these tests may be combined with othertoxicity studies. Level 3 chemicals (high production,high exposure) also require the core battery, and

TThe ac~~ n~ber depends on the breadth of the class designation U*.


Table 7-2-Chemicals Subject to Neurotoxicity Evaluation Under Section 4 of TSCA

Chemical Current status Neurotoxicity test; notes

Aniline and substituted anilines

Aryl phosphates

Cresols

CumeneCyclohexane’

Cydohexanone’

1,2-Dichloropropane

Diethylene glycol butyl ether(and corresponding acetate)

Diisodecyl phenyl phosphite (PDDP)Ethyltoluenes, trimethylbenzenes,

and C9 aromatic fractionCommercial hexaneHydroquinone and quinone

Isopropanol

2-MercaptobenzothiazoleMethyl ethyl ketoxime

Methyl-tert-butyl ether (MTBE)

Oleylamine

Unsubstituted phenylenediamines (o,m,p)

Tributyl phosphate

1,1,1 -Trichloroethane

Triethylene glycol ethers

Urea-formaldehyde resins

Enforceable consent agreement announced8/88 (53 FR 31 804)

Advanced notice of proposed rule-making12/83 (48 FR 57452)

Notice of final rule-making 5/87(52 FR 19082)

Final rule 7/88 (53 FR 28195)Proposed rule 5/87 (52 FR 19096)

Negotiated testing agreement 1/84(49 FR 136)

Final rule 9/86 (51 FR 32079); test standard10/87 (52 FR 37138)

Final rule 2/88 (53 FR 5932)

Consent order, 2/89 (54 FR 81 12)Final rule 5/85 (50 FR 20662); test standard

1/87 (52 FR 2522)Final rule 2/88 (53 FR 3382)Final rule 12/85 (50 FR 53145);

5/87 (52 FR 19865)Proposed rule 3/88 (53 FR 8638)

Final rule 9/88 (53 FR 34514)Proposed rule 9/88 (53 FR 35838)

Consent order 3/88 (53 FR 10391)

Final rule 8/87 (52 FR 31962)

Extension of comment period 1/88(53 FR 913)

Proposed rule 11/87 (52 FR 43346)

Consent order in preparation 8/87(52 FR 31445)

Consent order 4/89 (54 FR 13470); finalrule for DN (54 FR 13473)

Advanced notice of proposed rule-making

Not being pursued for neurotoxicity; origi-nally proposed on basis of ability toinduce anoxia

Proposed rule under development

FOB, MA, and NP (subchronic) added toongoing studies by Office of DrinkingWater

FOB, MA, NP (subschronic)FOB, MA, NP, (subchronic); SCOB (sub-

chronic and acute); DN if warrantedafter other studies completed

DN

FOB, MA, NP (subchronic)

FOB, MA, NP (subchronic)

NTE, delayed neurotoxicity (subchronic)FOB, MA, NP (subchronic)

SCOB (acute), FOB (subchronic), MA, NPFOB, NP (subchronic); existing data on

motor activityFOB, MA, (acute); FOB, MA, NP (sub-

chronic); DNFOB, MA, NP (subchronic)FOB, MA (acute and subchronic); NP (sub-

chronic)FOB, MA, (acute and subchronic); NP

(subchronic) testing begunNo neurotoxicity testing in final rule, al-

though was in proposed ruleRevised notice includes FOB, MA (acute,

all three isomers, subchronic triggeredfrom acute)

FOB, MA (acute and subchronic); NP (sub-chronic)

FOB, electrophysiology (acute and sub-chronic)

FOB, MA (acute and subchronic); NP (sub-chronic); DN

No rule issuedKEY:DN-developmental neurotoxicity testsFOB-functional observational batteryMA-motor activity testNP-directed neuropathological studiesNTE-neurotoxic esteraseSCOB-schedule-controlled operant behaviorRule-making began prior to issuance of neurotoxicity test guidelines.


developmental neurotoxicity tests may be required event that other tests indicated neurotoxic effects inin the near future. EPA neurotoxicologists may add adults.tests to any of the above requirements if existing data In the event that testing conducted under TSCAindicate the need.

section 4 indicates that a chemical poses an unrea-To date, test rules or consent decrees for 19 sonable risk, section 6 gives EPA the authority to

chemicals or chemical classes have included neuro- regulate production, distribution, use, or disposal oftoxicity testing (table 7-2). In four cases, a test chemicals in commerce, if there is “a reasonableprotocol for developmental neurotoxicity was also basis’ to conclude that any of these activitiesconsidered, either as a definite requirement or in the “presents or will present an unreasonable risk of


injury to health or the environment” [sec. 6(a)]. Inorder to take a regulatory action, the burden of proofagain falls on EPA to show that the listed activities“will present” a risk. EPA may then promulgaterules “to the extent necessary to protect adequatelyagainst such risk using the least burdensome require-ments” [sec. 6(a)]. This provision has been used forthe regulation of a very limited number of chemicals,among them PCBs, dioxin, and, most recently,asbestos.

Finally, TSCA authorizes EPA to require that newinformation regarding harmful effects of chemicalsubstances be reported:

. . . any person who manufactures, [imports,] proc-esses, or distributes in commerce a chemical sub-stance or mixture and who obtains informationwhich reasonably supports the conclusion that suchsubstance or mixture presents a substantial risk ofinjury to health or the environment shall immedi-ately inform the [EPA] Administrator of suchinformation . . . [sec. 8(e)].

STANDARD-SETTINGLEGISLATION AND REGULATIONS

These statutes authorize regulatory agencies to setstandards for chemicals in specific situations orenvironments. Emissions from smokestacks, auto-mobile exhaust, and sewage pipes, as well aschemicals found in the workplace and in consumerproducts, are subject to restrictions mandated byvarious standard-setting statutes. Some of the majorstandard-setting statutes—the Clean Air Act, theFederal Water Pollution Control Act as amended bythe Clean Water Act, and the Safe Drinking WaterAct-are pollution control measures. Others focuson the safety, labeling, and packaging of consumerand household products, including the ConsumerProduct Safety Act, the Federal Hazardous Sub-stances Act, and the Poison Prevention PackagingAct. A third type of standard-setting statute, charac-terized by the Federal Mine Safety and Health Actand the Occupational Safety and Health Act, ad-dresses issues of workplace safety. (See table 7-1 forkey features of these statutes.)

In contrast to the regulatory activity mandated bylicensing statutes, regulatory programs charged withsetting standards cannot require that chemical sub-stances be tested for toxicity. For the most part,standard-setting programs must base their decisionson reviews of existing literature on toxicology,


although some of them have limited research capa-bilities as well (see ch. 4). Once a standard is set, theprimary regulatory activity is enforcement—makingsure that standards are not exceeded.

Clean Air Act

The Clean Air Act (CAA) (Public Law 159) waspassed in 1955 “to provide research and technicalassistance relating to air pollution control. The Actcited “dangers to the public health and welfare” asan adverse effect of concern. The 1970 amendments(Public Law 91-604) defined more specific effectsand authorized an accelerated research program:

. . . to improve knowledge of the contribution of airpollutants to the occurrence of adverse effects onhealth, including, but not limited to, behavioral,physiological, toxicological, and biochemical ef-fects . . . and the short- and long-term effects of airpollutants on welfare [sec. 2(f) (l)] [emphasisadded].

The 1970 amendments also called for EPA to setstandards limiting hazardous air pollutants based ontheir effects on the public health and welfare. Recentamendments have refined the standard-setting pro-cedures further and have revised the schedule formeeting standards. The air pollution control frame-work set forth by the Clean Air Act calls for EPA toestablish standards for ambient air, emissions ofhazardous substances, and emissions from automo-biles, including fuel and fuel additives.

EPA regulates air pollutants by setting NationalPrimary and Secondary Ambient Air Quality Stan-dards as necessary to protect public health, with ‘anadequate margin of safety” [sec. lo] . EPA


has interpreted the requirement for “an adequatemargin of safety’ as intending:

. . . to address uncertainties associated with incon-clusive scientific and technical information availableat the time of standard setting. It is also intended toprovide a reasonable degree of protection againsthazards that research has not yet identified (50 FR37484).

The primary standard is to be based solely onhealth concerns (50 FR 37484). However, a regula-tory impact analysis is conducted to obtain informa-tion and provide a cost-benefit analysis for variousalternative standards (22).

The Act defines a hazardous air pollutant as:

. . . an air pollutant to which no ambient air qualitystandard is applicable and which in the judgment ofthe Administrator causes, or contributes to, airpollution which may reasonably be anticipated toresult in an increase in mortality or an increase inserious irreversible, or incapacitating reversibleillness [sec. 1 12(a)(l)].

It directs EPA to set emissions standards for suchpollutants at a level that will provide “an amplemargin of safety to protect the public health” [sec.1 lo]. In its promulgation of National Emis-sions Standards for Hazardous Air Pollutants, EPAhas interpreted “ample margin of safety” as notrequiring the total elimination of risk (40 CFR 19 ed.61).

The Act specifically prescribes that EPA setstandards for vehicle emissions, fuel, and fueladditives. A fuel or fuel additive may be regulatedonly on the basis of endangerment of the publichealth or welfare and then only”. . . after considera-tion of all relevant medical and scientific evidence. . . including consideration of other technologicallyor economically feasible means of achieving emis-sion standards . . .“ [WC. 21 l(c)(2)(A)].

EPA has promulgated Primary National AmbientAir Quality Standards for the following six pollut-ants: sulfur oxides, particulate matter, carbon mon-oxide, ozone, nitrogen dioxide, and lead (40 CFR50). Standards for carbon monoxide (36 FR 8186)and lead (43 FR 46254) were set in response toneurotoxic effects caused by these compounds.

The original carbon monoxide standards werebased on evidence that the ability to discriminatetime intervals was impaired in humans when 2 to 3

percent of the body’s hemoglobin—the oxygen-binding component of red blood cells—was boundto carbon monoxide (forming carboxyhemoglobin,COHb) and was therefore unable to bind to and carryoxygen (28). The impairment of time discrimination,a neurotoxic effect, was considered the most sensi-tive effect. The study from which these data werederived, however, has been discredited (45 FR55066). On August 18, 1980, after reviewing theliterature, including that published since the originalstandards were promulgated, EPA proposed reten-tion of the 8-hour primary standard [9 parts of carbonmonoxide per million parts of air (ppm)] andrevision of the l-hour standard (from 35 ppm to 25ppm), based on cardiotoxic rather than neurotoxiceffects (45 FR 55066). In order to set an ambient airstandard, the Agency used an equation to estimatethe concentrations of carbon monoxide in ambientair that were likely to result in COHb levels ofconcern (45 FR 5506).

Since that time, an expert committee convened byEPA has determined that EPA should not rely onthese data (50 FR 37484). After further review of thescientific literature, however, EPA decided to letstand the current primary carbon monoxide stand-ards, which are based on concern for central nervoussystem and cardiovascular effects, the latter beingconsidered to be the more sensitive (50 FR 37484).Effects on the central nervous system of low levelsof COHb include “impairment of vigilance, visualperception, manual dexterity, learning ability, andperformance of complex tasks” (50 FR 37484). Thepopulation most sensitive to the cardiovasculareffects included persons with angina and othercardiovascular diseases. The standard was set at alevel which was estimated to keep more than 99.9percent of this sensitive population below 2.1percent COHb (50 FR 37484).

The primary lead standard was based on impairedheme synthesis (heme is a nonprotein iron com-pound that gives hemoglobin its characteristic colorand oxygen-carrying properties) and nervous systemdeficits, which included cognitive deficits, encepha-lopathy, and peripheral neuropathy (43 FR 46254).Children were considered to be the most sensitivepopulation, and the standard was set at a levelestimated to keep 99.5 percent of children belowwhat was considered to be the maximum safe levelof 30 micrograms of lead per deciliter of blood (43FR 46254). The actual standard was calculatedbased on 20 percent of lead in the blood being


contributed from the air and 80 percent from othersources. 8 The lead standard is presently underreview by EPA, and nervous system disturbances arestill one of the most sensitive categories of effects(9).

National Emission Standards for Hazardous AirPollutants have been promulgated by EPA for thefollowing: benzene arsenic, beryllium, mercury,vinyl chloride, asbestos, and radionuclides. Only thestandard for mercury was based on concerns aboutneurotoxic effects (38 FR 8820). The endpoint thatwas the driving force behind this standard wasparesthesia (tingling, burning sensations) (45).

Automobile and other vehicle emissions areregulated by the Office of Mobile Sources. To date,carbon monoxide, nitrogen oxides, hydrocarbons,and particulate have been regulated. Of these fourpollutants, carbon monoxide was regulated in parton the basis of neurotoxic concerns, the sameconcerns on which the Primary National AmbientAir Quality Standard for carbon monoxide wasbased. The standard itself varies, depending on thevehicle class and model year.

EPA regulates the lead content of gasoline on thebasis of the same neurotoxic effects cited in theprimary national ambient air quality standard forlead (50 FR 9386). A standard of 0.1 gram of lead pergallon of leaded gasoline became effective January1, 1986. EPA was particularly concerned about theimpact of lead on the health of preschool childrenand has clearly stated that its long-term objective isto eliminate the use of lead in gasoline (50 FR 9386).

Proposed Amendments

Efforts to amend the CAA during the IOOthCongress were not successful. More than 30 differ-ent bills proposing amendments to CAA, includingan Administration proposal, have been introduced inthe House and Senate during the 10lst Congress, andhearings have been held on many of them. Althoughthe issue is being actively debated and the CAA willalmost certainly be amended, it is too early to tellwhat form the amendments will take and what directeffect, if any, the amendments will have on theregulation of neurotoxic substances.

Federal Water Pollution Control Act andClean Waler Act

The Federal Water Pollution Control Act (FWPCA)(33 U.S.C. 466) and amendments to it, including theClean Water Act (CWA), established a frameworkfor the control of water pollution based on humanhealth and environmental concerns. The 1972 amend-ments (Public Law 92-500), which completelyrevised earlier versions of FWPCA, authorized EPAto set effluent standards for a designated list ofhazardous substances (40 CFR 116). Further amend-ments to the FWPCA, including the 1977 CleanWater Act, authorized EPA to develop and periodi-cally review water quality criteria that accuratelyreflect ‘‘the latest scientific knowledge” on “thekind and extent of all identifiable effects on healthand welfare’ [sec. 304(a)(l)] [emphasis added]. Thecriteria are not regulations and, as such, carry noenforcement authority. However, they provide guid-ance for the derivation of regulatory standards,including general effluent limitations and toxicpollutant effluent limitations authorized by theFWPCA (45 FR 79319).

EPA is authorized to establish water qualitycriteria to protect human health and the environ-ment. The criteria to protect human health are“based solely on data and scientific judgments onthe relationship between pollutant concentrationsand environmental and human health effects. . . anddo not reflect considerations of economic or techno-logical feasibility” (45 FR 79319).

EPA’s Office of Water Regulations and Standardshas established three types of water quality criteriafor pollutants where sufficient data are available: 1)to protect freshwater aquatic life, 2) to protectsaltwater aquatic life, and 3) to protect humanhealth. Derivation of criteria to protect human healthwas based on three endpoints: carcinogenicity,adverse noncarcinogenic effects, and organolepticeffects (45 FR 79347). (Organoleptic effects refer totaste or odor characteristics of a compound and haveno demonstrated adverse effects on human health.)Criteria were based on organoleptic effects when theorganoleptic threshold was lower than that calcu-

g~e had ~dus~es Association, Inc., challenged the standard in court, arguing that EPA could only regulate based on “clearly adverse effwts’and that the nervous system effects had not been adequately documented at the levels cited by EPA (17). The court upheld EPA’s standard, however,noting that the EPA Administrator’s actions were reasonable, that EPA did, in fact, have sufficient evidence suggesting nervous system effects, that thestatute allows the EPA Administrator considerable discretion to determine adverse effects, and that in any event the standard was based in part onproviding an “adequate margin of safety,’ which is required by the Clean Air Act.


lated from toxicity data or when there were insuffi-cient toxicity data.

Water quality standards set to protect humanhealth and based on toxicological data have beenestablished for 86 compounds (45 FR 7931 8; 49 FR5831). For four of these, lead, mercury, thallium, andtoluene, neurotoxic effects were of major concern(34-44). A brief survey of the water quality criteriadocuments (34-44) indicates that at least eight otherchemicals are noted as causing neurotoxic effects,even though the standards for these chemicals werebased on other endpoints (9).

Safe Drinking Water Act

The Safe Drinking Water Act (SDWA) of 1974amended the Public Health Service Act ‘‘to assurethat the public is provided with safe drinking water”(Public Law 93-523). SDWA and its amendmentsinstituted a framework of primary and secondarywater regulations designed to control contaminantsin public drinking water supplies that EPA deter-mines ‘may have any adverse effect on the health ofpersons” [sec. 1401(1)(B)].

Under the Act, EPA was to establish RevisedNational Primary Drinking Water Regulations, usinga two-stage process. First, EPA was to establishrecommended maximum contaminant levels (RMCLs),which are nonenforceable health goals. RMCLswere to be set “at a level [at] which. . . no known oranticipated adverse effects on the health of personsoccur and which allows an adequate margin ofsafety” [sec. 1412(b)(l)(B)]. For carcinogenic pol-lutants, the RMCL was to be set at zero. Once anRMCL had been promulgated, EPA was to establisha maximum contaminant level (MCL) for thatpollutant. An MCL was an enforceable standard andis to be set:

. . . as close to the recommended maximum contami-nant levels. . . as is feasible. . . [i.e.], with the use ofthe best technology, treatment techniques, and othermeans, which the Administrator finds are generallyavailable taking costs into consideration [sec. 1412(b)(3)].

A treatment technique maybe established insteadof an MCL if “it is not economically or technologi-cally feasible to . . . ascertain the level of . . . [a]contaminant [in drinking water]” [sec. 1401 (C)(ii)].

When the Act was amended in 1986, the two-stepprocess was retained, with EPA to specify nonen-

forceable goals [RMCLs were renamed maximumcontaminant level goals (MCLGs)], on which MCLSwere to be based. EPA was required to propose andpromulgate MCLGs and MCLs simultaneously forany chemical. Another key feature of the amend-ments, from a neurotoxicological perspective, wasthe imposition of a ban on the use of lead pipe,solder, or flux in plumbing for drinking water afterJune 19, 1986.

The Office of Drinking Water of EPA has setMCLGs for carcinogenic pollutants at zero. MCLGsfor noncarcinogenic agents are set by establishingthe dose at which harmful effects may be observedand then compensating for uncertainties in theprocess (50 FR 46946). EPA then predicts exposuresfrom food and air sources and sets the MCLGsaccordingly (50 FR 46946).

Since the revision of the Act, MCLGs have beenset for fewer than 15 inorganic chemicals under theNational Primary Drinking Water Regulations (48FR 45502). Of the 10 MCLs issued, three were basedpartly or entirely on nervous system effects: 1)barium, 2) lead, and 3) mercury. For one, arsenic, thenervous system was mentioned as one of severalorgan systems affected with more severe intoxica-tion, but the MCL was not based on this (33).

The National Primary Drinking Water Regula-tions also contain MCLs for 10 organic chemicals:four pesticides, two herbicides, and four trihalo-methanes. It is difficult to ascertain the effects ofconcern for the four pesticide and two herbicideMCLs. According to one EPA document, theseverity of the symptoms of the pesticides (endrin,lindane, methoxychlor, and toxaphene) is related tothe concentrations of the compounds in the nervoussystem (33). Specific effects of concern for the twoherbicides [2,4-D and 2,4,5-TP (Silvex)] are notmentioned (33). The standard for the four trihalo-methanes was based on chronic low-level effects(primarily cancer), although these compounds dohave an acute effect on the nervous system.

In addition to setting drinking water standards, theOffice of Drinking Water publishes health adviso-ries describing levels of contaminants. These advi-sories cover l-day, 10-day, long-term (approxi-mately 7 years, or 10 percent of an individual’slifetime), and lifetime exposures. The advisories arenot federally enforceable but describe levels ofcontaminants in drinking water that are associatedwith adverse health effects. The advisories do not

I&f ● Neurotoxicity : Identifying and Controlling Poisons of the Nervous System

clearly indicate the effects that are of primaryconcern, but one or more of the advisories for sevencontaminants appear to have been based on neuro-toxic effects (50 FR 46936).

Consumer Product Safety Act andFederal Hazardous Substances Act

The Consumer Product Safety Act (Public Law92-573) of 1972 established the Consumer ProductSafety Commission (CPSC) as an independentregulatory commission charged with protecting thepublic from “unreasonable risks of injury associatedwith consumer products” [sec. 2(a)(3)]. Risk ofinjury is defined as “risk of death, personal injury,or serious or frequent illness” [sec. 3(a)(3)].

The Act authorizes CPSC to promulgate con-sumer product safety standards, including perform-ance requirements and warning or instructionallabels, necessary to ‘prevent or reduce an unreason-able risk of injury associated with such product”[sec. 7(a)]. The determination of whether or not aparticular risk of injury is unreasonable involvesbalancing “. . . the probability that the risk willresult in harm and the gravity of the harm against arule’s effects on the product’s utility, cost, andavailability to the consumer” (42 FR 44198). TheConsumer Product Safety Act’s broad authoritycould cover products with neurotoxic effects, buttoxic substances in general are more likely to beregulated under the Federal Hazardous SubstancesAct because the former prohibits the regulation of arisk that can be adequately regulated under the latter[sec. 30(d)].

The Federal Hazardous Substances Act (PublicLaw 86-613) was passed in 1960 to protect thepublic health by requiring that hazardous substancesbe labeled with various warnings, according to thenature of the hazard. The Act defines a ‘‘hazardoussubstance’ as:

Any substance or mixture of substances which (i)is toxic, (ii) is corrosive, (iii) is an irritant. . . if suchsubstance or mixture of substances may causesubstantial personal injury or substantial illnessduring or as a proximate result of any customary orreasonably foreseeable handling or use, includingreasonably foreseeable ingestion by children [sec.2(f)(l)] [emphasis added].

A toxic substance is defined as “any substance(other than a radioactive substance) which has thecapacity to produce personal injury or illness to man

through ingestion, inhalation, or absorption throughany body surface” [sec. 2(g)].

The Act directs CPSC to issue regulations clarify-ing which categories of substances fit the variousdefinitions of hazardous, if there is any uncertainty[sec. 3(a)(l)], and to ban substances through aformal rule-making procedure:

. . . on the basis of the finding that, notwithstandingsuch cautionary labeling as is or may be requiredunder this Act for that substance, the degree or natureof the hazard involved in the presence or use of suchsubstance in households is such that the objective ofthe public health and safety can be adequately servedonly by keeping such substance . . . out of thechannels of interstate commerce . . . [sec. 2(q)(l)].

The Act calls for banning substances that are toodangerous for household use.

Because of the interrelatedness of concerns em-bodied in the Consumer Product Safety Act and theFederal Hazardous Substances Act and because bothare administered by CPSC, regulatory actions underthe two statutes have been closely intertwined.CPSC has responded to its mandate by settingstandards for various consumer products. Its actionsbased on neurotoxicity concerns have been to banproducts with paint or other surface material con-taining lead in excess of 0.06 percent (42 FR 44199).This standard was designed “to reduce or eliminatethe unreasonable risk of injury associated with leadpoisoning in children’ (42 FR 44198) and addressedconsumer products that bear lead-containing paint,including toys and other items used by children andfurniture used by consumers (42 FR 44199). TheCommission cited the following as adverse effectsof lead on the nervous system: hyperactivity, slowedlearning ability, withdrawal, and blindness (42 FR44200).

CPSC has been involved in working out avoluntary consensus on the labeling of variousconsumer products containing organic solvents suchas n-hexane. Concern about these compounds wasbased on the association between repeated exposureto solvents and permanent neurological damage.CPSC recently hired a staff neurotoxicologist buthas not undertaken any specific neurotoxicity prod-uct evaluations lately. The Commission does, how-ever, plan to draft criteria for classifying, evaluating,and labeling products that warrant concern forneurotoxic effects (under the authority of both Acts).


Federal Mine Safety and Health Act

The Federal Mine Health and Safety Act of 1969(Public Law 91-173), as amended in 1977 (PublicLaw 95-173), grew out of congressional concernover the:

. . . urgent need to provide more effective means andmeasures for improving the working conditions andpractices in the Nation’s coal or other mines in orderto prevent death and serious physical harm, and inorder to prevent occupational diseases originating insuch mines [sec. 2(a)] [emphasis added].

Although no specific toxic effects are singled out forconsideration, the concern about physical harm andoccupational diseases could encompass neurotoxiceffects.

The Act established the Mine Safety and HealthAdministration (MSHA) in the Department of Laborand authorized it to “develop, promulgate, andrevise, as may be appropriate, improved mandatoryhealth or safety standards for the protection of lifeand prevention of injuries in coal or other mines’[sec. 10l(a)] [emphasis added]. MSHA is to ensurethat miners will not ‘‘suffer material impairment ofhealth or functional capacity even if such miner hasregular exposure to the hazards dealt with by suchstandard for the period of his working life” [sec.l o ] .

MSHA initially fulfilled its standard-setting man-date by adopting standards for airborne contami-nants recommended by the American Conference ofGovernmental Industrial Hygienists (ACGIH) (box7-F), and the American National Standards Institute(30 CFR 57.5). In 1981, MSHA began a comprehen-sive review of its safety standards, including thosefor air (46 FR 57253,46 FR 10190); since then, it hasmoved to update its regulations by incorporatingmore recent threshold limit values (see ch. 6).

Occupational Safety and Health Act

The Occupational Safety and Health Act (OSHAct) was enacted in 1970 to improve workplacesafety. The Act established the Occupational Safetyand Health Administration (OSHA) in the Depart-ment of Labor and directed it to promulgate healthand safety standards, defined in the Act as:

. . . conditions, or the adoption or use of one or morepractices, means, methods, operations, or processes,reasonably necessary or appropriate to provide safe

or healthful employment and places of employment[sec. 3(8)].

The Act also authorizes OSHA to promulgate newstandards for toxic materials and to modify or revokeexisting ones, to ensure “. . . that no employee willsuffer material impairment of health or fictionalcapacity even if such employee has regular exposureto the hazard dealt with by such standard for theperiod of his working life” [sec. 6(b)(5)] [emphasisadded].

In 1971, OSHA adopted existing Federal stand-ards, most of which had been adopted under theWalsh-Healy Act, and approximately 20 consensusstandards of the American National Standards Insti-tute as permissible exposure limits (PELs) (39 FR23540).

In addition to initiating a standard-setting frame-work, the OSH Act established the National Institutefor Occupational Safety and Health (NIOSH) as aresearch agency “authorized to develop and estab-lish recommended occupational safety and healthstandards” [sec. 22(c)(l)] and to set criteria for suchstandards. Although the Act directed that the stand-ards and criteria be used by OSHA in the promulga-tion of new or revised health and safety standards,OSHA has acted on few of NIOSH’s recommenda-tions. NIOSH is also responsible for assessingwork-related diseases and injuries, including thosecaused by toxic substances.

Since the adoption of initial standards, OSHA hasissued complete health standards for 25 substances(27). Of these, the one concerning lead was based, inpart, on nervous system effects (43 FR 52952). Fourother compounds, inorganic arsenic, acrylonitrile,ethylene oxide, and 1,2-dibromo-3-chloropropane,were cited as causing various disturbances in thenervous system, but the standards for these weredriven by concerns about carcinogenic effects (29FR 1910).

OSHA recently published a far-reaching revisionand update of existing standards (54 FR 2332). Therule affects standards for 428 chemical substances:it lowers PELs for 212 substances, establishes themfor 164 substances that were not formerly regulated,and maintains unchanged the existing levels for 52substances. The regulation addressed only chemi-cals that were covered by the most recent ACGIHrecommendations and whose threshold limit values(TLVs) differed from current PELs. No new stand-


Box 7-F—The American Conference of Governmental Industrial Hygienists

The American Conference of Governmental Industrial Hygienists (ACGIH) is a professional society organizedin 1938 by a group of governmental industrial hygienists. Its recommendations have played a major role in settingstandards under both the Occupational Safety and Health Act and the Federal Mine Safety and Health Act. ACGIHmembership consists of government or industrial hygienists involved in occupational safety and health programswho seek to establish a consensus among industrial toxicologists on the levels of chemicals that might reasonablybe considered safe in the workplace.

Over the years, ACGIH has set threshold limit values (TLVs) for hundreds of occupational substances andpublishes its recommendations annually. These values refer to airborne concentrations of substances that themajority of workers maybe repeatedly exposed to on a daily basis without adverse effect (ACGIH, 1985).

ACGIH sets three types of TLVs for chemical compounds: time-weighted average concentrations, which arefor an 8-hour workday and a 40-hour workweek; short-term exposure limits, which are 15-minute time-weightedaverage exposures not be exceeded at any time; and ceiling limits, which are not to be exceeded even for an instant(ACGIH, 1985).

There are no set guidelines for the establishment of TLVs. Rather, the values are based on the TLV committee’sprofessional judgment, after they have reviewed information from industrial experience, from experimental humanand animal studies, and, when possible, from a combination of all three. The basis on which the values areestablished may differ from substance to substance: protection against impairment of health maybe a guiding factorfor some, whereas reasonable freedom from irritation, narcosis, nuisance, or other forms of stress may form the basisfor others (ACGIH, 1985).

The TLVs are not legally enforceable but are meant to be used as guidelines. The 1968 ACGIH chemicalsubstance TLVs and the 1969 noise TLV, however, were adopted as Federal standards under the Walsh-Healy Actprior to enactment of the Occupational Safety and Health Act. In the early 1970s, these standards were adopted aspermissible exposure limits by the Occupational Safety and Health Administration, as mandated by the Act (OTA,1985).

As of 1985, ACGIH had set 605 TLVs covering a wide range of compounds (ACGIH, 1985); TLVs for 202of these substances were set in whole or in part to protect individuals from nervous system effects ranging fromdrowsiness to nerve damage. (This number does not include effects such as eye, nose, and throat irritation, althoughthese effects might be broadly construed as neurotoxic.)

OSHA recently published a revised standard that increased the protection of workers by implementing newor revised PELs for 428 toxic substances (53 FR 20960-20991). The final standard was published in January 1989.The new rule established lower exposure limits for approximately 212 substances already regulated by OSHA. PELswould be established for the first time for another 164 substances. A large number of these are established to preventadverse effects on the nervous system. The regulation addressed only chemicals that were covered by the most recentACGIH recommendations and whose TLVs differed from current PELs. No new standards were promulgated forchemicals for which NIOSH had specified recommended exposure levels, unless those chemicals were also on theACGIH list.

Critics of ACGIH argue that the TLVs are essentially industry consensus standards arrived at through a limitedreview of available toxicological information. Nevertheless, TLVs are widely used by both industry and governmentofficials.

SOURCES: American Conference of Governmental Industrial Hygienists, Threshold Limit Values for Chemical Substances in the WorkEnvironment Adopted by ACGIH for 1985-1986 (Cincinnati, OH: 1985); U.S. Congress, Office of Technology Assessment,Preventing Illness and Injury in the Workplace, OTA-H-256 (Washington, DC: U.S. Government Printing Office, 1985).

ards were promulgated for chemicals for which behind 410 of the standards. Of those, PELs for 20NIOSH had specified recommended exposure lev- compounds were based on the avoidance of directels, unless those chemicals were also on the ACGIH neuropathic effects. An additional 19 were based onlist. This issue is discussed in more detail in chapter the avoidance of narcosis. A total of 79 chemicals10. were regulated to prevent irritation, an effect that

does not necessarily imply neurotoxicity but mayTables in the Federal Register notice announcing include some neurotoxic effects. Methanol, a chemi-

the rule listed the explicit toxicological concerns cal that adversely affects the optic nerve, was one of


the five substances listed because of ocular con-cerns. Finally, 26 chemicals were listed under thecategory of avoidance of metabolic effects. Thiscategory contained several substances that causeneurotoxic effects, including carbon monoxide andsome types of cholinesterase inhibitors (cholines-terase inhibition is discussed in chs. 3 and 10).

The rule sets standards for an additional 73chemicals on the basis of structural analogies toother compounds with known effects. Of the 73, 18were selected because they are analogous to com-pounds that induce neurological effects, narcosis, orcholinesterase inhibition. PELs for 26 chemicalswere based on no observed adverse effect levels(NOAELs). For six of these, the adverse effectsnoted in the rule were neurological.

Although the chemicals discussed above havebeen regulated explicitly on the basis of neurologicalconcerns, it should be remembered that other neuro-toxic chemicals may have been regulated on thebasis of other undesirable effects they induce. Forexample, the PEL for carbon disulfide, a well-knownneurotoxicant, is based on avoidance of cardiovas-cular effects.

In addition to specifying PELs, OSHA has issued,and subsequently expanded, a hazard communica-tion standard (52 FR 3 1852). This requires manufac-turers and importers to assess the hazards of thechemicals they produce or import, requires employ-ers to provide information to their employeesconcerning hazardous chemicals (using training,labels, material safety data sheets, and access towritten records), and requires distributors of hazard-ous chemicals to provide information to theircustomers (via proper labels and Material SafetyData Sheets). It should be noted that many such datasheets contain very limited information on toxichazards.

CONTROL-ORIENTEDLEGISLATION AND REGULATIONS

Hazardous chemical substances in the environ-ment and in consumer products are the subject ofcontrol-oriented statutes such as the ComprehensiveEnvironmental Response, Compensation, and Lia-bility Act, the Controlled Substances Act, theLead-Based Paint Poisoning Prevention Act, theMarine Protection, Research, and Sanctuaries Act,the Poisoning Prevention Packaging Act, and the

Resource Conservation and Recovery Act. Thesestatutes, which are founded on a recognition of theproblems caused by predetermined or specified setsof hazardous chemicals, are focused on developingprocedures to control existing situations (see table7-l). Regulatory implementation under these lawsconsists primarily of setting allowable levels orreporting requirements and enforcing the limits thathave been set.

Comprehensive Environmental Response,Compensation, and Liability Act

The Comprehensive Environmental Response,Compensation, and Liability Act (CERCLA), alsoknown as Superfund, was enacted in 1980 to provideauthority for EPA to clean up hazardous waste sites.CERCLA defined hazardous substances as eithercompounds that have already been designated underother Acts or compounds designated by EPA” which,when released into the environment may presentsubstantial danger to the public health or welfare orthe environment” [sec. 102(a)] [emphasis added]. Inaddition to identifying hazardous substances,CERCLA directs EPA to “promulgate regulationsestablishing that quantity of any hazardous sub-stance the release of which shall be reported” [sec.102(a)], essentially supplanting a similar processestablished under the Clean Water Act. Thesereportable quantities (RQs) are used to trigger theappropriate response “necessary to protect thepublic health or welfare or the environment” [sec.l o ] .

Initially, all RQs were set at 1 pound, unless otherRQs were assigned under section 311 of the CleanWater Act. As authorized under section 102 ofCERCLA, EPA has adjusted RQs for approximately440 of the 717 substances on the list (40 CFR 302;51 FR 34534), based on “scientific and technicalcriteria which correlate with the possibility of hazardor harm on the release of a substance in a reportablequantity” (48 FR 23560). The criteria EPA usedwere aquatic toxicity, mammalian toxicity, ignita-bility, reactivity, chronic toxicity, and potentialcarcinogenicity. Of the 245 hazardous substancesevaluated by EPA’s Environment Criteria and As-sessment Office, 64 were reviewed for chronictoxicity. Of those 64, 22 could not be ranked due toinsufficient data. Of the 42 that were ranked, 5 wereranked on the basis of effects on the nervous system(11).

20-812 - 90 - 5 : QL 3



The Superfund Amendments and ReauthorizationAct (SARA) (Public Law 99-499) passed in 1986called for the development of a list of 100 high-riskchemicals from the chemicals on the Superfund listfor which available data were inadequate. SARAestablished a research program at the Agency forToxic Substances and Disease Registry to conductthe necessary research and to develop toxicologydata profiles on the 100 chemicals. Thus, althoughCERCLA as amended is not a testing program, itdoes sponsor research. The toxicological profilesbeing prepared under SARA provide an explicitdiscussion of health effects for various routes ofexposure to a chemical (oral, inhalation, dermal).The specific effects considered include systemiceffects, immunological effects, neurological effects,developmental effects, reproductive effects, geno-toxic effects, cancer, and death.

Controlled Substances Act

Congress passed the Controlled Substances Act in1970 as Title II of the Comprehensive Drug AbusePrevention and Control Act (Public Law 91-513).Finding that “. . . the illegal importation, manufac-ture, distribution, and possession and improper useof controlled substances have a substantial anddetrimental effect on the health and general welfare

of the American people’ [sec. 101(2)], Congress setforth a framework for restricting a defined list ofsubstances, many of which are drugs with beneficialas well as harmful uses.

The Act established five categories, or schedules,of controlled substances based on potential forabuse, severity of possible harmful effects, likeli-hood of dependence, and accepted medical uses [sec.202; 28 CFR]. The Act grants the Attorney Generaland the Department of Justice authority to regulateand enforce the control of scheduled substances andto add to, remove from, or amend the schedules asappropriate.

The Controlled Substances Act calls for coopera-tion between FDA and the Justice Department indetermining which drugs should be controlled. Inaddition, FDA is directed to notify the JusticeDepartment whenever “a new drug application issubmitted . . . for any drug having a stimulant,depressant, or hallucinogenic effect on the centralnervous system, [and] it appears that such drug hasabuse potential” [sec. 201(f)]. Thus, the primaryscientific and pharmacological investigations, in-cluding evaluations of toxicity or of effects on thecentral nervous system, are handled under the FDAprocedures described under FFDCA.

Marine Protection, Research, andSanctuaries Act

Finding that “unregulated dumping of materialinto ocean waters endangers human health, welfare,and amenities, and the marine environment” [sec.2(a)], Congress enacted the Marine Protection,Research, and Sanctuaries Act (MPRSA) (PublicLaw 92-532) in 1972 to:

. . . regulate the dumping of all types of materials intoocean waters and to prevent or strictly limit thedumping into ocean waters of any material whichwould adversely affect human health, welfare, oramenities, or the marine environment, ecologicalsystems, or economical potentialities [sec. 2(B)][emphasis added].

Materials are defined as:

. . . matter of any kind or description, including, butnot limited to, dredged material, solid waste, inciner-ator residue, garbage, sewage, sewage sludge, muni-tions, radiological, chemical, and biological warfareagents, radioactive materials, chemicals, biologicaland laboratory waste, wreck or discarded equipment

Chapter 7—The Federal Regulatory Response . 189


rock, sand, excavation debris, and industrial, munic-ipal, agricultural, and other waste [sec. 3(c)].

The Act prohibits dumping of the defined materialsin U.S. territorial waters and 12 miles beyond U.S.boundaries unless the dumper obtains a permit.

MPRSA does not establish any program orrequirement for ascertaining the toxic effects ofmaterials nor any mechanism by which specific,newly identified toxic materials may be added to thelist. EPA has restricted or prohibited the dumping ofseveral categories of substances because of toxic orradioactive effects or persistence. Mercury andmercury compounds—known neurotoxicants—areamong the compounds specifically restricted (40CFR 227.6), although the regulations do not mentionneurotoxic effects in particular.

. EPA’s primary regulatory responsibility underMPRSA has been control of ocean dumping sitesthrough the permitting process (40 CFR 220-31).EPA has delegated this authority to regional EPAadministrators (52 FR 25009). EPA considers theimpact of the proposed dumping on ‘‘aesthetic,recreational, and economic values, ” including the

“[presence in the material of toxic chemical con-stituents released in volumes which may affecthumans directly” (40 CFR 227.18). Apart fromrestrictions on mercury, however, there is no clearrecord of how or whether specific neurotoxic effectshave been regulated under MPRSA.

Lead-Based Paint Poisoning Prevention Actand Poison Prevention Packaging Act

The Lead-Based Paint Poisoning Prevention Act(LBPPPA) (Public Law 91-695) is the only statutebased primarily on concerns for neurotoxic effects(see ch. 10). The purpose of the Act-to eliminatelead-based paint poisoning—was to be accom-plished by screening and testing children, removinglead-based paint from buildings, and banning the useof lead-based paint in Federal construction orrehabilitation of residential housing. The 1973amendments (Public Law 93-151) defined lead-based paint as any paint which contains 0.06 percentlead. That 0.06 percentage was based on studiesindicating the permissible daily intake of lead to be300 micrograms, which the U.S. Public HealthService and the American Academy of Pediatrics

Household substances

then calculated to be a limitpercent lead by weight.


that pose a risk to children are regulated under the Poison Prevention Packaging Act.

of no more than 0.06

The Act was amended again in 1976 by theNational Consumer Health Information and HealthPromotion Act, which instructed the CPSC:

. . . to determine, by December 23, 1976, whether alevel of lead in excess of 0.06 percent but not over0.50 percent, was safe. If the Commission wereunable to determine a safe level of lead in this range,paint manufactured after June 22, 1977, containingmore than 0.06 percent would be considered ‘‘lead-based paint” (42 FR 44193).

The CPSC later ruled that available data did notsupport the establishment of a level in this range asbeing safe (42 FR 44193), so the 0.06 percent levelremained in effect.

The Poison Prevention Packaging Act (PPPA)(Public Law 91-601) was enacted in 1970 to preventinadvertent poisoning of small children by hazard-ous household substances. Packaging of these sub-stances was to be done in such a way as to make it

“significantly difficult for children under 5 years ofage to open or obtain a toxic or harmful amount ofthe substance therein within a reasonable time’ [sec.2(4)]. The Act authorizes the CPSC to promulgatestandard-setting rules for special packaging if theCommission determines that:

. . . the degree or nature of the hazard to children inthe availability of such substance, by reason of itspackaging, is such that special packaging is requiredto protect children from serious personal injury orserious illness resulting from handling, using, oringesting such substance [sec. 3(a)(l)] [emphasisadded].

The Act encompasses hazardous substances asdefined in the Federal Hazardous Substances Act;foods, drugs, and cosmetics as defined in theFFDCA; and fuels packaged for household use.

Because LBPPPA and PPPA are designed tocontrol acknowledged problems, most regulatoryactions undertaken by the CPSC under these twostatutes are aimed at enforcement. Under LBPPPA,the Commission may conduct periodic measure-


ments to ensure that lead in paints does not exceedthe mandated level. Under PPPA, the only regula-tory option is for CPSC to require protectivepackaging of hazardous household substances thatare identified or designated as toxic by other statutesor agencies; PPPA has little impact on the substan-tive regulation of toxic substances.

Resource Conservation and Recovery Act

The Resource Conservation and Recovery Act(RCRA) directs EPA to identify and list hazardouswastes. Generators, transporters, and facilities thattreat, store, or dispose of such wastes are then subjectto regulations promulgated by the Administrator asnecessary to protect human health and the environ-ment” [sec. 3002(a)] [emphasis added]. A hazard-ous waste is defined as a:

. . . solid waste, or combination of solid wastes,which because of its quantity, concentration, orphysical, chemical, or infectious characteristics may:

(A) cause, or significantly contribute to, an increasein serious irreversible, or incapacitating reversi-ble, illness; or

(B) pose a substantial present or potential hazard tohuman health or the environment when improp-erly treated, stored, transported, or disposed of,or otherwise managed [sec. 1004(5)] [emphasisadded].

EPA classifies a solid waste as hazardous basedon ignitability, corrosivity, and reactivity, as well ason various toxicity criteria, including fatality at lowdoses or the capability of “causing or significantlycontributing to an increase in serious irreversible, orincapacitating reversible, illness’ (40 CFR 261).Toxic wastes are designated on the basis of thenature of the toxicity of the constituent, its concen-tration, and its persistence (40 CFR 261.1 1). Thestatute allows for direct measurement of wastetoxicity in some cases.

EPA has adopted standards based on the chronichealth limits defined under the National PrimaryDrinking Water Standards; consequently, the sameeight chemicals that were identified for neurotoxicconcerns under the SDWA are regulated under theResource Conservation and Recovery Act.

NEW INITIATIVES INREGULATING NEUROTOXIC

SUBSTANCESA primary issue in regulating potentially neuro-

toxic substances is the adequacy of the data on whichevaluations are based. Representatives of Federalregulatory agencies disagree on whether or how wellcurrent toxicity tests predict neurotoxic effects ofchemicals on humans. Consequently, new initiativesfor regulating neurotoxic substances have emergedin agencies dissatisfied with existing approaches.

The first tangible result of attempts to improveregulatory testing for neurotoxic effects was thepublication in 1985 of a set of neurotoxicity testguidelines by EPA’s Office of Toxic Substances.The primary purpose of these guidelines was to aiddevelopment of test rules under section 4 of TSCA(50 FR 39458). The significance of the guidelines isdemonstrated by the fact that, since they wereintroduced, experimental protocols based on themhave been incorporated into a substantial number oftest rules and consent agreements. Studies to vali-date the scientific utility of the guidelines are nowunder way.

The two most notable ongoing regulatory initia-tives concerning neurotoxicants are also centered ondevelopment of test guidelines. These initiatives,one by EPA and one by FDA, are discussed in thesections that follow. A third new initiative, which isless a change in neurotoxicity regulation than anattempt to obtain international consensus on changesalready made by EPA, is an EPA proposal to theUnited Nations Organization for Economic Cooper-ation and Development (OECD) to add a mammal-ian neurotoxicity screening battery to OECD’s testguidelines.

Revision of EPA’s Neurotoxicity TestGuidelines for Pesticides

Recent efforts at EPA to coordinate evaluations ofneurotoxicity under TSCA and FIFRA highlightsome of the differences that have existed betweenthe regulatory programs of the Office of ToxicSubstances and those of the Office of PesticidePrograms (OPP). When OTS published its neurotox-icity guidelines in 1985, its Health and Environ-mental Review Division had been employing neuro-toxicologists for several years, reflecting OTS’sapproach of having chemicals reviewed by several


scientists with different areas of toxicological exper-tise. In contrast, OPP’s Hazard Evaluation Divisionhas traditionally assumed equivalency of trainingamong its toxicologists, which may have fosteredsome reluctance on OPP’s part to focus on specificorgan system tests, including neurotoxicity tests, inits evaluations. Since 1986, OPP has consulted OTSneurotoxicity test guidelines when requesting dataon the neurotoxicity potential of pesticides. In thatyear, OPP also hired two neurotoxicologists previ-ously employed by OTS.

Adoption of neurotoxicity testing guidelines byOPP was delayed by uncertainties regarding revi-sion of FIFRA by Congress in late 1986, but plansto add neurotoxicity guidelines to those specified in40 CFR 158 continued in 1987. Work on theguidelines received further impetus in February1987, when a coalition including the Center forScience in the Public Interest (CSPI) and 11 othergroups and individuals petitioned EPA to developmethods for assessing neurotoxic effects of activeand inert ingredients in pesticides (10). OPP submit-ted its response to a subpanel of the FIFRA ScienceAdvisory Panel (SAP) for review in October 1987,but SAP’s approval of those guidelines was super-seded by a decision to revise all of the part 158guidelines, eliminating tests that are outmoded oruninformative and adding tests in several areas,including neurotoxicity and immunotoxicity.

In May 1988, the director of OPP met withrepresentatives of CSPI and other groups who hadsigned the petition. In August 1988, CSPI sent aletter to EPA’s administrator for pesticides and toxicsubstances suggesting several modifications of therevised guidelines approved by SAP. CSPI called forroutine conduct of chronic neurotoxicity studies(rather than just when acute and subchronic studiesindicated neurotoxic effects) and for inclusion ofschedule-controlled operant behavior and develop-mental neurotoxicity tests on a regular basis (see ch.5 for descriptions of these tests). CSPI also pressedfor revision of the pesticide assessment guidelines(46) rather than promulgation of a regulation to addnew data requirements to 40 CFR 158.

EPA responded with a letter to CSPI in November1988, stating that the Agency intended to adhere to

the guidelines recommended by the SAP subpaneland that it was still considering appropriate criteriafor initiating tests beyond the base set of tests. EPAagreed to modify the pesticide test guidelines butstressed the need to coordinate OPP and OTSguideline revisions through an intra-agency workgroup. Draft EPA guidelines were supposed to becompleted by February 1990 and made available forpublic comment in May 1990.

Meanwhile, efforts to improve neurotoxicity test-ing requirements through the 1988 amendments toFIFRA resulted in changes in the principal reportaccompanying these amendments. Section 219 of S.1516 (reported by the Senate Agriculture Committeein May 1988) would have required the EPA Admin-istrator to “develop methods for testing to accu-rately detect neurotoxic and behavioral effects ofpesticides, and their ingredients,” and “as suchmethods are developed, require to the extent appro-priate and necessary that data from such testing besubmitted by persons seeking to obtain or maintainpesticide registrations.” This provision was notincluded in the amendments finally enacted, but theHouse Agriculture Committee’s report on the billthat became law noted the deficiencies of EPA’scurrent neurotoxicity testing and called for improve-ments:

In light of recommendations made by a number ofscientific and public health organizations urgingexpanded neurotoxic and behavioral testing, theCommittee requests that EPA intensify the degree ofsuch testing in its pesticide program, includingtesting related to chronic exposure, prenatal, andneonatal effects (26).

At present, scientists in OPP and OTS are workingtogether to produce a set of revised neurotoxicity testguidelines (see ch. 5). The test guidelines will beaccompanied by risk assessment guidelines to directthe scientific review of the data they provide (box7-G).

Revision of the FDA’s Red Book forFood and Color Additives

FDA’s Center for Food Safety and AppliedNutrition has been considering the utility of specifictests for neurotoxic effects for several years. In

9The co-petitioners were the State of New York, the Wisconsin Public Intervener’s Office, the Natural Resources Defense Council, the NationalCoalition Against Misuse of Pesticides, the Northwest Coalition for Alternatives to Pesticides, the American Psychological Association, the AmericanPublic Health Association, the Association of Children and Adults with Learning Disabilities, the U.S. Public Interest Research Group, and Drs. PhilipJ. Landrigan and Richard E. Letz, Mount Sinai School of Medicine.


Box 7-G-Flexibility in Neurotoxicological Testing

One controversy that has arisen with the introduction of neurotoxicity test guidelines by the EnvironmentalProtection Agency (EPA) is the assertion by some scientists that test guidelines impose excessively rigid limitationson toxicological testing. These scientists, both inside and outside regulatory agencies, have stated that testguidelines result in testing that may ignore important parameters influencing a chemical’s toxicity, preclude theeffective use of expert scientific judgment, and stifle innovation in testing.

While acknowledging the validity of some of these objections, scientists favoring test guidelines have observedthat the purpose of most toxicological testing in the regulatory context is not elucidation of mechanisms of toxicity,but rather clarification of the relative toxic hazards posed by various chemicals. (FDA’s preclinical studies of drugsrepresent an exception to this generalization.) If toxicity test protocols are designed independently for each chemicalunder review, it becomes nearly impossible to compare chemicals.

Scientists with opposing views on this issue have also advanced arguments on practical grounds. Thoseopposed to test guidelines have stated that few contract laboratories have the capabilities to perform all of theneurotoxicological tests specified in the current EPA Office of Toxic Substances’ guidelines. (However, scientistsat contract testing laboratories have stated that they can implement any test procedures that are supported by anadequate market.) Opponents of test guidelines have also noted that the laboratories frequently lack an adequate setof control data to demonstrate the validity and reliability of tests. Regulatory scientists have noted that therequirements of Federal rule-making procedures would make designing new studies for each chemical of concernan extremely protracted process. (In practice, regulatory agencies have sometimes negotiated the performance oftests that differ substantially from those specified in the guidelines.)

One compromise (which has received extensive discussion but apparently little effort toward implementation)is the specification of test guidelines in terms of sensitivity. Sensitivity could be defined as the detection of effectsof known toxicants (positive control studies) or as the detection of a specific decrease in neurological function (e.g.,a 30-degree narrowing of the visual field). Such a specification would provide for both scientific judgment andconsistency across tests of different agents.

In some areas of neurotoxicity testing, either form of sensitivity specification appears to be workable. This isthe case for tests of basic sensory functions, because there is wide agreement among scientists on functionaldefinitions, and probably also for various tests of motor function. It may also be possible to achieve consensus onthe sensitivity of various approaches to neuropathological examinations. Tests of more complex neural function,such as learning, while amenable to specification in terms of positive control studies, provide much greaterchallenges to other forms of validation. There is still considerable debate concerning the validity of variousmeasures of complex neural function (see ch. 5), and debates over the relative merits of test strategies are likely topersist for some time.

SOURCE: J.S. Young and W.R. Muir, ‘‘Survey of Major Toxicology Testing Laboratories on the Use of Organ Function Tests in Toxicology,’prepared for the U.S. Environmental Protection Agency, EPA contract No. 68-024228, work assignment No. 121415, Washington,DC, September 1986.

September 1985, it sponsored a conference on effects during any of the fret-tier tests. (These tests‘‘Predicting Neurotoxicity and Behavioral Dysfunc-tion from Preclinical Toxicologic Data, ” adminis-tered by the Life Sciences Research Office of theFederation of American Societies for ExperimentalBiology. At this conference, a panel of scientistsfrom academia, industry, and government recom-mended a two-tiered approach to neurotoxicologicalevaluations: the first was a screening test, whichincluded either a functional observational battery ora motor activity test, or both, with the use ofstructure-activity information as appropriate; thesecond contained more detailed tests, to be con-ducted on substances that produced neurotoxic

are described in more detail inch. 5.) This approachis comparable to the screening required by EPA’sOTS guidelines, although the FDA panel did notrequest direct neuropathological examination.

Since the 1985 meeting, CFSAN has continued toconsider revision of the Red Book guidelines fortesting of food and color additives. CFSAN scien-tists considered including some neurotoxicity testsbut perhaps not the full range of tests specified in theOTS guidelines. FDA believes that, in order toimpose additional testing requirements on industry,it must demonstrate that the tests would increase the


ability to detect neurotoxicants. CFSAN is seekingto demonstrate the utility of proposed neurotoxicitytests by supporting extramural research efforts thatfocus on neurochemical measures, animal behavior,and measurements of human performance.

The proposed CFSAN guidelines differ from theOTS guidelines in several respects. For example,FDA is reluctant to recommend screening tests thatrequire specific instrumentation, because agencyofficials believe that requiring industry to procurepotentially expensive new instruments would bedifficult to justify if less expensive methods wouldproduce adequate data. FDA is also reluctant torequire specific neuropathological examinations asscreening tests, instead reserving such studies, andbehavioral studies requiring instrumentation, assecond-tier tests for compounds that give indicationsof being neurotoxic. Finally, CFSAN is unlikely toinclude any structure-activity considerations in itsproposed neurotoxicity guidelines. CFSAN has yetto develop a specific proposal for a set of neurotoxic-ity tests or for indicators requiring the performanceof such tests.

Suggested Revisions of OECD ToxicityTesting Guidelines

In 1986, EPA, as the designated U.S. representa-tive to the OECD committee for updating toxicitytesting guidelines, suggested adding a mammalianneurotoxicity screening battery, which includeselements of the OTS functional observational bat-tery, motor activity test, and neuropathology evalua-tion (see ch. 5). The new battery would be moregenerally used, while the OECD’s current neurotox-icity guidelines, which specify hen tests, would beused for delayed organophosphate toxicity. In accor-dance with OECD updating procedures, the proposalwas circulated to member countries for review. EPAsubsequently revised the guidelines, and the com-plex OECD procedure for convening expert panelswas begun.

CONSISTENCY OF FEDERALREGULATION OF NEUROTOXIC

SUBSTANCES

General Toxicological Considerations

There are numerous differences in regulatorypractice under different laws, even within the groupof licensing laws (FFDCA, FIFRA, and TSCA). For

the most part, these differences do not applyspecifically to the regulation of neurotoxic effects,but rather to regulation of all toxic effects. Thus,consistency of regulation for specific neurotoxiceffects hinges on consistency of regulation ingeneral (14).

Consistency of Regulatory Requirements

Statutory requirements for chemical regulatoryprograms differ in several important respects, amongthem the number of chemicals evaluated, the timeavailable for review, the amount and type of dataavailable at the beginning of the review process, theability of the reviewer to acquire additional dataafter review has begun, and the burden of proofregarding safety. For example, the premanufacturenotice process under TSCA necessitates review ofhundreds of chemicals every year; each review isallotted only 90 days (although an extension ispossible), and substantive toxicity data are rarelysubmitted. EPA can obtain additional data or imposecontrols on chemicals only if it finds that there maybe an unreasonable risk associated with use of thechemical. Indeed, critics charge that the proceduralcomplexities of TSCA incorporated in the statuteimpose a considerable administrative burden onEPA and render any action under the law difficult. Incontrast, under FIFRA, applicants for registration ofa pesticide must submit extensive toxicological dataand follow specified test protocols, the reviewprocess extends over a period of years, the applicantis required to submit additional data if the basic dataset raises concerns, and the applicant must establishthat the pesticide will be both safe and effectiveunder the proposed conditions of use. Thus, legisla-tion is the root of some regulatory inconsistency,although there is little in legislative language thatwould preclude a significant increase in intra- andinteragency cooperation and coordination.

Consistency of Protection

That there are differences in the degree of scrutinyunder different regulatory programs is widely ac-knowledged. What is less certain is that thesedifferences correspond to differences in the degreeof protection offered by the laws and regulations.Often, these disparate requirements reflect realdifferences in the potential risks posed by thechemicals each program regulates. It maybe that themore intense scrutiny reserved for some types ofchemicals is an appropriate reflection of the likeli-


hood that they will harm human health or theenvironment.

Current laws are generally based on the premisethat chemicals for which there is a greater probabil-ity of exposure should meet a higher standard ofsafety. This is most clearly illustrated by explicitprohibition of carcinogenic substances as direct foodadditives and of pesticides that become concentratedin foods [FFDCA Delaney clause, sec. 409(c)(3),706(b)(5)(B)]. No such blanket prohibition appliesto general industrial or commercial chemicals (regu-lated under the OSH Act and TSCA), in part becausethere is less certainty concerning the likelihood ofhuman exposure to many of these chemicals. Somecritics of the mechanisms by which industrial andcommercial chemicals are regulated argue that theselaws do not adequately protect the public’s health.

The case is similar for chemicals causing non-carcinogenic toxic effects, which can be divided intochemical classes on the basis of both inherent hazardand expected level of exposure. Chemicals incommerce make up a vast universe—more than60,000 identifiable chemicals are in EPA’s inven-


tory. Many of these chemicals may be present inindustrial settings, and a large subset of them ispresent in consumer products. Pesticides, broadlydefined, form a slightly smaller universe, but thenumber of active ingredients used on foods is muchsmaller (approximately 600). These differences inthe size of chemical classes are reflected in thenumber of new members of each class introducedeach year.

The stringency of the evaluation process for newchemicals under the various laws generally matchesthe presumption of risk-the combination of hazardand exposure potential-posed by each class and thenumber of new class members introduced each year.Thus, drugs are not to be permitted to enter themarket until proven safe and effective in clinicaltrials. New pesticides and food additives are evalu-ated nearly as stringently; however, human trials arenot performed. Commercial chemicals, whetherintended for industrial or consumer use, receive theleast scrutiny.

There are two exceptions to these trends, oneminor and one significant. Consumer chemicals


have not received any procedurally different scru-tiny than those intended for industrial use, despitethe fact that larger numbers of persons may beexposed as consumers than as industrial workers.(EPA does take exposure patterns into account inevaluating chemicals in commerce.) Of much greaterpotential importance is the fact that cosmetics arenot required to undergo premarket toxicity testing.Industry voluntarily tests cosmetics and cosmeticingredients for acute toxic effects, but few areexamined for chronic toxicity. Some have beenfound to have acute and chronic neurotoxic effectson laboratory animals.

While many scientists find some comfort in theobservation that the stringency of review of achemical matches its presumptive risk (except forcosmetics), public interest groups and others havevoiced concerns over such odds playing. The transi-tion of chemical regulation in general from “assur-ance of safety” to “acceptable risk” remains asource of contention (16). A less comforting obser-vation, even to scientists, is that the stringency of

review of a chemical is often inversely proportionalto the size of the class of chemicals to be reviewed.For example, chemicals under TSCA make up thelargest chemical class, yet they receive relativelylittle scrutiny under the normal premanufacturenotice process. Critics of EPA argue that regulatoryresource considerations and a desire not to burdenindustry, rather than presumptive risk, are in factdriving chemical review criteria. (Economic consid-erations in regulating toxic substances are discussedin ch. 8.) They raise the question of whether theminimal screening given the majority of chemicalsis adequate to deal with high-risk chemicals that arenot members of known risk categories (see box 7-H).

Regulation of New v. Existing Chemicals

Existing chemicals in each of the classes consid-ered above are subject to varying degrees of reviewand reevaluation. In contrast to procedures forreviewing new chemicals, however, procedures forreexamining existing chemicals do not reflect theinherent risks of the chemical classes involved.



EPA attempts to ensure the adequacy of datasupporting continued pesticide registration througha regular review process. The registration standardsprogram, which examines 25 chemicals per year, hasthus far addressed only a small portion of the activeingredients of registered pesticides. At the presentrate, active pesticide ingredients would be reviewedon an average of only once every 12 years. The 1988FIFRA amendments mandated that the review sched-ule be accelerated so that all active ingredients arereviewed by 1997. To meet this goal, EPA will needto streamline its existing review process. Pesticidessuspected of being associated with unusually highrisks are examined through a separate special reviewprogram. EPA conducts special reviews of 12 to 15chemicals per year, reaching final decisions on a

Under section 4 of TSCA, existing chemicals areranked for probable risk or high exposures beforethey enter the test rule or consent decree process. Inthe period from 1977 to 1988, final rules were issuedon only 25 chemicals or related sets of chemicals,and consent decrees were reached on three, with nineproposed rules pending. Clearly, these rules addressonly a very small fraction of the 60,000 chemicals inthe TSCA inventory. Evidence that a chemical posesa significant risk must be reported to EPA undersection 8(e), but no data need be developed toevaluate the risks of most chemicals. Further evi-dence comes from sections 8(c) and 8(d) provisions,which require that manufacturers maintain and makeavailable to EPA records of adverse reactions and

third of them. Thus, it addresses only a small fraction the results of unpublished toxicological investiga-of the (presumably) high-risk pesticides. tions.

Box 7-H—TSCA’s Premanufacture Notice Program: Is More Toxicity Testing Feasible?

The thousands of new industrial and consumer chemicals manufactured each year are typically subjected tofar less toxicity testing and evaluation under the Toxic Substances Control Act (TSCA) than the smaller numberof new pesticide, food additive, and pharmaceutical chemicals registered under other Federal laws. Although TSCAdoes require a premanufacture notice (PMN) process—all manufactures must notify the Environmental ProtectionAgency (EPA) before they can begin the commercial manufacture or importation of a new chemical-the statutedoes not demand that toxicity tests be conducted prior to notification. Consequently, few PMNs include any toxicityinformation, much less data from specific tests for neurotoxicity. EPA must review PMNs for nearly 2,000 newchemicals each year, and notwithstanding a paucity of data, EPA has only 90 or 180 days (depending on the typeof chemical) to examine each PMN and determine whether the new chemical presents a significant risk.

TSCA does grant EPA the authority to require additional testing or to impose restrictions on the use of a newchemical if the Agency determines that the chemical will present an unreasonable risk. EPA has intervened in 10to 20 percent of the PMNs reviewed annually to restrict the use of the chemicals; most of these actions have beenaimed at lowering potential human exposure. In some cases, chemicals were withdrawn from consideration. In othercases, EPA has been successful in requiring manufacturers to conduct significant additional testing.

Critics have decried the lack of more comprehensive testing for this large set of chemicals. They argue thatthe public health cannot be adequately protected by the minimal testing conducted under TSCA. Why, they ask,doesn’t EPA require more testing for toxic effects? It is not because the statute has proven defective: whenever EPAhas intervened during PMN review, the Agency has prevailed. Nor is it because scientists in the Office of ToxicSubstances (OTS)—the scientists responsible for reviewing PMNs—have substantially different views than theircounterparts in other regulatory programs of what constitutes adequate testing.

Testing policies under TSCA are defended on the basis of practical reality: TSCA program officials rebut thecharge of insufficient toxicity testing by arguing that the amount of testing being pursued under TSCA is all thatcan reasonably be required under the circumstances. They note that most new industrial and consumer chemicalshave small, uncertain markets and that significant additional testing would cost more than the market for thechemical could cover—in effect banning the chemical based solely on a lack of information about it rather thanon any concern or even suspicion about it. Furthermore, OTS scientists point out that EPA does take action againstchemicals with high anticipated production volumes (and thus with substantial potential for human exposure) andchemicals suspected of causing adverse effects. Thus, they view the amount of testing of new chemicals beingsought under TSCA to be the only feasible amount unless (or until) less expensive, reliable testing methods aredeveloped that could reasonably be sought for a wider number of chemicals.



FDA’s procedures for reviewing existing drugsand food and color additives are less formal thanthose for pesticides or toxic substances. The Centerfor Drug Evaluation and Research tracks physicians’reports of adverse drug reactions and relays them tothe original evaluators of the drugs. Food and coloradditives have been notable exceptions to the reviewof existing chemicals. Until recently, there was noformal monitoring of adverse reactions after anadditive was registered. For aspartame, CFSANestablished voluntary reporting programs and subse-quently requested that physicians and other healthprofessionals inform it of any severe, well-documented reactions associated with foods, foodadditives, or dietary practices.

Although CFSAN does not require reporting onthe use of approved food and color additives, it couldtrack such information and use it to assess the risksassociated with approved uses. Under the Priority-Based Assessment of Food Additives Program, adatabase on uses, levels in food, toxic effects, andchemical structure was created. This system shouldenable CFSAN personnel to compare new toxicitydata to current use patterns or proposed changes inuse and to search for predictive trends (e.g., correla-tions of particular functional groups with toxiceffects). Without the ability to actively updateinformation, however, this system may be of limiteduse for regulatory purposes.

Redundancy of Effort Among Agencies

The definitions of the classes of chemicals ad-dressed in the various statutes have minimizedredundancy of regulatory effort. While some chemi-cals have multiple uses and may be regulated undertwo or more different laws-e. g., pesticide com-pounds that also have industrial applications—thedifferent uses dictate different risk evaluations.Under standard-setting and control-oriented laws,toxicity and risk evaluation are usually driven byconsiderations of probability of exposure; and dif-ferences in exposure potential probably precluderedundancy in the evaluation process. Althoughgreater coordination among the standard-setting andcontrol-oriented programs might be worthwhile,available evidence suggests that these programsdevote relatively little effort to evaluating toxichazards and much more to evaluating the risks posedby particular patterns of exposure.

Integration of Effort

EPA is the only regulatory agency discussed inthis chapter responsible for implementing a numberof very different laws. Other agencies considered inthis chapter address only one law or a few closelyrelated laws. The division of labor among regulatoryagencies raises the question of how well regulatoryefforts are being integrated within and betweenagencies.

EPA, which is charged with implementing sevenregulatory programs under eight of the laws re-viewed, does appear to be actively engaged inintegrating regulation. Although some integrationefforts have been initiated by legislation, the Agencyhas undertaken a number of initiatives on its own inthe recent past. For example, OTS issued a section4 test rule on chemicals referred by the Office ofSolid Waste Management under CERCLA; MCLGsand MCLs have been issued for hazardous wastechemicals that might affect drinking water, even ifthey have rarely been detected in drinking water; andthe drinking water priority list for regulation explic-itly includes both pesticides and chemicals listed forpriority review under SARA, Another example ofrecent efforts in regulatory integration is the attemptto produce consistent neurotoxicity test guidelinesfor both pesticides and toxic substances. Also, EPAis working to consolidate all its risk assessmentinformation into the Integrated Risk InformationSystem (IRIS). Finally, the creation of a discreteRegulatory Integration Division in EPA’s Office ofProgram Planning and Evaluation suggests a commit-ment to consistent regulation. The creation of aformal neurotoxicity working group, which wouldindicate an EPA commitment to regulatory integra-tion for the specific concern of neurotoxicity, hasbeen proposed.

There is less evidence of attempts at regulatoryintegration across Federal agencies than withinEPA. There is some collaboration on research butlittle coordination of regulatory efforts (see app. B).This may be due, in part, to the different-andsometimes conflicting-statutes. Legal requirementsfor dealing with confidential business informationpose barriers to sharing data in some cases; moreimportant is the focus of agency personnel oninternal priorities, which does not foster interagencycooperation. The apparent lack of coordination issometimes quite striking. For example, NIOSH isrequired by Congress to recommend exposure limits


for OSHA, but OSHA has rarely acted on thoserecommendations. In its recent rule, OSHA showeda decided preference for values recommended by theACGIH, despite the fact that NIOSH had establishedrecommended exposure levels (RELs) for 5 of the 20compounds listed as neuropathic and that four of thefive were lower than ACGIH’s TLVs. OSHA wouldbe expected, in some cases, to set PELs that werehigher than NIOSH’s RELs, based on technologicaland economic feasibility. ACGIH TLVs, however,are derived by a completely different process. OSHAappears to be giving equal or greater weight to theviews of a private organization than to those of theagency created to supply it with health assessments.

Specific Neurotoxicological Considerations

Regulatory differences in general strategies forevaluating toxicity entail corresponding differencesin the evaluation of neurotoxic effects. Thus forhuman therapeutic drugs, preclinical toxicity testsare used only to guide observations on clinical trialsand to elucidate possible mechanisms of toxicityrather than to assess toxic potential directly. Forpesticides and food and color additives, in contrast,animal toxicity data are used directly in predictinghuman risk. However, even within programs thathave essentially similar approaches to assessingtoxic risks, there are differences with respect toconsideration of neurotoxic risks.

Consistency of Protection

Regulatory programs have adopted one of threebasic approaches to toxicity evaluation, dependingon which of three underlying assumptions they hold.One approach is based on the assumption thatgeneral toxicity tests using high doses are adequateto detect neurotoxic potential and that specificneurotoxicological evaluations are needed only ifgeneral tests, data on structural analogs, or otherspecific knowledge about a chemical indicates apotential for neurotoxicity. Among these are FDA’spreclinical testing program for drugs and its currentprogram for approving food additives. The secondapproach, represented by the pesticide registrationprogram under FIFRA, accepts more general struc-tural information in guiding neurotoxicity testing.All organophosphorous compounds are evaluatedfor their potential to induce delayed neuropathy, butnonorganophosphorous compounds are not specifi-cally evaluated for neurotoxic potential. All pesti-cides undergo a general toxicity screen; however,

specific neurotoxicity tests are not conducted. Fi-nally, under section 4 of TSCA, specific neurotoxic-ity testing is required for any chemical with highexposure potential, as well as for chemicals specifi-cally suspected of being neurotoxic. Such testingpresumes that standard toxicity tests are not ade-quate to evaluate neurotoxic effects.

OTA found that Federal efforts to control neuro-toxic substances vary considerably between agen-cies and between programs within agencies. Improv-ing the Federal response will require increasedneurotoxicity testing, improved monitoring pro-grams, and more aggressive regulatory efforts.

Whether these different testing procedures corre-spond to different levels of protection dependsentirely on which assumption regarding the sensitiv-ity of standard toxicological tests is correct. Scien-tists inside and outside of Federal regulatory agen-cies have expressed a range of opinions regardingthe desirability of singling out neurotoxicity as aneffect of concern. Many argue that neurotoxic effectscannot be identified without undertaking specifictests. Others argue that there is no more justificationfor including neurotoxicity tests than for includingimmunotoxicity (immune system), cardiotoxicity(heart), hepatotoxicity (liver), nephrotoxicity (kid-ney), or other organ system tests as part of a standardtest battery. These scientists believe that general testprotocols in which high doses are used will besensitive detectors, if not elucidators, of neurotoxic-ity. Other scientists argue that potential noncancerhealth effects in general receive too little scientificand regulatory attention and believe that greateremphasis should be placed on all noncancer healthrisks.

There is a correlation between the opinionsexpressed and the actual testing approach of theprogram in which a particular scientist works. Thewide diversity of opinions expressed by knowledge-able scientists reflects individual views on the extentto which existing regulatory programs are protectingpublic health and the environment from noncancerhealth risks.

In principle, a study to evaluate whether neurotox-icity testing detects effects that would be missed byconventional toxicity tests is easy to design. How-ever, to be truly predictive for regulatory purposes,such a study would have to address a large numberof toxicologically dissimilar compounds. No suchstudy has yet been designed. FDA did sponsor a


review of whether conventional toxicity testing wasadequate for the prediction of neurotoxic potential(18). This review consisted of the deliberations of anad hoc expert panel and a symposium. The panelconcluded that explicit neurotoxicological evalua-tions should be incorporated into toxicity testing,using a tiered-testing scheme. However, its reportdid not present objective evidence of improvementsin test sensitivity as a result of neurotoxicologicaltesting.

As part of its effort to develop neurotoxicity testguidelines, OTS sponsored a retrospective compari-son of neurotoxicity tests with standard toxicity testsfor chemicals inducing narcosis, as well as acomparison of acute and chronic neurotoxicity teststhat addressed a somewhat broader range of chemi-cals (7,8). The choice of chemicals that inducenarcosis tends to bias the comparison in favor ofconventional tests, because this effect is relativelyeasy to detect.

The OTS-sponsored studies found greater sensi-tivity in acute tests when specific neurotoxicologicalevaluations were performed-i. e., the lowest ob-served effect levels were lower for a majority of the25 compounds evaluated (effects in humans werereported at even lower levels). Considerably greatersensitivity was shown by repeated-dose studies.Some compounds produced qualitatively differentneurotoxic effects after repeated dosing, and othersshowed irreversible effects after repeated, but notacute, tests. Quantitative extrapolation from acutetests was found to underpredict toxicity from re-peated exposures. The OTS studies suggest thatconventional toxicity tests, especially acute high-dose tests, are not an adequate substitute forneurotoxicological evaluations. The validity of thisconclusion for a broader range of compounds has notyet been established.

Coordination Among Agencies

Interviews with toxicologists and neurotoxicolo-gists in various Federal agencies indicated that therehas been, until recently, little formal coordinationamong agencies (see app. B). Regulatory scientistsare generally aware of the views of their colleaguesin other agencies. There are also several coordinatedresearch efforts mediated by interagency agreementsand by personal contact.

Contact among neurotoxicologists at differentFederal agencies has not, however, fostered any


unanimity of opinion on the best approach toregulating neurotoxic hazards. Real differences ofscientific opinion remain, and data that wouldresolve these differences have not been developedby the agencies involved. Moreover, even withinagencies, neurotoxicologists and other toxicologistssometimes disagree on the proper role of neurotoxic -ity in safety evaluations.

An agency’s approach to evaluating neurotoxicityoften corresponds to the presence or absence ofneurotoxicologists on its staff. Although this pre-sumably reflects personnel considerations-if anagency is not evaluating neurotoxicological data, itdoes not require people trained to do so-it doesraise the question of whether persons who evaluategeneral toxicological data understand the contribu-tions of directed testing to the prediction of neuro-toxic effects. General toxicologists are essential tothe review process, but individuals with specializedexpertise are often necessary to ensure a comprehen-sive evaluation. Variations in the perceived need forstaff neurotoxicologists reflect a more general prob-lem of toxicological assessment, that of determiningthe appropriate degree of specialization required to


evaluate the many organ systems potentially af-fected by a toxic substance.

The Federal regulatory response to neurotoxicityis fragmented not only by differences in scientificjudgment, but also by differences in regulatoryresponsibility. The decision to evaluate drugs, pesti-cides, and food additives by stricter standards thanare applied to commercial chemicals is not based onthe views of scientists in regulatory agencies, but onnational consensus, as expressed through Congress.

The Value of Establishing a Minimal Data Set

The most striking difference in regulatory pro-grams is between those that require routine testing ofall chemicals submitted for review and those thatmust establish some probability of unacceptable riskin order to require the manufacturer to submit data.These differences tend to reflect both a legislativeconsensus regarding the hazards posed by differentclasses of chemicals and the sheer number ofchemicals in each class that require review. Ifneurotoxic effects of chemicals are difficult topredict, it might follow that any regulatory schemethat does not routinely test for neurotoxicity offersdiminished or insufficient protection.

If no changes are made in the laws with respect towhich kinds of chemicals do and do not requirepremarket testing, the issue becomes one of whetherthere is a sound reason to require comparable tests inthe several programs that already require premarkettesting. Scientists charged with reviewing toxichazard data in the various programs disagree overthe desirability of standardized test guidelines ingeneral, and standardized neurotoxicity evaluationsin particular. EPA scientists have argued thatstandardization provides a distinct advantage forcomparing the hazards posed by disparate chemi-cals, while FDA scientists counter that it is moreappropriate to design specific tests to assess ex-pected toxic effects.

These arguments reflect real differences betweenprograms and the power to compel extensive testing.FDA’s Center for Drug Evaluation and Research hasperhaps the broadest power to compel testing, bothpreclinical and clinical, and is one of the strongestadvocates for flexibility in testing. On the otherhand, OTS must undertake arduous rule-makingprocedures to issue test rules and must carry outprotracted negotiations to obtain consent decrees; itis, perhaps, not surprising that OTS was the first

regulatory program to issue extensive neurotoxicitytesting guidelines. The presence of establishedguidelines diminishes the number of testing issuesthat have to be argued in each rule-making ornegotiation. The legal constraints on OTS—companies need not conduct any testing beyondwhat OTS explicitly rules-have favored a morerigid and explicit approach to testing requirements.

There seems to be general, if not complete,agreement among regulatory toxicologists that spe-cific neurotoxicological evaluation is valuable, onceevidence of neurotoxicity has been detected. Thereis also general agreement that such detailed evalua-tion should not be specified too rigidly but shouldallow for flexibility in designing tests to fit particularchemicals and to address particular questions.

ADEQUACY OF THE FEDERALREGULATORY FRAMEWORK

It is important to bear in mind that regulationshave implications reaching far beyond the letter ofthe law. Thus, measuring regulatory effectiveness isonly one aspect of gauging the broader set ofregulatory impacts. For example, regulations im-pose direct or indirect costs on industry that affecthow industry conducts its business. These consider-ations are addressed in more detail in chapter 8.

Measurements of Effectiveness

Any attempt to measure the success of Federalregulatory agencies in evaluating and controlling theneurotoxic risks posed by chemicals depends onhaving an independent measure of neurotoxic risks.Finding such a measure is difficult. Two alternativesare considered here. The frost is to compare theproportion of chemicals detected and controlled asneurotoxic substances by Federal regulatory pro-grams to estimates of the proportion of chemicalslikely to have neurotoxic effects. The second is toexamine evidence of regulatory failures-i. e., missesand false positives.

Expected and Detected Neurotoxicity

It is possible, for at least some regulatory pro-grams, to estimate how many of the chemicalsevaluated were reviewed for neurotoxic potential oridentified as posing neurotoxic risks. Thus, in thepremanufacture notice program under TSCA, ap-proximately 220 chemicals (4 percent of the approx-imately 5,500 chemicals reviewed during the life-


time of the law) have raised sufficient concernregarding neurotoxicity to merit standard review. Ofthe 220 chemicals receiving this detailed evaluation,180 were judged to pose neurotoxic hazards, al-though in many cases other hazards were judged tobe more significant. Due to exposure limitations,only 120 were judged to pose neurotoxic risks. Ofthese, neurotoxicity was the driving concern inapproximately 12 cases.

It is difficult to establish whether the PMNprocess is truly effective in assessing neurotoxicrisk. Generally, toxicity data to confirm the PMNpredictions are not available. Reports of significantrisk submitted under section 8(e) could be used toidentify regulatory failures resulting from inade-quate review, but because chemical identities areoften claimed to be confidential business informa-tion, they are open only to internal scrutiny (see box7-D).

Of the high-hazard or high-exposure chemicalsreviewed under section 4 of TSCA, 19 have been

considered for neurotoxicity evaluation since theneurotoxicity test guidelines were issued; three ofthese were judged not to require neurotoxicitytesting during the rule-making or consent decreeprocess. Three additional chemicals were proposedfor neurotoxicity testing prior to publication of thetest guidelines; one was the subject of negotiatedtesting, a second was the subject of testing byanother program office, and a proposed test rule isunder development for the third. Of the chemicalsfor which the Interagency Testing Committee rec-ommended neurotoxicological evaluation, EPA dis-agreed on the need for such testing in only two cases;in eight other cases, either testing was in progress orpotential exposures were determined to be minimal.

The chemicals evaluated for neurotoxic effectsrepresent a substantial fraction of the total number ofchemicals tested under section 4 of TSCA. There are25 final test rules, seven of which include neurotox-icity testing; nine pending proposed rules, five of


which include neurotoxicity; and three consentdecrees, two of which include neurotoxicity.

It is more difficult to gauge the extent ofneurotoxicity testing conducted under FIFRA.Whileannual registration totals are available, OPP trackingsystems are not yet able to determine the number ofchemicals evaluated for adequacy of neurotoxicol-ogical data. Only EPN and acrylonitrile could beidentified as chemicals for which regulatory actionwas taken on the basis of neurotoxicity. Otherpesticides are being evaluated for neurotoxicity, anddata call-ins have been issued, but EPA does nothave any accessible record of such data call-ins.

Applications for approximately 330 commercialinvestigational new drugs are presented to FDAevery year; approximately 20 percent of these areeventually approved. In recent years, perhaps 16percent of the applications submitted have involvedneuropharmacological agents. Of the 54 neurophar-macological agents for which FDA reviewed INDapplications in 1988, nine were put on hold, two ofthese because of concerns regarding their toxicity.Only one of these was judged to be neurotoxic.

The FDA annually reviews approximately 60indirect food additives, 10 direct food additives, and10 color additives. Many of these involve potentialexposures sufficiently low that only the most basictoxicity studies are performed. In the past 5 years,only three chemicals have raised sufficient concernregarding neurotoxic effects to be reviewed by theneurobehavioral toxicity team; this represents lessthan 1 percent of all applications received.

Under standard-setting or control-oriented legis-lation, it is not always possible to estimate accu-rately the proportion of chemicals regulated forneurotoxic concerns, both because the number ofchemicals regulated is small and because these lawsaddress chemicals already determined to pose exces-sive risks. The latest rule proposed by OSHA onpermissible exposure limits clearly considers a largenumber of chemicals (more than 400). Of theapproximately 300 for which a basis for a limit wasexplicitly stated, 20 were indicated as causing nervedamage and 19 as inducing drowsiness. Someneurotoxic chemicals (e.g., methanol) are includedin lists for ocular effects, and the list of chemicalsregulated for biochemical or metabolic effects in-cludes eight chemicals (out of 26) that inhibit, eitherdirectly or indirectly, the production or activity ofcholinesterase.

Interpretation of these percentages depends on theproportion of chemicals that would be expected tohave neurotoxic effects. Estimates of this proportionhave been made by several authors, and they varywidely. For example, Anger and Johnson estimatethat there are more than 850 known neurotoxicchemicals (4). Anger (3) reported that 167 of the 588TLVs promulgated by the ACGIH in 1982 werebased at least in part on neurotoxic effects, whileBass and Muir (9) determined that 202 of the 605TLVs promulgated in 1984-1985 met a similarcriterion. In contrast, O’Donoghue (21), summariz-ing basic toxicity data obtained from Kodak for 448high-volume chemicals, found only 12 to haveprimarily neurotoxic effects. Of the 167 chemicalslisted by Anger, O’Donoghue found only 28 to haveneurodegenerative effects. Differences such as theseare also due in part to differing views regarding thedefinition of neurotoxicity. The estimates givenabove are not necessarily incompatible. For onething, they reflect different starting sets of chemi-cals. For example, ACGIH lists all chemicals forwhich some toxic effect has been noted at or nearpotential levels of exposure.

Monitoring Mechanisms

An alternative approach to assessing the effective-ness of regulatory programs in controlling neuro-toxic hazards is to evaluate the rate of regulatoryfailure. Unfortunately, while several of the licensingprograms have procedures that enable them to trackchemicals after approval, these programs have notgenerally been used to assess the adequacy of theoriginal decisionmaking process.

The registration standards program under FIFRAis aimed at identifying deficiencies in data thatresulted from earlier regulatory practice and as-sumes that current registration practices are appro-priate. Reports of adverse reactions to drugs underFFDCA consider a wide range of adverse effects butare generally used on a chemical-specific basis.

Under TSCA, EPA receives and evaluates reportsthat may indicate significant risks of chemicals incommerce, some of which have been subject toPMN review. These data have not been regularlyused to assess the adequacy of the PMN process.EPA has, however, acknowledged the need toreview this process. Because EPA is forced to relysubstantially on structure-activity analysis, ratherthan experimental data, in predicting the risks posed


by new chemicals, it has a particularly active interestin assessing the accuracy of its efforts. In 1984, astudy was designed to obtain data on a small sampleof PMN chemicals that would be representative ofchemicals with the highest expected risk (those withintrinsic hazard and high exposure); of these datawould be compared with the results of PMN riskassessments to yield an estimate of the accuracy ofthe PMN process. Unfortunately, although the studywas proposed in five versions spanning a wide rangeof costs, not even the least expensive variant of thestudy was funded.

Many other statutes, including FFDCA, FIFRA,OSH Act, and the Consumer Product Safety Act,contain similar provisions for reporting adverseeffects of chemicals. Any of these reporting require-ments could potentially be used to track regulatoryeffectiveness.

Because EPA is testing chemicals with highproduction levels (100,000 kilograms in the thirdyear of production) and expectations of significanthuman exposure, it will be obtaining some data withwhich to evaluate the accuracy of PMN assessments.These tests will include a functional observationalbattery and neuropathological measurements, butthey will only be carried out for a long enough periodof time to measure subchronic effects. This set oftests, taken together, may indicate how the structure-activity predictions used in PMN assessments com-pare to assessments that have at least a minimal dataset.

SUMMARY AND CONCLUSIONSIt is the task of regulatory agencies to limit public

exposure to toxic chemicals through programsmandated by law. Because of the great diversity oftoxic substances, many statutes exist to control theiruse. These laws are administered by various Federalagencies, but primarily by EPA, FDA, and OSHA.

New and existing industrial chemicals are regu-lated by TSCA. Pesticides are controlled by FIFRA,and toxic substances in the workplace are regulatedby the OSH Act. The FFDCA regulates food andfood additives, drugs, and cosmetics. These lawsaddress the vast majority of toxic substances, andmore than a dozen other acts focus on othersubstances and sources of exposure. Although neu-rotoxicity is generally not explicitly mentioned inlegislation mandating the regulation of toxic sub-

stances, it is implicitly included as a toxicityconcern.

Regulatory differences in general strategies forevaluating toxicity entail corresponding differencesin the evaluation of neurotoxic effects. Thus forhuman drugs, preclinical toxicity tests are only usedto guide observations on clinical trials and toelucidate possible mechanisms of toxicity, ratherthan to directly assess toxic potential. For pesticidesand food and color additives, in contrast, animaltoxicity data are used directly in predicting humanrisk,

Regulatory programs have adopted one of threebasic approaches to neurotoxicity evaluation, de-pending on which of three underlying assumptionsthey hold. One approach is based on the assumptionthat general toxicity tests using high doses areadequate to detect neurotoxic potential and thatneurotoxicological evaluations are needed only ifgeneral tests, data on structural analogues, or otherspecific knowledge about a chemical indicate apotential for neurotoxicity. Among these are FDA’spreclinical testing program for drugs and its currentprogram for approving food additives. The secondapproach, represented by the pesticide registrationprogram under FIFRA, accepts more general struc-tural information in guiding neurotoxicity testing.All organophosphorous compounds are evaluatedfor the potential to induce delayed neuropathy, butnonorganophosphorous compounds are not specifi-cally evaluated for neurotoxic potential. All pesti-cides undergo a general toxicity screen; however,specific neurotoxicity tests are not conducted. Fi-nally, under section 4 of TSCA, specific neurotoxic-ity testing is required for any chemical with highexposure potential, as well as for chemicals specifi-cally suspected of being neurotoxic. Such testingpresumes that standard toxicity tests are not ade-quate to evaluate neurotoxic effects.

Critics of the regulatory framework voice concernover the odds playing they see in the current process.For example, the chemicals regulated under TSCAmake up the largest classes of chemicals, yet theyreceive relatively little scrutiny by EPA. TSCA doesoffer options for selecting high-risk chemicals forfurther scrutiny, but the vast majority of chemicalsreceive only a limited review. Without significanttoxicity data, predicting risk is difficult and mustrely on hypothetical relations between chemicalstructure and biological activity. However, little is


known about structure-activity relationships withrespect to neurotoxicity. Critics of EPA raise thequestion of whether the minimal screening given tothe majority of chemicals is adequate to deal withhigh-risk chemicals that are not members of well-understood risk categories.

OTA found that Federal efforts to control neuro-toxic substances varied considerably between agen-cies and between programs within agencies. Thisresponse is fragmented not only by differences inscientific judgment, but also by differences inregulatory responsibility. Moreover, the decision toevaluate drugs, pesticides, and food additives bystricter standards than are applied to commercialchemicals is based not only on the views ofscientists, but also on national consensus. Thus,improving the effectiveness of Federal programsdepends on many factors, including more publicawareness, greater involvement by neurotoxicolo-gists in regulatory program offices, increased neuro-toxicity testing, and improved monitoring programs.

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50. Young, J. S., and Muir, W. R., “Survey of Major Environmental Protection Agency, EPA contract No.Toxicology Testing Laboratories on the Use of Organ 68-024228, work assignment No. 121415, Wash-Function Tests in Toxicology, ’ prepared for the U.S. ington, DC, September 1986.

Chapter 8

Economic Considerations inRegulating Neurotoxic Substances

‘The higher environmental issues rise on the national agenda the more important it is that we have the bestpossible knowledge of the economic costs of undertaking particular environmental programs and the costsassociated with not undertaking them. ”

Russell E. TrainRemarks at the Library of Congress

October 18, 1989

“Although conventional regulatory policies have often worked well, they have also tended to pit economicand environmental goals against each other. These goals should complement one another in the long run ifeither of them is to be achieved. ’

Robert N. StavinsEnvironment, vol. 31, No. 1

February 1989

“One of the problems in relating economic health and environmental health is that the nation has notdeveloped a quality of life index that measures both. Environmental health factors such as morbidity andmortality, crop and forest damage, soil erosion, air and water pollution, and aesthetic degradation are givenlittle attention compared to such economic health factors as Gross National Product (GNP) andunemployment. Much work needs to be done to develop and use more comprehensive measurements ofquality of life. ”

An Environmental Agenda for the Future, Island Press, 1985

CONTENTSPage

ECONOMIC ANALYSIS OF REGULATIONS AFFECTING TOXICSUBSTANCES, PESTICIDES, AND DRUGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213Costs, Benefits, and Economic Efficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214Risks and Benefits . .. .. .+, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216Impacts on Market Prices and Industry Profits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Regulation and Incentives for Innovation.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218Utility of Regulatory Analyses in Devising Environmental Regulatory Policy . . . . . . 220Economic Principles of Cost-Benefit and Cost-Effectiveness Analyses . . . . . . . . . . . . . 221

THE COSTS OF NEUROTOXICITY TESTING .. .. .. .. ... .+. . . . . . . . ...4. . . . . . . . . . 221

Determinants of the Costs of Toxicity Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222Cost Estimates for Neurotoxicity Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

NEUROTOXICITY TEST COSTS AND INNOVATION . . . . . . . . . . . . . . . . . . . . . . . . . . 225Drug and Pesticide Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Neurotoxicity Tests and Innovation in Drugs and Pesticides . . . . . . . . . . . . . . . . . . . . . . . 226Neurotoxicity Tests and Innovation in Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

ECONOMIC BENEFITS OF REGULATING NEUROTOXIC SUBSTANCES . . . . . . 228Knowledge Requirements for Estimating Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228The Health Costs of Neurotoxicity ..,..,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .228

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

BoxesBox Page8-A. Economic Balancing Provisions of FFDCA, FIFRA, and TSCA . . . . . . . . . . . . . . . . 2128-13. Requirements of Executive Order 12291 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

TablesTable Page8-1.8-2.8-3.8-4.

8-5.

8-6.

8-7.

The Institutionalization of Regulatory Analysis, 1971-81 . . . . . . . . . . . . . . . . . . . . . . . . 215Comparison of Licensing and Notification Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . 218Protocols for Which Cost Estimates Were Solicited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Ranges in Cost Estimates for Animal Toxicity Tests Combined With NeurotoxicityEvaluations for 1988 . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .......,..............+.. . . . 225Median Cost Estimates for Animal Toxicity Tests Combined With NeurotoxicityEvaluations for 1988 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,....,.0. . . . . . . . . ,...,..+ 225Personal Health-Care Expenditures for the 10 Most Expensive Medical Conditionsin the United States in 1980 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229Estimates of the Health Benefits of Reducing the Neurotoxic Effects of Leadin Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Chapter 8

Economic Considerations in Regulating Neurotoxic Substances

The fundamental economic consideration in regu-lating neurotoxic substances involves balancing theeconomic benefits of utilizing these substancescommercially against their actual or potential risksto human health and the environment. The economicbenefits include the reduced cost and increasedproductivity brought about by drugs, pesticides, andchemicals in health care, agriculture, and industry.The risks are the probabilities of increased morbid-ity, mortality, and environmental contaminationstemming from uncontrolled or excessive uses ofthese substances (35).

Regulations designed to reduce or prevent neuro-toxic risks can benefit society by improving publichealth and the environment. Inmost cases, however,government and the private sector incur costs inorder to achieve these ends. The costs of regulatorycompliance may give rise to a number of additionaleconomic impacts, such as increases in marketprices, reductions in industry profits, and declines innew product innovation. The problem of balancingbenefits, costs, and risks of regulation is not uniqueto the control of neurotoxic substances; it arises in allforms of health, safety, and environmental regula-tion.

Many of the key Federal laws under whichneurotoxic substances are regulated require agenciesto ascertain the positive and negative economicconsequences of regulation (see box 8-A). In imple-menting these laws, Congress has generally intendedthat agencies prepare regulatory analyses l anddocument the balancing of benefits, costs, and risksof proposed alternatives. It is important to note,however, that Congress typically has not set priori-ties for the various economic issues arising fromregulation, nor has it specified the analytical criteriaor procedures that agencies must follow in evaluat-ing the economic impacts of regulation.

The preparation of regulatory analyses of propos-als to control neurotoxic substances is a two-stepprocess. The first step, risk assessment, involves

assessing the health and environmental risks posedby various levels of exposure to these substances.Risk assessment provides a scientific basis forregulatory analyses. The second step, risk manage-ment, is the end for which risk assessment isconducted (see ch. 6).

One economic consideration in conducting riskassessments is the costs and benefits of acquiring thereliable scientific and technical data needed toregulate neurotoxic substances. Many of these datamust be obtained through animal toxicity tests. Tworecent evaluations of Federal efforts to regulateneurotoxic substances concluded that there is a needfor more neurotoxicity testing of existing and newchemicals (30,43). To date, the EnvironmentalProtection Agency (EPA), Food and Drug Admini-stration (FDA), and other Federal agencies withauthority to regulate toxic substances have notwidely adopted or applied neurotoxicity test proto-cols (43). Consequently, available neurotoxicitydata are insufficient to determine reasonably or topredict the health or environmental effects of all buta few of the substances in commerce that haveneurotoxic potential, whether they be pesticides,industrial chemicals, food additives, or drugs.2

More testing of suspected neurotoxic substanceswill increase the chances of avoiding adverse healthand environmental effects. It will also increasedevelopment and regulatory compliance costs. In-dustry and government incur costs in expanding theknowledge base that is essential in regulating toxicsubstances, but development of this knowledgetheoretically improves the precision with which thebenefits of regulation can be ascertained. Therefore,the question arises: What is the appropriate eco-nomic balance between the costs of neurotoxicitytesting and the benefits of the resulting test data indeveloping regulations?

As discussed in chapter 7, the Federal Govern-ment can regulate neurotoxic substances under atleast 16 laws. With the exception of regulations to

lk his chapter, the term “regulatory analysis” refers to analysis used in judging the desirability of a regulation. The term “regulatory impactanalysis” (RIA) refers specifically to analysis performed under Executive Order 12291 (46 FR 13191-13196).

2A Nation~ ~~emy of Sciences (NAS) s~udy examined toxicity test~g results for a sample of substances that included chemicals in COInInerCe(manufactured in both small and large volumes), pesticides, cosmetics, drugs, and food additives. From a list of 53,500 chemicals, NAS selected aramdom sample of 675. A random subsample of 100 chemicals with at least minimal toxicity test information was examined in great detail, andconclusions were extrapolated from the review of test data on these 100 substances (30).

–21 1-


Box 8-A—Economic Balancing Provisions of FFDCA, FIFRA, and TSCA

The Federal Food, Drug, and Cosmetic Act (FFDCA), the Federal Insecticide, Fungicide, and Rodenticide Act(FIFRA), and the Toxic Substances Control Act (TSCA) are the primary laws under which neurotoxic substancesare regulated. Each contains provisions to encourage increased testing for neurotoxicity and to control theproduction, distribution, and use of substances that present unreasonable risks of neurotoxicity. The followingrequirements for economic balancing relate to the control provisions in each of these laws.

Federal Food, Drug, and Cosmetic Act—The economic balancing provisions of FFDCA are less explicit thanthose of the other two Acts. The various sections of the law reflect Congress’ intent both to provide for the safetyof food (including substances added to food) and to maintain an economically affordable and abundant food supply.Whether regulatory analyses are undertaken depends on which section of the law is being applied and the type ofregulatory action being considered. Because of amendments to FFDCA over the years, the regulation of chemicalsin food is quite complex (18). Food-related substances addressed under the Act may fall into one or more categories,namely, food, direct or indirect food additives, color additives, naturally occurring environmental contaminants,inherent constituents of raw agricultural commodities, pesticide residues, and animal drug residues.

Finally, procedural considerations are important. The Bureau of Foods does not consider the process ofapproving and publishing a regulation that permits the safe use of a new food or color additive as formal rule-makingsubject to the cost-benefit analysis requirements of Executive Order 12291. Proposals to ban or limit the use of foodadditives that are already approved, however, are regarded as formal rule-making and are subject to the order’srequirements, A proposal to establish a formal tolerance for environmental contaminants, a procedure that is rarelyundertaken, is also regarded as formal rule-making and would require a cost-benefit analysis.

Federal Insecticide, Fungicide, and Rodenticide Act—In order to register a new pesticide under FIFRA, EPAmust ascertain whether it will ‘‘cause unreasonable adverse effects on the environment. ’ FIFRA defines theseeffects very broadly, to include ‘‘any unreasonable risk to man or the environment, taking into account theeconomic, social, and environmental costs and benefits of the use of any pesticide” (7 U.S.C. 136(bb)).

Under section 6 of FIFRA, EPA may cancel, restrict, or suspend the current registration of a pesticide if theAgency determines that the pesticide causes unreasonable adverse effects on the environment when used accordingto commonly recognized practice. In proposing such action, EPA must take into account the impact it will have onthe prices of agricultural commodities, retail food prices, and the agricultural economy.

Toxic Substances Control Act—Section 6 of TSCA gives EPA broad authority to regulate manufacturing,processing, distribution, use, and disposal of chemical substances that present an unreasonable risk of injury tohealth or the environment. Section 6 states that in proposing any such regulation, EPA must consider and document:the effects of such substance or mixture on health and the magnitude of the exposure of human beings to suchsubstance or mixture; the effects of such substance or mixture on the environment and the magnitude of the exposureof the environment to such substance or mixture; the benefits of such substance or mixture for various uses and theavailability of substitutes for such uses; and the reasonably ascertainable economic consequences of the rule, afterconsideration of the effect on the national economy, small business, technological innovation, the environment andpublic health.

Congress (42) intentionally did not define “unreasonable risk,” but indicated that determining whether achemical posed such a risk should involve:

. . . balancing of the probability that harm will occur and the magnitude and severity of that harm against the effectof proposed regulatory action on the availability to society of the benefits of the substance or mixture, taking intoaccount the availability of substitutes for the substance or mixture which do not require regulation, and other adverseeffects which such proposed action may have on society.

Congress further elaborated on the extent to which economic analysis was needed in the balancing process:The balancing process described above does not require a formal benefit-cost analysis under which a monetary

value is assigned to the risks associated with a substance and to the cost to society of proposed regulatory action onthe availability of such benefits. Because a monetary value often cannot be assigned to benefit or cost, such an analysiswould not be very useful.

Congress cited the National Academy of Sciences (27) as support for the last statement.

SOURCES: Office of Technology Assessment, 1990; U.S. Congress, 1976; Hattan, 1983; National Academy of Sciences, 1975.

Chapter Economic Considerations in Regulating Neurotoxic Substances . 213

reduce human exposures to lead, 3 the greatestamount of regulatory activity specifically directedtoward neurotoxic concerns has occurred underthree laws: the Federal Insecticide, Fungicide, andRodenticide Act (FIFRA), as amended by theFederal Environmental Pesticide Control Act (FEPCA)(7 U.S.C. 135-136y); the Toxic Substances ControlAct (TSCA) (15 U.S.C. 2601-2629), as amended;and the Federal Food, Drug, and Cosmetic Act(FFDCA) (21 U.S.C. 301-392). Each of these lawsprovides authority to obtain scientific and other dataon which to assess risks and to control the use oftoxic substances.

As with their assessments of health risks, agenciesdiffer greatly in their approaches to evaluating andbalancing the economic impacts of regulation. EPA,for example, has developed rigorous guidelines forevaluating the costs, benefits, and alternatives ofregulations having major economic consequences(19). At the other end of the spectrum, FDA, inregulating food additives, carries out balancing in aless formal, more qualitative manner (22,25 ),4 Thesedifferences reflect differences in legislative require-ments for balancing benefits, costs, and risks (seebox 8-A), as well as differences in agency views onthe applicability of Executive Order 12291 (46 FR13191), which defines current policies and require-ments for the executive branch in evaluating regula-tory proposals (see box 8-B).

The purpose of this chapter is to examine andevaluate several salient economic issues involved inregulating neurotoxic substances. Economic issuesthat arise from requirements to test for neurotoxicityas well as from restrictions on production and use ofneurotoxic substances are discussed. Also discussedare the different forms of regulatory analysis thatagencies have applied in addressing these issues.

Economic issues are common in the regulation ofall toxic substances, regardless of the health end-points of concern. However, since (with the excep-tion of lead) the regulatory record for neurotoxicsubstances is limited, the present discussion isgeneral in scope. No attempt has been made topresent a comprehensive economic evaluation of thecosts and benefits of a test rule or use regulation fora specific neurotoxic substance. Nor has an attempt

Ff__l?7 Wplw<.——. .—— —.——— —

—


been made to conduct a technology assessment ofthe impacts of regulating a class of neurotoxicchemicals.

ECONOMIC ANALYSIS OFREGULATIONS AFFECTING TOXIC

SUBSTANCES, PESTICIDES,AND DRUGS

As noted above, current laws for controllingneurotoxic substances do not specify which analyt-ical procedures Federal agencies must use in evalu-

3Re@ations t. r~uce occupational and environmental exposures to lead have been promulgated under at least 10 different Federal statutes (28).4h exception OCCWS in the regulation of food additives that are known or suspeeted carcinogens. Under the 1962 Delaney amendment to ~CA

(21 U.S.C. 348(c)(3)(A)), the use of these substances in any quantity is prohibited, regardless of the impact on food costs or supply or any offsettingbenefits of use (25).


Box 8-B—Requirements of Executive Order 12291

President Ronald Reagan signed Executive Order 12291 in 1981 (46 FR 13191) to increase agency accountabilityfor regulatory actions. To achieve this goal, the order specifies that, in promulgating, reviewing, or developingregulations, all agencies, to the extent permitted by law, adhere to the following requirements:

Administrative decisions shall be based on adequate information concerning the need for and consequencesof proposed government action.Regulatory action shall not be undertaken unless the regulation’s potential benefits to society outweigh itspotential costs to society.Regulatory objectives shall be chosen to maximize the net benefits to society.Among alternative approaches to any given regulatory objectives, the alternative involving the least net costto society shall be chosen.Agencies shall set regulatory priorities with the aim of maximizing the aggregate net benefits to society,taking into account the condition of the particular industries affected by the-regulations, the condition of thenational economy, and other regulatory actions contemplated for the future.

The regulatory impact analysis (RIA) is the means for ensuring that agencies meet these requirements. TheOrder requires that agencies submit RIAs to the director of the Office of Management and Budget at least 10 daysbefore publication in the Federal Register of a notice of proposed rule-making or final rule. For major rules, apreliminary RIA must be prepared and submitted at least 60 days before publication of a notice of proposedrule-making, and a final RIA must be submitted at least 30 days prior to publication of a final rule. A major ruleis any regulation that is likely to have an annual effect on the economy of $100 million or more, to result in a majorincrease in costs or prices, or to have significant adverse effects on competition, employment investment,productivity, innovation, or the competitiveness of domestic firms relative to foreign counterparts.


ating the economic impacts of regulatory decisions.Regulatory agencies have not interpreted statutoryrequirements to evaluate proposed regulatory alter-natives as imposing certain limits on the scope orapproach of analyses that are undertaken. Instead,agencies like EPA have adapted various evaluativeapproaches, depending on the regulatory and eco-nomic issues involved.

The executive branch, through the Office ofManagement and Budget (OMB), has independentlydeveloped and implemented a requirement thatagencies produce specific kinds of economic evalua-tions for regulatory actions that have major eco-nomic impacts. The current OMB requirement forregulatory impact analysis of such actions hasevolved through a series of executive orders, and theOMB has incorporated the Regulatory Impact Anal-ysis (RIA) requirement into its executive oversightfunction (see table 8-l).

This section examines four economic issues andthe analytical approaches agencies have applied inaddressing these issues as they have emerged indecisions to regulate toxic substances.

Costs, Benefits, and Economic Efficiency

Thus far, the terms “costs” and “benefits” havebeen used in a generic sense to indicate negative andpositive economic impacts of regulation. Althoughthis usage is correct, it is important to recognize that,for the purposes of analysis, these terms are narrowlydefined to have specialized meanings. The preciseoperational definitions depend on the type and scopeof analysis and the economic issue being assessed.

Accordingly, cost-benefit analysis (CBA) andcost-effectiveness analysis (CEA) have come torefer to analytical techniques in which macroecon-omic analysis serves as the basis for evaluating thepositive and negative economic consequences of aprogram or decision. For both techniques, costs referto the resource inputs required to implement aprogram. Benefits and effectiveness refer to programoutputs. Costs are computed in dollars, using valuesthat the resource inputs would have had in alterna-tive uses—their opportunity cost. In cost-benefitanalysis, program consequences are also evaluatedin dollar terms. In cost-effectiveness analysis, pro-gram consequences are measured in natural orphysical units.

Chapter Economic Considerations in Regulating Neurotoxic Substances . 215

Table 8-l—The Institutionalization of Regulatory Analysis, 1971-81

Act. Executive Order Year Title Type of analysis

OMB memo 10/5/71 1971 Quality of Life Review Costs, benefitsExecutive Order 11821 1974 Inflation Impacts Statement Costs, benefits, inflationary impactsExecutive Order 11949 1976 ~ Economic Impact Statement Costs, benefits, economic impactsExecutive Order 12044 1978 Regulatory Analysis Costs, economic consequencesRegulatory Flexibility Act 1980 Regulatory Flexibility Analysis Impacts on small businessesExecutive Order 12291 1981 Regulatory Impact Analysis Costs, benefits, net benefitsSOURCE: Office of Technology Assessment, 1990.

In the application of cost-benefit and cost-effectiveness techniques to evaluate health andsafety regulations, costs and benefits are generallydefined and measured from the perspective ofachieving intended regulatory objectives of riskreduction. Cost-benefit or cost-effectiveness analy-sis is employed to evaluate whether the benefits ofa regulation exceed its costs, or whether a regulationis cost-effective. That is, are the resources requiredto implement regulations being utilized in an effi-cient manner? The concept of economic efficiencyrefers to gains derived from resources allocated toachieve stated objectives.

In cost-benefit and cost-effectiveness analyses oftoxic substances regulations (e.g., premanufacturingapprovals, test rules, and use restrictions), the costsconsist of those resources expended for the purposesof regulatory development, implementation, andcompliance. They include expenditures by bothgovernment and the private sector. Governmentincurs expenses in: 1) developing regulatory proce-dures, including toxicity test methods, test rules, andchemical production, distribution, and use restric-tions; 2) reviewing premanufacture notices (PMN),registration, and other requests by industry toproduce and sell new chemical substances; and 3)carrying out necessary monitoring, inspection, andenforcement responsibilities.5 The private sectorusually bears compliance costs, which consist oflabor, materials, equipment, and other expenses for:1) obtaining premanufacturing approvals; 2) con-ducting animal toxicity tests,6 keeping records, andsubmitting reports on chemicals of concern; and 3)altering production processes and products to con-form with production, distribution, and use restric-tions.

Evaluation of the benefits of controlling toxicsubstances involves first assessing the effectivenessof regulation in achieving risk reductions. Riskreduction is measured as reductions in mortality,morbidity, and ecological dysfunction that wouldoccur as a consequence of changes in exposure totoxic chemicals. In cost-effectiveness analysis, ben-efits are measured in natural units, such as years oflife saved, incidence of disease averted, and days ofwork loss avoided. In cost-benefit analysis, riskreductions are evaluated in monetary units.

Net efficiency refers to the difference betweenbenefits and direct costs, or the difference betweenthe value of reductions in health, safety, andenvironmental risks achieved through regulationand the value of the resources employed to achievethose reductions. It is important to note that theefficiency criterion of cost-benefit and cost-effectiveness analyses does not encompass anypositive or negative impacts that regulation mayhave on industry employment, profits, or newproduct innovation. Other forms of economic analy-sis, some of which are discussed below, are utilizedin assessing these so-called secondary economicimpacts of regulation.

Under sections 4 and 5 of TSCA (15 U.S.C. 2604and 2605), EPA typically has not conducted cost-benefit or cost-effectiveness analyses in implement-ing test rules or reviewing PMNs. The economiccosts of complying with individual test rules forexisting chemicals or production prohibitions fornew chemicals are generally relatively small;7 theyare not likely to reach the $100 million per yearspecified by Executive Order 12291 for a major rule.Furthermore, analysis of the health and environ-mental benefits achieved by these actions can be

51n practice, it is difficult t. appofion tic g~vernrnent’s program costs to individual proposals. Consequently they are ofien omit~ from an~YSis.

6Estimates of tie costs of conducting anim~ ~oxlcity tests hat include ce~in neurolqjc~ evacuations are present~ later in t.hls Chapter.TEven when tie total costs of comp]yi~g Writh test ~]es are sm~l, hey may represent a S@ifiCant potion of tie s~es revenues fOr IOW-VOILlme,

specialty chemicals. As discussed below, EPA recognizes the distributive effects of test rule costs in an analysis of impacts on market prices and profits.


speculative. To quantify these benefits, many as-sumptions must be made about a chemical’s rate ofmarket penetration, projected sales volume, types ofuses, and likely disposal practices.

Under section 6 of TSCA (15 U.S.C. 2605), EPAconsiders all aspects of formal cost-benefit analysisin evaluating the impacts of a proposed regulation(48). The balancing language of section 6 (box 8-A)encourages cost-benefit analysis whether or not aregulation is likely to have major economic impacts.Since the enactment of TSCA, however, EPA haspromulgated only a handful of regulations undersection 6 (41).8

EPA’s Office of Toxic Substances recently com-pleted a preliminary risk assessment for environ-mental and occupational exposures to acrylamide, inwhich risks for carcinogenic reproductive effectsand neurotoxic effects were evaluated (49). Al-though this assessment may lead to use restrictionsthat are based on neurotoxicity, further action byEPA under section 6 is contingent on reviews of theacrylamide risk assessment by the OccupationalSafety and Health Administration and other agen-cies having potentially applicable regulatory author-ities.

Under FIFRA, EPA’s decisions to approve newpesticide registrations or to cancel, suspend, or alterexisting registrations are not regarded as rule-making that is subject to the cost-benefit require-ments of Executive Order 12291 (48). However,because of the specific balancing language ofsections 3(c) and 6(b) of FIFRA (box 8-A), EPA hasdeveloped a methodology for evaluating the eco-nomic impacts of registration decisions. This proce-dure is discussed in the next section.

For pesticides that are applied in the production,storage, or distribution of raw agricultural commodi-ties, part of the registration process may include anEPA review to establish a tolerance under FFDCA[21 U.S.C. 346a(b)]. EPA’s granting of such atolerance is considered rule-making, but cost-benefitanalyses of these decisions are not developed,because all of the economic consequences of atolerance are regarded as positive. Finally, therevocation of a pesticide tolerance by EPA is alsoconsidered rule-making. Although cost-benefit eval-

uations are developed for these decisions, they havebeen of limited utility in the regulatory developmentprocess.

Although few WA’S to control neurotoxic sub-stances have been conducted, EPA has conductedcost-benefit studies of regulatory proposals to re-duce human exposures to lead under other environ-mental statutes. Under the provisions of the CleanAir Act for regulating fuel additives [42 U.S.C.7545(c)], EPA developed a cost-benefit analysis ofseveral options for phasing out the use of leadadditives in gasoline (39). In addition, EPA hasevaluated the economic benefits of options forreducing lead in community water supplies underthe Safe Drinking Water Act (42 U.S.C. 300f-j) (23).Both studies estimated the health benefits of reduc-ing lead’s neurotoxic effects in children.

Risks and Benefits

A second economic issue that arises in regulatingchemicals, pesticides, and drugs concerns balancingthe economic benefits of a substance that are lostthrough a restriction or ban on its use against therisks of continued use at unregulated levels (27,29).Risk-benefit analysis is used to address this issue.

As noted above, in a cost-benefit analysis ofchemical regulation, the benefits consist of improve-ments in public health and environmental qualitythat would result from restricting the use of toxicsubstances. However, in risk-benefit analysis oflicensing and approval regulations, in particularunder FIFRA and FFDCA, the term “benefit” hasacquired a different meaning. In this instance,benefits are defined in terms of the opportunity costof switching to substitutes for the chemical inquestion. In registration decisions for agriculturalpesticides, for example, EPA’s Office of PesticidePrograms assesses benefits in terms of changes inthe value of crop yields and pest control costs (29).Similarly, in approving new drugs, FDA assessesbenefits in terms of therapeutic efficacy.

Risk-benefit analysis recognizes that, on the onehand, chemicals, pesticides, and drugs generateeconomic benefits that manifest themselves in theform of increased output and lower product prices.On the other hand, the increased use of toxic

8@e ~emon fm limit~ ~ew]atog ~ctlvity ~der ~W 6 is hat EpA reg~ds TSCA as tie re@ato~ authori~ of 1~t resort. Under TSCA sec, 9 (15U.S.C. 2608(b)), for example, EPA must provide other appropriate Federal agencies with the fust opportunity to regulate substances that presentunreasonable risks.

Chapter 8--Economic Considerations in Regulating Neurotoxic Substances ● 217

chemicals may introduce more of these substancesinto the environment, at the time of initial use orsubsequently in waste disposal. The risks to healthand the environment from increased exposures totoxic chemicals, therefore, may also increase.

Risk-benefit analysis can also be used to comparethe change in environmental and health risks to thechange in economic benefits resulting from regula-tion. If the use of an existing chemical is increased,the analysis compares the potential increase in riskswith the anticipated increase in benefits. If the use ofa chemical is reduced, the analysis compares theexpected reduction in risks with reduction in bene-fits.

EPA initiates risk-benefit analysis for proposedrestrictions on pesticide use when it receives toxicitydata that trigger questions about potential risks tohuman health. Although these analyses may be donewhen new compounds are preregistered, they aretypically undertaken in response to toxicity datagenerated through the special review process forexisting pesticides (see ch. 7). When special reviewleads to proposed use restrictions or suspension orcancellation of a registration for an agriculturalpesticide, for example, analysts estimate the healthrisks and net values of crop production for projecteduncontrolled and the proposed controlled applica-tions of the pesticide. The risk-benefit ratios forthese scenarios are then compared in assessing theeconomic impact of the proposed regulation.

The 1988 amendments to FIFRA call for anaccelerated review of pesticides that were firstregistered under the pre-1972 FIFRA guidelines (1).Because this group includes a number of widelyused agricultural insecticides that function by at-tacking the nervous systems of target organisms, itis likely that special reviews will trigger somerisk-benefit evaluations for neurotoxicity.

In conducting risk-benefit analysis of new drugs,FDA is more qualitative in its approach. In ascertain-ing the benefits, FDA distinguishes between theefficacy and the effectiveness of the candidatechemical. Efficacy refers to the ability of thesubstance to alter the symptoms or pathological

condition for which it was developed. Effectivenessrefers to the degree of reduction in disease or death,and hence in health-care expenditures, a drug mightachieve when optimally prescribed and taken. FDAweighs test evidence of adverse reactions to the drug(risks) against its demonstrated therapeutic proper-ties (benefits). The 1962 amendments to FFDCA(Public Law 87-781) require that manufacturerssubmit sufficient data to demonstrate a new drug’sefficacy but not its effectiveness.

Impacts on Market Prices and Industry Profits

A third issue of economic importance that arisesin the regulation of toxic substances concerns theimpact of the direct costs of regulation on marketprices and industry profits. Although industry ini-tially pays the compliance costs of regulation, itattempts to pass these increases on to customers inthe form of higher product prices. Higher pricesmay, in turn, discourage sales and reduce industryprofits. If there is a major expansion of regulationscovering abroad range of industrial and commercialactivities, as there was in the 1970s, the costs ofregulation may contribute to the Nation’s rate ofinflation.9

TSCA stipulates that EPA consider “the relativecosts of the various test protocols and methodolo-gies” when implementing chemical test rules [sec-tion 4(b)(l); 15 U.S.C. 2603(b)(l)]. In 1980, with thefirst test rule issued under section 4 (45 FR48524-48566), EPA outlined procedures for esti-mating the relative costs of test protocols and theprojected impact of these costs on the marketabilityof the chemicals to be tested. These proceduresremain in use today (24,40). EPA evaluates theimpact of anticipated testing costs for each manufac-turer or processor by estimating unit10 test costs andthen comparing these unit values to the market priceof the chemical. A market analysis may be con-ducted to assess four key features of the market forthe chemical being tested: 1) responsiveness ofdemand to changes in price; 2) expectations formarket expansion or decline; 3) industry costcharacteristics; and 4) industry structure (40).

90MB and tie f&gm Administration ernphasl~ed the cumulative inflationary effects of regulation in implementing Executive Order 12291.l~nlt test ~05ts me estimated by fir5t computing he annualized v~ue of total direct test costs and then dividing by the Wd SUpply (i.e., pK)dUCtiOIl

and imports) of the chemical. In annualizing test costs, EPA uses the expected product lifetime for the annualization period and the estimated cost ofcapital in the chemical industry for the annualization rate. If available, sales volume information is used in estimating expected product lifetimes. Productlifetimes are longer for commodity chemicaIs (i.e., chemicals with multiple uses and large-volume sales) than for specialty chemicals. lf sales volumedata are unavailable, EPA uses a 15-year annualization period. The Agency currently uses 7 percent as the annualization rate (1 1).


Table 8-2-Comparison of Licensing and Notification Mechanisms

Factor affecting incentives to innovate Licensing (FIFRA or FFDCA) Notification (TSCA)

Burden of proof Fails on innovating firm Initial burden falls on regulatory agencyAgency’s authority to compel testing of Withhold approval until desired informa- Requires agency finding that a product

new products tion is submitted may pose an unreasonable riskBurden of delay Fails on innovating firm Falls on publicSOURCE: Office of Technology Assessment, 1990.

EPA uses an informal rule of thumb to deter-mine adverse economic impacts of testing. If theunit costs of testing a chemical are less than 1percent of the price of the chemical, then thepotential for adverse economic impact due to thetest rule may be low. Conversely, if the unit testcosts exceed 1 percent of price, then the potentialfor adverse economic impact may be high (24).

Regulation and Incentives for Innovation

An issue that is related to the impact of compli-ance costs on profitability is the effect of regulationon incentives for innovation. The development andintroduction of new chemicals, pesticides, and drugshave produced benefits in virtually every area ofhuman need: food, health, shelter, clothing, trans-portation, communication, and energy. On the otherhand, extensive use or misuse of these substanceshas increased risks to public health and the environ-ment. Hence the question, ‘‘Does regulation toprotect health and the environment alter industry’sincentives to develop new drugs and chemicals?’ ’11

Companies develop and introduce new productsas a means of competing in a given market andmaking a profit. Profitability depends on salesvolumes and the cost and time required to develop,produce, and market new products. It also dependson the availability of competing products andpatents and other factors that protect the marketposition of the innovating company. Finally, be-cause there is uncertainty surrounding each facet ofthe development and commercialization of newproducts, innovation in the private sector will takeplace only if the prospective reward-risk ratio isconsidered favorable.

Regulation can affect each of these factors. First,the compliance costs of regulation increase the costsof developing new products. Second, the regulatoryprocess adds to the time required to develop andintroduce new products. Third, use restrictions canlimit the market for a product, or in the extreme caseof a ban, eliminate the market altogether. Fourth,reporting requirements may lead to the disclosure ofproprietary information that may compromise thecompetitive position of the innovating company.Finally, because regulation can add uncertaintiesregarding costs, delays, protection of proprietarydata, and so on, it adds to the financial risk ofdeveloping new products.

An important aspect of how a regulation affectsincentives for innovation concerns the manner inwhich the regulatory process acts as a barrier to thecommercialization of new products. In this regardthere are important differences between the pre-market screening requirements of TSCA versusthose of FIFRA and FFDCA. The key difference isin the way the prescreening process assigns theburden of proof to demonstrate that a new productdoes or does not pose unreasonable risks (see table8-2). Under the notification requirement of TSCA,the burden falls on the regulatory agency to make afinding that a product may pose an unreasonablerisk. Under the licensing mechanisms of FIFRA andFFDCA, the burden falls on the innovating com-pany. The regulatory agency can withhold approvalfor marketing of a new product until it is satisfiedthat the firm has conducted sufficient testing toestablish that the product poses no unreasonablerisks.

Numerous studies have sought to assess theaggregate effects of Federal regulatory changes on

11A ~elat~ but ~n~@c~ly more complica[~ issue concerns whe~er he impact of health and safety re@ations on incentives tO hmovate prOdUCe

a net gainor loss to society. The temporal framework for analysis must be long enough to consider the positive and negative impacts of emerging chemicaland drug technologies under various levels of regulatory control. Regulatory analyses usually lack this perspective. Risk-benefit analysis of proposedpesticide controls, for example, usually focuses on short-term economic impacts (3 to 5 years) and considers only currently registered chemical andnonchemical controls as alternatives (31).

Chapter 8-Economic Considerations in Regulating Neurotoxic Substances . 219

innovation in the drug, pesticide, and chemicalindustries. 12 These studies have measured changesin an industry’s innovative efforts in terms of theresource inputs and outputs of the innovative proc-ess. Measures of inputs into innovation have in-cluded: total research and development (R&D)expenditures per year; R&D expenditures as apercentage of annual sales or profits; time frominitial discovery to commercialization; and develop-ment cost per new chemical entity. Typical outputmeasures have included the number of new productsregistered or licensed per year and effective patentlifetimes. These measures have been examinedbefore and after implementation of a change in aregulatory program or a change to ascertain whetherthere are significant quantitative differences. Al-though it is beyond the scope of this chapter toevaluate these studies critically, it is useful tosummarize their findings and discuss some of thedifficulties encountered in measuring the impact ofregulation on innovation in the chemical, pesticide,and drug industries.

One difficulty in using total R&D expendituremeasures has been the difficulty of distinguishingbetween R&D costs of truly new compounds (i.e.,new chemical entities or new active ingredients forpesticides) and costs of new applications and combi-nations of previously discovered compounds. Asecond difficulty is that a substantial amount of theR&D expenditures for testing new chemicals isintegral to their development. For pesticides, forexample, toxicity testing and metabolism and resi-due studies are essential in understanding theproperties and mechanisms of action on targetorganisms. Similar test information is needed indrug development. In other words, there is consider-able overlap in the generation of test data needed todevelop an application for a new substance and dataneeded to ensure its safety.

Drug R&D Studies

The most studied area of regulatory impact oninnovation to date has been the effects of the 1962amendments to FFDCA on R&D in the pharmaceuti-cal industry. For the most part, studies agree that theoverall rate of new drug introductions declinedsubstantially from the 1950s to the 1960s and evenmore into the 1970s (see, e.g., 15,17,32,51). Studies

have shown that development time and cost tomanufacturers increased significantly after enact-ment of the 1962 amendments (see, e.g., 7,20,26,38).

Although these studies demonstrate consistent,adverse effects on drug innovation after a change toa more stringent regulatory regime, they do not agreeon the relative importance of regulation as a factorin these impacts. Other influences not related toregulation, for example, declining drug researchopportunities and exogenous increases in R&Dcosts, have been hypothesized as being partiallyresponsible for the observed declines in drug innova-tion during this period. U.S. data showing that thedecline in new approvals was already under waybefore 1962 and international data demonstratingcomparable trends in other countries tend to supportthe conclusion that regulation has been only partiallyresponsible for these declines (15).

Pesticide R&D Studies

Although there have been no studies of howregulatory efforts directed specifically toward neu-rotoxicity have affected pesticide innovation, therehave been studies of the aggregate effects of pesticideregulation on R&D. A study by the Council onAgricultural Science and Technology (8) found thatfrom 1968 to 1978—before and after enactment ofthe 1972 amendments to FIFRA-direct costs ofbringing anew pesticide to market increased, delaysfrom discovery to registration grew, and the compo-sition of R&D expenditures shifted from synthesis,screening, and field testing to registration, environ-mental testing, and residue analysis.

Studies conducted by EPA (5) found little evi-dence of a reduction in pesticide innovation thatcould be attributed to EPA regulatory requirements.This conclusion was corroborated in an unpublishedOTA study (45). OTA reported that after 1972, totalpesticide industry R&D expenditures continued togrow at the same rate as pesticide sales. In addition,there was no apparent trend in pesticide registrationsover the period 1966 to 1980 that could be attributedto regulation.

Chemical R&D Studies

In the late 1970s and early 1980s, prior to EPA’sissuance of a final rule for premanufacturing notices

l~mrment ~view~of ~tudie~ of tie fipact of Feder~ re@ations on innovation in tie d~g, pesticide, and chemic~ industries, seerefs. 16,19,31.


(PMNs),13 many parties expressed concern that themajor economic effect of section 5 of TSCA wouldbe to reduce innovation by chemical companies(46,37,36). Several studies were conducted to esti-mate the impacts of the PMN process on theintroduction of new chemicals (see, e.g., 3,37).Impacts were assessed for several alternative PMNfiling formats proposed by EPA and were dependenton the direct costs of preparing and submitting thePMN as well as the indirect costs of delays anduncertainty associated with the ultimate dispositionof the PMN.

One of the difficulties in assessing the impacts ofthe PMN rule on innovation in the chemical industryis that data on the number of new chemicalsintroduced annually, prior to the implementation ofthe PMN rule, are quite limited. It has not beenpossible, therefore, to establish a good baselineagainst which to measure the rate of chemicalinnovation since implementation of the rule.

EPA’s estimates of direct filing costs for the finalPMN rule were rather nominal ($3,000 to $18,000 in1983 dollars per new chemical introduction) (19).However, some parties, notably the Chemical Spe-cialties Manufacturing Association, argued thateven costs in this range would have a disproportion-ate distributional impact on introductions of small-volume chemicals (19). Some of the smaller-volume, lower-value chemicals are not able toabsorb even the relatively low compliance costburdens represented by these estimates.

Utility of Regulatory Analyses in DevisingEnvironmental Regulatory Policy

It is the need to document the economic impactsand potentially high costs of Federal regulatorydecisions that continually motivates agencies toevaluate the effectiveness of these decisions. Thegoal in conducting these evaluations has been toimprove regulatory decisionmaking through sys-tematic development of information, preferablyquantitative information, about the positive andnegative economic impacts of proposed regulations.

From an analytical point of view, the ability of anyevaluative technique to influence the selection of aparticular regulatory alternative depends on thedegree to which that technique can provide clear-cutdistinctions among alternatives. Because of largegaps in underlying scientific information, estimatesof costs, risks, and benefits are more often than notquite crude and highly uncertain. Consequently,cost-benefit and other regulatory analysis tech-niques are approximate and capable usually ofdistinguishing only between clearly superior andclearly inferior alternatives.

Improving Regulations

Despite their limitations, cost-benefit and cost-effectiveness analyses have influenced the develop-ment of regulations. In a recent assessment of impactanalyses for 15 major regulations, EPA concludedthat cost-benefit analysis had improved individualenvironmental regulations by:

●

●

●

●

●

guiding the development of the regulation (i.e.,showing that net benefits increase or decreaseif the proposed regulation is made more or lessstringent);leading to the specification of additional alter-natives for analysis and consideration;eliminating alternatives that are clearly notcost-effective;adjusting alternatives to account for differencesbetween industries or segments of industry; andsupporting decisions (i.e., showing that thereare net benefits for a regulatory decision thathave been formulated under a different decisionframework).

EPA noted that in some cases it is precluded bylaw from allowing the results of a cost-benefitanalysis to influence rule-making. 14 In some of theseinstances, the Agency has prepared cost-benefitanalyses anyway, to conform with the requirementsof Executive Order 12291.

The General Accounting Office, in reviewing theutility of cost-benefit analysis at EPA, noted thisdifficulty and recommended that the Agency for-ward its analyses to Congress, since they could still

lsAlthou@~e ~atutow r~uirements for prernanufacturenotif ication and review ( 15 U.S.C. 2604(a)(l )(A)) do not stipulate that these processes mustbe stated in a rule or that the information be provided in a particular form, EPA ( 19) determined that the issuance of a PMN rule was in the best interestof all concerned parties. Toward this end, the Agency began operating the PMN program on an interim basis in July 1979. The final rule establishingPMN requirements and review procedures was not issued until 1983 (48 FR 21742).

ldunder tie Clean Air ~t, for exap]e, Pnmq national ~bient ~ qll~ity s~nd~ds must ~ bad solely on he~ti effwts, without considerationof benefits, costs, or economic impacts (42 U.S.C. 7409(b)(l).

Chapter 8-Economic Considerations in Regulating Neurotoxic Substances ● 221

provide useful information for congressional over-sight (41). EPA supported this recommendation butnoted that care should be taken in interpreting thefindings because of the uncertainties and gaps indata that are likely to exist (48).

Additional Contributions

EPA noted several other contributions that cost-benefit analysis has made. As the Agency has gainedexperience in quantifying benefits, it has been ableto transfer analytical expertise from one regulatoryarea to another. For example, part of what EPAlearned from evaluating the health benefits ofremoving lead from gasoline has been applicable inestimating the benefits of reducing lead in drinkingwater.

Application of the cost-benefit approach hasimproved the consistency and comprehensiveness ofregulatory analyses of proposed rules. Evaluation ofregulations to control pollutants that have the samehealth outcome (e.g., cancer) has encouraged moreuniformity in analyzing data on health effects. Formultimedia pollutants, the application of cost-benefit analysis has increased awareness that regula-tory action against pollution of one medium hasramifications for human exposures to pollutants inother media.

Economic Principles of Cost-Benefit andCost-Effectiveness Analyses

As indicated above, cost-benefit and cost-effectiveness analyses seek to quantify and comparethe economic inputs and outputs of a regulatorydecision. If cost-benefit analysis confirms that thenet benefits (i.e., the benefits minus the costs) of aregulatory proposal are positive, the regulation issaid to produce an economically efficient allocationof resources. Thus, implementation of that regula-tion will result in a net economic gain to society.

Concepts and Definitions

In general, the concepts of cost-benefit andcost-effectiveness rest on the basic economic con-cept of opportunity cost: that is, the true cost of anyactivity consists of the value of alternative endeav-ors that might have been undertaken with the sameresources. For example, the opportunity cost ofpremarket testing of a chemical is the value thatresources used for toxicity testing would have had ifused in production, sales, or other research activities.

The principal technical distinction between CBAand CEA, as noted earlier, is that CBA benefits arevalued in monetary units, whereas CEA benefits arevalued in natural, or nonmonetary, units. Because allcosts and benefits are measured in the same units inCBA, this technique can be used to compare similaror widely divergent types of decisions. Thus CBAmight be used to compare different regulatoryoptions such as protective labeling, use limitations,or a total product ban. In the health area, analystsfrequently prefer CEA to CBA because of thedifficulty or undesirability of placing a dollar valueon life. When using CEA to evaluate health pro-grams that have both mortality- and morbidity-reducing consequences, analysts must often com-pare noncommensurable outcomes. How are twoprograms to be compared when one saves severallives but has a limited impact on morbidity, whilethe other saves a few lives and has a more extensiveimpact on illness? To address this problem, analystshave developed a measure called quality-of-life-adjusted years.

Cost-effectiveness is useful in making relativecomparisons among regulatory options, and it ismore meaningful when two or more alternatives arecompared. For example, instead of considering thecost-effectiveness of toxicity test A standing alone,analysts examine the cost-effectiveness of testprotocol A compared to protocol B or protocol C.Protocol A is cost-effective if it yields the requiredtest data at a lower cost than protocol B or C; or Ais cost-effective if it produces more useful data thanB or C when the same level of resources is utilizedin each test protocol. In both of these comparisons,protocol A would be regarded as the most economi-cally efficient alternative of the three (economicefficiency is also a relative concept and refers to thealternative that provides the greatest return for agiven level of resource expenditures).

THE COSTS OFNEUROTOXICITY TESTING

Animal toxicity testing and the resources ex-pended for this purpose are now considered essentialfeatures in the development of new chemicals anddrugs. FFDCA and FIFRA require demonstration ofthe ability of drugs and pesticides, that is, of thedesigned toxic properties, to attack diseases or targetorganisms. The relative safety of a drug (as meas-ured in terms of unintended toxic effects) or a


pesticide (as measured in terms of morbidity ormortality to nontarget organisms) must also bedemonstrated. TSCA emphasizes establishing aminimal set of information about a chemical’s toxicproperties before it is introduced into commerce.Under TSCA, manufacturers can also be requestedto provide additional test data if there is cause tobelieve that a chemical may present an unreasonablerisk to human health or the environment (see ch. 7).

Over the years, Federal authorities responsible forregulating chemicals have paid attention primarilyto the potential carcinogenic, mutagenic, and terato-genic effects of pesticides and toxic substances.Although concerns regarding neurotoxic effectswere occasionally mentioned, in most cases theywere of secondary importance. With steady ad-vances in the field of neurotoxicology and corre-sponding improvements in the ability to understandand to test for the neurotoxic effects of chemicals,the adverse effects that a substance may have on thenervous system have become of increasing interestand importance in regulatory decisionmaking.

In order to gauge the economic significance ofrequirements for increased neurotoxicity testing,this section discusses factors in the costs of animaltests for neurotoxicity. Estimates obtained by theOffice of Technology Assessment (OTA) of thecosts of conducting certain neurotoxicity tests arethen presented. Finally, the incremental effects thatthe costs of neurotoxicity testing will have on totalR&D costs for new chemical technologies arediscussed.

Determinants of the Costs of Toxicity Tests

The costs of animal toxicity tests vary greatlyfrom laboratory to laboratory. Many factors contrib-ute to these variations, but they can be placed intotwo categories: scientific, or differences in protocolrequirements, laboratory personnel, facilities, and soon; and financial, or differences in laboratory costs,rates, and fees.

Scientific Determinants

There are five major scientific considerations thatdetermine the costs of any toxicity testing: protocolrequirements, quality assurance, personnel, labora-tory capabilities, and laboratory automation. Each ofthese is discussed below.

Protocol Requirements—The requirements ofthe test protocol are the single most important factor

in determining the costs of toxicity testing. Of theserequirements, duration of exposure has the greatestimpact on costs. Tests to identify the adverse effectsof acute exposures are usually completed within 1month; tests for chronic exposures may require up to2 years of animal dosing and observation. Becauseof the time difference alone, direct labor costs maydiffer by as much as a factor of 40.

Route of exposure is the next most important costfactor in protocol design. Because of the relativeease of dose administration, oral exposure viagavage (force-feeding) is least costly, followed byoral feeding, dermal exposure, and inhalation expo-sure. Dermal and inhalation exposures require spe-cial preparations and equipment. Inhalation alsorequires special monitoring equipment to measurethe concentration of the test substance in the airbreathed by the animals.

Although EPA has promulgated toxicity testingguidelines (50 FR 39397-39470), these protocols arenot rigid recipes. Chemical manufacturers mayexceed EPA requirements (e.g., an increased numberof dosage groups or animals per group) or suggestadditional testing based on previous experience andtest findings.

Quality Assurance-Quality assurance affectsthe costs of toxicity testing in proportion to theaccuracy and precision of the measurements re-quired by the protocol. To achieve greater accuracy,more effort is needed in controlling contaminationor other factors that may bias measurements. Toachieve greater precision, more effort is needed inmaking duplicate measurements and analyses.

Federal good laboratory practice guidelines andregulations have, for the most part, required labora-tories to establish in-house quality assurance units.The number of persons in these units varies bylaboratory. Some laboratories do not have fill-timequality assurance personnel and rely on outsideconsultants or part-time personnel, whose costs maybe lower. Laboratories with large quality assuranceunits perform functions well beyond the basic testrequirements, and their costs usually are muchhigher.

Quality assurance personnel perform protocolevaluations, general laboratory inspections, evalua-tion of technical procedures, verification of raw data,interim and final report audits, and verification of thefinal report. The time required for these procedures


varies with the degree of automation at the labora-tory, the degree of report standardization and com-puterization, the amount of data audited (which mayrange from 10 to 100 percent), and the experienceand efficiency of the personnel.

Personnel—The levels of professional and tech-nical expertise required for a particular toxicity testcan significantly influence costs, particularly inacute studies. The education and experience re-quired may be specified by the protocol, Federalregulatory requirements, or general consensus, anyof which will result in cost variations. Smallerlaboratories may have only limited personnel availa-ble for performing the tests (i.e., senior scientistsmay be performing procedures that would normallybe done by technicians).

Laboratory Capabilities-Cost may also varywith mix of capabilities within a laboratory. Manylaboratories do not perform the full complement ofrequired test functions (i.e., analytical chemistry orelectron microscopy) in house. Laboratories that useconsultants or subcontractors to perform these func-tions increase costs by adding general and adminis-trative fees. Laboratories that have extensive in-house capabilities but do not operate at full capacityincur greater overhead.

Laboratory Automation-There are major costdifferences between manual and automated methodsof data collection. Highly sophisticated, on-linecomputer systems can capture data electronically,lowering facility and animal monitoring costs.Examples include automatic control, monitoring,and recording of environmental conditions withinthe laboratory, as well as computerized data stationsfor animal body weights, food consumption, andclinical observations.

Financial Determinants

Four financial factors influence laboratory costs:1) overhead rates, 2) general and administrativerates, 3) fees, and 4) labor rates.

Overhead Rates-Overhead costs are the indirectexpenses, such as rent, heating, lighting, equipment,computer services, telephone, insurance, and so on,associated with the operation of a laboratory. Over-head costs are usually computed as a percentage—called the overhead rate-of total direct labor costs.

Overhead rates vary significantly among labora-tories, for numerous reasons. Geographical location

can affect overhead rates through variation in utilitycosts; rent, land, or construction costs; propertytaxes; State income taxes; and Federal corporateincome taxes. The number of years the commerciallaboratory has been in business may influence itsoverhead rate. Newer firms typically have a smallerwork force, a large capital investment in newequipment, and sizable expenses in order to generatenew business. Older, established firms often supporta significant portion of employees on overhead,offer a better benefits package, and buy moreup-to-date instrumentation.

The overall capabilities offered by a laboratoryalso affect the overhead rate. The more varied thecapabilities, the more equipment and personnel arerequired. On the other hand, laboratories with morelimited capabilities must hire consultants and sub-contractors to perform certain tests, which may bequite expensive,

General and Administrative Rates-General andadministrative costs represent the salaries of admin-istrative and support personnel who do not engage inthe study, but whose functions are essential to theoperation of the laboratory. Examples include man-agement, personnel, accounting, contracts, market-ing, and legal employees. Usually, commerciallaboratories have general and administrative rates of5 to 25 percent of total direct labor costs. The moreestablished laboratories tend to have higher generaland administrative rates because of higher ratios ofsupport to nonsupport personnel.

Fees—Fees refers to the profit expected from astudy. Due to the confidential nature of suchinformation, it is difficult to obtain data on feesreceived by commercial laboratories, but they rangefrom 5 to 40 percent.

The wide range in profits may reflect marketingstrategy and the volume of studies being performed.If volume is low, lower fees may be charged toattract new business. To encourage volume testing,many laboratories will also offer discounted pricesfor multiple testing packages. These package dealsmay be significantly lower than the sum of the unitcosts for each of the individual tests in the package.Furthermore, acute toxicity protocols are often bid ator below actual cost in order to encourage futurebusiness.

Labor Rates-Labor rates vary substantially fromone laboratory to another, depending on the mix of


individuals required to conduct a specific test.Salaries for similar types of technical positions alsovary with regional economic conditions.

Cost Estimates for Neurotoxicity Testing

Because experience with neurotoxicity testing isstill relatively limited, there is considerable uncer-tainty regarding testing costs. Recently, in support ofthe TSCA Test Guidelines Program, EPA (50)prepared estimates for several toxicity testing proto-cols that include neurotoxicity testing. These esti-mates were constructed by a senior toxicologist whois experienced in managing contract laboratoryoperations for toxicity testing. Because of theuncertainty regarding the representativeness of testcost estimates that are essentially from one source,it was decided as part of this study to obtainindependent estimates of the costs of neurotoxicitytesting.

To obtain these estimates, OTA surveyed re-searchers in several industrial, government, andcontract laboratories (35). Researchers were selectedon the basis of their experience in neurotoxicitytesting, not the type of laboratory in which theywork. Because the potential pool was small, it wasnot possible to obtain enough individuals to repre-sent in a statistically valid way each of the threelaboratory settings.

The chief purpose of the survey was to obtain abetter understanding of the range of costs for animaltests to characterize the neurotoxicity of a specificchemical. A questionnaire was prepared to obtaincost estimates for acute, subchronic, and chronictoxicity tests of a single chemical that includevarious neurological evaluations. Cost estimateswere requested for acute, subchronic, and chronictoxicity tests augmented with four neurotoxicitytests: functional observational battery, motor activ-ity, neuropathologica1 evaluations, and schedule-controlled operant behavior. (See ch. 5 for adescription of these tests.) Duration and route ofexposure were specified for each protocol. Theprotocols for which cost estimates were solicited areindicated in table 8-3.

In addition to total costs for each test protocol,respondents were asked to provide separate esti-mates of the incremental costs for each of the fourneurotoxicity tests. The purpose was to assess howmuch each type of neurotoxicity test would contrib-

ute to total test costs and whether neurotoxicity testrequirements would lead to substantial increases incosts. This information is not available in the EPAestimates (50).

The ranges for the different test cost estimates thatwere obtained from this survey are presented in table8-4. These are the highest and lowest cost estimatesfor the indicated toxicity tests and the highest andlowest incremental cost estimates for each of theadded neurotoxicity tests. As expected, estimates ofacute toxicity test costs are lower than those forrepeated-dose studies, and estimates of costs fortests using the oral route of exposure are lower thanthose for tests using the inhalation route.

Median cost estimates for each of the base testprotocols and each of the added neurotoxicity testsare presented in table 8-5. (Because this kind ofsurvey is likely to yield outliers at both the high andlow ends of distribution, the median is the preferableestimate.) The median estimates indicate that acomplete set of core neurotoxicity tests, including afunctional observational battery, motor activity, andneuropathology, may add from 40 to 240 percent tothe cost of conventional toxicity testing of a singlechemical. The major portion of the added cost is dueto the requirements of the neuropathological examina-tions. Based on its survey, OTA found that acuteneurotoxicity tests (including EPA’s functionalobservational battery, motor activity test, and neuro-pathology evaluations) are likely to add a total ofabout $50,000 to standard toxicity test costs of asingle chemical. Subchronic neurotoxicity tests mayadd up to $80,000, and chronic tests may add wellover $100,000. The EPA subchronic schedule-controlled operant behavior test (which is only likelyto be done after the other neurotoxicity tests) mayadd about $64,000. However, the functional observa-tional battery alone would add only $2,500 to thecost of a conventional acute toxicity test. The addedcost impact is highest for the acute test protocols. Aconventional acute test involving oral exposurecosts about $21,000.

EPA median cost estimates (50) are considerablylower than OTA survey estimates for identicalprotocols—from one-half to nearly one-fourth. Al-though the EPA estimates were developed approxi-mately 6 months before the OTA study, the 1988inflation rate of 4 to 5 percent during this period doesnot account for differences of this magnitude.

Chapter 8--Economic Considerations in Regulating Neurotoxic Substances ● 225

Table 8-3-Protocols for Which Cost Estimates Were Solicited

Neurotoxicity TestSchedule-

Functional ControlledObservational Motor Neuro- Operant

Protocol Battery Activity pathology Behavior

Acute inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x xAcute oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x xSubchronic inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x xSubchronic oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x xSubchronic oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x xChronic oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x xSOURCE: Office of Technology Assessment, 1990.

Table8-4-Ranges in Cost Estimates for Animal Toxicity Tests Combined With Neurotoxicity Evaluations for 1988(thousands of dollars)

Neurotoxicity Test (incremental costs)Schedule-

Functional ControlledToxicityTest Observational Motor Neuro- Operant

Protocol Base Cost Battery Activity pathology Behavior

Acute inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $8.8-47.2 $11-213 $1.2-12.3 $4.7-187.6 NAAcute oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9-39.7 1.1-21.3 1.2-11.3 4.7-179.6 NASubchronic inhalation . . . . . . . . . . . . . . . . . . . . . . . . 99.1-391.0 2.9-32.9 2.1-11,8 6.2-362.9 NASubchronic oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69.5-183.0 2.7-32.9 2.1-11.8 6.2-271.5 NASubchronic oral (NP & SCOB)* . . . . . . . . . . . . . . . . 69.5-183.0 NA NA 6.2-271.5 11.0-80.3Chronic oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234.0-783.9 3.8-85.8 4.8-38.2 11.3-602.0 NA“Neuropathology (NP);schedule-controlled operant behavior (SCOB)

SOURCE: Office of Technology Assessment 1990.

Table 8-5-Median Cost Estimates for Animal Toxicity Tests Combined With Neurotoxicity Evaluations for 1988(thoussnds of dollars)

Neurotoxicity Test (incremental rests)

Schedule-Functional Controlled Median Increment

Toxicity Observational Motor Neuro- Operant Total as a PercentProtocol Base Costa Battery Activity pathology Behavior lncrementa of Base

Acute inhalation . . . . . . . . . . . . . . . . . . . . $ 26.6(7) a $ 2.5(5) $ 4.5(6) $42.0(5) NA $ 49.9(5)b 188Acute oral . . . . . . . . . . . . . . . . . . . . . . . . . 21.2(7) 2.4(5) 4.4(6) 42.0(5) 49.9(5) 235Subchronic inhalation . . . . . . . . . . . . . . . 190.6(7) 4.8(5) 4.7(6) 42.0(5) NA 79.1(5) 42Subchronic oral . . . . . . . . . . . . . . . . . . . . 111.0(7) 4.8(5) 4.7(6) 29.7(5) 79.1(5) 42Subchronic oral(NP & SCOB)* . . . . . . . 109.8(5) NA 41.7(4) 64.1(5) , 87.0(4) 79Chronic oral . . . . . . . . . . . . . . . . . . . . . . . 308.0(6) 12.5(5) 19.8(6) 59.7(5) NA 113.2(4) 37aNumbr ofobservations shown inparentheses.b~cau=ofinmmplete responses, columnsdo notadd tototal.*Neuropathology (NPhschedule-controlled operantbehavior (SCOB)

SOtJRCE: Office ofTechnology Assessmen~ 1990.

NEUROTOXICITY TEST COSTSAND INNOVATION

In order to assess the impacts of testing forneurotoxicity on innovation in the drug, pesticide,and chemical industries, it is essential to describe thepatterns of innovation for drug, pesticide, andchemical products. While there are certain similari-ties among the three, there are important economic

differences between the development process fornew chemicals and that for new drugs or pesticides.

Drug and Pesticide Development

There are many similarities in the process ofdeveloping new drugs and pesticides. The keyfactors governing the pattern of innovation in theseindustries are the high costs and long developmenttimes experienced from discovery of a new com-pound to commercialization of it. Hundreds of new


compounds may be screened for each new pesticideand drug that is eventually marketed. Approximately10 years may elapse from discovery to first registra-tion (31,33). The pharmaceutical industry esti-mates that it currently costs well over $100mil1ion to develop, test, and bring to market anew drug product (52). The pesticide industryestimates development costs for anew pesticide ofabout $25 million, with another $25 to $50 millionrequired for building and equipping productionfacilities (4).15

Agrichemical and pharmaceutical companies spendfrom 9 to 15 percent of sales revenue on R&D(31,33). Most R&D in pesticide and pharmaceuticalcompanies is internally financed and conducted inorder to protect the proprietary status of newinnovations. The disadvantage of this practice is thatuncertainties imposed by the regulatory process,either as delays in the introduction of new productsor as unexpected limitations or bans on the sale ofthese products, may reduce the return on industry’sinvestments in research.

The high costs and long time from discovery tocommercialization force the development processfor new pesticides and drugs toward those applica-tions that are likely to have very high returns. Onlya relatively small number of markets are largeenough to make it economically worthwhile forfirms to develop these products. Consequently,pesticides are developed and initially registered formajor uses, for example, on crops such as corn orsoybeans. Subsequently, they are tested for use onminor crops.

The actual discovery of a new drug entity-anewchemical with therapeutic potential-is just the firststep in a lengthy process of R&D. The discoveryphase of the process consists of chemical synthesisand animal testing to establish a compound’stoxicology and pharmacology. The developmentphase encompasses clinical testing to assess poten-tial toxic effects in healthy humans and, subse-quently, to establish in patients the therapeuticefficacy of a new drug candidate.

The average effective period of patent protectionfor anew chemical entity declined between 1966 and1979 (16). The estimate of 9.5 years of protection isabout one-half the maximum period of patentprotection of 17 years. This decline in patent life,

which has been largely attributed to longer develop-ment and regulatory approval times, became a majorpolicy issue in the early 1980s. Congress addressedthe problem in 1984 with the Drug Price Competi-tion and Patent Restoration Act (Public Law 98-417)0 This law allows restoration of part of the patentprotection time that elapses during development andFDA approval.

The recent estimate of $125 million (1986 dollars)as the total research and development cost for anapproved new drug is based on new drugs approvedbetween 1970 and 1985 (52). The increasing costs ofdeveloping new drugs are due in part to an increasingfocus on therapies for chronic conditions. Thedevelopment of drugs of this kind requires moreextensive testing (33).

Neurotoxicity Tests and Innovationin Dregs and Pesticides

The above discussion of the processes for devel-oping drugs, pesticides, and chemicals provides aframework within which the innovation impacts ofconducting animal tests for neurotoxicity may beassessed. The impacts of testing on innovationdepend on overall test costs, duration of the tests,and the timing (scheduling) of the tests within theinnovation period.

One possibility would be for the animal toxicitytests with combined neurological evaluations to takeplace during the preclinical and pre-field testingphases for drug and pesticide development, respec-tively. In this scenario, the additional costs of testingfor neurotoxicity would occur during the second orthird years of a 10-year developmental period.

If neurotoxicity test protocols are totally incom-patible with other concurrent animal toxicity testing,then the additional costs of obtaining neurotoxicitydata would be the capitalized value of the full testcosts at the expected date of marketing approval.The expected date of marketing approval is 7 to 8years in the future. At the assumed 10 percent rate ofinterest, the capitalized value of $190,000-themedian cost estimate for subchronic oral toxicitytesting with functional observation, motor activity,and neuropathology evaluations-is from $370,000to $430,000. The capitalized value of $420,000-themedian cost estimate for chronic oral toxicity testingwith the same neurotoxicity evaluations-is from

15~e= ~omt~ ~PPW t. ~ in ]~e wi~ ealier &~~l~ e5tirnate5 by Gofig ( 14) of tie coss of commercializing a new pesticide.


$820,000 to $900,000. These amounts are small,compared to current estimates of total capitalizedcosts of developing a new drug or pesticide.

A second possibility would be for neurotoxicitytest data to be requested at the very end of the drugor pesticide development process. In this instance,timing of the tests is of much greater importancethan their costs. Testing that, for example, extendsthe innovation period by 1 year at the end of thedevelopment period has an associated opportunitycost equal to the interest on the total cumulativeR&D investment. For drugs and pesticides, the costsof delaying marketing approval at this point clearlyovershadow any outlays required to conduct thetests.

Neurotoxicity Tests and Innovationin Chemicals

The pattern of new product innovation in chemi-cals is considerably different from that of drugs orpesticides (45). For one thing, there is greaterdiversity among chemical products, which includeplastics, solvents, fibers, detergents, catalysts, andbasic organic and inorganic chemical feedstocks.More important from an economic perspective,however, is the fact that new drugs and pesticides aredeveloped for quick penetration into large markets.In contrast, the initial market for the vast majority ofnew chemical products is very small, and failurerates are high. Markets for large-volume chemicalsdevelop slowly over a number of years.

Data on the number of new chemicals introducedannually into commerce before TSCA are uncertain.Estimates of the rate of new chemical innovationrange from 700 to 1,400 compounds annually (3,12).Of these, as many as 70 percent were estimated tohave annual production volumes of less than 1,000pounds, which is regarded as a threshold level ofoutput for a viable commercial product (3). Further-more, many low-volume products were, in alllikelihood, developed and marketed by very smallfirms in the business of “custom-manufacturing”chemicals. Since the implementation of the finalPMN rule in 1983, the annual receipt of PMNs by


EPA has increased steadily, to nearly 1,700 com-pounds in 1986 (6).

Under section 5 of TSCA, EPA does not requirethat chemical manufacturers conduct toxicity testingprior to submission of a PMN; manufacturers areonly required to supply any health or environmentaltest data that are available at the time of submission.Although EPA can request additional toxicity test-ing of new chemicals, it has used this authoritysparingly.lb In a recent analysis of 8,000 PMNsreceived by EPA from July 1979 through September1986, fewer than one-half contained toxicity testdata (6).

Although data are not readily available on theaverage costs of developing and introducing a PMNchemical, as noted above, many of them are pro-duced and marketed as specialty products. Expectedprofits from the sale of small-volume chemicals

161f, ~ ~evie~ng tie pMN subnlisslon, EpA decides the chemical may pre~nt ~easonab]e risks to hea.1~ or tie environment, the a$pCY Call lh’ilit

production and utilization of the substance while more test data are developed ( 15 U.S.C. 2604(e)). If EPA decides the chemical will present unreasonablerisks, the agency can require the development of additional test data (15 U.S.C. 2604(0). Aw and Gould repoti hat EPA had order~ submissionof more test data for about 200 PMN chemicals from 1979 to 1986. An additional 150 PMNs had been subject to voluntary actions, some of whichinvolved testing. Finally, 164 chemicals were voluntarily withdrawn by the submitted when presented with the likely prospect of conducting more testing(6).


cannot, in most cases, cover the costs of extensivetesting, especially if there are substitute productsalready on the market. Thus, a request for neurotox-icity testing, which could add substantially to costsof testing currently being done, could lead to areduction in the rate of innovation in certain classesof low-volume products, particularly those that arevulnerable to even modest regulatory compliancecosts.

ECONOMIC BENEFITS OFREGULATING NEUROTOXIC

SUBSTANCESIt is important to distinguish between the adverse

effects of neurotoxic substances and the benefits ofreducing or “preventing these adverse effects. Theadverse effects of neurotoxic substances are ex-pressed as impacts on human health and the environ-ment and are measured in terms of mortality,morbidity, disability, and environmental damage.They should include effects on mental status, such asmemory loss and cognitive dysfunction, that may beassociated with exposures to neurotoxic substances.

Reducing or preventing the risks of exposure toneurotoxic substances means reducing the magni-tude of these adverse effects. The human andmonetary values placed on risk reductions are ameasure of the benefits of regulation. In the econom-ics of health and safety, several approaches havebeen used to assign monetary values to reduced riskof mortality, morbidity, and disability. These ap-proaches have been broadly categorized as valuationthrough adjudication (jury awards), political proc-esses, individual preferences, and resource or oppor-tunity costs.17 Valuation through resource or oppor-tunity costs will be discussed here.

Knowledge Requirements forEstimating Benefits

To estimate the benefits of policies to reduce orprevent neurotoxic risks requires knowledge andquantification of the following:

. the relationship between economic activitiesand the rates of use of neurotoxic substances;

. the relationship between the environmental fateand transport mechanisms that determine ambi-

●

●

●

ent environmental concentrations and, hence,human exposures to these substances;the relationship between the activities of indi-viduals (e.g., eating, working, exercise) and therates of human intake of these substances;the biological mechanism by which thesesubstances cause disease in humans; andthe relationship between changes in healthstatus and the utilization of health care.

Only the first and the last of these relationships arebasically-although not exclusively—in the realmof economics. The intervening ones represent theinterface of science and economics-in particular,they are the substance of risk assessments ofexposures to neurotoxic substances (35).

The fact that exposures to neurotoxic substancesresult in more effects and more varied effects onhealth than, say, exposures to carcinogens is animportant distinction and one that poses analyticaldifficulties in risk assessment and benefits analysis.In contrast to carcinogenicity, which can usually becharacterized as a single outcome with discretemeasures of health status (i.e., the disease is presentor it is not), neurotoxicity may be manifested asmultiple effects, each of which may produce acontinuum of health states ranging from mild tosevere.

The Health Costs of Neurotoxicity

As noted above, the opportunity costs of morbid-ity and mortality that can be attributed to neurotoxic -ity provide a measure of the potential economicbenefits of reducing neurotoxic risks to humanhealth. These opportunity costs, frequently calledthe social costs of illness, include direct and indirectcosts of illness and death. The direct costs of illnessconsist of the payments for health-care products andservices utilized in providing patient care. Theindirect costs of illness encompass the expectedearnings an individual loses as a result of notworking. Medical care costs and foregone earningsare estimated for each year from the onset of illnessto expected year of death. This time stream of costsis then discounted to present values.

Estimating benefits in this manner is known as theproductivity, or human capital, approach. Mosteconomists regard this approach as providing lower-

17v~UatiOn ~Wor&ng t. individU~ preferences, or Wi]]ingness to pay, is frequently c,it~ by ~onomists as the most appropriate measure Of the V~U(?

of redueing the risks of adverse health effects (13).

Chapter 8--Economic Considerations in Regulating Neurotoxic Substances .229

Table 8-6-Personal Health-Care Expenditures for the 10 Most Expensive Medical Conditions in the United Statesin 1980 (millions of dollars)

Medical condition All ages Under 65 65 or over

Diseases of the circulatory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $33,184 $13,078 $20,015Diseases of the digestive system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31,755 26,084Mental disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20,301 14,612 5,689Injury and poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19,248 15,042 4,206Diseases of the nervous system and sense organs. . . . . . . . . . . . . . . . . . . . . . . . . . . 17,499 13,028 4,471Diseases of the respiratory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17,305 13,164 4,141Diseases of the musculoskeletal system and connective tissue . . . . . . . . . . . . . . . . . . 13,645 9,821 3,824Neoplasms . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13,623 8,302 6,322Diseases of the genitourinary system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13,162 10,721 2,441Endocrine, nutrition metabolic system, and immunity disorders. . . . . . . . . . . . . . . . . 7,656 4,689 2,968SOURCE: U.S. Department ofHealth and Human Services, PubiicHeaith Servie8, National CenterforHealth Statistics, /+ea/th UntiedStates, 1983, DDHS

Pub. No. (PHS)84-1232 (Washington, DC: U.S. Government PrintingOffiee, 1983)

bound estimates of the benefits of improving healthbecause it does not attempt to measure and includethe disutility experienced by persons having thesediseases or by their families and friends. This kindof disutility is particularly relevant for dementia,retardation, and other mental disorders in whichneurotoxicity may be a causative or contributingfactor.

The Costs of Mental Disorders and Diseasesof the Nervous System

Mental disorders and diseases of the nervoussystem contribute substantially to health costs in theUnited States. In 1980 (the most recent year forwhich costs of illness were estimated for specificdisease categories) they ranked as the third and fifthmost expensive medical conditions, respectively, interms of personal health-care expenditures (table8-6). The estimate of nearly $40 billion (1980dollars) for these two categories of morbidity doesnot include values for lost productivity, restrictedactivity, and other social costs (e.g., rehabilitationfor drug and alcohol abuse) that may accompanymental illness or other forms of cognitive andbehavioral impairment.

The Costs of NeurotoxicityAs an Element of Dementia

Dementia is defined as the loss of intellectualfunction. It is manifested as a complex of symptomsthat can be caused by as many as 70 underlyingconditions. The causes of disorders that produce thevast majority of dementia cases are still not under-stood (44); however, some dementias maybe causedor exacerbated by neurotoxic substances in prescrip-tion drugs, metals, solvents, and other chemicals

(21). Other dementia diagnoses include necrosis ofbrain tissue due to vascular obstruction, variousinfectious diseases, tumors, and toxicity from alco-hol (21).

Although the costs of dementia to the Nation canbe only crudely approximated, they are high and arebound to increase as the population ages. Estimatesof the costs of dementia are presented here as a basisfor estimating the health costs of neurotoxicity. Onestudy has estimated that at least 2 to 3 percent ofdementia patients were diagnosed as having disor-ders involving drug toxicity (21). If this can beregarded as a lower-bound estimate, then from 2 to3 percent of the costs of dementia may be taken asa lower-bound estimate of the social costs ofneurotoxicity. Applying 2 to 3 percent to each of theabove estimates for the overall costs of dementiayields estimates of $0.5 billion to $1.5 billionannually for neurotoxicity alone.

The Costs of Exposure to Lead

Epidemiologists have demonstrated associationsbetween excessive lead exposure, particularly dur-ing childhood, and several kinds of adverse neuro-logical and behavioral effects.18 In the past, publichealth agencies focused principally on severe leadexposure and the resultant symptoms of overt leadpoisoning.

More recently, medical scientists have shown thatimportant neurochemical changes are induced bylead in much smaller amounts than those generallyassociated with clinical symptoms of lead poison-ing. Finally, there is considerable epidemiologicalevidence that low-level exposure can result inaltered behavior, including attentional disorders,

lwor a r~ent comprehensive review of the adverse health effecrs of lead, s= ref. 47.


learning disabilities, or emotional disorders thatimpair classroom performance.

For these reasons, an analysis of the health costsattributable to excessive lead exposure during child-hood must recognize at least three categories ofcosts:

●

●

●

direct medical care expenditures, includinghospitalization, doctors’ fees, drugs, and con-valescent care for preschool children who havebeen diagnosed as being at risk with respect tolead absorption;special education or institutionalization costs,or both, for school-age children who sufferpermanent neuropsychological effects fromexposure to lead; andcosts to society in terms of reduced productionand tax contibutions from adult members ofthe labor force who have permanent impair-ments stemming from excessive exposure tolead during childhood.

Calculating health costs of lead exposure involvesmultiplying estimates of the number of preschool,school-age, and adult individuals with lead-inducedhealth and intelligence deficits by cost factors thatrepresent the opportunity costs to avoid or correctthose deficits (34). Two recent analyses of regula-tory proposals to reduce human exposures to leadused this approach.

In a cost-benefit analysis of options for removinglead additives from gasoline, one study (39) esti-mated the reduction in the number of children whowould have elevated levels of lead in their blood(defined in this study as more than 25 grams perdeciliter) as a consequence of removing lead fromgasoline.19 The study assumed that 20 percent of allchildren with elevated levels would be affectedseverely enough to warrant compensatory educationfor up to 3 years. Other studies suggest that thecognitive effects and lead-induced behavioral prob-lems may persist for at least 3 years (9,10). In thevaluation step, the number of person-years incompensatory education was multiplied by an esti-mate of the additional costs of providing part-timespecial education to a child for 1 year. Theseestimates are presented in table 8-7. The benefits of

reducing lead in gasoline continue to increase for anumber of years, as the use of leaded gasoline isgradually phased out. As the table indicates, the totalhealth benefits of reducing the neurotoxic effects oflead on U.S. children was estimated to total morethan $500 million annually between 1986 and 1988.If adult exposure to lead, including workers’ expo-sure, were included, the benefits would be consider-ably greater.

Another study developed similar estimates of thesavings in medical care and compensatory educationcosts that would occur in a single year as aconsequence of reducing the maximum contaminantlevel for lead in drinking water from 50 to 20 gramsper liter (23). The health benefits estimate for thisone-time reduction were $81.2 and $27.6 million (in1985 dollars) for compensatory education and medi-cal care costs, respectively.

SUMMARY AND CONCLUSIONS

Regulating neurotoxic substances involves con-sideration of both the economic benefits of usingthese substances and their actual or potential risks tohuman health and the environment. The problem ofbalancing benefits, risks, and the costs of regulationis not unique to the control of neurotoxic substances;it arises in all forms of health, safety, and environ-mental regulation. Regulations that are designed toreduce or prevent neurotoxic risks can benefitsociety through improvements in public health andenvironmental amenities. In most cases, however,society incurs costs to achieve these regulatory ends.The costs of complying with health and safetyregulations may also result in increases in marketprices, reductions in industry profits, and declines innew product innovation.

Many of the key Federal laws under whichneurotoxic substances are regulated require agenciesto ascertain the positive and negative economicconsequences of regulation. In implementing theselaws, Congress has generally intended that agenciesprepare regulatory analyses and document the bal-ancing of benefits, costs, and risks of proposedalternatives.

191n order tO ~~fiate fie he~~ ~nefi~ of controlling neurotoxic substances, it is important to have good data on tie extent to which humanpopulations are exposed, as well as epidemioiogical data that link exposures to adverse health effects. Estimates of the benefits of reducing humanexposures to lead were greatly facilitated by the availability of national estimates of the prevalence of lead exposure obtained through the National Healthand Nutrition Examination Survey (NHANES-11) (2).

Chapter 8--Economic Considerations in Regulating Neurotoxic Substances . 231

Table 8-7-Estimates of the Health Benefits of Reducing the Neurotoxic Effects of Lead in Children(millions of 1983 dollars)

SavingsService 1985 1986 1987 1988 1989 1990Compensatory education. . . . . . . . . . . . . . . . . . . . . .,. $187 $447 $408 $374 $338 $309Medical care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 155 141 130 117 107

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 602 549 504 455 416SOURCE: J. Schwartz et al., Costs and Benefits of Reducing Lead in Gasoline: Final Regulatory Impact Analysis, EPA-230-05-85-O06 [Washington, DC: U.S.

Environmental Protection Agency, 1985). -

In addition to these legislative provisions, theexecutive branch,. through the Office of Manage-ment and Budget, has also mandated that agenciesconduct regulatory impact analyses for regulationsthat may have major effects on the economy. Thecurrent OMB requirement, which has evolvedthrough a series of executive orders, specifies thatagencies must conduct benefit-cost evaluations forany regulatory proposal that is likely to have anannual effect on the economy of $100 million ormore.

To date, only a small number of regulatoryactions, and hence a small number of regulatoryanalyses, have been directed at reducing the risks ofneurotoxicity. Most of these actions have been takento control environmental and occupational expo-sures to lead. Regulatory impact analyses of regula-tions to reduce the amounts of lead in gasoline andin drinking water provide some of the best examplesto date of assessments of the economic consequenceof controlling neurotoxic risks.

Analyzing the economic consequences of control-ling neurotoxic risks is a two-step process. The firststep, risk assessment, involves using data fromepidemiological, toxicological, and other studies toestimate the health and environmental risks associ-ated with various levels of exposure to the substancein question. The second step involves makingestimates of the costs, benefits, and other economicimpacts associated with achieving a specific level ofrisk reduction.

One economic issue that has emerged in regulat-ing neurotoxic substances concerns the costs ofscreening and testing these substances for theirneurotoxic hazard potential. Experience with neuro-toxicity testing is still relatively limited, creatinguncertainty regarding the available cost estimatesfor this type of testing. Because of the uncertaintyregarding these costs, OTA obtained estimates of thecosts of several types of neurotoxicity tests from a

. . . , “ ,

number of individuals in government, industry, andacademia.

Cost estimates were obtained for standard acute,subchronic, and chronic toxicity test protocolsaugmented with four neurological evaluations: func-tional observational battery, motor activity, neuropatho-logy, and schedule-controlled operant behavior. Themedian estimates derived from OTA’s survey indi-cate that a complete set of core neurotoxicity tests,including a functional observational battery, motoractivity, and neuropathology, may add from 40 to240 percent to the costs of conventional toxicity testscurrently required by EPA. By far the largest portionof the added cost comes from the addition ofneuropathology evaluations, which are needed todetermine whether structural change in the nervoussystem has occurred and the nature and significanceof the change. Based on its survey, OTA found thatacute neurotoxicity tests (including EPA’s func-tional observational battery, motor activity test, andneuropathology evaluations) may add about $50,000to the cost of standard acute toxicity tests. Sub-chronic neurotoxicity tests may add $80,000, andchronic tests may add about $113,000. The EPAsubchronic schedule-controlled operant behaviortest may add about $64,000. However, the functionalobservational battery alone would add only $2,500to the cost of conventional acute toxicity test. Aconventional acute test involving oral exposurecosts about $21,000.

Testing costs should be viewed in the context ofthe total cost to industry of marketing anew product,potential profits resulting from the sale of theproduct, the impact of initially high test costs on theinnovation process, and the health benefits ofminimizing public exposure to neurotoxic sub-stances.

For the development of new drugs and pesticides,which have development times of 8 to 10 years anddevelopment costs of $50 million to $100 million or


more, the costs of additional neurotoxicity testingare very small. For industrial chemicals with spe-cialty uses, on the other hand, additional neurotoxic -ity testing could add substantially to costs of teststhat are currently done and could lead to a reductionin the innovation of certain classes of low-volumeproducts.

The benefits of regulating neurotoxic substancescan be measured in terms of the human and monetaryvalues placed on reduction of risk. A number ofapproaches have been used to assign monetaryvalues to reducing the risks of mortality, morbidity,and disability. Lead has been the subject of anin-depth economic analysis. A 1985 study estimatedthat the total health benefits of reducing the neuro-toxic effects of lead on U.S. children would be morethan $500 million annually between 1986 and 1988.If adult exposure to lead, including workers’ expo-sure, were included, the benefits would be consider-ably larger.

Although the health and economic benefits oflimiting public exposure to neurotoxic substancesare more difficult to estimate than the costs ofregulation, the example of lead illustrates theimportance of considering the potentially largemonetary benefits of regulatory actions. Like othertoxicity testing, neurotoxicity testing is conducted toprevent adverse health effects; hence, the benefits ofsuch testing may not be readily apparent and mayaccrue well into the future. Often, the immediatecosts of testing receive considerable attention, butthe sizable potential benefits of preventing publicexposure to a hazardous substance receive compara-tively little attention.

As indicated earlier, neurotoxic substances, inparticular abused drugs, play a significant, causalrole in the development of neurological and psychi-atric disorders; however, the precise extent of thecontribution remains unclear. Mental disorders anddiseases of the nervous system contribute substan-tially to health costs in the United States. In 1980,they ranked as the third and fifth most expensivemedical conditions in terms of personal health-careexpenditures (see table 1-3 in ch. 1). The estimate ofnearly $40 billion (1980 dollars) does not includevalues for the lost productivity, restricted activity,and other social costs that frequently accompanymental illness or other forms of mental impairment.

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Chapter 9

International Regulatoryand Research Activities

‘‘The need for generally accepted scientific principles and requirements in all areas of toxicology particularlyapplies to the newly developed field of neurotoxicology. Methods continue to be developed in isolation, andthe comparability of results is often in doubt. Furthermore, until scientific principles have been agreed on,internationally accepted strategies to test the effects of chemicals on the many functions of the mammaliannervous system will not be developed. ”

Principles and Methods for the Assessment ofNeurotoxicity Associated With Exposure to Chemicals

World Health Organization, 1986

“The NACA supports additional neurotoxicological and behavioral effects testing as a legitimate componentof the requirements for re-registration and registration.

John F. McCarthyVice President for Scientific and Regulatory AffairsNational Agricultural Chemicals Association, 1989

“Exporting banned pesticides demonstrates that from the cradle to the grave---or from production to use anddisposal--dangerous chemicals are discharged into our environment, and threaten the public health both hereand abroad. ”

Sandra MarquardtExporting Banned Pesticides: Fueling the Circle of Poison

Greenpeace USA, 1989

CONTENTSPage

INTERNATIONAL REGULATORY ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . + + .U.S. Regulation of Neurotoxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .International Effects of U.S. Export Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Regulatory Policies in Other Industrialized Nations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Regulatory Issues in Developing Nations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

INTERNATIONAL NEUROTOXICOLOGICAL RESEARCH . . . . . . . . . . . . . . . . . . . . .Major Directions of Academic, Industrial and Government Research . . . . . . . . . . . . . .Neuroepidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .* .. .. .. .. ..+. . . . . . . . . . . . . .International Cooperation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Comparison of U.S. and Foreign Research Programs . . . . . . . . . . .. .. . ... ... ...+....Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Foreign Governments Likely To Take Leadership Roles . . . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. $.. ... .......+

Box9-A.9-B.

Problems With Neurotoxic Pesticides

Boxes

237239242245248256256259259259259259260260261

Pagein Developing Countries . . . . . . . . . . . . . . . . . 251

Incident at Lake Volta. Ghana .. .. .. .. .. ... ... ~..._... . . . . . . . . . . . . . . . . . . . . . . . . . 252

FiguresFigure Page9-1. Total U.S. Pesticide Exports, 1983-88 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ● . . . . . . 2379-2. U.S, and World Pesticide Sales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2379-3. Total U.S. Food Imports, 1983-88 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2399-4.9-5.

Domestic Production v. Imports of Selected Major Crops . . . . . . . . . . . . . . . . . . . . . . . 239Pictograms for Agrochemical Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

Table9-1. Neurotoxic Substances Investigated in Papers Published

Journals, by Country, 1979-87 . . . . . . . . . . . . . . . . . . . . . .9-2. Subjects of Neurotoxicological Research Presented at a Major

International Conference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

Pagein Two International

. . . . . . . . . . . . . . . . . . . . . . . . . 258

Chapter 9

International Regulatory and Research Activities

This chapter examines the international regula-tory and research programs devoted to neurotoxicsubstances in general and neurotoxic pesticides inparticular. The first part of the chapter addresses theexport of neurotoxic pesticides that have beenbanned or severely restricted (a limited ban) in theUnited States. Regulatory programs in foreigncountries, both industrialized nations and develop-ing nations, are discussed. The second part of thechapter focuses on international research activities.This chapter does not address the export of foodadditives, drugs, and other chemicals.

INTERNATIONAL REGULATORYACTIVITIES

According to the U.S. General Accounting Office(GAO), from 1977 to 1987, the worldwide agricul-tural chemical market doubled in size, to morethan $17 billion. U.S. pesticide export salescurrently represent approximately one-quarterof the world pesticide market. Although U.S.export statistics vary, the best estimates concludethat about 400 to 600 million pounds of U.S.-manufactured pesticides are exported each yearto foreign countries. According to GAO, unregis-tered pesticides, including banned or restrictedpesticides as well as pesticides that may neverhave sought U.S. registration, now account forabout 25 percent of all U.S. pesticide exports (61).

7.5

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6.0

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5.0

4.5

Figure 9-l—Total U.S. Pesticide Exports, 1983-88

Billions of dollars

4.8

m1983

6.3

7

1984 1985 1986 1987 1988

SOURCE: Office of Technology Assessment, 1990, based on U.S. Depart-ment of Commerce, Bureau of the Census, Statistical Abstractof the United States 1989, 109th ed. (Washington, DC: 1989).

According to other estimates, the United Statessupplies approximately one-half of the pesticidesimported in most Latin American countries,where a substantial amount of the fresh fruits andvegetables eaten in the United States in the wintermonths are grown (42). Figure 9-1 illustrates U.S.pesticide exports for 1983 to 1988. In recent years,approximately 50,000 different pesticide productshave been registered for use by the EnvironmentalProtection Agency (EPA) (61). This figure does notinclude pesticides that have never been registeredbut are manufactured and exported for use outsidethe United States. Figure 9-2 compares U.S. pesti-cide sales with world pesticide sales for 1987.

Some developing nations have few or no regula-tions to protect workers and consumers from theharmful effects of neurotoxic substances. Develop-ing nations that do have regulations often do nothave adequate resources to implement and enforcethem. This lack of effective regulation and enforce-

Figure 9-2—U.S. and World Pesticide Sales(Basic Producer Level, 1987)

20 Billions of dollars1

18+

16

14

12

i

1 0

8

6

4[

JzLHerbicides Insecticides Fungicides Other Total

Iz2 Us. = World

SOURCE: Pesticide Industry Sales and Usage: 1987 Market Estimates,Economic Analysis Branch, Biological and Economic AnalysisDivision, Office of Pesticide Programs, Environmental Protec-tion Agency, Washington, DC, September 1988.


ment in developing nations has a negative impact notonly on the public health and environment in usercountries, but also in industrialized nations, includ-ing the United States, where people process andconsume imported crops that may contain pesticideresidues.

Despite many regulations promulgated in thiscountry for the protection of consumers and workers,U.S. citizens are exposed to banned and severelyrestricted pesticides through what has come to bereferred to by critics as the ‘‘boomerang effect’ orthe “circle of poison” (41,70). At times, food inU.S. supermarkets has been imported from develop-ing countries where farmers use pesticides manufac-

.’-”. ‘<

. . \ ‘ . .. “ - . \“ ---


tured in the U.S. that have been banned, severelyrestricted, or never registered for use here. Figure 9-3indicates the dollar value of total U.S. food importsfrom 1983 to 1988. One organization has estimatedthat 70 percent of the pesticides exported to develop-ing countries are used on crops grown for export toindustrialized countries (70). This effectively cir-cumvents the protection that the regulatory actionwas intended to provide.

Federal law currently permits U.S. companies tomanufacture and distribute banned, severely re-stricted, and never registered pesticides for use indeveloping nations, despite the possibility that foodproducts containing residues of these pesticides maybe imported to the United States and made availableto U.S. consumers. Little definitive informationexists on the identity and quantity of residues ofbanned, severely restricted, and never registeredpesticides that return to the United States onimported crops and meats. This is due in part to therelatively small number of Food and Drug Adminis-tration (FDA) and U.S. Department of Agriculture(USDA) personnel available to screen sufficientquantities of imported crops and to limitations in thetechnology for detecting residues (62). However,data are available on the dollar value of crops that areproduced domestically versus the value of crops thatare imported. Figure 9-4 compares domestic produc-tion with imports of selected major crops. Somecrops, such as coffee, are not produced domestically,so the United States must depend entirely on importsto supply consumer demand.

One example of the effect of current policies is theexport of the insecticide chlordane. This product wastaken off the U.S. agrichemical market in 1978 dueto concerns about its carcinogenicity (it is alsoneurotoxic) and its persistence in animal fatty tissueand in the environment. Yet Federal law allows it tobe manufactured and exported, without prior notifi-cation, to developing countries which do not have toadhere to U.S. use controls. Chlordane and hep-tachlor export formulations were both registeredunder section 3 of the Federal Insecticide, Fungi-cide, and Rodenticide Act (FIFRA) and as such areexempt from the export notification requirementsimposed by language in section 17 of FIFRA. Atleast twice in 1988, adulterated beef from Honduras,contaminated with chlordane, was imported into theUnited States and consumed by people in Florida,Kentucky, and Minnesota before the contaminationwas discovered (33,54). In one such instance, the

Chapter 9-International Regulatory and Research Activities ● 239

Figure 9-3-Total U.S. Food Imports, 1983-88

Millions of pounds

aoo~

4 0 0 -

2 0 0 -

414

1983

527

1984

598

492

1986

507

.

550

1987 1988

SOURCE: Office of Technology Assessment, 1990, based on U.S. Depart-ment of Commerial-, Bureau of the Census, Statistical Abstractof the United States 1989, 109th ed. (Washington, DC: 1989).

Figure 9-4-Domestic Production v. Importsof Selected Major Crops

Billions of dollars3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

1,8s

Tobacco Olives Bananas Pine- Straw- Coffee Tomatoesapples berries

_ Domestic production [“’”~ Imports

SOURCE: Office of Technology Assessment, 1990, based on U.S. Depart-ment of Commerce, Bureau of the Census, Statistic/Abstractof the United States 1989, 109th ed. (Washington, DC: 1989).

chlordane residue was reported to be eight times theapproved tolerance (33). Chlordane has been bannedfor all agricultural use in the United States yet iswidely used in agricultural settings in countries suchas Argentina, Australia, Colombia, and the Domini-can Republic (33). In some cases, residues are notthe result of direct application to crops or livestock.The Honduran problem was attributed to the use ofchlordane on nearby sugarcane.

The misuse of registered chemicals, many of themneurotoxic, is an equally important issue (38).

Registered chemicals used by untrained farmwork-ers without proper protective clothing and equip-ment, in inappropriate amounts on inappropriatecrops, and without attention to other safety regula-tions, have been known to cause significant publichealth and environmental problems. Moreover, asubstantial proportion of all pesticides are used todestroy pests that primarily affect the appearance ofagricultural crops. Consumers often demand thattheir fruits and vegetables look “picture perfect”;however, cosmetic imperfections usually do notaffect either the taste or the nutritional value of mostfoods (22). Although limited use of less hazardouspesticides is generally considered to be economi-cally beneficial and to pose a minimal health risk,overuse of the more hazardous pesticides is anincreasing concern among public health officialsworldwide.

U.S. Regulation of Neurotoxic Substances

Export Laws

The United States has several laws governingexport of toxic substances. The Toxic SubstancesControl Act (TSCA) was enacted in 1976 to addressthe risks presented by hazardous chemicals and isthe primary statute regulating the export of industrialchemicals. Section 12 of TSCA addresses exporta-tion of hazardous chemicals. Section 3017 of theResource Conservation and Recovery Act (RCRA)discusses the export of hazardous waste, and section17 of FIFRA governs importation and exportation ofpesticides and devices.

Under TSCA, chemicals for domestic use thatpresent an unreasonable risk of injury to humans andare imminent hazards to the environment can beregulated. The Act requires that regulation be donein such a way as not to impede unduly or createunnecessary economic barriers to technologicalinnovation. Section 12 provides that, in mostinstances, the requirements of TSCA do notapply to substances manufactured, processed, ordistributed for export. The requirements willapply, however, if it is determined that thesubstance, mixture, or article will present anunreasonable risk of injury to the health ofpersons within the United States or to theenvironment of the United States. The Act alsoprovides that any person who exports or intends toexport a substance for which submission of data isrequired under this Act must notify the Administra-


tor of the Environmental Protection Agency of theexportation or intent to export. Moreover, theAdministrator shall then furnish to the governmentof the importing country notice of the availability ofthe data submitted for each substance.

RCRA provides for the management and disposalof solid wastes to avoid contamination of theenvironment. Section 3017 prohibits any exportingof hazardous waste unless the importing country hasbeen given notice of and has consented to theshipment of the waste. However, exporters are notrequired to describe the contents or toxicity of thewaste they are shipping. In addition, incinerator ashand municipal waste, both of which contain neuro-toxic metals and chemicals, are not covered by theconsent scheme.

Section 17 of FIFRA states that pesticides anddevices intended solely for export are exempt fromthe testing and review requirements of the Act.Accordingly, pesticide manufacturers and dis-tributors can legally export pesticides that havebeen banned or never registered for use in thiscountry. Little is known about pesticides that havenever been registered because they are exempt frompublic health and environmental testing require-ments if domestic use is not intended (32).

U.S. pesticide manufacturers are required tonotify the importing purchaser, and EPA notifies thecountry, if the pesticide to be exported has beenbanned or never registered for use in the UnitedStates. EPA requires these statements annually forthe first shipment of each banned or unregisteredproduct to a particular purchaser for each importingcountry. Although EPA has streamlined the trans-mittal process for export notices to U.S. embassies,no formal procedures govern the processing andtransmittal of FIFRA notices once they arrive at anembassy (61). Most embassies destroy files as recentas 1985, and staff at every embassy surveyed byGAO indicated that they sometimes do not retaincopies when transmitting files to the foreign govern-ments (61 ). According to GAO, as recently as 1988,EPA had no program to determine whetherpesticide manufacturers were complying with theexport notification requirements and had noassurance that importing countries were ade-quately notified of unregistered U.S. pesticidesentering their borders (61 ). Moreover, shipment ofthe unregistered pesticide may proceed before the

foreign government has received the notice, since itspurpose is only informational.

Although the language in section 17(a) of FIFRAgoverning notification requirements for unregisteredpesticides provides for no exceptions, EPA, in 1980,established a policy that effectively waives notifica-tion requirements for unregistered pesticides that are“minor variations” on formulations and activeingredients registered in the United States and thatare ‘‘similar in composition and use” to registeredpesticides. These exempted pesticides are com-monly referred to as “me-toos.” Thus, never-registered pesticides must bear the statement “NotRegistered for Use in the United States of America’when they are exported to foreign markets, butme-toos are exempt from the labeling requirement,despite the fact that the active ingredient and inertingredient formulation may be different from thatregistered in the United States and thus pose adifferent risk (32). Accordingly, it would be difficultfor an importing foreign purchaser or nation to knowthe degree of hazard of such a product. Moreover,GAO determined that EPA did not send requirednotices for three of four pesticides, despite the factthat they were voluntarily canceled because ofconcern about toxic effects (42). Although EPAfinalized cancellations of these four pesticidesbetween 1975 and 1987, a notice was issued on onlyone of them (42). Consequently, foreign govern-ments may not be alerted to unreasonable hazardsassociated with using particular pesticides.

Section 17(b) of FIFRA requires that EPA notifyforeign governments and appropriate internationalagencies “[whenever a registration, or a cancella-tion or suspension of the registration of a pesticidebecomes effective, or ceases to be effective. . . .“EPA has no regulation or formal policy statement onwhen to issue such a notice. Instead, the Agencyissues notices for cancellations and suspensions itdeems to be of “national or international signifi-cance” (42). EPA periodically publishes a bookletsummarizing and clarifying its actions on canceled,suspended, and restricted pesticides (67); however,this booklet was last published in 1985. If updatedannually, this booklet could be used by foreigngovernments and others as a reference guide to U.S.regulatory actions on pesticides (42).

On January 15, 1981, several days before the endof his term, President Jimmy Carter issued Execu-tive Order No. 12264, “On Federal Policy Regard-

Chapter 9-international Regulatory and Research Activities ● 241

ing the Export of Banned or Significantly RestrictedSubstances,’ including pesticides. This order putcontrols on exports of substances that were bannedor severely restricted in the United States. Severaldays after becoming President, Ronald Reaganrevoked the order.

Regulation of Pesticide Residues inDomestic and Imported Food

Federal jurisdiction over pesticide residues infood is divided among three agencies—EPA, FDA,and USDA. Their authority derives primarily fromfive laws: FIFRA; Federal Food, Drug, and Cos-metic Act (FFDCA); Federal Meat Inspection Act(FMIA); Poultry Products Inspection Act (PPIA);and Egg Products Inspection Act (EPIA) (62).

Under FIFRA, a pesticide must be registered(even conditionally) or have its registration pendingbefore it can be used in the United States. Inregistering a pesticide, EPA considers the results ofnumerous public health and environmental fatestudies (submitted by the manufacturer) to deter-mine the risks and benefits associated with the useof that pesticide. Registration includes identificationof the specific commodities on which the pesticidecan be used. During the registration process, EPAattempts to determine if the pesticide’s use willcause an unreasonable risk to humans or theenvironment (see ch. 7). The registration require-ments for pesticides are set forth in section 3 ofFIFRA and are defined more fully in EPA regula-tions (40 CFR 1987 ed. 158, 162).

If use of a pesticide will leave a residue on foodor feed commodities, EPA, under FFDCA, estab-lishes a legal maximum level, or “tolerance,” forthe pesticide residue. A tolerance, or an exemptionfrom a tolerance, must be granted before a pesticideis registered. Tolerances cannot be legally exceeded,and residues of pesticides for which no tolerance hasbeen established or exempted are prohibited onfoods. Commodities that violate these prohibitionsare subject to seizure by FDA, USDA, or a Stateenforcement agency (62).

If a pesticide has never been registered for use inthe United States and the manufacturer does notexpect residues to occur on imported foods, atolerance will not necessarily have been set. Also,tolerances may not have been established if a

Photo credit: Michael Hansen

registration application is pending. Any importedfood contaminated with a pesticide that does nothave a tolerance is considered adulterated and issubject to seizure at the U.S. border. However, ifUSDA and FDA border inspectors are not told thatthese pesticides have been used or they are unable totest for them, illegal residues in imported food willnot necessarily be detected.

One pesticide industry spokesman has indicatedthat increased monitoring for pesticide residueswould strengthen and bolster U.S. consumer confi-dence in the quality of the food supply (35).Additional testing of agricultural chemicals, called‘‘reregistration, ‘‘ is under way, and over the next 9years, the agricultural chemical industry expects topay $170 million in fees to help EPA finance theeffort (35).

FDA, under FFDCA, is responsible for enforcingtolerances established by EPA for food and animalfeed in interstate commerce. It is also responsible forenforcing the prohibition in food or animal feed ofresidues of pesticides for which no tolerance hasbeen set or exemption given. In the past, when FDAconsidered low levels of a residue to pose little riskto human health, it would set informal residue levels,called action levels. At these levels, FDA wouldtake regulatory action; below them the food wasconsidered safe. A recent court opinion struck down


this practice, and EPA and FDA are currentlydetermining how to address this issue.1

The USDA is responsible for enforcing tolerancesin meat and poultry under authority of the FederalMeat Inspection Act and the Poultry ProductsInspection Act. It is also responsible for monitoringpesticide residues in raw egg products (dried, frozen,or liquid eggs) and for enforcing tolerances atestablishments having official USDA egg productsinspection services, under authority of the EggProducts Inspection Act (62). While most of thefocus has been on food crops, more insecticide isused on cotton on a worldwide basis than any othercrop (23).

International Effects of U.S.Export Practices

Regulations governing the export and import ofneurotoxic substances are far from uniform. Manynations, including the United States, have policiesand procedures in place, but too often they work onlyon paper. In practice, they may allow neurotoxicsubstances to slip through the regulatory cracks.Regulatory requirements designed to protect work-ers and consumers from the harmful effects of toxicsubstances may be ineffective in some countries.The United Nations Food and Agriculture Organiza-tion (FAO) has implemented an International Codeof Conduct on the Distribution and Use of Pesticidesto outline responsible behavior on the part of personswho deal with pesticides. Pesticides are known asthe group of chemical products that includes insecti-cides, acaricides, molluscicides, rodenticides, ne-maticides, anthelmintics, fungicides, and herbicides(26). Although many consider the code a step in theright direction in terms of providing notification,use, and transport protections (among others), it isonly a voluntary code, and FAO has no enforcementauthority. The objectives of the code are to set forthstandards of conduct for all entities engaged indistributing and using pesticides. Pesticides arebiologically active, and their uncontrolled releasewill always present a potential threat to the environ-ment (27). The code describes the shared responsi-bility of many segments of society, government,industry, trade, and international institutions to usepesticides when necessary without adversely affect-ing people or the environment (40).

The Pesticide Development and Safe Use Unit ofthe International Program on Chemical Safety hastoxicologically evaluated 83 pesticides widely usedin agriculture and public health and establishedaverage daily intake and maximum residue limits for23 of them (43). The Codex Alimentarius Commis-sion (Codex) has established maximum residuetolerances for numerous chemical residues, contam-inants, and food additives (43). Sampling andanalysis principles to determine pesticide residues infood and animal feed have also been developed (43).

Despite numerous regulations governing the ex-port and import of pesticides and other neurotoxicproducts in the United States and abroad, somecountries do not have the regulatory framework andresources to adequately protect human health andthe environment from these substances. Nearly allmajor U.S. corporations producing pesticidesthat have been banned, severely restricted, ornever registered for use in the United States aremultinational and have subsidiaries or otherdistributors in developing countries. In somecases it is through these subsidiaries and distribu-tors that such pesticides are imported and dis-tributed in developing countries. This also allowscorporations with stocks of toxic substances thatcan no longer be sold in the United States to sellexisting products.

In addition to concern about food products that areimported into the United States with residues ofbanned, severely restricted, or unregistered pesti-cides, critics are concerned that exported pesticidesmay not be properly packaged or labeled. At times,the package labeling and instructions may be writtenin English instead of the native language of theimporting country. In some cases, farmworkersusing the pesticides are illiterate and thus could notread the labels even if they were written in theirnative language.

Improper labeling may prevent implementation ofappropriate safety measures or precautions by farm-workers and consumers. In July 1986, phosdrin, apotent neurotoxic insecticide classified by the WorldHealth Organization (WHO) as “extremely hazard-ous, ” was purchased in Benguet Province, Philip-pines. The product label had seven labeling infringe-ments, all of them in direct violation of the FAOcode (20). Similar violations of the FAO code have

ISCX 21 cm WCS. 109 and 509, 1987; FDA Compliance Policy Guides, 1986. The informal process by which these action levels wem set wu vac~~by the Federal Appeals Court in the District of Columbia Consumer Nutrition institute v. Young, 818 F.2d 943 (D.C. Cir. 1987).


been discovered recently in Ecuador, Papua NewGuinea, Thailand, Senegal, Colombia, South Korea,Sudan, and Mexico (18). In Iraq in 1973, anepidemic of methyl mercury poisoning resulted fromimproper labeling. Farmers and their families atebread made from seed treated with mercury. Thebags in which the grain was imported were clearlylabeled in English and Spanish (neither of which isa native language of Iraq). More than 1,000 peopledied from mercury poisoning, and 10 times morewere hospitalized (see box 2-A, in ch. 2) (2).

In some instances, even if the pesticide is properlypackaged and labeled when it leaves the exportingcountry, it is repackaged in the importing countrywithout the necessary labeling. Accordingly, thepesticide product that actually reaches the user maylack very important health and safety information.Repackaging is frequent, because pesticides areoften shipped in 35- to 100-gallon drums and arethen transferred into smaller, more manageable sizesfor the consumer. On an international scale, pesti-cides are widely available to the general public, andfew warnings are given (18). In some countries,pesticides are sold in markets alongside vegetablesand grains. People can scoop up pesticides incartons, bottles, cans, plastic or paper bags—whatever they bring to the market. Often they do notknow the name of the chemical they are purchasingbecause the container is not labeled. In somecountries, pesticides are marketed as ‘‘plant medi-cines, " and farmers are encouraged to use them tokeep their crops healthy in much the same way thatmedicines are used to keep people healthy (24).

The pesticide industry is aware of the illiteracyproblem and is taking steps to circumvent it. Oneapproach is to use illustrations, or ‘‘pictograms, ’that convey to an illiterate worker the appropriateway to mix, use, store, or clean up pesticides. Thesepictograms were designed by the InternationalGroup of National Associations of Manufacturers ofAgrochemical Products, an international consortiumof pesticide manufacturers, formulators, and distrib-utors, in cooperation with the FAO. Figure 9-5shows examples of pictograms currently used bysome pesticide companies in developing countries.It is not yet known how extensively the pictogramsare used or with what degree of success.

It is not only in export and use that pesticides poseproblems, however. Pesticides are frequently manu-factured in developing countries, where there are

less stringent regulations. U.S. manufacturers claimthat it is safer to produce pesticides in the UnitedStates, with its many regulations, than in developingcountries. The combination of lethal ingredients anddeficient safety precautions was dramatically dem-onstrated by the 1984 leak at the Union Carbidepesticide plant in Bhopal, India, which killed morethan 2,000 people and injured tens of thousands (69).

Pesticide manufacturers justify U.S. export prac-tices and advocate increased use of pesticides bymaintaining that developing nations need pesticidesto combat famine. The world population is growingrapidly: in 1975 it was 4.1 billion; in 1987 it hadgrown to 5,1 billion; and the projected figure for2005 is 6.7 billion (64). Feeding this ever-increasingpopulation is a problem because land available forfarming is not increasing significantly. Moreover,the population increase is greatest in developingnations.

Critics of U.S. export practices argue that pesti-cides in the developing world are more often appliedto luxury export crops than to staples eaten by localinhabitants and that, in any case, nonchemicalmethods of pest control could and should beimplemented (70). According to the World Bank, theworld produces enough grain alone to provide everyhuman being on the planet with 3,600 calories a day(72). In a major 1986 study of world hunger, it foundthat a rapid increase in food production does notnecessarily result in less hunger. Hunger can only bealleviated by redistributing purchasing power andresources to those who are undernourished (72). InIndia, for example, despite a 24-million-ton grainsurplus (25), per-capita consumption of grain has notincreased in 20 years and nearly half the populationlacks the income necessary to buy a nutritious diet(63). Availability of grain in India has actuallydeclined in recent years, despite a rise in pesticideuse (57). Furthermore, numerous plantations andother agricultural areas have been forced to turnaway from pesticide use due to resistance problemsdeveloped by insects, weeds, and fungi overdosedwith pesticides (23).

The USDA has addressed the issue of worldhunger, particularly in developing nations, as fol-lows:

First, the food problem of the developing coun-tries is not a global lack of food. More than enoughfood is produced and stored in the world to provide


Figure 9-5-Pictograms for Agrochemical Pesticides

Storagepictogram

Activitypictograms

Keep lockedaway andout of reachof children

Handlingliquidconcentrate

\

\ n

Handling

b

ApplicationdryConcentrate

:.... ..... . .

w %

,,:.,,., ,..,,,, ,.,, ,. , $ ., , . .

Weargloves

Advicepictograms

Wearboots

Warningpictograms

Dangerous/harmful toanimals

Wearprotectionover noseand mouth

Dangerous/harmful tofish–do notcontaminatelakes, rivers,ponds,orstreams

Wearrespirator

SOURCE: International Group of National Associations of Manufacturers of Agricultural Products, 1988 Pictograms for Agrochemical Labels: An Aid to theSafe Handling of Pesticides.


people everywhere with adequate diets. In times ofcrises, countries have the capacity to respond quicklywith food and other needed supplies to alleviatehunger and suffering. Unfortunately, political differ-ences within and between countries and logisticssometimes impede the efforts to save lives, as in thecurrent food crisis in sub-Saharan Africa (59).

Regulatory Policies in OtherIndustrialized Nations

For the most part, regulations in industrializedcountries are enforced, and public health and envi-ronmental problems from pesticide importation,distribution, and use are not as severe as in develop-ing nations. However, this does not mean thatpesticide problems are nonexistent in industrializednations. The following discussion summarizes theactivities of some industrialized nations with majorregulatory programs.

Canada

Within Canada primary responsibility for envi-ronmental issues with international and interprovin-cial components lies with the federal government,while the provinces are generally responsible forenforcing regulations governing industries withintheir borders (12). Environment Canada, establishedin 1971, is the federal department that administerslegislation relating to environmental protection. Amajor reorganization of Environment Canada in1986 and 1987 consolidated the department’s activi-ties into three main branches: Conservation andProtection, Atmospheric Environment (responsiblefor meteorology), and Parks (responsible for mainte-nance of national parks). Conservation and Protec-tion includes the Canadian Wildlife Service, Environ-mental Protection, and the Inland Waters and LandsDirectorate.

The primary federal legislation controlling theavailability, sale, and use of pesticides is the PestControl Products Act, administered by AgricultureCanada (12). The Act requires annual registration ofpesticides and prohibits import or sale of unregis-tered pesticides. It is intended to ensure that noperson shall use a pesticide under conditions that areunsafe to human or animal health or that willadversely affect the environment. The Act alsorequires that such products be effective for theirintended purposes (46). There are currently plans toupgrade the legislation to require more stringenttesting of pesticide products.

Agriculture Canada calls on various federal de-partments to provide expert advice on hazards thatmay be associated with the use of a product. Healthand Welfare Canada requires and reviews a range oftoxicological studies to assess potential healthhazards that may be associated with exposure to achemical, including acute, subacute, chronic, repro-duction, teratology, and metabolism studies. Inaddition, studies to estimate anticipated humanexposure during typical field use of the chemical arerequired.

The federal departments primarily involved in thepesticide review process are Agriculture Canada,Fisheries and Oceans Canada, Environment Canada,and Health and Welfare Canada (12). The PesticidesDirectorate of Agriculture Canada receives themanufacturer’s application for registration of thepesticide and is responsible for the evaluationprocess and the coordination of reviews from theother agencies (46).

Federal Republic of Germany

The Federal Republic of Germany, one of theworld’s largest exporters of pesticides, divides andsometimes shares lawmaking and enforcement pow-ers between the federal government (Bund) and the11 states (Lander). The Federal Ministry for Envi-ronment, Nature Protection, and Nuclear Safety wascreated in 1986, in the aftermath of the accident atthe nuclear power plant in Chernobyl in the SovietUnion. It was created out of the Environment andNuclear Safety divisions of the Ministry of Interiorand the Nature Protection Division of the Ministryof Nutrition, Agriculture, and Forest (MNAF) (14).

Pesticides are regulated under the Pfalnzen-schutgesetz (Plant Protection Law), which outlinesthe terms of licensing, prohibition, or restriction ofuse, application, and export (43). Licensing, whichis issued only if the pesticide is safe, efficacious, andin compliance with requirements for human andanimal health and safety, provides for classification,testing, labeling, and packaging (43).

The Federal Environmental Agency (FEA), underthe authority of the MNAF, is responsible forgeneral environmental policy-related research, in-cluding maintenance of an environmental informa-tion planning system, collection of informationnecessary to develop and implement federal laws,and preparation of legislation and administrativeregulations. The FEA has done considerable work


on the development of environmental impact assess-ment procedures (14). A separate organization, theConference of State Ministers for the Environment,which includes the Federal Environment Ministry, isthe major forum for coordination of state and federalenvironmental policy. Federal-state working com-mittees have been established to coordinate pro-grams in all major areas of environmental protection(14).

The Federal Ministry for Foreign Affairs isresponsible for international relations and environ-mental policy. The Federal Ministry of Food,Agriculture, and Forestry houses the AgriculturalResearch Center, which monitors soil biology,agrichemicals, agricultural waste recycling, plantecophysiology, and water pollution, and the FederalCenter for Biological Research in Agriculture andForestry, which is responsible for pesticide measure-ment and control, biological pest control, andinspection of commercial chemical preparations forplant protection and pest control (14).

A number of environmental laws are in effect. TheAct on Protection Against Dangerous Substances,which was adopted in 1980 and amended in 1986,establishes a testing and notification system for newchemical substances placed on the market afterSeptember 1981. The Act seeks to protect publichealth and the environment from harmful effects ofdangerous substances by: 1) compulsory testing ofand notification regarding substances; 2) compul-sory classification, labeling, and packaging of dan-gerous substances and preparations; 3) prohibitionsand restrictions on use; and 4) specific legalprovisions concerning toxicity and occupationalsafety. The Act covers foodstuffs, tobacco products,cosmetic agents, animal feedstuffs and additives,pharmaceuticals, wastes, radioactive wastes, wastewater, and waste oils (14).

The Act requires notification at least 45 days priorto placing a substance into initial circulation in acountry that is a member of the European Commu-nity (EC), whether on a commercial basis or withinthe framework of any other business undertaking.There is no requirement for notification if thesubstance was manufactured and notified by anequivalent procedure in any other EC membercountry (14). Six administrative regulations havebeen adopted concerning information required innotifications, designation of the Federal Office foroccupational and Safety Policy to receive notifica-

tions, inventory of existing chemical substances,labeling of hazardous substances, and general ad-ministrative procedures.

Criminal violations of environmental legislationare generally codified in division 28 of the criminalcode, adopted in 1975 and last amended in 1987.Penalties range from fines to jail sentences and areusually defined in the particular environmental law(14).

Belgium

Environmental programs in Belgium are less welldeveloped than those in other European countries.Because implementing legislation must, in mostinstances, be enacted by the regional administra-tions, norms and enforcement vary throughout thecountry (11).

A 1969 act regulates the manufacture, composi-tion, storage, transport, and marketing of pesticides.Such activities may be carried out only by licensedpersons. The maximum concentrations of residueafter decomposition may also be controlled underthe act, as well as the conditions of use of pesticides.Pesticides themselves are subject to an approvalprocedure, and the license usually lasts for 10 years.The approval is made subject to conditions, and it isan offense to use pesticides other than in accordancewith these conditions (1 1).

A royal order of 1975 regulates the storage, trade,and use of pesticides and plant protection products.Pesticides are subject to premarket registration, andcertain labeling and packaging requirements are setout (11). A royal decree of 1977 implements ECDirective 76/1 16, which prohibits the marketing ofmanure and fertilize, as well as all products with aspecific action to stimulate crop production. Thisdecree also regulates the information and indicationsto be put on the package, the documents required fortransport, the packaging requirements, and themethod of taking and analyzing samples (11).

A royal decree of 1982 requires that beforeplacing a dangerous substance on the market, anymanufacturer or importer must submit to the Minis-ter of Public Health a dossier that includes adeclaration of the unfavorable effects of the sub-stance for the various uses envisaged. The decreeestablishes a Committee on Dangerous Substances,composed of officials of different ministerial depart-ments and attached to the Ministry of Public Health.The committee is responsible for examining the


notification procedure and advises on the complete-ness of the application. A dangerous substancecannot be placed on the market during the 45 days ittakes to complete the notification procedure (1 1).

France

Pesticides for agricultural use are governed by a1972 law that controls manufacture, sale, and use aswell as packaging and labeling (43). Prior toapproval for production, toxicity and efficacy mustbe assessed, and the pesticide must be classified interms of toxicity (43). Tolerance limits in foods areprescribed by presidential decree (43).

The Chemicals Control Law, adopted in 1977,governs hazardous substances. It is intended toprotect public health and the environment againstrisks that may arise from natural or industriallyproduced chemicals, but it does not apply tochemicals used in research or to food additives,cosmetics, or drugs (13). The law provides forpremanufacture notification for all chemicals thathave not yet been marketed. Producers or importersmust declare any new risk that may result from achange of manufacturing process or from emissionof the said chemical into the environment (37).

Producers or importers of new chemicals mustalso submit a technical dossier providing the infor-mation needed for assessment of potential hazards.The competent authority may classify a substance asa “dangerous product’ request from the manufac-turer or importer any relevant information withrespect to potential health or environmental effects;and prohibit or restrict the production, composition,storage, transportation, conditioning, labeling, mar-keting, use, or disposal of any chemical wheredeemed necessary to protect the public (37).

Producers of already marketed substances mayberequired to provide public authorities with appropri-ate technical or toxicological data to evaluatepotential health or environmental risks. Violation ofthe law may result in imprisonment or fines or both.

Japan

Agricultural chemicals are regulated by a 1948law that has been amended several times, mostrecently in 1983 (43). It requires that pesticides beregistered with appropriate government agencies,which classify pesticides according to persistence incrops and soil and water pollution potential (43).Limits are placed on the amount of active ingredi-

ents and the maximum allowable harmful ingredi-ents for each pesticide (43). The applicant mustprovide test results on pesticide effectiveness, toxic-ity, phytotoxicity, and persistence (43). Labelingand packaging must represent truthfully all state-ments and facts on which the pesticide was regis-tered and must include, among other things, thedangers posed and precautions to be taken forstorage and use (43).

Other toxic substances are regulated by theChemical Substances Control Law of 1973. Theneed for comprehensive measures to prevent envi-ronmental pollution has been recognized followingenvironmental crises such as the mercury poisoningincident at Minamata Bay in the 1950s (see ch. 2).

The law requires notification and testing of allnew chemical substances produced in quantitiesexceeding 100 kilograms. The law does not apply tochemicals in use before the law came into effect, butan agreement reached in the Diet makes some 800existing chemicals subject to the same reviewstandards as the new substances. The law alsoprovides that, prior to production or importation, allnew chemicals must be submitted to official exami-nation regarding persistence, accumulative ten-dency, and toxicity to human beings.

A substance may be classified as a “specifiedchemical substance” if it accumulates easily inbiological organisms, if it resists chemical changescaused by natural effects, and if it may harm humanhealth when ingested over a period of time. The lawwas passed in response to polychlorinated biphenyl(PCB) poisoning (9). Chemicals tested and desig-nated ‘‘specific substances’ are subject to prohibi-tion or restriction. Although only PCBs have beenformally listed as specific substances under the law,government officials say that two or three chemicalsare withdrawn from testing every month whenmanufacturers learn that the chemicals probablywould be specified and the manufacturer’s namerevealed. Another two or three applications forapproval are suspended each month for lack of data(9).

The Pollution-Related Health Damage Compen-sation Law of 1974 was further modified, in the caseof Minamata victims, by the Minamata Relief Lawin 1978. The beneficiaries of this law are the victimsof certain pollution-related diseases who have ‘lived,worked, or otherwise been present” in designatedareas. Testing for functional developmental disor-


ders, including behavior disorders, has become oneof the most important aspects of the evaluation ofdevelopmental toxicity of chemicals, especiallypharmaceutical drugs. There are two guidelines fordevelopmental toxicity testing of chemicals-one athree-segment study for drugs, the other a multigen-eration study plus embryotoxicity for environmentalchemicals (56). In the case of specific diseases,where the source of pollution is known, the companyresponsible must pay compensation. In nonspecificcases, there is a levy on polluting industries to coverclaims. Certified victims, that is, persons who havebeen examined by government medical panels, areentitled to medical care expenses and a monthlyphysical handicap payment, the amount being deter-mined by the victim’s age, sex, and ability to work.There are also child compensation allowances andsurvivors’ benefits. Payment is made by localgovernments through the Pollution-Related HealthDamage Compensation Association. The govern-ment covers the association’s overhead costs, butpayments to victims are financed by polluters.

United Kingdom

Pesticides are regulated under the DangerousSubstances Regulations and the Food and Environ-ment Protection Act (43). The regulations specifywhich toxicity tests are necessary to categorize eachpesticide, based on EC Directive 78/631 of 1978(43). Packaging and labeling requirements are alsoset out in the regulations (43). Pesticide manufactur-ers must notify the government prior to marketing anew pesticide or suggesting new uses of an old one(43). Manufacturers must also provide sufficientdata to enable government assessment of pesticidedangers, and warnings, precautions, and names ofactive ingredients must be included on all labels(43). The government has authority to requestwithdrawal of unsafe products and to specify maxi-mum pesticide residues on crops, foods, and live-stock feed (43).

Responsibility for protection of the environmentlies primarily with the Department of the Environ-ment. It has responsibility for introducing andimplementing acts of Parliament and statutoryinstruments. Other ministries also have some re-sponsibility for environmental protection. Theseinclude the Ministry of Agriculture, Fisheries, andFood, which controls the ocean disposal of wastesand has joint responsibility with the Department ofthe Environment and the Welsh Office for control of

radioactive discharges from nuclear sites; the De-partment of Employment, which is responsible forhealth and safety; the Department of Health andSocial Security; and the Department of Transport.Within the Department of the Environment is theCentral Directorate on Environmental Pollution,staffed by a pool of scientists and administratorscoordinating national regulatory policy in the envi-ronmental protection field, including participationin international activities (10).

Numerous divisions within the department areconcerned with land use, conservation of wildlifeand habitats, control of toxic substances, air andwater pollution, and wastes. The Toxic SubstancesDivision, for example, is responsible for developingpolicy aimed at protecting human health and theenvironment. Its responsibilities also extend toparticipation in international initiatives. However,the International Division has prime responsibilityfor coordinating United Kingdom policies on envi-ronmental affairs and presenting those policiesbefore the United Nations, the Organization forEconomic Cooperation and Development, the EC,and other bodies (10).

In 1987, a new, centralized agency was formed toenforce environmental laws and regulations inEngland and Wales. Her Majesty’s Inspectorate ofPollution brought together several existing pollutioncontrol agencies: HM Industrial Air Pollution In-spectorate, for controlling major emissions to theatmosphere; HM Radiochemical Inspectorate, forcontrolling all radioactive discharges and disposals;the Hazardous Wastes Inspectorate, for monitoringthe activities of local Waste Disposal Authorities;and the divisions of the Department of the Environ-ment and the Welsh Office responsible for issuingconsents for discharges by the Water Authorities.

Regulatory Issues in Developing Nations

Developing nations, especially those with a largeagricultural economy, depend on pesticides to pro-duce maximum yields. In many of these nations,agriculture is the primary industry and provides thecountry’s primary income. In Ghana, for example,cocoa exports provide a majority of foreign ex-change earnings (8). Misuse and excessive use ofpesticides and chemicals are a significant andwidespread problem in developing countries (15).The WHO has estimated that someone in adeveloping country is poisoned by pesticides


every minute (65). This is due in part to lack of apesticide policy in many developing nations. TheFAO estimated in 1988 that some 50 countriesstill did not have pesticide regulations (20). Thosenations with a policy often do not have the infra-structure or economic resources to implement thepolicy. Moreover, in some developing nations,government officials charged with enforcing pesti-cide policies have a vested financial interest inmaintaining a strong pesticide economy (20). In fact,the governments of many countries are pesticideimporters, manufacturers, and exporters, as well asregulators of pesticides (20). Consequently, regula-tions designed to protect public health and theenvironment may receive little attention. In othercases, pesticides are heavily subsidized, making itcheaper to use pesticides than not (45).

Because of the lack of governmental controls,many developing nations must depend on thepesticide industry to regulate the importation, distri-bution, and use of pesticides, as well as to safeguardpublic health and the environment. In light of this,discussions of regulatory policy often focus on howmuch responsibility pesticide manufacturers and thegovernments of pesticide exporting countries shouldassume. Nations around the world agree that respon-sibility for safety and efficiency in distribution anduse of pesticides must be shared by foreign manufac-turers, exporters, and importers, as well as localformulators, distributors, repackers, advisers, andusers (58). To facilitate the implementation of thisduty, FAO adopted in 1985, and amended in 1987,a code covering such issues as proper pesticidetransport, marketing and advertising, recalls, andnotification on the part of regulators and manufac-turers.

The code calls on industry to adhere voluntarily toits provisions and places an even higher responsibil-ity on industry in countries that lack appropriatepesticide legislation and advisory services (58). Thecode maintains that manufacturers have a duty toretain an active interest in following their prod-ucts to the ultimate consumer. Some assert that theultimate consumer is the local farmer who buys asmall amount of repackaged pesticide product foruse. Following this line of reasoning, the manufac-turer’s duty would end with this purchase. On theother hand, there is the argument that a farmer whoproduces cash crops, as distinguished from a subsis-tence farmer, is not a consumer but a producer (6).These producer-farmers use factors of production—

land, seed, labor, water, fertilizer, pesticides-toproduce a cash crop. The consumerism the person whobuys the produce with the intent of eating it.Accordingly, the pesticide manufacturers have aduty to retain an active interest in following theirproducts—pesticides-to the dinner tables of thefamilies and individuals of the world community(6).One could further argue that U.S. manufacturershave a special duty to protect and ensure the safetyof food treated with U.S.-manufactured pesticidesand eaten by U.S. consumers, regardless of wherethat food is grown.

One controversial provision of the code intendedto address the issues of regulation and education isthat of prior informed consent (PIC). Under PIC, apesticide that has been banned or severely restrictedin one country cannot be exported to another countryunless the importing country’s government has beenfully informed of the reasons for the regulatoryaction and has consented to the importation of thepesticide (58). Pesticide exporting countries gener-ally do not favor PIC and assert that it is tootime-consuming, expensive, and burdensome forindustry (20). Representatives of importing coun-tries, on the other hand, claim that, in the absence ofregulatory controls, PIC is the only avenue forallowing governments to determine if pesticidesbanned in other countries should be permitted withintheir borders. Although PIC is still a voluntarypractice, the Netherlands became the first coun-try to incorporate it into legislation and seek tomake it legally binding (20).

The WHO has classified pesticides on the basis ofthe hazards they pose. Hazard is defined as thelikelihood that a pesticide will cause immediate orshort-term adverse effects or injury under circum-stances of ordinary use. These classifications arebased on the oral and dermal toxicity of thepesticide’s active ingredient. Countries adopting theFAO code are also supposed to adhere to thefollowing WHO toxicity classification in labelingtheir pesticides:

. IA Extremely Hazardous,

. IB Highly Hazardous,

. 11 Moderately Hazardous, and

. III Slightly Hazardous.

In addition, the Pesticide Action Network (PAN)has initiated a Dirty Dozen Campaign on aninternational scale to publicize the 12 most hazard-ous pesticides used worldwide, most of which are


neurotoxic. Since the campaign began, some coun-tries have banned certain pesticides on the DirtyDozen list, and others have restricted the availabilityof them (20). The pesticides are:

●

●

●

●

●

●

●

●

●

●

●

●

camphechlor (toxaphene),chlordane/heptachlor,chlordimeform (Galecron),dibromochloropropane (DBCP),DDT,aldrin/dieldrin/endrin,ethlene dibromide (EDB),lindane/hexachlorocyclohexane (HCH),paraquat,ethyl parathion,pentachlorophenol (PCP), and2,4,5-T.

Pesticide workers in developing countries arefrequently not provided with appropriate protectiveclothing and equipment to guard against oral anddermal exposure when applying pesticide products(30). In tropical or semitropical climates, the temper-ature is often too hot to permit workers to comforta-bly wear protective clothing designed for use inmore temperate climates (protective clothing isoften made of plastic, rubber, or other nonporousmaterial). Despite workers’ lack of protective cloth-ing, pesticides are sometimes sprayed from aircraftwhile workers are in the fields. Pesticides may alsobe sprayed from canisters strapped to the backs ofunprotected workers.

Besides allowing the export of pesticides thathave been banned or severely restricted for use inthis country, present EPA regulations allow theexport of pesticides that have never been reviewedby the Agency. Some critics argue that if a pesticideis not safe enough for use in the United States, itshould not be exported. The FAO code holds that thefact that a product is not used or registered in theexporting country is not necessarily a valid reasonfor prohibiting export of that pesticide (58). Mostdeveloping countries are located in tropical andsemitropical regions. Their climatic, ecological,agronomic, and environmental conditions, as well astheir social and economic needs, may be differentfrom those of industrialized nations. Accordingly,their pest problems may be quite different. Thegovernment of the exporting country, therefore, maynot be in the best position to judge the suitability,efficacy, safety, or fate of the pesticide under

conditions in the country where it may ultimately beused.

Critics of this export policy argue, however, thatforeign relations problems could arise if productsconsidered too unsafe and hazardous for use bypeople in the United States are deemed safe for useby people abroad. Although people in developingcountries use only 10 to 25 percent of the world%pesticides (7,21), it is estimated that they accountfor as much as 50 percent of the acute poisoningsof pesticide applicators and between 73 and 99percent of their deaths (15). Furthermore, residentsof the exporting nation are exposed to potentiallydangerous chemicals during domestic productionand eventual consumption of imported foods treatedwith the pesticides.

Following is a summary of regulatory activities incertain developing countries where pesticides areused. Boxes 9-A and 9-B illustrate problems thathave occurred in developing nations. Although eachof the profiled countries has some regulatory struc-ture in place, each also has many problems with theimport, distribution, and use of pesticides, resultingin health problems of varying degrees for farmwork-ers and consumers. In selecting the countries for thissection, an attempt was made to obtain a geographicspread.

Malaysia

The Pesticides Board under the Malaysian De-partment of Agriculture has regulatory authority forpesticides in Malaysia. The Pesticides Act, thePesticide Registration Rules of 1976, the PesticideRules on Importation for Educational or ResearchPurposes of 1981, and the Food Act of 1983 set outthe language governing pesticide use (39).

Malaysia follows FAO guidelines with respect todata requirements for pesticide registration. How-ever, all data, including efficacy data, may be fromforeign sources. Data are evaluated and a recommen-dation is submitted to the Pesticides Board, whichhas authority to grant registration (39). Accordingly,a pesticide may be reviewed and approved for use inMalaysia with the approving authority dependingentirely on data from the country of export.

The Department of Customs controls the importof all pesticides except those imported for researchpurposes, which are controlled by the MalaysianDepartment of Agriculture. The Department ofAgriculture also controls the production, sale, and

Chapter %-international Regulatory and Research Activities . 251

Box 9-A—Problems With Neurotoxic Pesticides in Developing Countries

Irregularities concerning labeling, packaging, storage,sale, import, and advertising of pesticides have causedillness, injury, and death in many developing countries, asthe following examples illustrate:

Pesticides are commonly repackaged without labelsin Senegal, but labels are of little use anyway,because most pesticide users are illiterate. Instruc-tions such as “in case of intoxication, call a doctor”are meaningless in rural areas where there are nodoctors for miles, no telephones, and only sporadictransport.

. In Indonesia, an outbreak of mosquito-spread denguefever caused several deaths. The Ministry of Healthsent an officer to spray the area with malathion, aclass HI, slightly hazardous pesticide. The officer wasphotographed spraying malathion while children

Photo credit: Widjanarka

were running behind him to play in the pesticide mist (see photograph above).● In Papua, New Guinea, very few companies provide labels in Tok-Pisin, the widely spoken local language.

Some pesticide products had labels in French. One pesticide, selecron, was found in stores with no label atall.

● Many of the pesticides in Thailand, Indonesia, and the Philippines do not have child-proof packaging. Someliquid pesticides have easily opened screw caps, and powdered pesticides can be bought in plastic bags thatan older child can open.

. In Indonesia, some pesticides were repackaged into clear plastic bags without labels. Workers wore no masksor gloves. Unlabeled bags of temik, which is 10 percent aldicarb, a class IA, extremely hazardous neurotoxicpesticide, were available in stores. Aldicarb is more acutely toxic to mammals than any other pesticidepresently in use.

. In the Sudan, a family of eight died in 1985 from eating pesticide-poisoned bread made from pretreatedwheat meant for seed. The pretreated wheat had been in badly labeled sacks stacked next to consumablewheat in an agricultural store.

In Brazil, a 1987 advertisement described deltamethrin as “the safest insecticide in the world.”Deltamethrin is classified as class II—moderately hazardous by the International Code of Conduct on theDistribution and Use of Pesticides of the Food and Agriculture Organization of the United Nations.

● In Senegal, used pesticide containers are often recycle-d to carry food, milk, or cooking oil. In one village,19 people from two families died as a result. The cook used oil sold in a bottle that had previously containedethyl parathion, a class Ia, extremely hazardous pesticide.

. In Brazil, when a number of states passed laws banning imports of pesticides banned in their countries oforigin, translational pesticide corporations and importers filed legal action and succeeded in getting the lawsdeclared unconstitutional.

SOURCE: G. Goldenman and S. Rengam, Problem Pesticides, Pesticide Problems (Penang, Malaysia: International Organization of ConsumersUnions and Pesticide Action Network, 1988).

use of pesticides and checks for compliance with killed by exposure to just that one pesticide (48).regulatory policies. The Pesticides Board regulatesadvertisements of pesticides (39).

Residues on vegetables are monitored under theFood Act of 1983. To date, there is no system formonitoring pesticide poisoning except for occa-sional reports from hospitals. Following the deathsof two teenage girls from field exposure to paraquatin 1985, it was revealed that 1,200 workers had been

Both government and the private sector have imple-mented training programs on the safe handling ofpesticides. These programs are geared toward farm-ers, applicators, dealers, distributors, manufacturers,and medical personnel (39).

Residues on vegetables are monitored under theFood Act of 1983, which prescribes maximumresidue limits (5). In reality, monitoring and testing


Box 9-B—Incident at Lake Volta, GhanaIn Achedemade Bator, a fishing village on Lake Volta, a serious poisoning incident resulted from improper

use of Gammalin 20, the trade name for lindane, a potent neurotoxic substance. The villagers, almost all of themilliterate, derived their income through fishing on the lake. The village fishermen discovered that by pouring lindaneinto the lake, fish would float to the surface and could be easily caught. This proved to be a very quick and efficientway of hauling in a catch. Any fish not consumed were salted, smoked, or sold.

Exposure to lindane may cause dizziness, headaches, convulsions, muscle spasms, brain disturbances, andunconsciousness. Some villagers experienced symptoms of lindane poisoning from consuming poisoned fish andusing the lake as a source of drinking water but never associated their health problems with use of the chemical.Fishermen knew something was wrong when the fish population in the lake rapidly declined, and housewives couldeasily identify Lake Volta fish by their smell, but villagers continued to eat the deadly fish. When a connection wasmade between the illnesses and fish consumption, villagers cut off the heads of the fish and continued to eat thebodies, believing that decapitation would rid the fish of all poison.

Other plants and animals in the lake were killed as well. It was not until the intervention of the Associationof People for Practical Life Education, a Ghanian organization, and the blessing of the village witch doctor that thevillagers stopped using lindane for fishing and returned to nets and traps. In villages throughout Africa, fishing withpesticides continues where people have not been educated about the safe and effective use of these toxic substances.

SOURCE: R. Norris (cd.), Pills, Pesticides & Profits (Croton-on-Hudson, NY: North River Press, 1982).

are minimal (5). Concern about pesticide residues in Philippine Institute for Pure and Applied Chemistry,food has resulted in the formation of the ConsumersAssociation of Penang (CAP), the largest and mostvocal citizens’ organization in the developing worldfocusing specifically on consumer rights (70). CAPhas discovered organochlorine pesticides (DDT,aldrin, BHC, dieldrin, chlordane), many of which arebanned in the United States, in Malaysia’s rainwater,soil, drinking water, and food crops. CAP monitorspesticide poisoning of workers and residues in foodand has pressured the Malaysian government totighten its regulations on pesticides (70). In a recentstudy conducted by the Malaysian Department ofAgriculture, it was discovered that 54 percent ofthe 1,214 agricultural workers studied had expe-rienced some form of pesticide poisoning (22,44).

Philippines

In the Philippines the private sector controls thepesticide industry, which is dominated by localorganizations representing the major multinationalcompanies (5). Virtually all of the pesticide businessis transacted by some 20 companies in the tradeassociation-the Agricultural Pesticide Institute ofthe Philippines (5).

There are several laws affecting the pesticideindustry. A presidential decree enacted in 1977regulates pesticides. Quality control of pesticides isdone by the Fertilizer and Pesticide Authority (FPA)through the Bureau of Plant Industry (BPI) and the

on the basis of complaints from users (39). Qualitycontrol during production and for imports is done byprivate companies. Pesticide dealers and ports ofentry in the 72 provinces and 12 regions areinspected, but critics argue that this system needsimprovement and strengthening (39). An FPA per-mit is required for all imports of pesticides, regard-less of quantity. The FPA controls production, sale,and use of pesticides through a licensing scheme,and in collaboration with the Philippine Board ofAdvertisers controls advertisements of pesticides(39).

There is no system in operation to monitorpesticide poisoning cases in humans except foroccasional reports from hospitals and doctorstrained under the FPA Agro-Medical Program.Pesticide dealers must be trained in the safe handlingof pesticides before they can obtain a retail license.Commercial pest control companies must obtaincertification for all of their operators (39). Market-basket samples of vegetables are routinely analyzedfor residues, particularly for organochlorines andorganophosphates, by the BPI (5). Other agenciesmonitor residues in lakes, rivers, and streams, whileexporters of agricultural products analyze shipmentsprior to export (5).

The Philippines is the home of the InternationalRice Research Institute, which helped create thegreen revolution of the 1970s. This revolution saw


the production of new hybrid seeds, developed toproduce higher yields with the correct amount offertilizer and water (70). These laboratory-bredseeds were more susceptible to pests and requiredincreased use of pesticides. Although the new seedshave increased production, the Philippines remainsone of the hungriest nations in Asia, according to theAsian Development Bank and WHO (70).

Some. years ago, the Farmer’s Assistance Boardwas formed by peasants and students to studypesticides. The board blames the large volume ofpesticide use in the Philippines on the big exporters,as well as on the International Rice ResearchInstitute. The board points to the demand for highestyield and blemish-free products as the reasons forthe country’s continued dependence on large quanti-ties of pesticides.

India

The Insecticides Act (1968) and the InsecticidesRules (1971) govern pesticides in India. The Actregulates manufacture, formulation, distribution,and sale of pesticides through a licensing system.Five agencies have been created to implement theselaws. Locally generated toxicity and residue data forformulations are required in most instances; how-ever, complete efficacy data are required only forregistration of a new pesticide. The Pesticide Regis-tration Committee and the Central InsecticidesBoard review data for registration, referring topublications and decisions by FAO, WHO, andEPA, among other organizations. India does notadhere to FAO guidelines with respect to labeling. Itdoes follow the FAO color coding of labels based ontoxicity, but the warning symbols differ from thosesuggested by FAO. Pesticides are classified intovarious categories of toxicity, but the limits set differfrom those recommended by WHO (39). To date,119 active ingredients and their formulations havebeen registered.

The improper use of pesticides is a major problemin India (5). Few farmers are aware of the potentialhazards associated with the use of pesticides (5).Crops are often sprayed with insecticide immedi-ately before and after harvest because of a belief thatpre- and postharvest spraying will increase freshnessand preservation (5).

India “phase registers” new pesticides. Firstthere is a trials clearance, then a provisional registra-tion, which is valid for 2 years and subject to certain

conditions, and finally a full registration. There isalso “me-too” registration, which allows a secondregistrant to obtain registration for a pesticidesubject to proof that the product is identical to theone already registered. There is usually a letter ofagreement between parties on use of data (39).

The Insecticides Act mandates that pesticidequality be checked by the Central Insecticide Labo-ratory. Rigid controls are set for preregistrationpurposes, but once a product is on the market,quality control is not pursued (39). Quality controlof products during production is monitored not bythe government, but by private companies. Compli-ance with regulatory policies is enforced by stategovernments, and imports are allowed only throughcertain ports of entry (39). No pesticide may beimported without a registration certificate. It isinteresting to note that many pesticides which havebeen banned or severely restricted in the UnitedStates are produced in India (70). Several foreignmanufacturers have plants in India (70).

Increased agricultural output does not necessarilymean increased food consumption for local residentsif the residents are too poor to afford food. Despitethe fact that there were vast increases in wheat yieldsin the Punjab district in the 1960s, the portion of therural population living below the poverty lineincreased from 18 to 23 percent (28). While true thatpesticide use may increase crop yield and bolster theeconomy of a developing country, in this particularinstance the economic prosperity of the local inhabi-tants declined.

The Central Food Laboratories monitor pesticideresidues and adulterants in food, but this systemneeds strengthening. State governments are requiredto obtain reports from their officers on pesticidepoisonings, but this is not a thorough monitoringsystem. Both state and central governments and thepesticide industry have implemented training pro-grams for safe use and application of pesticides (39).

Costa Rica

The Law for the Control of Pesticides (1979) andthe Law Governing Occupational Health (1981)regulate pesticides in Costa Rica. Along with otherCentral American countries, Costa Rica has adoptedthe provisions of the Basic Document on Regulationof Registration, Marketing and Control of Agricul-tural Chemicals for Countries of Central America,prepared under the auspices of the Inter-American


Institute for Cooperation on Agriculture in 1985. APesticide Commission has also been formed to carryout the pesticide registration program (39).

Registration requirements are generally in accor-dance with FAO guidelines. Local efficacy data fornew products are to be generated either directly bygovernment research organizations or by privatecompanies under government supervision. Efficacydata from other Latin American countries areacceptable for products already registered. EPAtolerances must also be submitted, along with acertificate of registration and a certificate of analysisfrom the country of origin and evidence of registra-tion from other countries. Labeling is evaluatedaccording to guidelines agreed on under the BasicDocument. Full registration is valid for 3 to 5 years,experimental permits are issued, and me-too regis-tration is allowed. As with Mexico and Ecuador, allchlorinated compounds that accumulate in the foodchain are banned, but the government reserves theright to use them in cases of emergency wheneconomical substitutes are not available (39).

Costa Rica has one of the strongest enforcementsystems in Central America. Import permits are

necessary, and there is a licensing scheme forformulation, distribution, and sale of pesticides. TheMinistry of Health has done some monitoring offood residues and keeps a record of poisoning cases.The government and private sector carry out trainingprograms for pesticide workers, and the governmenthas published a training manual for physicians.

Mexico

In Mexico, the principal pesticide legislation isthe Law on Plant and Animal Protection, which wasadopted in 1940. The law was amended in 1974, andrules were added in 1980 to implement it. FAOguidelines are generally followed, with local effi-cacy data generated either directly by governmentresearch organizations or by private companiesunder government supervision (39). All test proto-cols must be approved by the government. Emphasisis on evaluation of efficacy data, while toxicologicaland residue data are reviewed by experts. Labelevaluation follows the Basic Document guidelinesagreed on by Latin American countries, and theWHO classification system for pesticides has beenadopted, with certain modifications (39). Full regis-tration is valid for 3 to 5 years, with permits issued

Photo credit: Kay Treakle, Greenpeace

Unprotected workers spray paraquat on coffee plants, Chiapas, Mexico

Chapter International Regulatory and Research Activities . 255

for experimental purposes. Me-too registration isallowed with the same data and information require-ments as for all registered products.

All chlorinated compounds that accumulate in thefood chain are banned, but the government reservesthe right to use them in cases of emergency wheneconomical substitutes are not available (39). Asrecently as 1987, some 28 pesticides that werebanned or severely restricted in the United Stateswere being used in Mexico (18). Endrin, which wasseverely restricted in the United States in 1979, wasgiven a renewal registration for 2 years in 1984 (18).Mexico imports a large percentage of pesticides, butthere are also some 300 formulation plants in thecountry (18). In 1987, domestic production ofpesticides was estimated at 32,000 tons per year(18).

The government and private industry share re-sponsibility for quality control, but compliance withregulatory policies is usually enforced only aftercomplaints from the field. Training programs forfarmers, distributors, and physicians are sponsoredby government and private industry, but monitoringof pesticide poisonings is sporadic. Imports arecontrolled through the issuance of import permits,and formulation, distribution, and sale of pesticidesis controlled through a licensing scheme (39).Residues in export crops are monitored regularly,following regulations imposed by the importingcountry (39).

Ecuador

In addition to enacting its own legislation in 1984,Ecuador has consented to implement guidelinesdealing with registration data and labeling agreed onby Latin American countries in the Andean region.FAO guidelines form the basis for data require-ments. Either government research organizations orprivate companies under government supervisionmust generate local efficacy data. Further, proof ofregistration in the country of origin and registrationin other countries is required (39).

There is little evaluation of data except forefficacy. Labeling is strictly evaluated, based on theguidelines agreed on by the Latin American coun-tries. Other organizations are looked to for guidance,among them FAO, WHO, EPA, the National Agri-cultural Chemicals Association, and the Interna-tional Group of National Associations of Manufac-turers of Agrochemical Products.

Photo credit: Amerkan Cyanamid

Worker spraying banana plants in Ecuador

All chlorinated compounds that accumulate in thefood chain are officially banned, but the governmentreserves the right to use them in cases of emergencywhen economical substitutes are not available (39).Parathion and toxaphene are two pesticides bannedin Ecuador, while DDT and methyl bromide areamong those restricted to specified uses. U.S. EPAregulations regarding banning and restrictions aresupposed to be closely followed (39), yet DDT,which has been banned by EPA for use in the UnitedStates, can be used in certain circumstances inEcuador.

Both government and private industry have qual-ity control programs. The Fundacion Natura (NatureFoundation), an environmental group, monitorscompliance with regulatory policies and reportsviolations to the government. Government inspec-tors are also assigned to monitor compliance. TheDepartment of Commerce and the Ministry ofAgriculture issue import permits, and there is alicensing scheme for formulation, distribution, andsale of pesticides.

Prior government approval is needed for anypesticide advertising, but there has been minimal


monitoring of residue on food and crops. A record ofany poisoning cases reported by hospitals is main-tained by the Ministry of Health. Government andthe private sector, as well as industry, have trainingprograms for extension workers, farmers, distribu-tors, doctors, and technical and sales representatives.

Kenya

In Kenya, the Pesticide Control Board Act wasimplemented in 1982, with regulatory authorityvested in the Pesticide Control Product Board. TheSpecialist Approval Committee for AgriculturalPesticides evaluates data generally, in accordancewith FAO guidelines. At present, there is noinformation available concerning labeling require-ments, no national residue tolerances, and no systemof pesticide classification, although WHO classifi-cation is being reviewed for possible adoption. Onlyregistered products can be imported and used, butthere are no restrictions regarding the availability ofthese products (39).

For the most part, quality control is left toindustry. Residue monitoring is not usually done,and there is no system in operation for monitoringpesticide poisoning cases (39).

INTERNATIONALNEUROTOXICOLOGICAL

RESEARCHActive interest in neurotoxicity began in the

United Kingdom during and after World War II.Since that time, research efforts in the United Stateshave gradually increased. The United States is nowthe world leader in environmental legislation and ingovernment funding of neurotoxicology research.Research in other countries has been narrower andmore specific. The Scandinavian countries havebeen active in research on the neurotoxicity oforganic solvents (73), and other European countrieshave supported research on compounds of particularconcern in occupational settings, such as pesticidesand heavy metals (16,36). In most cases, however,no systematic national effort has been undertakensimilar to that in the United States (2).

Several international conferences have taken placeduring the past 10 years on the subject of neurotoxi-cology, some of which were sponsored by EPA andthe National Institutes of Health. Two internationaljournals published in the United States, Neurotoxi-cology and Teratology and Neurotoxicology, were

Photo credit: Monsanto Agricultural Co.

Surveying the harvest, Kenya

established in 1979, and the Society of Toxicologyin the United States has a sizable subsection devotedto neurotoxicology. Outside the United States,sufficient interest has been generated in neurotoxi-cological issues that a new society, the InternationalNeurotoxicology Association, has been formed.This society held its first meeting in 1987, withattendance by approximately 200 scientists fromEurope and the United States. The first comprehen-sive text on neurotoxicology was published in 1980(52).

Major Directions of Academic, Industrial, andGovernment Research

In the past, research efforts were often initiatedfollowing industrial exposures that caused severehuman intoxications. For example, with the adventof the vulcanization of rubber, carbon disulfidepoisoning in workers in the rubber industry becamecommon in many European countries (71). With theintroduction of rayon, the manufacture of which alsorequired the use of carbon disulfide, poisonings dueto use of this solvent became a worldwide problem(68). Improvements in occupational hygiene havelargely eliminated cases of severe poisoning; never-theless, what has emerged instead is the problem ofchronic low-level exposures to this and other com-pounds. The development of human testing proce-dures to measure more subtle symptoms has beenlargely accomplished in Finland (49).

The toxicity of lead has been known sinceantiquity (51 ). Nonetheless, large-scale lead poison-ing continues to be an international public healthproblem because of lead water pipes, the use of

Chapter 9-International Regulatory and Research Activities . 257


lead-based paints, and the addition of lead togasoline. Much of the basic research involvinganimal models of lead toxicity was done in theUnited States (67). Using the diagnostic proceduresdeveloped for the detection of exposure to organicsolvents, Finnish researchers have demonstratednervous system damage in low-level occupationalexposures of adults to lead (49). Research into leadtoxicity is still supported enthusiastically in manycountries because of accumulating evidence thateven exposure levels previously considered harm-less (particularly in children) have been shown tohave adverse effects on health (ch. 9). This has ledthe WHO European Office to sponsor a multina-tional study of the effects of childhood lead intoxica-

tion. As of 1989, lead additives have been restrictedin the United States and in some parts of Europe.Thus, worldwide interest in lead toxicity continues,although outside the United States research is notsupported in a programmatic way by individualgovernments. It appears that this role has been takenover by international bodies such as WHO.

Another major environmental contaminant ismercury. Exposures to mercury in industrial settingshave been well described since the 19th century (34).Mercury became a public health problem because ofthe widespread use of organic mercury compoundsin agriculture as fungicides. The first major outbreakof methyl mercury poisoning occurred in Japan in1953 and was followed by outbreaks in many otherparts of the world, notably Iraq (see ch. 2). Japanesescientists have actively pursued research on themechanism of neurotoxicity of organic mercurycompounds (55). This was followed by a largeScandinavian (mostly Swedish) research effort be-cause of contamination of lakes by mercury runoff(19). U.S. investigators have been involved inmercury research since the Iraq episode, in 1971 to1972, and have examined such problems as theteratogenic effects of methyl mercury on the behav-ior of animals (17). Other metals that have beenstudied internationally include manganese, cad-mium, and the organotins.

Interest in the neurotoxicity of organic solventshas increased in recent years. Pioneering work inScandinavia was followed by mechanistic studies inthe United States (47) that revealed the relationshipbetween human symptoms and underlying biologi-cal alterations. Scandinavian workers have been thefocus of a number of occupational hazard studies. Arecent monograph entitled Organic Solvents and theCentral Nervous System was published jointly byWHO and the Nordic Council of Ministers (73). Thisdocument addresses the problems of occupationalexposures, the illness caused by these exposures,and the diagnostic procedures for identifying theillness. In 1988, the WHO-Nordic Council ofMinisters met to design the “definitive” study ofchronic effects of exposure to solvents on thenervous system of workers (75).

The widespread use of highly toxic pesticides hasled to intense worldwide research on the neurotoxic-ity of these compounds. In fact, the beginning of theenvironmental movement has been attributed to thepublication of Rachel Carson’s book Silent Spring,


which dealt with the ecological effects of indiscrim-inate pesticide application. The continuing develop-ment of new pesticides has caused the research effortto be sustained, not only to protect human popula-tions, but also to safeguard nontarget populationsfrom inadvertent exposure to these compounds.

One way to document international researchtrends is to summarize the distribution of researchpapers published by non-U.S. authors in the twointernational journals devoted to neurotoxicology.Table 9-1 indicates the various neurotoxic sub-stances investigated in papers published in twojournals between 1979 and 1987.

Heavy metals as a group clearly represent themajor area of interest. They are followed by organicsolvents, pharmaceutical agents, and pesticides.Since the two neurotoxicology journals are rela-tively new, one can assume that a large proportion ofneurotoxicological research has also been publishedin other journals. In addition, each of the non-English-speaking countries listed has journals in its ownlanguage, and researchers also publish in thosejournals. This is particularly true of scientists in theSoviet Union, who publish only infrequently inEnglish-language journals. Thus, while this surveyof published research outside the United States maynot be truly representative of international neurotox-icological research, it is probably a reasonableindicator of general trends in international research.

To gain another view of current research trends, itis useful to examine projects presented at the firstmeeting of the International Neurotoxicology Asso-ciation in the Netherlands, May 10-16, 1987. Themeeting was attended by 135 scientists from 21countries. The largest contingent came from theUnited States (23), followed by the Netherlands(20), West Germany (15), England (1 1), Italy (1 1),and all other countries (fewer than 10 each). Anexamination of their places of employment indicatesthat 37 percent of the attendees were from govern-ment laboratories, 37 percent from academia, 23percent from industry, and the remainder from avariety of institutions. Of the U.S. participants, 22percent were from government laboratories, 65percent from academia, and 9 percent from industry.An examination of the topics presented indicatesthat the trends outlined above have not changedmarkedly (table 9-2). Following tradition, 50 percentof the papers dealing with solvent toxicities camefrom Scandinavian countries.

Table 9-1-Neurotoxic Substances Investigated inPapers Published in Two International Journals,

by Country, 1979-87

Country Substances investigated (No. of papers)Canada

England

Italy

India

Japan

FranceMexicoFinland

Ethanol (3); manganese (2); cadmium (2); lead (2);pharmaceutical agents (2); acrylamide (1 ); zinc (1 );aluminum (1); herbicides (1); hydrogen peroxide (1);chlorinated hydrocarbons (1)Pyrethrins (7); pharmaceutical agents (7); or-ganophosphates (2); solvents (l); acrylamide (l);mercury (1); herbicides (1)Pharmaceutical agents (8); organophosphates (2);mercury (1); solvents (1); bismuth (1); caffeine (1)Manganese (4); organophosphates (l); lead (l);cadmium (1); solvents (l); sulfur dioxide (1); zinc(1); styrene (l); herbicides(1)Mercury (5); solvents (3); cadmium (l); pyrethron(1); pharmaceutical agents (1)Mercury (3); solvents (1); tellurium (l); lead (1)Solvents (6)Lead (4): solvents (4): ethanol (1)


Table 9-2-Subjects of Neurotoxicological ResearchPresented at a Major International Conference

Chemical Papers (No.)Insecticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8PCBs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Acrylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Methyl mercury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Styrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Carbon monoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Nitrous oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Pharmaceutical agents . . . . . . . . . . . . . . . . . . . . . . 4Experimental compounds . . . . . . . . . . . . . . . . . . . . 6SOURCE: Office of Technology Assessment, 1990.

One meeting may not represent a typical sampleof international research in neurotoxicology, but itprovides a useful example of current neurotoxicol-ogical research in the Western industrialized world.No researchers from the Soviet Union attended thismeeting; however, two individuals from EasternEurope, one each from Hungary and Czechoslova-kia, attended. The number of neurotoxicologists inboth of these countries is very small, as determinedby publications in the literature. For much of the restof the world, neurotoxicology as a discipline doesnot exist. There are some exceptions, however. Forexample, there are active researchers in Japan, India,China, and Argentina, with well-identified centersfor such research. Indian researchers have tradition-ally published in English, and this practice isbecoming increasingly common among Chineseresearchers as well. In addition, experimental re-


search on the neurotoxicity of the grass pea is nowunder way in Ethiopia.

Neuroepidemiology

International activities in neuroepidemiology havetaken place on all six inhabited continents. Neuroep-idemiologists in England are currently studying riskfactors for stroke and are investigating the epidemi-ology of multiple sclerosis. In Japan, epidemiologi-cal inquires into the etiology of neurodegenerativedisorders (including amyotrophic lateral sclerosis,Parkinson’s disease, Alzheimer’s disease) have beenundertaken. One country with a major effort inneuroepidemiology is Italy. Italian efforts in thisarea may be traced back to a series of courses onneuroepidemiology taught in 1979 by a group ofU.S. and Italian epidemiologists. The fruits of theseefforts have included major work in the epidemiol-ogy of dementia. More recently, WHO has begun aninternational initiative in the epidemiology of de-mentia. It is not clear, however, whether this workwill be extended to other neurodegenerative condi-tions. It is possible that some of these efforts will befocused on geographic isolates of neurologicalconditions, for example, the Faroe Islands andmultiple sclerosis, Guam and dementia, and Guamand amyotrophic lateral sclerosis. An internationalcollaboration to investigate the latter two phenom-ena is now forming and will likely begin its activitieswithin the next year (31 ).

International Cooperation

Neurotoxicological research has been primarilyan intranational effort. In recent years, some interna-tional cooperation has been initiated by WHO andthe U.S. National Toxicology Program, but thus farthis has occurred only in specific areas, such as leadtoxicity, solvent toxicity, and the development oftesting methodologies (74). The limited scope ofinternational cooperation is large] y due to the lack offunds available for such efforts.

Comparison of U.S. and ForeignResearch Programs

The neurotoxicity research effort in the UnitedStates is larger in depth and scope than that in othernations. Both leading books in this area were writtenby American authors and editors (4,52). Bothinternational journals in the field are published in theUnited States, and a review of the publishedliterature in neurotoxicology reveals that about 90

percent originates in the United States. The qualityof the work is generally considered to be excellent.As mentioned previously, other countries haveexcelled in some areas of research; this is particu-larly true with respect to the solvents researchconducted in Scandinavia. American research on themechanisms of toxicity of solvents is generallyconsidered to be outstanding.

Resources

The United States has a limited number ofdoctoral-level training programs in neurotoxicol-ogy. Because of its unique educational system, morescientific manpower is available in the United Statesthan in other countries. In most European countries,the standard educational program in the life sciencesis the medical degree, or the equivalent of the M.D.Consequently, almost all researchers in Italy, Scan-dinavia, and Germany are trained first as physiciansand then as researchers. These individuals mayeventually obtain a doctorate if they choose aresearch career. In countries such as Italy, whereresearch positions are very difficult to obtain, mostphysicians choose nonresearch careers rather thanrisk being unemployed. Although employment op-portunities are somewhat better in Scandinavia thanin Italy, it is still difficult to establish a researchcareer because of the scarcity of positions.

The success of the American research enterpriseis due not only to the relative availability of funding,but also to the manner in which the funds areadministered. Despite some inherent flaws, the peerreview system in the United States generally ensuresthat the best scientists in a given field obtainfunding. In many other parts of the world, researchis often supported by a system in which fundingdecisions are made solely by the director of aninstitute or the chairman of a department, withoutpeer review of the proposed research.

Future Directions

A recent review (1) listed 850 chemicals in theworkplace that may be neurotoxic. Apart from thesubstances listed in tables 9-1 and 9-2, most of thesechemicals have not been studied. The internationalchemical industry produces several thousand newchemicals every year, most of which are not testedfor neurotoxicity. Japan and France now requireneurotoxicity testing for new chemicals (53), butthese tests are elementary in nature and are likely tomiss more subtle and insidious toxic effects.


Photo credit: Jerry Deli

At present, the major classes of neurotoxicsubstances-heavy metals, solvents, and pesticides—have been identified. However, despite major re-search efforts, there is still no clear understanding ofthe mechanisms of toxicity of most of these chemi-cals. In order to protect human populations fromchronic low-level intoxication, it is essential tounderstand the properties and potential health ef-fects of new and existing chemicals. Because of theenormity of the testing task, a coordinated interna-tional approach would be highly beneficial.

Foreign Governments Likely To TakeLeadership Roles

In some European countries, notably West Ger-many and Sweden, environmental movements arebecoming increasingly influential. It is likely thatthese nations will play leading roles in supportingresearch and in developing regulations to controltoxic substances. The Federal Republic of Germanyhas already acted to remove lead from gasoline andto fund studies of lead toxicity in children. As

outlined above, all of the Scandinavian countries(Sweden, Denmark, Norway, and Finland) havetraditionally supported research on solvents. Thesepatterns are likely to continue and may broaden tothe investigation of other agents as environmentalmovements grow. Political events in the SovietUnion have led to the emergence of an environ-mental movement, and it appears that the Sovietgovernment will also take a more active role in theseissues. In the Far East, both the People’s Republic ofChina and Japan are faced with major pollutionproblems and are becoming increasingly involved intoxicological issues.

SUMMARY AND CONCLUSIONS

Like most environmental concerns, neurotoxicityis a problem not limited by national boundaries.Pollutants can readily cross national borders, haz-ardous chemicals are frequently imported and ex-ported among both industrialized and developingnations, and adulterated food and commercial prod-ucts enter the United States despite current regula-tory efforts. Strategies to limit human exposure toneurotoxic substances should be devised in thecontext of both national and international regulatoryand research initiatives.

Despite numerous regulations governing the ex-port and import of neurotoxic chemicals and prod-ucts containing them, most countries do not ade-quately protect human health and the environmentfrom these substances. Most industrialized nationshave policies and procedures in place to regulate theimport, distribution, and use of toxic chemicals,implicitly including neurotoxic substances. Somedeveloping nations have limited regulations toprotect workers and consumers from the adverseeffects of neurotoxic substances. Developing na-tions that do have regulations often do not have theresources to enforce them. Developing countries useonly 10 to 25 percent of the world’s pesticides, butthey account for as much as 50 percent of the acutepoisonings of pesticide applicators and between 73and 99 percent of their deaths. This lack of effectiveregulation and enforcement in developing nationshas a negative impact not only on public health andenvironment in the user country, but also in industri-alized nations, including the United States, wherepeople process and consume pesticide-treated cropsimported from developing nations.

Chapter 9-Internatioral Regulatory and Research Activities ● 261

Both TSCA and FIFRA contain provisions ex-empting certain products produced for export fromthe requirements that apply to products sold for usein the United States. In most instances, TSCArequirements do not apply to substances manufac-tured, processed, or distributed for export. Therequirements do, however, apply if it is determinedthat the substance will present an unreasonable riskof injury to public health or the environment withinthe United States. In addition, because pesticidesintended solely for export are exempt from thepublic health protection provisions of FIFRA, pesti-cide manufacturers can legally export banned, se-verely restricted, or never registered substances thathave been deemed too hazardous for use in thiscountry. Companies that do so are required to notifythe importing country that the exported pesticideshave been banned, severely restricted, or neverregistered for use in the United States. Some suchpesticides are used on food crops that are importedback into the United States for consumption. Criticsof this practice have termed it the ‘circle of poison.

On January 15, 1981, several days before the endof his term, President Jimmy Carter issued anExecutive Order which put controls on exports ofsubstances that were banned or severely restricted inthe United States. Several days after Ronald Reaganbecame President, he revoked the order.

While pesticides may be needed to obtain suffi-cient food to feed the ever-increasing world popula-tion, many observers argue that ample food suppliesare currently available and that better distribution ofexisting food stores is necessary. Responsible con-duct on the part of persons who manufacture,distribute, and use pesticides is mandatory if irre-versible harm to world public health and the worldenvironment is to be minimized. Education andliteracy levels of persons handling pesticides mustbe considered and appropriate information tailoredto their needs. Regulations currently in place must beadhered to and new legislation enacted when theneed arises. Alternative methods of pest controlshould be investigated and developed. Cooperativeefforts on the part of governments in industrializedand developing countries, industry, environmentalgroups, and other international organizations arenecessary to ensure the safety of the world commu-nity.

Active interest in neurotoxicity began in Englandduring and following World War H. Since that time,

efforts in the United States have gradually increased.Today, the United States is the world leader inenvironmental legislation and government fundingof neurotoxicological research. The Scandinaviancountries have been active in research on theneurotoxicity of organic solvents. Other Europeancountries have supported research on compounds ofparticular concern in occupational settings, such aspesticides and heavy metals.

International research activities tend to focus onthe heavy metals (lead and mercury), organicsolvents, and pharmaceutical agents. Foreign neuro-toxicology-related scientific papers published ininternational journals most often originate fromauthors in Canada, England, Italy, Australia, andJapan. A number of papers originate from authors inFrance, India, Sweden, Finland, and Mexico, aswell.

International cooperation in the neurotoxicologyfield is very limited. Neurotoxicological researchhas been primarily an intranational effort. In recentyears, some international cooperation has beeninitiated by WHO and the U.S. National ToxicologyProgram, but thus far this has only occurred inspecific areas, such as lead toxicity, solvent toxicity,and the development of testing methodologies. Thelimited scope of international cooperation is largelydue to the lack of funds available for such efforts.

In some European countries, notably the FederalRepublic of Germany and Sweden, environmentalmovements are becoming increasingly influential. Itis likely that in the future these governments willplay leading roles in supporting research and indeveloping regulations to control toxic substances.The Federal Republic of Germany has already actedto remove lead from gasoline and to fund studies oflead toxicity in children. All of the Scandinaviancountries have traditionally supported solvent re-search. This will likely continue and may broaden toinclude the investigation of other agents as environ-mental movements grow.

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71.

72,

Weir, D., The Bhopal Syndrome: Pesticide Manufac-turing and the Third World (Penang, Malaysia: 73.International Organization of Consumers Unions,1986).Weir, D., and Schapiro, M., Circle of Poison:Pesticides and People in a Hungry World (San 7 4 .Francisco, CA: Institute for Food and DevelopmentPolicy, 1981).Wood, R. W., “Neurobehavioral Toxicity of Carbon 75.Disulfide,” Neurobehavioral Toxicology and Tera-tology 3:397-405, 1981.World Bank, Poverty and Hunger: Issues andOptions for Food Security in Developing Countries

(Washington, DC: 1986).World Health Organization, Organic Solvents andthe Central Nervous System, Report on a JointWHO/Nordic Ministers Working Group (Copen-hagen: 1985).World Health Organization, Principles and Methodsfor the Assessment of Neurotoxicity Associated WithExposure to Chemicals (Geneva: 1986).World Health Organization, “Chronic Effects ofOrganic Solvents on the Central Nervous System—Development of Core Protocol for InternationalCollaborative Study,” meeting in Copenhagen, Den-mark, Nov. 15-18, 1988.

Chapter 10

Case Studies: Exposure to Lead,Pesticides in Agriculture, and

Organic Solvents in the Workplace

“If we were to judge the interest excited by any medical subject by the number of writings to which it hasgiven birth, we could not but regard the poisoning by lead as the most important to be known of all those thathave been treated up to the present time. ”

M.P. OrfilaA General System of Toxicology

1817

“mere is . . . no systematic monitoring of the health or exposure to pesticides of the more than 2 millionfarmworkers, applicators, harvesters, irrigators, and field hands who work around pesticides. Industrialworkers who produce these pesticides receive the benefits of such monitoring. ”

National Academy of SciencesAlternative Agriculture

1989

“When I was in the Navy, I remember my commanding officer called me in and he was very upset becausean air control operator had abandoned the tower, his position of duty, with seven aircraft stacked up callingfor landing instructions. I was supposed to examine him. As I look back, I completely missed what was

happening until years later. He was working in his off hours loading pesticides into spray planes, which causeda tremendous change in his personality and his behavior and his ability to cope. ”

Gordon Baker, M.D.Testimony before the Committee on Environment and Public Works

U.S. SenateMarch 6, 1989

t< ..+ doctors tell me my nervous system has been heavily damaged, my brain has been damaged, and I sufferchemically induced asthma. I also have kidney, liver, and vision difficulties. I had a tumor removed from myeyes less than 1 year ago, and have been told that I have more, not to mention the chronic muscle painsthroughout my body . . . . Throughout my entire 8 years at this truck manufacturing company, I was neverinformed of the hazards of the solvents I used, None of these products were adequately, clearly, or should Isay, truthfully labeled. Yet the hazards for most of the products had been known for years by the chemicalmanufacturers and other people.

Frank CarsnerTestimony before the Committee on Science and Technology


CONTENTSPage

INTRODUCTION .. .. .. .. .. .. .. .. .. ... .+. ......+ .. .. .. .. .. .. ”” .0 +. ”O”. sD”o+QIo. 267ExPOSURE TO LEAD . . . . . . . .. .. .. .. .. .. .. .. .. ..+. ... +....”+ ..+~’”0+”””+’~~o+T” 267

Sources of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . ......”””””””..”””~”””o”Qo ““+0”+0”~ 268Routes of Exposure . . . . . . . . . . . . . . .. .. .. .. .. .+ .. ... ... ..+..... ..”+++~n....o+o.+. 269Levels of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .+ .. ~.. .. ””.””.”. “++” ~~~Effects of Lead on the Human Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Regulatory Activity Regarding Exposures to Lead. .. .. .. ... ... .....+. ,.......~.. 273Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .+ .. ”~. ”+. ~.. .o.’~. + 281

EXPOSURE TO NEUROTOXIC PESTICIDES IN AGRICULTURE . . . . . . . . . . . . . . . . 281Extent of Exposure of Agricultural Workers .. .....................++. ... .......+ 283Documented Adverse Effects on the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283Federal Regulation .. . .. .. .. .. ...+.... . . . . . . . . . . . . . . . . . ......”...”.””... ‘.””.”.. 285State Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . .. ................+.. “..+...o.”s.”s. 289Examples of Neurotoxic Pesticides .. .. .. +. . . . . . . . . . . . . . . .. .............++.. .“+.+ 290Summary and Conclusions . . . . . . . . . . . . . . . . . . . .. .. .. .. .. . .. .. ... ..”..++ ...”.++... 295

EXPOSURE TO ORGANIC SOLVENTS IN THE WORK PLACE . . . . . . . . . . . . . . . . . . 296Uptake, Distribution, and Elimination of Solvents .. .. .. .. *. .. .. C. ... .+. .+...+. . . . 298Neurological and Behavioral Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .?. ... ..+....” 298The Solvent Syndrome: A Current Controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299Health Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..............+”...~”.+..+ ● +.. 300OSHA Regulations . . . . . . . . . . . . . . . . . . . .. ........,....”..+.. .....+.”.+.”~~..00.. 301Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........,.~””.”...””.. 304

CHAPTER 10 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...* 304

BoxesBox Page

10-A. Lead: A Historical Perspective .. .. .. .. .. .. ... .. .+....... ..........+..”””~+”~ 268IO-B. Lead Poisoning and IQ . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .+ .. .. .. ... ... ,.. .,*.o 27310-C. State Wad Poisoning Prevention Programs . . . . . . . . . . . . . . . . . . . .. ..........9+.. 27810-D. Lead in Water Coolers . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .+ ... ... ......+” ~...~.~.. 28010-E. Pesticides in Food .. .. .. .. .. .. .+ . . . . . . . . . . . . . .. .. .. .. . .. .+ .. ... .. ”..+”.”. f++ 2$210-F. Organic Farming and Alternatives to Chemical Pesticides .. ................,.+ 29110-G. Engineering Controls v. Personal Protective Devices . . . . . . . . . . . . . . . . . . . . . . . . . 301

FiguresFigure Page. . . . . . .10-1.10-2.10-3.10-4.10-5.10-6.

Table1o-1.10-2,10-3.10-4.

10-5.10-6.

eChildren’s Blood Lead Levels Considered Acceptable by Various Agencies . . . . .Adverse Health Effects of Lead . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .+ +. ... ... .~~.”..Lead Used in Gasoline Production and Average Blood Lead Levels . . . . . . . . . . . .Dietary Lead Intake .. .. . .. . .. .. ..+. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~a”+~~”+Food Can Shipments .. .. .. ... ..+. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Classes of Organic Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .cO. .9+. .40t.

Tables

Significant Sources of Exposure to Lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Estimated Number of Children Exposed to Sources of Lead . . . . . . . . . . . . . . . . . . .Organophosphorous and Carbamate Insecticides . . .. .. .. .. . .. .+. . . . . . . . . . . .+..Neurotoxic Effects of Acute Exposure to High Levels of Oganophosphorous orCarbamate Insecticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... +......Organochlorine Insecticides . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .. ~. .+ ... +. ”......+.Representative Exposure Limits to Solvents . . . . . . .. .. .. .. .. .. ... ~.. ....+... .-.

271272275275275297

Page269269292

294294303

Chapter 10

Case Studies: Exposure to Lead, Pesticides in Agriculture,and Organic Solvents in the Workplace

INTRODUCTIONThe best way of illustrating the adverse effects of

toxic substances on the nervous system is by lookingat substances or classes of substances that are knownto be neurotoxic. These case studies discuss attemptsto control human exposure to lead, pesticides, andorganic solvents. They illustrate the prevalence ofneurotoxic substances, the susceptibilities of certainsubpopulations, special hazards in occupationalsettings, and how Federal agencies address theseconcerns.

As it exists in the earth, lead is bound in chemicalcompounds and presents little risk to humans. As itis mined and utilized, however, it is distributedthroughout the environment, presenting a risk to theentire population, but especially children, who aremost vulnerable to its effects. Research shows thatchildren are directly exposed to multiple sources oflead, are more sensitive to exposure, and sufferworse effects than adults. A great deal of progresshas been made by Federal agencies in reducingpublic exposure by regulating the lead contents ofpaint, gasoline, plumbing systems, and food contain-ers, but lead poisoning continues to be a majornational health problem.

Chemical pesticides also present a significant riskto the population as a whole, but especially toagricultural workers and others who apply them orwork close to them. Several Federal agencies haveregulations that are intended to protect these workersfrom pesticide poisoning, but critics argue that morecould be done. Many States have their own regula-tions, some of which are more stringent than Federalregulations, especially in protecting farmworkers.This chapter reviews the different types of pesticidesin use and summarizes what is known about theirneurotoxic effects.

Many solvents are neurotoxic and threaten thehealth of the industrial workers who come in contactwith them. Solvents may cause a variety of func-tional changes, ranging from temporary memoryloss to unconsciousness, depending on the durationand extent of exposure; major structural changes inthe nervous system may also result. Engineeringcontrols to avoid contamination, isolation of work-

ers, and issuance of protective equipment to workersare some of the preventive measures currently in use.This chapter gives examples of how various solventshave been regulated under the Occupational Healthand Safety Act, including the new standards forworker protection proposed by the OccupationalHealth and Safety Administration in 1988. It dis-cusses criticisms of the existing regulations andoffers suggestions as to how they might be im-proved.

EXPOSURE TO LEADAs discussed in previous chapters, regulation of

neurotoxic substances is a two-part process, onebeing identification of new hazardous chemicals andprevention of human exposure to them, the otherbeing reduction of exposure to existing toxic sub-stances. Lead is a prominent example of a substancelong known to be toxic to the human nervous system(see box 1O-A). Unlike some elements, such assodium or zinc, lead serves no useful biologicalpurpose; since the body can neither use nor metabo-lize it, lead accumulates in body tissues, especiallybones and teeth. Debate continues as to whatmaximum level is tolerable, although the only wayto prevent any toxic accumulation is to limitexposure to zero. This chapter highlights some of thedifficulties of removing or preventing exposure to aneurotoxic substance that has been extensively usedin industry and therefore is especially prevalent inthe environment.

Efforts to reduce public exposure to lead byremoving current sources and preventing new oneshave been undertaken by several Federal agencies.The Environmental Protection Agency (EPA) andthe Food and Drug Administration (FDA) havetaken steps to reduce the amount of lead in gasolineand food, and EPA is currently considering morestringent methods for controlling exposure to leadfrom drinking water. Other sources of lead, however,are more difficult to control. Lead has been usedconsistently in industrial and commercial activitiesand, despite awareness of its inherent dangers,continues to be used in product manufacturing. Theuse of lead in manufacturing ultimately results in itsdistribution in the environment in the form of waste.

–267-


Box 10-A—Lead: A Historical Perspective

Lead is the oldest, most extensively studied, and probably most ubiquitous neurotoxic substance. It ismentioned in ancient Egyptian manuscripts and was used by the Egyptians as a cosmetic; both the Egyptians andthe Remans used lead in cooking tools and vessels. The Remans used it as a sweetener and preservative in winesand eiders; lead acetate is often called “sugar of lead” because of its sweet taste. The Remans also used lead inbuilding houses and transporting water. In fact, the words plumber and plumbing originate from the Latin word forlead, plumbum. Lead was mined in Great Britain as far back as the reign of Julius Caesar. Remnants of these minescontaminate local farms and gardens today.

At least some of the toxic effects of lead were known early on. The Greek thinker Dioscorides stated in the2nd century B.C. that “Lead makes the mind give way.’ Pliny the Elder cautioned that inhaling the fumes of moltenlead was dangerous (although he continued to recommend that it be used in making wine). Indeed, the continueduse of lead, despite recognition of its dangers, has caused many outbreaks of lead poisoning over time. BenjaminFranklin may have been the first person to recognize lead as an occupational hazard: in a letter about lead poisoninghe wrote, “How long a useful truth may be known and exist, before it is generally receiv'd and practis’d on.”

SOURCES: A. Fischbein, “Environmental and Occupational Lead Exposure, ” Environmental and Occupational Medicine, W.N. Rom (cd.)(Boston, MA: Little, Brown, 1983); J.S. Lin-Fu, “Lead Poisoning and Undue Lead Exposure in Children: History and currentStatus,’ Low Level Lead Exposure: The Clinical lrnplications of C“urrent Research, H.L. Needleman (cd.) (New York, NY: RavenPress, 1980); R.H. Major, ‘‘Some Landmarks in the History of bad Poisoning, “ Annals of Medical History 3:218-227, 1931; H.L.Needleman and D. Bellinger, “The Developmental Consequences of Childhood Exposure to Lead: Recent Studies andMethodological Issues,’ Advances in Clinica/ Child Psychology, vol. 7, B,B. Lahey and A,E. Kazdin (eds.) (New York, NY: PlenumPress, 1984); H. Waldron, “kad Poisoning in the Ancient World,” Medicaf History 17:391-398, 1973.

For example, lead is found in commodities such as sources of exposure to inorganic lead include water,solders, batteries, and paint, but it is also present indust and soil as waste material. There is noagreement as to who bears responsibility for remov-ing the various forms of lead from the environment.Although the Consumer Product Safety Commis-sion has reduced the amount of lead permitted inpaint to prevent future exposure, the danger of leadpoisoning from leaded paint in old housing remains.

In addition to the remedial measures being taken,preventive measures must be considered for somecurrently minor sources that may become largerproblems in the future, Incinerators, for example,may significantly increase exposure to lead in theenvironment as we attempt to reduce our reliance onlandfills.

Sources of Exposure

Lead exists in both organic and inorganic forms.Although organic lead is more toxic than inorganiclead because it degrades quickly in the atmosphereand the body, it constitutes only a small proportionof the total lead to which the population is exposed(16). Organic lead is most commonly found as a fueladditive and can reach significant levels in heavytraffic areas and underground garages (16), but it israpidly converted to the inorganic form. This chapterwill therefore focus on inorganic lead. Significant

food, soil, lead-based paint, leaded gasoline, andindustrial emissions (see table 10-1).

Levels and sources of exposure vary according tosurroundings. In remote areas, proximity to station-ary sources of lead such as smelters maybe the mainsource of exposure, whereas in older cities leadedpaint may be the most common source (165).Individuals living near industrial sources of lead,people who drink contaminated water, adults withoccupational exposure, and children who ingestlead-contaminated paint, soil, or dust have thegreatest exposure to lead (109,172).

When discussing exposure to lead, a distinction isoften made between children and adults, sincechildren both ingest and inhale more lead perunit of body weight than adults and are morevulnerable to its effects (165). Children, given theirnormal tendency to put things in their mouths, arelikely to ingest paint, soil, or dust, all of which arepotential sources of lead. Lead gives paint a sweettaste, increasing its appeal for children. Childrenalso have a higher absorption rate of ingested leadthan adults: whereas adults absorb between 5 and 15percent of ingested lead and usually retain less than5 percent of what is absorbed, one study found thatinfants on regular diets absorb an average of over 40percent of ingested lead and retain over 30 percent

Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 269

Table 10-l Significant Sources of Exposure to Lead

Leaded paint. lead released into the air through destruction and weathering of

structures painted with leaded paint● lead ingested by children from household dust, less commonly

by eating leaded paint chipsLeaded gasoline. lead released into the air in exhaust fumes. lead released into the air during fuelingStationary sources. lead released into the air by industrial activity, e.g., smelting,

refining, and battery recycling. occupational exposure of factory workers, exposure of children

to lead on the clothing of parentsDust, soil. paint. industrial activity. gasolineWater, plumbing. lead in water source. leaching from lead pipes. leaching from lead solder. leaching from brass or bronzeFood. lead contained in food items from contaminated water or soil. lead-soldered food cans● lead deposited on crops from automobile exhaust. lead deposited on crops from industrial activity● lead contamination during food processing. lead glazes in dishes and potterySOURCE: Office of Technology Assessment, 1990.

of that amount (57). Children also retain more of thelead they absorb than do adults, since lead in bloodis stored in growing bones (165). The effects of leadon children are more severe than the effects of leadon adults: children have less bone tissue in whichlead can be stored, and thus lead remains in thebloodstream, free to exert toxic effects on variousorgans of the body. Nutritional deficiencies, morelikely to occur in the growing child, can alsocontribute to higher absorption levels of lead (165,169).Children’s nervous systems, especially their blood-brain barriers, are not yet fully developed, and thesame cellular lead exposure may produce dispropor-tionate results in children compared to adults (84,145).Also, cognitive effects occur at lower levels inchildren. For similar reasons, fetuses may be evenmore vulnerable to lead’s toxicity than children (84).There is some evidence that lead stored in women’sbones from previous exposure may be mobilizedduring pregnancy and lactation, and thus expose thefetus and infant through the placenta and breast milk(148).

Estimates of the number of children exposed tolead, listed by source, are found in table 10-2. The

Table 10-2-Estimated Number of ChildrenExposed to Sources of Lead

Number of childrena

Source (millions)

Leaded paint . . . . . . . . . . . . . . . . . . . . . . . . . . 12.00Leaded gasoline . . . . . . . . . . . . . . . . . . . . . . . . 5.60Stationary sources. . . . . . . . . . . . . . . . . . . . . . 0.23Dust, soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.90-11.00Water, plumbing . . . . . . . . . . . . . . . . . . . . . . . . 10.40Food . . . . . 0 . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.00~umbers in the table are not additive since children are usually exposed

to multiple sources of lead in the environment.

SOURCE: U.S. Department of Health and Human Services, Public HealthService, Agency for Toxic Substances and Disease Registryand Center for Environmental Health and Injury Control, “Child-hood Lead Poisoning—United States: Report to the Congressby the Agency for Toxic Substances and Disease Registry,”Morbidity and Mortality VMsek/y Report 37:4S1-4S5, 19S8.

type and availability of data for each of these sourcesvary considerably, therefore the estimates are notcomparable and cannot be used to rank the severityof the problem by source of exposure (165).

For adults, the workplace is a major source ofexposure. The National Institute for OccupationalSafety and Health has listed 113 occupations thatpotentially increase workers’ exposure to inorganiclead (74). In adults not exposed to occupationalsources of lead and in children older than 6 to 8years, food and water are most likely to be the majorsources (74). For most adults, lead in the air is nolonger as significant a source of exposure as lead inthe diet, but as one study found, levels of lead in theblood of adults remain correlated with levels of leadin air (74), as do levels of lead in children’s blood(15). Before the phase-out of lead from gasoline,however, airborne lead was the predominant sourceof exposure to lead for adults and children (6,173,175).

Routes of Exposure

Lead can enter the human body through threeroutes: inhalation, ingestion, or absorption throughthe skin, although the latter is significant only fororganic compounds of lead (51). Intake throughinhalation depends on particle size and volubility inbody fluids (51). Gastrointestinal absorption isinfluenced by a number of factors, primarily age andnutritional status (72). The proportion of leadabsorbed through ingestion and inhalation differs byage and principal source of exposure, as discussedearlier.


Levels of Exposure

Lead is stored in the circulating blood, soft tissue,and bone. Because it has a long biological half-lifeand is only slowly excreted from bone, lead canaccumulate in the body. Thus, the concentration oflead in the blood (the blood lead level) is not anaccurate indicator of total exposure to lead, only ofrecent exposure. The amount of lead found in teethand bones is a more useful indicator of cumulativeexposure, but it yields no information about the timeor duration of exposure, nor of current exposure.Furthermore, teeth are easily obtained only fromyoung children, who lose their baby teeth. A

technique using X-ray fluoroscope was developed in1984 to measure lead in bone (28,77); its feasibilityas a testing method is being evaluated (186).

For the most part, neurological deficits in adultshave not been noted below a blood lead level of 40micrograms of lead per deciliter of blood (ug/dl)(192), although elevations in blood pressure havebeen noted at 5 ug/dl (125, 126, 144). In children,however, adverse neurological effects are seen atmuch lower levels (33,87,165), and since 1943 theblood lead level found to be associated withneurobehavioral dysfunction has steadily de-creased. Before that year, the cumulative effects of


EPA has estimated that exposure to lead in drinking water is keeping more than 240,000 children from realizing theirfull intellectual potential.


lead poisoning went unrecognized, and physiciansgenerally believed that if a child did not die of leadpoisoning there would be no lasting effects (1 18). In1943, however, researchers found that a group ofchildren with mild lead poisoning in infancy did notprogress satisfactorily in school, and they suggestedthat lead poisoning early in life might be widespread(22). Since then, the aggregate effects of leadpoisoning have been recognized and its long-termeffects have been studied. Researchers have corre-lated blood lead levels with neurobehavioral dys-function.

Before the 1960s a blood lead level below 60ug/dl was not considered dangerous (169). In 1975,the Centers for Disease Control (CDC) lowered theacceptable level for children to 30 ug/dl, and in 1985it lowered the level again, to 25 ug/dl (169). TheWorld Health Organization (WHO), in a 1986report, stated that 20 ug/dl was the upper acceptablelevel (193). EPA% Clean Air Scientific AdvisoryCommittee associated lead levels of 10 to 15 ug/dland possibly lower with adverse effects (see figure10-1) (172) and recommended 10 to 15 ug/dl asthe maximum acceptable level. Recently, subtledeficits in neurobehavioral performance have beenreported in fetuses and newborn babies exposed tolow levels of lead (12,33,87,121,165).

In 1986, Congress requested that the Agency forToxic Substances and Disease Registry (ATSDR)prepare a report on lead poisoning in children. Oneof the report’s mandates was to estimate the totalnumber of children exposed to potentially hazardousconcentrations of lead. Approximately 2.4 millionU.S. children age 6 months to 5 years living inStandard Metropolitan Statistical Areas (SMSAs)(or 17.2 percent) have blood lead levels greater than15 ug/dl; 200,000 (1.5 percent) have blood leadlevels greater than 25 ug/dl. No economic stratumof children was found to be free from thepotential health risk of lead poisoning. However,since the data covered only black and white children,no reliable prevalence rates could be calculated forHispanic children and children of all other races;further, since SMSAs include only about 80 percentof the children in the United States, the actualnumber of children with blood lead levels above15 ug/dl may be higher than the ATSDR reportindicates: more likely estimates are between 3and 4 million affected children (21.4 to 28.6percent) (165). The CDC is considering loweringits target level for medical intervention again.

Figure 10-l- Children’s Blood Lead LevelsConsidered Acceptable by Various Agencies

Blood lead level (ug/dl)35

CDC3 0 -

2 5 -

2 0 -

1 5 -

1 0 -

5 -

WHO

EPA

1975 1985 1986 1986Year level set or recommended

= 10 to 15 ug\dl IS the recommended maximum acceptable level.


It is significant that some of the studies onchildren have not detected a threshold for adverseeffects of lead (87,117,123), indicating that as testsfor various impairments become more sensitive, thelevel at which adverse effects are observed maydecrease further. Accurate, current information asto the lowest blood lead levels associated withneurotoxic effects is crucial for policymaking,since the regulations that set safety levels at 25ug/dl do not adequately protect the many chil-dren whose blood lead levels fall below that; thesechildren may be endangered at levels of 10 to 15ug/dl, or possibly lower.

Effects of Lead on the Human Body

Lead causes numerous adverse health effects. Asummary of some observable effects and the bloodlead levels with which they have been correlated isgiven in figure 10-2. In children, brain damageresulting from exposure to lead can range in severityfrom inhibited muscular coordination to stupor,coma, and convulsions at high levels (72). Acutebrain damage is rare in adults; when it appears it isusually a result of high exposures to lead and is oftenaccompanied by other factors, such as alcoholism.High exposures to lead can also damage the periph-eral nervous system.

Since the discovery of chelation treatment, whichremoves lead from the blood, mortality from acutelead poisoning has declined. Yet as our ability to


Figure 10-2-Adverse Health Effects of Lead

Lowestobserved Brain, Pregnant

effects of lead nervous woman or Red blood(ug/dl)

Cardiovascularsystem fetus Kidney cells system

100

90

80

70

60

50

40

30

20

10

rClinical signsof brain injury

Nervedysfunction

DecreasedI.Q.

Alteredperformance onneurobehavioral

tests

i?

TPregnancy

complications

1

Chronicneuropathy

I

IHeartinjury

1

1-Anemia1

1-Reduced

heme synthesis

T IByproductsof heme in

Premature Impaired blood and urinebirth vitamin D I

tDecreased

growthi?

synthesis

7 LEnzvme

inhibition1?

TElevated

blood pressure

I?

o

SOURCE: U.S. Environmental Protection Agency, “Drinking Water Regulations; Maximum Contaminant Level Goals and National Primary Drinking WaterRegulations for Lead and Copper; Proposed Rules” (53 FR 31565), 1966.

detect subtle neurological deficits has improved, Chronic low-level exposure may ultimately be moreestimates of morbidity have increased. Effects of damaging than acute exposure that is treated imme-permanent damage to the central nervous system— diately (21).for example, mental retardation, hyperactivity, sei-

Factors such as genetic variation in susceptibility,zures, optic atrophy, sensory-motor deficits, andbehavioral dysfunctions-have been observed (see nutritional status, behavior, and age may alter an

box 10-B). There is also some recent evidence thatindividual’s vulnerability to lead poisoning (1 18).Most of these factors affect toxicity by altering the

lead may cause minor hearing impairments (146). absorption of lead.

Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace .273

Box IO-B—Lead Poisoning and IQA study in 1979 found that children exposed to Cumulative frequency distribution (%)

lead had intellectual, attentional, and behavioral deficits, Italso found a difference of about 5 points in the mean IQ 100

(intelligence quotient) of children with elevated lead levelsand those with low lead levels. While this number is 90-

statistically significant, some question was raised as towhether it was biologically significant. 80-

As the figure shows, the significance of this difference in 7O

IQs shows up most clearly at the ends of the IQ spectrum. I High lead

Children with elevated lead levels were three times more 60 \likely to have a verbal IQ below 80; furthermore, none of 50

them had superior IQ scores (greater than 125), while 5 — Low leadpercent of the children with low lead levels had scores in that 40range.

30A follow-up study published in January of 1990 concluded

that the effects of lead exposure upon cognitive development 20in early years persist into early adulthood. In this study,children who were originally examined in the first grade

10-

were reexamined as high school students. The subjects ounderwent extensive neurobehavioral analysis using a vari- 50 60 70 80 90 100 110 120 130 140ety of tests for hand-eye coordination, grammatical reason- Verbal IQ

ing, and reaction times. Deficits in central nervous system functioning resulted in poorer classroom performance,reduced vocabulary and reasoning scores, and higher absentee rates in school.

SOURCES: H,L. Needleman, C. Gunnoe, A, Leviton, et al., “Deficits in Psychologic and Classroom Performance of Children With ElevatedDentine bad hvels,” New England Journaf of Medicine 300:689-695, 1979; H.L, Needleman, A. hviton, and D. Bellinger,“Lead-Associated Intellectual Deficit,” New EnglandJournal of Medicine 306:367, 1982; B. Weiss and ‘EW, ClarkSon, “’IbxicChemical Disasters and the Implications of Bhopal for Technology Transfer,” The Milbank Quarterly 64:216, 1986. H.L.Needleman, A. Schell, D. Bellinger, et al., ‘‘The Imng Term Effwts of Exposure to Low Doses of Lead in Childhood,’ New EnglandJournal of Medicine 322(2):83-88, 1990.

Regulatory Activity Regarding Exposures gasoline and stationary sources, such as lead smelt-

to Lead ers.

Action by Congress and various executive agen- In 1978, EPA promulgated regulations stating thatcies has led to a reduction in exposure to lead in the the level of lead in the air must not exceed 1.5United States. Their response marks the first time micrograms per cubic meter (ug/m3). Under thethat specific neurobehavioral effects of a toxic Clean Air Act, the States had to take steps to meetsubstance were considered in determining regula- that standard by 1982. The standard includes contri-tory policy. Although progress has been made, butions from both automobiles and industrial sourcesthere is evidence that lead poisoning in the United and was designed to prevent children from beingStates still occurs in epidemic proportions. exposed to concentrations of lead in the air that

could lead to blood lead levels of more than 30 ug/dlLead in the Air (96).1

Removing lead from the air is the responsibility of In 1973, EPA promulgated regulations requiringEPA, whose statutory authority comes from the that major gasoline dealers sell at least one grade ofClean Air Act, passed in 1970 and amended in 1977. “unleaded” gasoline (defined as containing noThe two major sources of lead in the air are leaded more than 0.05 gram of lead per gallon of gasoline).

lme r~ornrncndcd rn~imurn for children’s blood lead levels has been repeatedly revised: EPA Science Advisory Bowd establlslm.1 10 to 15 W@and possibly lower as the blood lead level of concern in 1986 (173).


Lead in Food

Regulation of lead in food is the responsibility ofFDA. Although the agency has set acceptable levelsof lead for pesticides and food utensils in domesti-cally produced food, much of its activity has focusedon eliciting voluntary cooperation from domesticfood manufacturers and processors (165). The suc-cess of this effort is illustrated in figure 10-4.

Regulation of lead by FDA began in the 1930s,when the agency established guidelines for limits onthe use of lead in pesticides.2 The next item ofconcern was lead in canned evaporated milk. In1974, the agency proposed a tolerance level of 0.30part of lead per million parts of milk (ppm) (39 FR

-H I!iil—-.— .—- . .

HB------- .-~..+

.4

iiiiii/ iijiiij

.“.~,,”

..”.

. - .-. ‘?. -:


zCurrent permissible levels of lead in pesticides are 1 microgram per gram (u~g) on citrus fruits and 7 qzJg on otier fi~ and veget~les.


Figure 10-3-Lead Used in Gasoline Production andAverage Blood Lead Levels

Total lead used per Average blood lead6-month period (thousands of tons) W levels (ug/dl) (=)

““~1”1 1 0 -

Lead used100- In gasollne

+

/9 0 - Averageblood

lead levels8 0 -

0

7 0 -+

1 16

15

50 J*

~ 10

~ ~40 ‘–--1—9-7–6---T

—1 977 ‘T 1978 11 9

1 9 7 9 1 9 8 0

Yeal

SOURCE: J. Schwartz, H. Pitcher, R. Levin, et al., Costs and 8er?efits ofReducing Lead in Gasoline: Final Regulatory Impact Analysis,EPA-230-05-85-O06 (Washington, DC: U.S. Government Print-ing Office, 1985).

Figure 10-4-Dietary Lead Intake

Average lead intake (ugtday)100 I I

9 0 - -

8 0 - -

70

60

50

{

Toddler (2 Yeara)

40\~

\

30

20 + /Infant (6-11 montha)

10-~Y

o ~+1975 76 77 78 79 80 81182 82184 84186 86188

Year

SOURCE: U.S. Department of Health and Human Services, Public HealthService, Food and Drug Administration, Center for Food Safetyand Applied Nutrition, FDA Total Diet Study (Washington, DC:1989).

42745). As a result of its own studies and FDA’srecommendations, the milk industry reduced thelevels of lead in evaporated milk from 0.52 ppm in1972 to 0.08 ppm in 1982 (30,109). Manufacturersof infant juices also took steps to lower lead levelsin their products, eventually switching voluntarilyfrom tin cans to glass jars (109), as did manufactur-ers of canned infant formula, who switched fromlead-soldered cans to other types of cans (96).

There has been a significant decrease in the use oflead solder for food cans manufactured in the UnitedStates. In 1979, more than 90 percent of such canscontained lead solder; by 1989, less than 4 percentdid. Figure 10-5 demonstrates the trend in reducinglead solder in cans and reflects the can manufactur-ing industry’s plans to eliminate lead solder in alldomestically produced food cans in the next 2 to 3years (24). The number of imported cans containinglead solder is not known but maybe large (165).

Materials used for packing food have also been asource of concern. These materials are consideredindirect food additives, because contaminants maymigrate from packaging materials into the food. Asof 1980, three indirect food additives were subject tolimitations on the amount of lead they can contain(109)0

Regulations concerning lead used in food uten-sils, specifically ceramic and hollowware products,have been promulgated by FDA (54 FR 23485).Large containers (in which food is likely to bestored) and cups used by children have lower limitson permissible lead content than do small utensils(100,109). FDA is currently considering loweringthe acceptable limit for large containers. Althoughthese limits apply to both imported and domesticutensils, few imported utensils are tested for leadcontent. In response to public concern, some retail-ers are testing imported dishes on their own (100,182).

Figure 10-5-Food Can Shipments

Billions of cans

3 0

20

10

I[

Total food can.

/

cans

I1 1 I I1 1 1 , 1I i

1979 1980 1981 1982 1983 1984 1985 1986 1987 1988Year

SOURCE: Can Manufacturers Institute, Washington, DC, personal com-munication, 1989.


Occupational Exposure to Lead

In contrast to the reduction of lead in food, wherestrict regulations have not had to be imposed bygovernment, the reduction of occupational exposureto lead has required more intervention. In responseto the Occupational Safety and Health Act of 1970,the Occupational Safety and Health Administration(OSHA) promulgated regulations in 1978 (29 CFR1910.1025) that set a maximum permissible level forlead in the air inhaled by workers.3

The lead industries immediately sued OSHA,challenging the validity of the standard. In 1980, theU.S. Court of Appeals for the District of ColumbiaCircuit upheld the limit and most other provisions ofthe regulation but ordered that the feasibility ofengineering controls be reconsidered for manyaffected industries (180). OSHA states explicitlythat industries must use engineering controls toreduce the overall level of lead in the air at theworkplace, as opposed to simply giving workersrespirators to remove lead from the air they inhale.The court instructed OSHA to reassess the feasibil-ity of such engineering and work controls forapproximately 40 industries. Only one of thesestudies has not been completed; however, becausethe courts will reexamine all the studies at once,these 40 industries are currently exempt from therequirement to achieve 50 ug/cm3 through engineer-ing and work practice controls.

The regulatory framework for ensuring minimaloccupational exposure to lead is in place. Occupa-tional exposure has been reduced considerably inmost large industries, as indicated by decreases incases of high-dose lead poisoning, mean blood leadlevels in workers, and mean air lead levels in mostworkplaces (75). It remains a problem in smallshops, however, which are covered by OSHAregulations but may not be routinely inspected.Some critics assert that enforcement of OSHAregulations is inadequate. Others state that, asrevealed by several State screening programs, manyemployers are unaware of their responsibilities, andothers ignore them. Many employees are not aware

of their rights or are reluctant to report employers forfear of losing their jobs.

Lead in Paint

Although lead-based paint is now only rarelyused, the paint that remains on the walls of olderhousing is the most significant source of leadpoisoning today. Many children are exposed tolead-based paint, and efforts to remove paint fromthe walls as a preventive measure vary greatly fromState to State. The U.S. Department of Health andHuman Services reported in 1988 that 52 percentof all residential buildings have paint containinglead in concentrations greater than or equal tothat considered dangerous by the CDC (165, 169).

In 1971, Congress attempted to address the issueof lead poisoning from lead-based paint. The Lead-Based Paint Poisoning Prevention Act and its 1973and 1976 amendments directed the Consumer Prod-uct Safety Commission (CPSC) to establish a levelof safety for lead in paint.4 Most paints are regulatedunder this standard, but lead is still used in somepaints (most often as a weather-resistant coating formetals) (51), and the yellow paint used for lininghighways and roads contains lead as well (42). TheCPSC has no control over lead-based paints alreadyin houses and other dwellings or lead-based paintmanufactured before 1977, when the regulation wentinto effect (165).

A second aspect of the lead-based paint legisla-tion involves removing lead paint from housingunder Federal jurisdiction, an activity that falls to theDepartment of Housing and Urban Development(HUD). HUD can only regulate paint in publichousing or federally assisted dwellings (165). TheDepartment’s regulations currently ensure notifica-tion of residents in and purchasers of HUD-associated housing constructed before 1950 of thehazards of lead poisoning from lead-based paint.The regulations also prohibit the use of lead-basedpaint in HUD housing and federally owned andassisted construction or rehabilitation of residentialstructures, and ensure removal of lead-based paint inHUD-associated housing and federally owned prop-

3Bef~ 1978, tie permissible ~xw~me ]fiit ~m 200 @mq (over an average time period of 8 hours). me regulations lowed tie limit to 50 ug/t’t13(43 FR 52952 and 43 FR 54354) and set an action level of 30 u@q (an action level is based on the same criteria as a tolerance). At this action level,the industry must initiate environmental monitoring, recordkeeping, education, training, and medical surveillance. Medical removal protection(removing the employee to an area with exposure below the action level) is directed by the medical surveillance findings (109).

4c~c*s au~onty ~ ~s ~ea ~omes from the con~wer ~~Wt Stiety ~t, which gives the Commission the power to ban ~ hz~dous myconsumer product that presents an unreasomble risk of injury (15 U.S.C. 2057). The current regulations state that paint may contain no more than 0.06percent lead.



The paint that remains on the walls of older housing is asignificant source of lead poisoning.

erties (109). Removal of lead-based paint from wallsis dangerous in itself. Workers can be exposed tolead dust if not adequately protected, and dust andpaint chips can be released into the nearby environ-ment if not properly disposed of, resulting inmarkedly increased exposure of inhabitants. HUD iscurrently conducting a study to determine the extentof the lead-based paint problem in public housingand to study the efficacy of alternative abatementprocedures.

The Lead-Based Paint Poisoning Prevention Actalso created a Federal program to fund lead poison-ing prevention programs for children. Initially fundedthrough the Bureau of Community EnvironmentalManagement, the program was transferred to theCDC in 1973, and until 1981 the CDC administeredgrants to the States for prevention programs. In

1981, the Omnibus Budget Reconciliation Actrolled a number of categorical health programs,including the lead poisoning prevention program,into the Maternal and Child Health Services BlockGrant. Thus, the allocation of money among thevarious health programs, previously dictated by theFederal Government, became the decision of eachindividual State. Accordingly, States now choosehow much money, if any, to apply to lead poisoningprevention programs (see box 10-C). Because manyof these programs have been reorganized at the Statelevel and because reporting of lead poisoningprevention expenditures is now voluntary, it isdifficult to determine how expenditures on leadpoisoning prevention programs have changed. Ac-cording to a 1984 General Accounting Office studyon the Maternal and Child Health Block Grant, leadscreening projects have received “the greatestreduction in emphasis’ (179), and a 1987 survey bythe National Center for Education in Maternal andChild Health indicated 10 States have no leadpoisoning prevention activities at all (1 11). In 1988,the Lead Poisoning Prevention Act authorized $66million for community screening between 1989 and1991 in order to compensate for deficits in leadpoisoning prevention programs at the State level.Lead-based paint remains a significant source oflead poisoning, despite the laws and regulationsthat specifically address this problem.

Lead in Drinking Water

Both EPA and Congress are currently addressingthe problem of lead in drinking water. In 1986, EPAestimated that 42 million Americans drank tapwater containing more than 20 parts of lead perbillion parts of water, the proposed drinkingwater standard (which has since been lowered).The Agency further estimated that exposure tolead in drinking water is keeping more than240,000 children from realizing their full intellec-tual potential (171).

Lead rarely originates from source water butleaches out of plumbing containing lead pipes andfixtures or lead solder. EPA estimates that there areapproximately 4.4 million lead service lines in use inthe United States and that approximately 25 percentof water suppliers have some lead service lineswithin their distribution system (53 FR 31521).Since more acidic water leaches more lead out ofplumbing systems, lead in drinking water may beregulated by controlling its pH (a measure of


Box 10-C-State Lead Poisoning Prevention Programs

Some States do nothing about lead poisoning, largely because it is not considered a significant problem. Othersidentify children with high blood lead levels through mandatory reports from laboratories that conduct blood tests,then follow up by treating the children and removing the environmental source of lead, if possible. Other States havean outreach program, whereby children in high-risk areas are screened and appropriate follow-up action is taken.Some communities have lead poisoning prevention programs.

A number of States have either passed legislation or are considering legislation addressing the issue ofchildhood lead poisoning. Massachusetts, for example, has extensive legislation that requires statewide screeningof children under age 6, reporting of cases of childhood lead poisoning by physicians, and art education campaignabout the dangers and sources of lead poisoning. The law also outlines lead-based paint abatement standards anda program for removing or covering lead in soil, among other provisions. Generally, areas of the country withindustrial pollution, older housing, and large cities appear to have the most active lead poisoning prevention efforts.

Given the variability of these prevention efforts, it is difficult to characterize the extent of screening at the Stateand local levels. However, a survey conducted by the Public Health Foundation in 1983 yields some relevant data.Of the 48 State and territorial health agencies surveyed, 33 operated lead poisoning prevention services. Thirty ofthese programs reported screening 676,600 children ages 1 to 5. Of the children screened, 9,317, or 1.6 percent, hadconfined lead toxicity (defined as blood lead levels greater than 30 ug/dl and erythrocyte protein levels greater than50 ug/dl, the CDC standard at that time). Of these children, 92 percent received medical care,l and environmentalinvestigations were conducted for 96 percent. The source of lead was determined in 80 percent of the cases ofconfirmed lead toxicity, and 98 percent of those sources were lead-based paint. Of the children with identifiedhazards, the hazards were abated for 91 percent.

In one sense, these data are encouraging, since the majority of children with elevated blood lead levelsevidently obtained medical treatment and hazard abatement. On the other hand, the number of children identifiedand treated is only a small percentage of the 200,000 children estimated to have elevated blood lead levels. Thus,a large number of children with potentially dangerous exposure to lead are not being helped.

IFr~m ~~ ~~t on, ~rcentages we b- on data reported by those State and territorial health agencies hat co~d provide ~~ thenumerator and the denominator for their percentages. As not all agencies reported all the relevant data, not all are represented in these numbers.

SOURCES: Public Health Foundation, Special Report: State Health Agency Lead Poisoning Prevention Activities, 1983 (Washington, DC:1986); U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry,The Nature and Extent of Lead Poisoning in Chila?en in the United States: A Report to Congress (Washington, DC: 1988).

acidity), and EPA argues that the least expensive Water Act listed 83 contaminants, including lead,method for reducing lead in drinking water is centralcorrosion control treatment (84,171).

Under the Safe Drinking Water Act (1974), EPAmust establish maximum contaminant level goals(MCLGs) and national primary drinking waterregulations (NPDWRs) for contaminants that mayhave an adverse effect on the health of the populationdrinking the water. While MCLGs are nonenforcea-ble health goals, NPDWRs are enforceable stand-ards. NPDWRs include maximum contaminant lev-els (MCLs) or treatment technique requirements, orboth. In 1986, amendments to the Safe Drinking

for which EPA had to develop MCLGs andNPDWRS.5

In 1988, EPA proposed an MCLG of zero for lead.The proposed NPDWRs establish an MCL of 0.005milligram of lead per liter of water (mg/l) for waterentering the distribution system (to replace thecurrent MCL of 0.05 mg/l); require corrosion controltreatment techniques if specified levels of lead,copper, and water acidity are not met (the Agencyissued regulations for copper and lead simultane-ously); and require public education if other meas-

5The 1986 ~en~ents to the Stie Dritiing Water Act also banned the use of lead solder or flux and lead-bearing pipes and fittings. This ban waseffective in 1986, and States were required to implement and enforce it as of June 1988. EPA is currently developing a program to withhold Federalgrants for programs to improve the quality of drinking water from States that fail to enforce the ban (53 FR 31516).


l——


ures fail.6 Some argue that the proposed regulationsare not strict enough and claim that EPA has both theauthority and the responsibility to set MCLs at thetap.7 Water suppliers, on the other hand, find thecorrosion control program to be unwarranted andexpensive.

The debate over regulation of lead in drinkingwater focuses on whether the public water supplier

.

or the consumer is ultimately responsible for pre-venting high levels. Public water systems control thequality of the water they distribute, including theparameters that determine how much lead will leachfrom plumbing into the water. On the other hand, thewater passes through a distribution system that isowned partially by the water supplier and partiallyby the consumer. If the regulation is enforced at thetap, the water supplier must assume responsibilityfor some lead contributions from the consumer’splumbing. If lead levels are enforced at the begin-ning of the distribution system, the consumer mustassume responsibility for some of the water sup-plier’s plumbing or the corrosivity of the watersupplied by the water system, or both. UndercurrentEPA regulations, the supplier is responsible both forlead levels in the water in the distribution system andfor the water quality at the tap.

Lead in drinking water remains a seriousproblem in some water supplies, especially inschools. The efficacy of the regulations promul-gated by EPA will be crucial in determining howserious a problem it remains. (Another widelydiscussed issue concerns lead in water coolers-see box 10-D.)

Lead in Incinerator Ash

The United States produces approximately 160million tons of solid waste every year. Currently,approximately 83 percent of this waste is put inlandfills, 11 percent is recycled, and 6 percent isincinerated (86). As landfills are rapidly being filled,there is much discussion concerning other methodsof disposing of this waste. EPA estimates there willbe a sixfold increase in the capacity for wasteincineration in the United States over the next 15years (76).

Incineration has both advantages and disadvan-tages. Its major advantage is that it reduces thevolume of waste by 75 to 80 percent. Furthermore,it can be used to generate electricity and can belinked with recycling methods to remove such solidsas iron, steel, glass, and paper from the waste stream

GUnder hew pmPd relations, all water leaving the treatment plant would have to meet the O.(N5 m#l st~dtid. TO ref@ate how much ledthe water can pick up as it travels from the distribution point to the consumer, EPA proposed that targeted samples be taken from consumers’ taps. Ifthe average lead level is less than orqual to 0.01 mg/1, the average copper level less than or equal to 1.3 mg/1, and the pH greater than or equal to 8.0in at least 95 percent of the samples, then the supplier is not required to take any further action. If any of these three standards is not met, the water supplierwould be required to implement or improve its corrosion control. If the lead levels are above 0.02 m~, the supplier would have to launch a publiceducation program to encourage consumers to reduce their exposures to lead in drinking water (53 F’R 31516).

T~ere is ~me concern that EP”S measures do not adequately treat the problem, since: 1) the NPDWR of 0.005 mg/1 does not reflect the MCLGof O mg/l; 2) the tap standard is not enforceable; and 3) limited sampling at the tap will necessarily overlook some households with high lead levels (1 16).


Box 10-D-Lead in Water CoolersAnother source of lead in drinking water, water coolers, has received considerable attention in the press and

is the subject of legislation passed in the 100th” Congress. Some water coolers may contain lead-lined tanks or leadsolder that comes into contact with the water. Data solicited by Congress from manufacturers reveal that close to1 million water coolers currently in use contain lead (U.S. Congress, Committee on Energy and Commerce, 1988).These water coolers are of special concern because they are frequently used in schools.

The Lead Poisoning Prevention Act of 1988 addresses this situation through the following provisions: 1)recalling all water coolers with lead-lined tanks; 2) banning the manufacture or sale of water coolers that containlead; 3) setting up a Federal program to assist schools in evaluating and responding to lead contamination problems;and 4) making funds available for the initiation and expansion of lead poisoning prevention programs (for all sourcesof lead poisoning). This last provision is designed to expand on Federal funds for lead screening from the Maternaland Child Health Services Block Grants. The legislation also requires that the Environmental Protection Agencypublish a list of water coolers that are not lead-free within 100 days of enactment (U.S. Congress, Committee onEnergy and Commerce, 1988). The Agency released a proposed list in April 1989. The original draft of thelegislation contained a section that set a Safe Drinking Water Act maximum contaminant level at the tap, but thissection was eventually deleted because of political pressure (’‘House Staffers, ’ 1988).

SOURCES: “House Staffers Scrap Lead Standard to Speed Drinking Water Bill’s Passage,” inside EPA 9:6, 1988; U.S. Congress, Committeeon Energy and Commerce, Subcommittee on Health and the Environment, Lead Contamination (Washington, DC: U.S. GovernmentPrinting Office, 1988).

(76). However, byproducts of incineration may have Although the amount of human exposure toadverse effects on the environment and on humanhealth. Residue remaining from incineration (bot-tom ash), particles removed from the air aftercombustion (fly ash), and airborne emissions (stackemissions and fugitive emissions) may contain highconcentrations of toxic substances, including leadand other toxic heavy metals (76). Compared tolandfills, stack and fugitive emissions may greatlyincrease exposure. On the other hand, when ash isplaced in landfills, the lead may leach out of the ashinto the groundwater, eventually ending up in lakes,ponds, and rivers that may be used for recreation ordrinking water.

EPA has the authority to regulate incinerator ashunder the Resource Conservation and Recovery Act,but there is some debate as to whether incineratorash should be considered a hazardous substancebecause the municipal solid waste which is burnedto create it is not designated hazardous waste. Someenvironmentalists call for testing all incinerator ashand treating it as hazardous waste if the tests indicateit has hazardous properties.

Congress has been interested in this issue as well.Legislation has been introduced in the 10lst Con-gress to amend the Clean Air Act, directing EPA topromulgate regulations that would control emissionsof specified air pollutants, including lead, frommunicipal waste incineration sites and ensure safemanagement of municipal incinerator ash.

lead from municipal waste incinerators is notlarge now, the projected increase in the numberof such incinerators indicates that it could be-come a problem in the future.

Lead in Soil

EPA is conducting a project under the Compre-hensive Environmental Response, Compensation,and Liability Act (CERCLA, or Superfund) todetermine whether abatement of soil lead (byremoval or some form of isolation) will reduce


Lead may be released into the air through theweathering of structures painted with

lead-based paint.


childhood exposure to lead (as determined by theamount of lead measured on the hands and in theblood of children). Studies are being conducted inBoston, Cincinnati, and Baltimore. The studies willnot focus on high-lead areas, such as areas near leadsmelters, or on children who need clinical attention.Instead, the focus is on intermediate lead levels,which are more typical urban exposures (42).

Summary and Conclusions

Public health measures have achieved a substan-tial decrease in human exposure to lead in recentyears; lead poisoning, however, remains a signifi-cant problem, especially in children. As tests be-come more sensitive, studies indicate that neurobe-havioral dysfunction is associated with lower bloodlead levels than previously believed. The preciselevel of exposure which causes impairment iscontroversial: there may be no threshold level foradverse effects, in which case the more sophisticatedour ability to detect impairments from lead poison-ing becomes, the lower the levels at which impair-ments may be found. Since 10 to 15 ug/dl is the limitmost recently proposed as a maximum blood leadlevel and the medical treatment techniques nowavailable are not able to reduce blood lead levelsbelow approximately 20 ug/dl, prevention is crucial.

Since lead poisoning was clearly identified as apublic health problem, it has received a great deal ofattention from Congress and a number of Federalagencies. EPA’s reduction of lead in gasoline hasgreatly reduced the amount of lead in the air; FDAand the food industry have together reduced theamount of lead in food; and EPA has recentlyimplemented a regulatory program to control theamount of lead in water. OSHA regulations havereduced lead exposure in most large lead-usingindustries. Federal and State programs have begun toremove lead paint from older housing. The regula-tory framework that now exists, if properly enforced,could continue to reduce many sources of exposureto lead.

Despite these areas of success, progress remainsto be made. Not everyone is satisfied with the stepsthat have been taken. Some argue that the existingregulations fail to treat the problem of lead indrinking water adequately. Some feel the OSHA

regulations for lead exposure in the workplace arenot properly enforced and have too many excep-tions. Also, there are no Federal programs to removelead-based paint in old houses or to establishmandatory, centralized reporting of lead poisoning.

Many argue for stronger measures to prevent leadtoxicity. Prevention might be improved by a generalscreening program for all children and by adoptingalternatives to incineration of waste, thus avoidingincreased exposure to lead in the air. Federalprograms to improve conditions in the workplaceand remove lead-based paint from all houses couldbe implemented. Lead content in water could bemonitored strictly, and if need be, regulations couldbe revised. Public education programs could beintroduced in high-risk areas near industrial orwaste-disposal sites. Federal money could be desig-nated for specific lead poisoning prevention pro-grams rather than including lead poisoning pro-grams under the block grant umbrella.

Designing programs to remove lead from theenvironment is most problematic when responsibil-ity for removing contamination is not clear. A babypoisoned by lead from canned milk is clearly thefood industry’s responsibility, therefore that indus-try was prompt and thorough in its response to thelead poisoning problem. In many cases, however,such as controlling lead in drinking water, responsi-bility for lead poisoning cannot be so clearlyascertained: some public water suppliers questionwhether they or consumers are responsible forplumbing with lead pipes or lead solder. The Nationmust address difficult questions such as this ifcontinued progress is to be made in reducing publicexposure to lead.

EXPOSURE TO NEUROTOXICPESTICIDES IN AGRICULTUREThe Federal Insecticide, Fungicide, and Rodenti-

cide Act (FIFRA) of 1947 defines a pesticide as:

. . . any substance or mixture of substances intendedfor preventing, destroying, repelling or mitigatingany insects, rodents, nematodes, fungi, or weeds orany other form of life declared to be pests. . . and anysubstance or mixture of substances intended for useas a plant regulator,8 defoliant or dessicant.

8AlW (daminozide), for example, is called a pesticide for regulatory purposes, even though it dws not kill Psts. It is u~ as a gro~ ~@at~ bpromote a uniform red color in apples and to prolong shelf-life.


Human exposure to pesticides can occur in a numberof ways—through contaminated drinking water,through eating foods containing pesticide residues(see box 10-E), through pesticides used in the yard,home, and office, and through exposure in variousoccupational and agricultural settings. Besides fieldworkers and pesticide applicators, those at risk inagricultural settings include nursery, greenhouse,forestry, and lawn care workers. Although pesticidesare a major health concern in the home and forexterminators, highway workers, grain elevatoroperators, and pesticide manufacturing and formu-lating employees, this section focuses on pesticideexposure in the agricultural setting.

Approximately 1 billion pounds of pesticides areused annually in agriculture in the United States, andapproximately 4 billion pounds are used annuallyworldwide (102,174). Approximately $7 billion isspent annually on pesticides in the United States.Agriculture accounts for more than two-thirds of theexpenditures and approximately three-fourths of thequantity used (174).

Agricultural workers who may be exposed topesticides include pesticide handlers (handling isdefined as mixing, loading, applying, flagging,9 andequipment cleaning, repairing, and disposal), whowork with concentrated forms of pesticides; workersperforming hand labor in fields treated with pesti-

Box 10-E—Pesticides in FoodA report released in February 1989 by the Natural Resources Defense Council (NRDC), Intolerable Risk:

Pesticides in Our Children’s Food, has spurred considerable debate about the risks to humans, particularly children,of pesticide residues in food. The report analyzed the extent of children’s exposure and attempted to determine thepotential hazards, focusing on increased risk of cancer and neurobehavioral damage. Data analyzed in the study wereobtained from the Environmental Protection Agency (EPA), the Food and Drug Administration, and the Departmentof Agriculture.

After examining 23 pesticides known to have adverse health effects, the report concluded that preschoolers arebeing exposed to hazardous levels of pesticides in fruits and vegetables. Twenty of these pesticides were found tobe neurotoxic. NRDC estimated that, from raw fruits and vegetables alone, at least 17 percent of the preschoolpopulation, or 3 million children, are exposed to neurotoxic organophosphorous pesticides above levels the FederalGovernment has described as safe.

NRDC criticized EPA for setting legal limits for pesticides in foods based on data collected 20 years ago andon adult consumption of fruit and vegetables (children generally eat more produce than adults). A few of NRDC’sprimary recommendations follow:

Congress must clarify EPA’s authority to change tolerance levels quickly.. EPA must consider risks from ‘‘inert’ ingredients when regulating pesticides.. Neurotoxicity testing should be required for all pesticides used on food.. Congress should establish national definitions of “integrated pest management” and ‘‘organic” farming

technologies and develop a national certification process for goods grown using these technologies.The report also includes recommendations to the public to reduce their exposure to pesticides.

EPA believes that the NRDC study overstates the risks from pesticides. The Agency stated that the benefits ofpesticide use outweigh the minimal risks and that EPA routinely takes into account the potentially higher exposureof children. However, EPA officials do concede that the report raises valid questions. In a news release distributedthe same day as the NRDC study, the National Food Processors Association (NFPA) stated that pesticides arevirtually nonexistent in packaged foods and that, when detected, they are far below allowable levels. The NFPAattributes this absence of residues mainly to the NFPA Pesticide Protective Screen Program, which spells out properpesticide control and monitoring practices for growers producing crops for the food industry.

SOURCES: (Mice of Technology Assessment, 1990; D. Duston, ‘‘Hotline Helps Growers Find Alternatives to Pesticides,’ Associated Press,Mar. 22, 1989; D. Duston, “Eight in 10 Americans Prefer Chemical Free Food; Half Would Pay More,” Associated Press, Mar.19, 1989; A.K. Naj, “Panel Assails Pesticide Study, Calls Food Safe,” Waff Street Journal, Apr. 6, 1989, sec. B, p. 3; NaturalResources IXfense Council, intolerable Risk: Pesticides in Our Children’s Food (Washington, DC: 1989).

g~aggers are worke~ who direct crop dusters as they spray pesticides on fields.

Chapter 10-Case Studies: Exposure to Lad, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 283

cides (called farmworkers in this report); and work-ers in forests, nurseries, and greenhouses wherepesticides are used.

Extent of Exposure of Agricultural Workers

Agriculture is the primary source of income for anestimated 4 to 5 million Americans, a significantproportion of whom are children under the age of 16(102). Many of these persons are exposed to higherlevels of pesticides than the general public. Approx-imately 2.7 million agricultural workers in theUnited States are migrant and seasonal farmworkers(164), and most seasonal work involves contact withpesticide residues on crops such as cotton, vegeta-bles, fruits, and nuts. Another group with significantexposure to pesticides is pesticide handlers: EPAestimates there are approximately 1.3 million certi-fied pesticide applicators in the United States (176).The number of agricultural workers performingother pesticide-handling jobs is unknown.

The seventy of illnesses caused by pesticidesdepends mostly on the dose absorbed and theinherent toxicity of the product. Farmworkers areexposed to pesticides primarily through residues onfoliage and crop surfaces, during aerial and handspraying, picking, packing, and sorting, but alsoduring hoeing and other field work. Forest, green-house, and nursery workers are exposed by similarmeans. Mixers, loaders, and applicators may beexposed to concentrated doses of pesticides in thecourse of their daily work. Exposure usually occursby absorption through the skin, except in the case offumigants, which are inhaled. The amount of pesti-cide absorbed depends on the nature of the workbeing performed, the clothing the worker is wearing,the part of the body exposed, and the condition of theworker’s skin (absorption increases with dermatitis,cuts, and abrasions). Another relevant factor inexposure is the rate at which pesticides degrade,which varies with conditions such as heat andmoisture.

Estimates of the incidence of pesticide-relatedhealth problems among workers vary. The annualworldwide incidence of pesticide poisonings isestimated to be between 500,000 (192) and 2.9million (69), with a fatality rate of approximately1 percent (102). In the United States, the preva-

lence of pesticide-related illness among farm-workers may be as high as 300,000 cases,l0 only1 to 2 percent of which are thought to be reported(31). The majority of reported cases of pesticide-related illness involve exposure to neurotoxic pesti-cides (102,185), but the lack of reporting of mostcases complicates the assessment of any persistingneurological and psychiatric problems. Some ob-servers have estimated that in developed countries 4to 9 percent of acutely poisoned individuals sufferlong-term neurological and psychiatric effects (46).

Special Risks to Children

Pesticides are thought to pose a considerablyhigher risk to children than to adults (106,114).Children can be exposed in a number of ways:through prenatal maternal exposure, from being inthe fields where their parents work, contact withpesticide residues on parents’ clothing, living inmigrant camps next to fields being treated, andworking in the fields themselves. Since they absorbmore pesticide per pound of body weight, childrenmay receive substantially higher doses of pesticidesthan adults, and their immature development maymake them more susceptible to neurotoxic effects.EPA and OSHA standards for worker safety arebased on adult exposure only.11 Many organ sys-tems, including the nervous and reproductive sys-tems, are still developing in infants and youngchildren. The effects of pesticides on these develop-ing systems are largely unknown. There are impor-tant lessons to be drawn from the case of lead, whichhas severe effects on the developing nervous systemand other organs of children.

Documented Adverse Effects on theNervous System

Although many pesticide-induced illnesses amongagricultural workers are thought to be severe andacute, some evidence suggests that they are in factmoderate and chronic (31). The full effects onlearning and perception and the emotional changesassociated with pesticide exposure are not knownbecause of the difficulty of testing these functionsand establishing a normal range (5). Failure to reportillness and the lack of comprehensive studies of theagricultural worker population may result in under-

l~is fi~ is based on extrapolation of data collected in California. Tracking the prevalence of farmworkers’ pesticide-related il~ews is difflc~tbecause of the lack of reporting requirements in most States and the limitations of those that do exist. These limitations are discussed later in this chapter,

llThe N~on~ Actiemy of Sciences recently initiated a 2-year study to assess the risk of exposure of children to p=ticides.

20-812 - 90 - 7 : CL 3



Current EPA regulations establish basic protective clothingrequirements for agricultural workers who enter treated

fields. However, recent studies document significantpesticide exposures despite the use of typical

protective clothing.

estimation of the true extent of both short- andlong-term neurological effects. Organophosphorousinsecticides, which make up approximately 40percent of all pesticides used in the United States, arecurrently the most commonly reported source ofworker illness. The more persistent organochlorinepesticides, used extensively in the 1940s through1970s, are now either banned or restricted in theUnited States and thus do not contribute as much toworker illness. What is known about the effects onworker health of a few commonly used classes ofpesticides is examined later in this chapter.

Short-Term Effects on theCentral Nervous System

Some cases of worker illness are mild and persistfor a few hours. In more severe cases, symptoms maynot peak until 4 to 8 hours after onset and may persistfrom 1 to 6 days. Some recovery periods are longer(90):

●

●

In a moderately severe poisoning of 24 fieldworkers, including children, exposed to resi-dues of two pesticides, mevinphos (Phosdrin)and phosphamidon (Dimecron), in California,anxiety and other symptoms were reported after70 days (98,184). In this case, farmworkerswere working in cauliflower fields prior to thelegal reentry interval.There have been several documented poison-ings of entire crews who entered fields after the

permissible reentry interval. In 1987,78 farm-workers in three different crews developedmoderate to severe pesticide poisoning fromcontact with phosalone (Zolone), used in Cali-fornia vineyards, long after it was thought safeto reenter. Because of its persistence and risk tofarmworkers, phosalone is no longer used ongrapes in California (23).

● In 1988, two crews were poisoned by a highlytoxic insecticide, methomyl, in California. Inthe first case, 34 orange harvesters went into amethomyl-treated orchard 1 day after applica-tion, and 17 developed symptoms of pesticidepoisoning that required hospital treatment. Inthe second case, grape workers were hospital-ized after exposure to methomyl. As a result ofthese poisonings, the reentry interval for meth-omyl in California was increased from 2 to 14days (23).

Long-Term Effects on theCentral Nervous System

The nature of long-term neurobehavioral effectsof exposure to organophosphorous insecticides isunresolved and deserves further investigation. Theevidence supporting the existence of delayed, persis-tent, or latent effects in humans includes casereports, epidemiological studies of agricultural work-ers with and without histories of acute poisoning,and deaths resulting from neurobehavioral diseaseamong agricultural workers.

Case Studies—The pesticides parathion, mev-inphos (Phosdrin), and malathion are frequentlyreported as causing health problems. Case reportsand studies of acute poisonings of agricultural andother workers indicate that 4 to 9 percent of theacutely poisoned individuals experienced delayed orpersistent neurological and psychiatric effects (46).These effects include agitation, insomnia, weakness,nervousness, irritability, forgetfulness and confu-sion, and depression (56,64,65,1 55); persistent men-tal disturbances—reported as delirium, combat-iveness, hallucinations, or psychoses—are noted insome cases of pesticide poisonings (62). Occupa-tions most frequently mentioned in case reportsinclude mixers, loaders, applicators, pilots, flaggers,nursery and greenhouse workers, pesticide manufac-turing workers, agricultural and pest control opera-tors, and inspectors. Farmworkers tend not to appearin the reports, for reasons that are discussed later inthis chapter.


Epidemiological Studies-Although few epidemi-ological studies of agricultural workers have beendone, approximately 500 subjects from variouscohorts have been subjected to standardized neu-robehavioral assessments examining memory, reac-tion time, behavior, visual ability, and mood. Sub-jects tend to be young, mostly male, and employedin agricultural occupations for unspecified periods.In field studies, quantitative data on exposure arelacking.

In general, this research demonstrates that pesti-cide poisoning can lead to poor performance on testsinvolving intellectual functioning, academic skills,abstraction, flexibility of thought, and motor skills;memory disturbances and inability to focus atten-tion; deficits in intelligence, reaction time, andmanual dexterity; and reduced perceptual speed.Increased anxiety and emotional problems have alsobeen reported. Exposed groups included farmerswithout symptoms (73), industrial workers withaccidental exposures (97), pest control workers (90),and a wide variety of agricultural workers tested anaverage of 9 years after an acute poisoning wasdiagnosed by a physician (140).

Neurobehavioral Disorders, Mortality, and Acci-dents—Analysis of occupation and causes of deathreported on death certificates suggests that agricul-tural workers are at risk of dying from neurobehav-ioral disorders and accidents. Approximately twicethe expected mortality from behavioral disorders(i.e., those resulting from altered perception orjudgment) has been reported among white malefarmworkers and orchard laborers from Washington(99) and among California farmworkers (154).

Both of these studies and one of British Columbiafarmworkers (55) found disproportionate mortalitydue to external causes, particularly motor vehicleaccidents. The precise role of pesticides, if any, inthe mortality patterns is unknown. Based on workerreports of feeling “fuzzy” at the end of the workday, researchers have speculated that farmworkerexposure to pesticides impairs judgment and coordi-nation and may contribute to motor vehicle acci-dents (155). There are numerous case reports of nearmisses and fatal workplace accidents involving farmmachinery and crop-dusting aircraft in which behav-ioral effects of pesticides are implicated (38,62,135,136,149,191).

Suspected Adverse Effects andLimitations of Existing Data

The occurrence of neurobehavioral disorders afterchronic low-level exposure in the absence of acutepoisoning has not been adequately studied. Neuro-psychological assessments of occupational groupshave yielded inconsistent results, perhaps reflectingdifferences among pesticides and differences in thetype and scope of tests used. Subtle neurobehavioraleffects have been observed most consistently inyoung, asymptomatic male workers who have beenemployed for a long time (19,194), who have beenpreviously diagnosed as having acute pesticidepoisoning, or who are recovering from an acuteexposure (38,73,140). Few studies have assessed theduration of impairment. Field studies have notprovided sufficient data on exposure levels orduration to understand dose-response relationships,nor have most studies controlled for age, education,or other potential confounding factors. Few studieshave examined exposed workers prospectively,subgroups of women or aging workers, interac-tions between pesticides, or interactions betweenpesticides and pharmacological agents (includingethanol or common medications).

Federal Regulation

Most workers in the United States are protectedby the Occupational Safety and Health Act, whichaffords them certain rights, including permissibleexposure limits, personal protective equipment andclothing, access to medical and exposure records,training about the risks of exposure, and protectionagainst employer retaliation. Pesticide handlers andworkers in forests, nurseries, and greenhouses arecovered under these regulations. OSHA requires thatfield workers be provided with toilets, drinkingwater, and water for hand washing; however, han-dling of pesticides is covered under FIFRA, whichis administered by EPA. Since 1983, manufacturingworkers have had the right to information on thehazards of the chemicals with which they workunder OSHA’s Hazard Communication Right-to-Know Standard. Since 1988, other industrial work-ers have also had this right.

FIFRA was enacted in 1947 to protect farmersfrom ineffective and dangerous pesticides by requir-ing that a pesticide be registered before it ismarketed. The legislation was amended extensivelyin 1972 (Public Law 92-516), with new provisions


allowing for direct controls over the use of pesti-cides, classification of selected pesticides into arestricted category, registration of manufacturingplants, a national monitoring program for pesticideresidues, the inclusion of environmental effects inthe cost-benefit analysis of the pesticide regulationprocess, and the required reregistration of olderpesticides to ensure that they meet new datarequirements (2).

Since FIFRA was amended in 1972, controversiesabout its implementation and its ability to protectfarmers and farmworkers have received repeatedcongressional attention. In 1988, after considerablepolitical debate, a compromise bill (dubbed “FIFRAlite” because of its restricted scope) was passed byCongress and signed by the President.

The new law requires EPA to review within thenext decade the 600 active pesticide ingredients andto charge manufacturers for some of EPA’s costs(under previous law, the government was responsi-ble for virtually all of the cost). The bill also partiallyrepeals the indemnification provision that requiredthe government to pay manufacturers or users ofpesticides for existing stock whose registration wascanceled by the Agency. This provision was a majorobstacle to EPA’s cancellation or suspension ofsome of the most toxic pesticides.12 Many issues,however, were lost in the final bill, includingfarmworker protection standards and specific re-quirements for EPA review and testing of pesticides.Two efforts to strengthen Federal authority weredefeated: 1) synchronization of data requirements,which would have prevented States from requiringadditional data before registering pesticides, and 2)preemption of States from setting more stringenttolerances for pesticide residues in food.

EPA promulgated regulations under FIFRA in1974. Of particular interest here are those regula-tions dealing with the occupational safety and healthof agricultural workers (40 CFR 170 and 156). The1974 regulations apply only to workers performinghand labor in fields during or after pesticide applica-tion. Their main provisions are a prohibition againstspraying workers; specific reentry intervals (i.e., thetime that must elapse between application of apesticide and the return of workers to the treated

Photo credit: Douglas Watts/Christophar Brady

area) for 12 pesticides and a general reentry intervalfor all other agricultural pesticides; a requirementthat protective clothing be worn by any worker whohas to reenter a treated area before the reentryinterval has expired; and a requirement for “appro-priate and timely” warnings to workers when theyare expected to work in fields that have been or willbe treated with pesticides.

FIFRA has been criticized as inadequate toprotect workers and the public from pesticidesknown to cause or suspected of causing seriouschronic effects, including cancer, reproductive prob-lems, and neurological damage (178). EPA has setreentry intervals for only 68 of more than 400 activeingredients currently used to manufacture thousandsof agricultural pesticide products.

In addition, FIFRA requires a balancing of risksand benefits to determine whether a hazardouspesticide should be canceled or suspended. Thisprovision can delay or prevent EPA from regulatingpesticides that are potentially neurotoxic, dependingon whether the perceived benefits of its use out-weigh the perceived risks. Risk-benefit analysis,however, rarely includes the costs of ill health tothose exposed, including lost work time, hospitalcare, and other medical care.

In 1983, EPA reviewed the regulations underFIFRA and determined that they were inadequate toprotect workers occupationally exposed to pesti-

l~~ordane was on~nally prop~ for cancellation in 1974 because of its adverse health effects. There is some fwlkg that the considerable Cmtto EPA of indemnifying chlordane’s manufacturers and users may have influenced its decision not to cancel the registration. While agricultural uses ofchlordane were canceled in 1984, it was still used widely to kill termites until 1988. On Feb. 3, 1989, the U.S. Court of Appeals overturned an earlierdecision and permitted the sale of existing chlordane stocks (112).

Chapter 10--Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 287

cides. The Agency proposed new regulations in1988. These regulations would cover workers inforests, nurseries, and greenhouses; pesticide han-dlers; and workers performing hand labor in treatedfields. Some of the key items of the proposedregulations follow:

●

●

●

●

●

●

General pesticide safety information must beplaced in a prominent location at each farm,forest, nursery, and greenhouse during thegrowing season. Workers who do not speakEnglish must be given a written warning intheir own language to obtain a translation ofthis information. Training must be provided forall persons who handle agricultural pesticidesand for all persons who enter treated areasbefore the reentry interval has expired. Anyperson who handles a pesticide must be pro-vided, on request, all information from thelabeling of that pesticide.All workers must be clearly and adequatelynotified about pesticide application and rele-vant reentry intervals. The methods of notifica-tion will vary according to the site, but willinclude a requirement that warning signs beposted outside pesticide-treated areas with areentry interval of more than 48 hours.All pesticide handlers and early reentry workersmust wear minimum personal protective equip-ment, as specified by pesticide labels. Determi-nation of the appropriate equipment must takeinto account the toxicity of the pesticide, thehandling technique, and the route and type ofexposure.The minimum reentry interval will be “untilsprays have dried, dusts have settled, or vaporshave dispersed. ” Reentry intervals will be setat 48 hours for organophosphorous and n-methyl carbamate insecticides in toxicity cate-gory I (most acutely toxic) and 24 hours for thesame pesticides in toxicity category II and allother pesticides in toxicity category I.Workers must be provided with water, soap,and disposable towels after exposure to pesti-cides or pesticide residues. Information aboutand transportation to nearby medical facilitiesmust be provided to workers in emergencycases of pesticide poisoning or injury.Commercial handlers who are exposed totoxicity category I or II organophosphorousinsecticides for 3 consecutive days or any 6

days in a 21-day period must be monitored forcholinesterase inhibition (177).

The proposed regulations have been criticized byfarmworkers’ and farmers’ groups, growers, andpesticide users and producers. Critics argue that thestandards fail to address many needs, includingthose for mandatory education of all farmworkersconcerning the neurotoxic and other health effects ofpesticides and safety training in the use of pesticides;telling workers what pesticides they have beenexposed to; more protective reentry intervals; andconsideration of the additive and synergistic effectsof exposure to multiple pesticides. Critics also arguethat the proposed standard could increase farmwork-ers’ risks by permitting early reentry into treatedfields as long as workers are given protectiveequipment.

Pesticide regulation and policy have historicallybeen made at the Federal level, yet the Office ofPesticide Programs has consistently had one of thesmallest budgets of any EPA program. Resources forthe review of toxicological data, monitoring pro-grams, and worker protection standards have beenlimited. EPA currently provides no funds to Stateagencies to conduct worker and public healthevaluations. Indeed, EPA officials have stated thatfarmworker protection standards are not part ofcurrent State enforcement grants under FIFRA(105).

Areas of Particular Concern

Pesticide Registration-An important obstacle toprotecting farmworkers from neurotoxic pesticidesis the major gaps in data in many pesticide registra-tion files. In 1984, the National Academy ofSciences found that 67 percent of pesticidesstudied had undergone no neurotoxicity testingat all, and all of the neurotoxicity tests performedwere judged inadequate (108). The 1988 FIFRAamendments gave EPA 9 years to complete itspesticide registration review, but the battery of testscurrently required by EPA for pesticide registrationis geared toward detecting only the most obviousneurotoxic effects. Only one type of test specificallyintended to detect nervous system impairments iscurrently included in EPA’s pesticide assessmentguidelines, although new test guidelines are beingdevised (see ch. 5). EPA was petitioned by a groupof consumer advocates and professional organiza-tions to develop more extensive neurotoxicity testguidelines (26).


Another gap in protection is the lack of data oneffects of exposure to the so-called inert ingredientsin pesticides. These ingredients are used as carriersof the active ingredient and do not appear onpesticide labels because of their trade secret status. 13

They are inactive only to the extent that they arethought to have no effect on the targeted pest. Hence,they may be defined as inert yet be toxic to humans.Of the 1,200 substances designated as inert, EPAconcludes that 55 are “toxicologically signifi-cant,” with another 65 structurally related tosubstances known to be toxic. As of 1987, EPA didnot know the toxicity of some 800 inert ingredientscontained in pesticide products and regarded some200 as generally safe (2); the Agency has sinceincorporated inert ingredients into its ongoing re-view of the toxicity of pesticide ingredients.

FIFRA permits States to register for 5 to 8 yearspesticides needed to fill “special local needs” and“crisis” situations. This may, under certain condi-tions, provide a substantial loophole in farmworkerprotection, because it allows States to registerpesticides that have not met Federal testing require-ments. There has been considerable criticism of thispractice.

Public attention was drawn to the issue of thequality of data submitted for the registration of newproducts by the discovery that one of the majorlaboratories providing data to EPA had falsifiedfindings (31,143). In 1984, EPA’s internal reviewprocess for evaluation of toxicological data wascriticized because of cases in which EPA reviewershad incorporated information provided by manufac-turers, apparently without any independent analysis.In 1989, the Senate Environment and Public Workscommittee initiated an oversight review of EPA’sregistration standards when it was learned that sevenof the eight members of EPA’s Science AdvisoryPanel had apparently served as consultants to thechemical industry (93,163). Thus, although EPA isworking to fill the data gaps in pesticide registration,there remain questions about the impartiality of theAgency’s regulation process.

Reentry 1ntervals-Unlike industrial workers,farmworkers are not protected by specific maximumlevels of exposure to chemicals. Rather, they areprotected by reentry intervals, which restrict entry to

a field after pesticide application (40 CFR 1988 ed.170). When they were first instituted in 1974,specific reentry intervals were set only for the 12chemicals with the highest observed toxicity; accessto all other active ingredients was restricted only“until sprays have dried or dusts have settled. ”Currently, specific reentry intervals have been setfor 68 active ingredients for which animal studiesdemonstrated need. These 68 active ingredients areused in about 90 percent (by volume) of pesticidesused in agriculture.

EPA claims that these reentry intervals protectworkers from the most toxic active ingredients usedin pesticides, but many observers are concerned thatthe existing regulations do not adequately protectfarmworkers from neurotoxic pesticides. Farm-worker protection advocates argue that the blanketreentry interval which covers other pesticides im-proves farmworker safety somewhat, but moreadjustments need to be made for specific chemicals.There have been episodes of worker poisoning andeven fatalities, particularly involving parathion, dueto inadequate reentry intervals (102,151). Toxicresidues can persist on foliage for weeks afterapplication and are known to persist longer in dryclimates (102). In California, most farmworkerpoisonings from neurotoxic pesticides have oc-curred because of inadequate reentry intervals (185).Several States have gone beyond EPA’s standardand imposed longer reentry intervals based on localconditions. California, for example, has set manylonger reentry intervals based on local conditions.Texas has set a minimum 24-hour reentry for alllabor-intensive activities and has set longer reentryintervals for a number of pesticides. New Jersey andNorth Carolina require a 24-hour reentry interval forall toxicity category I pesticides. Other States, too,are revising their standards for reentry intervals.

The 1988 FIFRA amendments address some ofthe shortcomings of piecemeal regulation. EPA iscurrently drawing up proposals for stricter regula-tions, including longer reentry intervals for morechemicals.

Protective Clothing-current EPA regulationsestablish a basic protective clothing requirement forworkers who must enter treated fields before thereentry interval has elapsed. Proposed EPA regula-

lspeaiciks ~ not ~ncr~ly appli~ ~ a Pwe f-. me ~sticik (~so ~o~ ss tie active in@ient) is USU@ diluted by a solv~t or ~ inactivesolid (known as the inert ingredient).


tions would specify particular items to be worn,depending on the task being performed, the circum-stances of potential exposure, and the toxicity classof the pesticide. However, some persons argue thatprotective clothing and equipment are not adequateto protect workers from harmful exposures. All toofrequently, employers do not provide protectiveclothing and equipment or employees do not wearthem because of the excessive heat or their con-straints on movement. Furthermore, recent studiesdocument the significant exposures workers mayreceive even while using an approved respirator orwearing typical protective clothing (48).

Lack of Pesticide Illness Reporting—Becausethere are inadequate reporting mechanisms for acutepesticide poisoning episodes and none for adversechronic effects among farmworkers in the UnitedStates, the true rate of pesticide-related illnessamong farmworkers may be underestimated. Even ifthere were more centralized reporting, physiciansoften have little training in occupational medicineand thus may not recognize instances of pesticidepoisoning, and patients rarely have access to infor-mation about the pesticides to which they areexposed. The lack of occupational histories andaccurate exposure data make proper diagnosisand treatment difficult, if not impossible (103).Furthermore, many ill workers never actually see adoctor.

Farmworkers, especially migratory farmworkers,whose immigration status and language barriersmake them especially vulnerable, are often notrepresented by unions that influence standards ofhealth and safety in the workplace. On a State level,most migrant farmworkers are excluded from work-ers’ compensation and unemployment insurance(103). These exclusions from governmental protec-tions prevent accurate estimates of pesticide illness,lost work time, and medical costs. Persons whoadvocate greater protection for farmworkers arguethat reporting requirements for national pesticideillness and pesticide use would enable regulators totarget pesticides for regulatory action and betterassess their effects on health (134).

Monitoring Methods and Needs

There is no regular or required biological monitor-ing of agricultural workers exposed to pesticides inthe United States, except for periodic cholinesterasetests for a small group of certified applicatorsexposed to organophosphorous and carbamate in-

secticides on a regular basis in California. ProposedEPA regulations would require monitoring of com-mercial pesticide handlers under certain circum-stances. One direct means of assessing workers’exposure to chemicals is by measuring the parentsubstance or its metabolizes in the blood or urine;however, this methodology is available for only alimited number of pesticides (101). A promisingnew field cholinesterase test has been developed andused in Central America to identify workers suffer-ing adverse effects (88); such a test might improveworker awareness and enhance preventive medicalcare (157) if workers can be induced to participate.

Monitoring programs are most effective whenthey are based on an understanding of the nature offarmworker exposure and the patterns of pesticideuse. More extensive monitoring would allow betterassessment of the extent of neurobehavioral prob-lems caused by pesticide exposure among farm-workers; but conducting assessments of non-English-speaking, migratory populations may be difficult,there may not be qualified medical personnel andadequate equipment in rural areas, and the availabil-ity of monitoring devices may be a disincentive foremployers to prevent exposures in the first place.

State Regulation

Under current law, States may set more stringentrequirements for pesticide use than those provided inFederal statutes. Several States, notably Texas,California, and Washington, have initiated their ownworker and public programs to fill the gaps inFederal regulations. Other States, for example, Iowa,Minnesota New Jersey, New York, North Carolina,and Wisconsin, have also taken steps to addresscritical needs at the State level. Nine States havelaws requiring reporting systems for pesticide illnessor pesticide use, although most of them are unen-forced; 16 other States have limited forms of datacollection; and 16 States have mandatory workercompensation programs for agricultural workers (53FR 25973).

California has an extensive and well-fundedpesticide registration and worker safety program thatexceeds EPA standards in addressing local condi-tions and patterns of pesticide use. As mentionedearlier, California and Washington require reportingof pesticide illness. California enacted the BirthDefects Prevention Act of 1984 to require adequatedata on the 200 most widely used pesticides


suspected to be hazardous to humans. This lawprohibits the conditional registration of any newpesticide without complete and valid data on healtheffects. It also requires cancellation of any pesticidecontaining an active ingredient that causes signifi-cant adverse effects on health.

Texas has adopted several farmworker protectionmeasures, including a 24-hour minimum reentryinterval for all pesticides used on labor-intensivecrops and certain prior notification and postingprovisions for workers and other persons adjacent totreated fields. The most far-reaching development isTexas’ Agricultural Hazard Communication (right-to-know) Law, the first such law in the Nation. Itrequires agricultural employers to provide theirworkers with information about the health risks ofpesticides and ways to minimize these risks. Em-ployers are required to maintain a list of allpesticides used and to make it accessible to workers,their physicians, and other designated representa-tives. Farmworker training (in a form and languageunderstood by workers) is also guaranteed by thislaw, through crop sheets and other written andaudiovisual materials (185,187).

New Approaches to Pest Control

The simplest way to protect farmworkers is toreduce the overall use of pesticides, particularly themost toxic ones. Movements to build sustainableagricultural systems based on limited use of pesti-cides and fertilizers and on integrated pest manage-ment (IPM) systems have been initiated in severalStates (see box 10-F). IPM relies on the coordinationof a number of control tactics. It attempts tominimize the use of pesticides by making maximumuse of biological controls (e.g., natural predators andparasites, disease-causing microorganisms, phero-mones, and pest-resistant plants) and cultural con-trols (e.g., crop rotation and removal of crop residuesthat shelter pests after harvest). Chemical controlsare used prudently, in conjunction with these othermethods (176). IPM practices can potentiallyreduce pesticide use by as much as 50 percent(161).

Research on IPM techniques is slowly spreadingto the more labor-intensive crops, but limitedFederal funding has delayed implementation of thispromising technology (187). The U.S. Departmentof Agriculture is researching and developing sus-tainable agriculture strategies which include IPM[14 U.S.C. 1463(C)]. In 1988, an estimated 8 percent

of crop land (27 million acres) was enrolled in some30 State IPM programs (104).

Examples of Neurotoxic Pesticides

The following discussion introduces several ofthe most common classes of pesticides known tohave neurotoxic effects.

Cholinesterase-Inhibiting Insecticides

Organophosphorous and carbamate insecticides,the cholinesterase-inhibiting pesticides, represent alarge and important class of neurotoxic substances(see table 10-3). Because of their widespread use andhigh toxicity at acute exposures, they are the mostcommon cause of agricultural poisonings. Bothaffect target insects and humans by inhibitingacetylcholinesterase, an enzyme that breaks downthe neurotransmitter acetylcholine. Inhibiting thisenzyme creates a build-up of the transmitter, whichcauses nervous system dysfunction.

Some cholinesterase-inhibiting pesticides causehyperactivity, neuromuscular paralysis, visual prob-lems, breathing difficulty, abdominal pain, vomit-ing, diarrhea, restlessness, weakness, dizziness, andpossibly convulsions, coma or death (see table10-4) (102,141,195). The extensive literature onneurobehavioral toxicology in laboratory animalsexposed to pesticides has been reviewed by others(14,29,34,41,71,189). The onset and duration ofsymptoms in acute poisoning of workers depends onthe inherent toxicity of the insecticide, the dose, theroute of exposure, and preexisting health conditions.Deaths have occurred in the past when workers werenot treated properly for their exposure. The inhibi-tion of acetylcholinesterase by both organophosphor-ous insecticides and n-methyl carbamates is reversi-ble; however, inhibition caused by n-methyl car-bamates is generally considered more readily andrapidly reversible than that caused by organo-phosphorous insecticides. For several of the organo-phosphorous insecticides, inhibition of acetylcholin-esterase is so slowly reversible that an accumulationof the effect can occur. Once exposure ceases,however, full recovery usually results (102,106).

Some researchers have found delayed effects afteran episode of acute organophosphorous insecticidepoisoning: these include irritability, depression,mood swings, anxiety, fatigue, lethargy, difficultyconcentrating, and short-term memory loss. Thesesymptoms may persist for weeks and months after


Box 10-F-Organic Farming and Alternatives to Chemical Pesticides

In response to growing consumer demand, the cost of chemical fertilizers and pesticides, and evidence of riskto human health and the environment more farmers are turning to organic production. There is no single definitionof organic farming, but it generally requires some degree of abstinence from use of chemical fertilizers andpesticides. In Texas, a farm is only certifiably organic if no pesticides have been used for 3 years and no chemicalfertilizers have been used for 2 years, but standards may vary from State to State. Where there is no State regulationof organic farming, responsibility for setting standards usually falls to trade organizations, and there is frequentcontroversy over how strictly to limit pesticide use.

Organic farming is gaining the attention of consumers, growers, and legislators. A California trade organizationreported that sales of organic produce in the United States doubled between 1983 and 1988, to $1 billion. A 1989Harris poll reported that 84,2 percent of Americans would buy organic food if it were available, with 49 percentof those willing to pay more for it (organic produce currently costs between 5 and 15 percent more than crops onwhich pesticides are used). This public concern is reflected by distributors such as Sunkist Growers, Inc., and DoleFoods Co., who are beginning to grow organic produce, and by supermarkets, which are beginning to issue writtenpolicies requiring chemical-free produce from suppliers. State legislatures have been slower to address the pesticideproblem. To date, only a small percentage of States has any regulations for organic farming, and only a few of thesehave certification programs.

Historically, organic farming has been more expensive because it is more labor-intensive, it is done on smallerfarms, and it results in smaller yields. The resulting products, however, tend to have a higher profit margin than themore abundant crops grown on large farms where pesticides are used, As biological alternatives to pesticides areresearched and developed, costs of alternative farming might be reduced further.

Despite the promises organic farming offers for human health and the environment there is awareness of itsdrawbacks even within the organic farming community. Complete rejection of chemical pesticides may reduce cropyields. Even some environmentally aware and health-conscious farmers agree that chemical pesticides areoccasionally required.

Insufficient regulation of organic foods and farming methods is another drawback to organic farming. Apartfrom the lack of precise definition of what organic farming is, public safety maybe threatened by lack of enforcedregulation of so-called organic produce, as well as a lack of testing at the supplier level to confirm that foods arefree of toxic substances. According to the Consumers Union, most grocery stores rely on their suppliers’ word thatproduce is pesticide-free, yet when that organization tested apples bought in stores which claimed not to sell applestreated with Alar, 55 percent of the apples contained it.

Rather than attempting to end all use of chemicals in agriculture, a solution may be found in integrated pestmanagement or other alternative agriculture systems, which use chemicals discriminately, if at all, in conjunctionwith biological controls designed to fit local conditions. A National Research Council report released in September1989 concludes that Federal farm subsidy programs encourage the use of chemical pesticides when nonchemicalalternatives may be as or more effective. The report recommends that at least $40 million be allocated annually forresearch on alternative farming.

SOURCES: “Apple Grower Says Chemicals Sometimes Needed When All Else Fails,” Associated Press, Apr. 3, 1989; D. Duston, “Eight in10 Americans Prefer Chemical Free Food; Half Would Pay More,” Associated Press, Mar. 19, 1989; “Entomologists DefendChemicals as Necessary in Food Production,” Associated Press, Mar. 25, 1989; “Farmers Hope to Replace Chemicals withBiological Fertilizers,’ Associated Press, Apr. 3, 1989; P. Fikac, “Consumers Union: Ask Grocers About Reduce,” AssociatedPress, Mar. 30, 1989; National Academy of Sciences, National Research Council, Alternative Agriculture (Washington, DC:National Academy Press, 1989); S.L. Nazario, “Big Firms Get High on Organic Farming: Pesticide Scare Reinforces Shift inTechniques,’ Wall Street Journal, Mar. 21, 1989; ‘‘Pesticide Scares Fuel Already Growing Organic Food Popularity,” AssociatedPress, Apr. 10, 1989.

the initial exposure (17,82,83,137,147). Whether persistent alteration of brain function (36,56,59,97,there are significant chronic effects of exposure to 141), while others have noted no long-term effectslow-level organophosphorous and n-methyl car- (10,13,29,153,155).bamate insecticides (and, indeed, of exposure to Some organophosphorous insecticides can pro-pesticides in general) is a matter currently under duce delayed and persistent neuropathy by damag-debate. A number of researchers have observed ing certain neurons in the spinal cord and peripheral


Table 10-3-Organophosphorous and Carbamate Insecticides

Highly toxica Moderately toxica

tetraethyl pyrophosphate (TEPP) - - -

dimefox (Hanane, Pestox XIV),phorate (Thimet, Rampart, AASTAR)disulfoton b (Disyston)fensulfothion (Dasanit)demeton b (Systox)terbufos (Counter, Contraven)mevinphos (Phosdrin, Duraphos)ethyl parathion (E605, Parathion, Thiophos)azinphos-methyl (Guthion, Gusathion)fosthietan (Nem-A-Tak)chlormephos (Dotan)sulfotep (Thiotepp, Bladafum, Dithione)carbophenothion (Trithion)chlorthiophos (Celathion)fonofos (Dyfonate, N-2790)prothoate b (Fac)fenamiphos (Nemacur)phosfolanb (Cyolane, Cylan)methyl parathion (E 601, Penncap-M)schradan (OMPA)mephosfolanb (Cytrolane)chlorfenvinphos (Apachlor, Birlane)coumaphos (Co-Ral, Asuntol)phosphamidon (Dimecron)methamidophos (Monitor)dicrotophos (Bidrin)monocrotophos (Azodrin)methidathion (Supracide, Ultracide)EPNisofenphos (Amaze, Oftanol)endothionbomyl (Swat)famphur (Famfos, Bo-Ana, Bash)fenophosphon (trichloronate, Agritox)

nervous system. The resulting muscle weakness mayprogress to paralysis. Onset is usually 2 to 4 weeksafter the acute exposure (27,70,150). The initialsymptoms of peripheral neuropathy are usuallycramps in the calves and numbness and tingling inthe feet. Increased weakness and flaccidity of thelegs follows, accompanied by varying amounts ofsensory disturbance. The arms may also be affected(106). There is no specific treatment, and the rate andextent of recovery vary considerably.

Organochlorine Insecticides

The organochlorine insecticides are chlorinatedhydrocarbon compounds that act as central nervoussystem stimulants (see table 10-5). Organochlorinesaccumulate in both the environment and the body. Ingeneral, they are considered less acutely toxic thanorganophosphorous and n-methyl carbamate insecti-cides, but they have a greater potential for chronictoxicity. The prototype organochlorine, DDT, wasdiscovered in 1939 and was used extensively in

bromophos-ethyl (Nexagan)Ieptophos (Phosvel)dichlorvos (DDVP, Vapona)ethoprop (Mocap)demeton-S-methyl b (Duratox, Metasystox (i))triazophos (Hostathion)oxydemeton-methyl b (Metasystox-R)quinalphos (Bayrusil)ethion (Ethanox)chlorpyrifos (Dursban, Lorsban, Brodan)edifenphosoxydeprofosb (Metasystox-S)sulprofos (Bolstar, Helothion)isoxathion (E-48, Karphos)propetamphos (Safrotin)phosalone (Zolone)thiometon (Ekatin)heptenophos (Hostaquick)crotoxyphos (Ciodrin, Cypona)phosmet (Imidan, Prolate)trichlorfon (Dylox, Dipterex, Proxol, Neguvon)cythioate (Proban, Cyflee)phencapton (G 28029)pirimiphos-ethyl (Primicid)DEF (De-Green, E-Z-Off D)methyl trithiondimethoate (Cygon, DeFend)fenthion (mercaptophos, Entex, Baytex, Tiguvon)dichlofenthion (VC-13 Nemacide)bensulide (Betasan, Prefar)EPBP (S-Seven)diazinon (Spectracide)profenofos (Curacron)formothion (Anthio)pyrazophos (Afugan, Curamil)

agriculture and against mosquitoes and other insectsthat transmit human disease before it was bannedfrom most uses in the United States in 1972.

From 1940 through the 1970s, a number of otherorganochlorine compounds, such as aldrin, dieldrin,toxaphene, mirex, endrin, lindane, heptachlor, andchlordane, were widely used as insecticides. Follow-ing recognition of their accumulation in the environ-ment and in human and animal tissues, and observa-tion of some adverse effects on wildlife, most havebeen banned or severely restricted in use. Forexample, chlordane, introduced in 1947 and sincethen one of the most widely used of this family, wasoriginally targeted by EPA for restricted use in 1974.It was banned for most uses except termite control in1978 (102). A decade later, EPA banned almost alluses of chlordane.

The organochlorines are easily absorbed by inha-lation or ingestion and may also be absorbed throughthe skin. They are generally distributed to fatty

Chapter 10-ase Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 293

Table 10-3-Organophosphorous and Carbamate Insecticides-Continued

Highly toxica Moderately toxica

dialifor (Torak) naled (Dibrom)cyanofenphos (Surecide) phenthoate (dimephenthoate, Phenthoate)dioxathion (Delnav) IBP (Kitazin)mipafox (Isopestox, Pestox XV) cyanophos (Cyanox)

crufomate (Ruelene)fenitrothion (Accothion, Agrothion, Sumithion)pyridaphenthion (Ofunack)acephate (Orthene)malathion (Cythion)ronnel (fenchlorphos, Korlan)etrimfos (Ekamet)phoxim (Baythion)merphos (Fo!ex, Easy off-D)pirimiphos-methyl (Actellic)iodofenphos (Nuvanol-N)chlorphoxim (Baythion-C)propyl thiopyrophosphate (Aspen)bromophos(Nexion)tetrachlorvinphos (Gardona, Appex, Stirofos)temephos (Abate, Abathion)

Carbamate Insecticidealdicarb b (Temik)oxamyl (Vydate L, DPX 1410)methiocarb (Mesurol, Draza)carbofuran (Furadan, Curaterr, Crisfuran)isolan (Primin)methomyl (Lannate, Nudrin, Lanox)formetanate (Carzol)aminocarb (Matacil)cloethocarb (Lance)bendiocarb (Ficam, Dycarb, Multamat, Niomil,

Tattoo, Turcam)

dioxacarb (Elocron, Famid)promecarb (Carbamult)bufencarb (metalkamate, Bux)propoxur (aprocarb, Baygon)trimethacarb (Landrin, Broot)pirimicarb (Pirimor, Abel, Aficida, Aphox, Fernos,

Rapid)dimetan (Dimethan)carbaryl (Sevin, Dicarbam)isoprocarb (Etrofolan, Ml PC)

Wompounds are listed in order of descending toxioity. “Highly toxic” organophosphates have listed oral LDW (medianlethal dose) values (rat) less than 50 mgkg; “moderately toxic” agents have LDW values in excess of 50 mgkg.

bThe~ in~ticides are systemic; they are taken up by the plant and translocated into foliage and sometimes intO thefruit.

SOURCE: D.P. Morgan, Recognition and Management of Pesticide Poisoning, EPA pub. No. 540/9-S8-001(Washington, DC: U.S. Government Printing Office, 19S9).

tissue, the liver, and the nervous system. Most aremetabolized by the liver and excreted in urine. Forsome pesticides, accumulation in fat tissue occursduring chronic exposure, so elimination is slow.DDT, for example, is metabolized and excretedslowly and can still be found in the fat of most peopleexposed to it years after its use was terminated (62).

Acute intoxication from organochlorines canproduce nervous system excitability, apprehension,dizziness, headache, disorientation, confusion, lossof balance, weakness, muscle twitching, tremors,convulsions, and coma. Uncontrolled seizures, res-piratory problems, or both, may lead to brain or otherorgan damage. Children may be particularly sensi-tive to brain and nerve damage from organochlorinepesticides and may suffer from long-term behavioraland learning disabilities as a result of exposure (41).

One of the most serious cases of severe poisoningoccurred in manufacturing workers handling chlor-decone, commonly known as Kepone (see ch. 2).These workers suffered tremors, disturbances invision, and difficulty in walking (156). As a result,this pesticide’s registration was canceled by EPA in1977 (42 FR 18855).

Fumigants

Fumigants-used to kill insects, insect eggs, andmicroorganisms-are the most acutely toxic pesti-cides used in agriculture. Because they are gases,fumigants are usually taken directly into the lungs,where they readily enter the blood and are distrib-uted throughout the body. Although inhalation is themost serious source of exposure and can lead rapidlyto death, absorption of fumigants through the skincan also be a significant hazard (103).


Table 10-4-Neurotoxic Effects of Acute Exposureto High Levels of Organophosphorous or

Carbamate Insecticides

Function of nervous systemwhen stimulated by Effect of excessive stimulationacetylcholine of the nervous system

Activate salivary, sweat,and tear glands

Constrict bronchi

Contract pupil of eye

Control heart function

Increase spasms indigestive tract

Increase spasms inurinary tract

Activate skeletalmuscles

Alter brain function

Increased salivation, sweating,watering of eyes

Tightness in chest, coughingand wheezing, difficultybreathing

Pinpoint pupils, blurring ofvision

Abnormal heart beat, changein blood pressure

Stomach cramps, nausea, vom-iting, diarrhea

Urinary frequency and inconti-nence

Twitching, restlessness, tremu-Iousness, impaired coordina-tion, generalized muscleweakness, paralysis, anddeath or brain injury causedby asphyxiation after mus-cle paralysis

Headache, giddiness, anxiety,emotional instability, leth-argy, confusion; eventuallysevere central nervous sys-tem depression and coma

SOURCE: B.B. Young, Neurotoxicity of Pesticides,” Journal of PesticideReform 6:8-11, 1986.

Table 10-5-Organochlorine Insecticides

Insecticideendrin (Hexadrin)aldrin (Aldrite, Drinox)endosulfan (Thiodan)dieldrin (Dieldrite)toxaphene (Toxakil, Strobane-T)Iindane (gamma BHC or HCH, Isotox)hexachlorocydohexane (BHC)DDT (chlorophenothane)heptachlor (Heptagran)chlordecone (Kepone)terpene polychlorinates (Strobane)chlordane (Chlordan)dicofol (Kelthane)mirex (Dechlorane)methoxychlor (Marlate)dienochlor (Pentac)TDE (DDD, Rhothane)ethylan (Perthane)SOURCE: D.P. Morgan, Recognition and Management of Pesticide Poi-

soning, EPA pub. No. 540/9-88-001 (Washington, DC: U.S.Government Printing Office, 1989).

Fumigants have caused severe illness and death inhuman beings (11,63,81,132). Poisoning initiallycauses headache, nausea, vomiting, and dizziness,followed by drowsiness, fatigue, slurred speech, lossof balance, and disorientation. In severe poisonings,

seizures, loss of consciousness, respiratory depres-sion, and death may occur. Tremors and generalizedseizures may also occur, particularly from methylbromide poisoning.

Methyl bromide, one of the most widely usedpesticides in the United States, is a colorless gas atroom temperature. It has a faint, somewhat agreeableodor, making it difficult to detect, even at toxiclevels (127). This pesticide has caused death andsevere neurotoxic effects in fumigators, applicators,and structural pest control workers. Acute exposureto methyl bromide can result in visual and speechdisturbances, delirium, and convulsions. Both acuteand chronic poisoning from methyl bromide may befollowed by prolonged, and in some cases perman-ent, brain damage marked by personality changesand perception problems. Chronic exposure can resultin progressive peripheral neuropathy, with loss ofmotor control, numbness, and weakness (4,63).

Chlorophenoxy Herbicides

Chlorophenoxy herbicides include 2,4-dichloro-phenoxyacetic acid(2,4-D),2,4~-trichlomphenoxyaceticacid (2,4,5-T), 2-methyl-4 -chlorophenoxyacetic acid(MCPA), and 2,4,5 -trichlorophenoxypropionic acid(Silvex). These herbicides were among the mostwidely used until EPA suspended many of their usesbecause of potential adverse effects on human health(43 FR 17116). The chlorophenoxy herbicidescontinue to be used widely in forestry and weedcontrol in agricultural and urban settings. Farm-workers can be exposed to these pesticides duringmixing and loading or by drift from nearby applica-tions. Although these compounds are readily me-tabolized and excreted and are of relatively lowtoxicity to mammals, they are often contaminatedwith dioxins, which may be toxic themselves (102).There are more than 75 different dioxin isomers, butTCDD, a contaminant of 2,4,5-T, is believed to bethe most toxic (68).

Most current knowledge of the effects of TCDDon humans comes from overexposures of workersmanufacturing 2,4,5-T or the compound from whichit is derived (61,66,68). Acute exposure to highdoses has led to peripheral neuropathy, sometimesaccompanied by difficulty in walking and coordinat-ing the legs. Irritability, insomnia and hypersomnia,lethargy, impotence, and psychiatric disturbanceshave also been reported in cases of acute exposure(102). Peripheral neuropathy resulting from dermal


absorption and death resulting from ingestion havebeen reported for 2,4-D (102).

The most notorious chlorophenoxy herbicide isthe defoliant Agent Orange. Agent Orange consistsof a 1:1 mixture of 2,4,5-T and 2,4-D and was widelyused in Vietnam from 1962 to 1970. A number ofadverse effects on Vietnamese and on Americansoldiers in Vietnam have been alleged. A recentreport indicates that the probability of exposure ofU.S. veterans was small (162), and whether AgentOrange was the cause of the alleged health effects isstill unresolved (102).

Pyrethroids

Pyrethroids, a group of insecticides, are highlytoxic to insects but less toxic to mammals, whichmetabolize and excrete them quickly. Pyrethroidsact by altering the flow of sodium ions through thenerve cell membrane, resulting in repeated firing ofthe nerve cell (106).

Because pyrethroids appear to be less acutelytoxic than other insecticide groups, their use is likelyto increase. In response to the observation of axonalswelling in rats subsequent to pyrethroid ingestion,EPA requires a special new pathological evaluationas part of the 90-day rodent feeding study from allcompanies attempting to register a pyrethroid (37).


Approximately 1 billion pounds of pesticides prod-ucts, made up of 600 active pesticide ingredients, areused annually in agriculture in the United States(102). Many of these active pesticide ingredientshave never been tested for potential neurotoxic orneurobehavioral effects, damage to the reproductivesystem, or other effects on human health. Historically,few pesticides have been banned or restricted by EPA.

Although everyone is exposed to low levels ofpesticides in food and water, an estimated 2.7million migrant and seasonal farmworkers facegreater risk because they are regularly exposed tohigher levels of pesticides and because existingprotections do not always cover them adequately.Pesticide applicators, loaders, and mixers, as well asnursery, greenhouse, forestry, and lawn care work-ers, may be exposed to particularly high levels ofpesticides as well. Children, who constitute asignificant proportion of the agricultural work force,are especially vulnerable because their nervoussystems are not fully developed. The majority of

pesticides used are organophosphorous and n-methyl carbamate insecticides, both of which areneurotoxic. They can produce acute effects (rangingfrom moderate symptoms to death) and perhapschronic effects as well, although the data areinconclusive. Some organophosphorous insecticidescan also cause delayed damage to the peripheralnervous system.

It is not possible to estimate accurately the extentof illness among farmworkers because there is nonational pesticide illness reporting system or workermonitoring program. Extrapolations by others fromavailable data suggest a prevalence of more than300,000 pesticide-related illnesses among farm-workers, although only a small percentage of thesecases are reported (31). The total number of workerdeaths and the extent of chronic health problemscaused by exposure to pesticides are also unknown.

Limiting the use of neurotoxic pesticides wouldbe a straightforward way to control exposure.Integrated pest management systems offer alterna-tive approaches to pest control and minimize the useof pesticides.

More research is needed to understand the neuro-toxic effects of new and existing chemicals and toprotect agricultural workers from them. EPA’spesticide registration review should require informa-tion on pesticide neurotoxicity based on the mostcurrent knowledge of dose-response relationships,mechanisms of action, and structure-activity rela-tionships. Premarket testing could include effects onlearning, memory, conditioned behavior, and emo-tional disorders, rather than being limited to motorfunction. More information is needed on the long-term effects of pesticides on the fetus, on children,and on the aged.

The need for epidemiological studies of theeffects of pesticides on agricultural workers iscritical. Reporting and monitoring procedures couldbe established and enforced to provide more accu-rate information on the prevalence and incidence ofpesticide illness; furthermore, to facilitate reporting,both physicians and workers could be better edu-cated in the signs and symptoms of pesticide illness.

In the near term, several actions could be taken toprovide greater protection to agricultural workers.Establishing more specific reentry intervals, whichtake into account the chemical and neurotoxicproperties of certain chemicals, would be a positive


step forward. EPA might also adjust its risk-benefitassessment criteria for pesticide registration toinclude the costs of pesticide poisoning of workers.Workers could be regularly monitored for exposureto pesticides, provided with appropriate protectiveclothing, trained in safe application for specificcircumstances, educated about the health effects ofexposure, and better informed about the chemicalsthey use under right-to-know laws. Mandatoryrecordkeeping on pesticide application could beincluded in the latter to ensure that workers canobtain information about previous exposures. EPAhas proposed decontamination facilities and emer-gency provisions for all workers, but more could bedone to prevent pesticide poisoning. Since thechronic effects of pesticide poisoning remain un-known, efforts may be best directed toward preven-tion.

EXPOSURE TO ORGANICSOLVENTS IN THE WORKPLACE

According to the National Institute for Occupa-tional Safety and Health (NIOSH), approximately9.8 million workers are exposed to solvents everyday through inhalation or skin contact (166).Acute exposure to organic solvents can affect anindividual’s manual dexterity, speed of response,coordination, and balance; it can also producefeelings of inebriation. Chronic exposure to someorganic solvents can result in fatigue, irritability,loss of memory, sustained changes in personality ormood, and decreased learning and concentrationabilities; in some cases, structural changes in thenervous system are apparent.

Organic solvents are a group of simple organicliquids that are volatile; that is, in the presence of airthey change from liquids to gases and therefore areeasily inhaled. Figure 10-6 illustrates the generalclasses of organic solvents. Solvents usually serveone of two general functions. They may be used inseparation processes to selectively dissolve onematerial from a mixture, or they may act as aprocessing aid, facilitating fabrication of a material(usually a polymer) by reducing its viscosity (188).They are components of a variety of products,including paints, paint removers and varnishes;adhesives, glues, coatings; decreasing and cleaningagents; dyes and print ink; floor and shoe creams,polishes, and waxes; agricultural products; pharma-ceuticals; and fuels. In 1984, approximately 49

million tons of industrial organic solvents wereproduced in the United States (167).

There are many occupations in which workers areexposed to solvents. For example, painters maycome in contact with methyl alcohol, acetone,methylene chloride, toluene, and complex mixturesof petroleum products. Depending on the exposurelevels in air, house painters may experience a varietyof adverse effects, including fatigue, impaired mem-ory, difficulty in breathing, slurred speech, nausea,dizziness, difficulty in concentrating, and dermatitis.Some researchers believe that painters may developa “psycho organic syndrome” from exposure tochronic low levels of solvents (49,58). The syn-drome is characterized by fatigue, difficulty concen-trating, learning, and remembering, and personalitychanges (32).

In order to protect workers, NIOSH recommendsthat employers educate them about the materials towhich they are exposed, the potential health risksinvolved, and work practices that will minimizeexposure to these substances (166). NIOSH alsorecommends that employers assess the conditionsunder which workers may be exposed to solvents,develop monitoring programs to evaluate the extentof exposure, establish medical surveillance for anyadverse health effects resulting from exposure, androutinely examine the effectiveness of the controlmethods being employed in order to reduce expo-sures to the permissible exposure limits (PELs)mandated by OSHA. There are three basic methodsfor minimizing worker exposure to organic solvents:using effective engineering controls, isolating work-ers from the source of exposure, and using personalprotective equipment (8).

Organic solvents are of particular concern be-cause most are toxic in different ways and to varyingdegrees and many are also flammable. The increasein the number of available organic solvents and thedevelopment of new processes utilizing them pre-sent major occupational health challenges (8,166).

Some organic solvents are also subject to abuse byinhalation. The extent of this abuse is much greaterthan is generally recognized. The National Instituteon Drug Abuse reports that the lifetime incidence ofsolvent abuse among seniors in high school (thusexcluding dropouts) is exceeded only by alcohol,tobacco, marijuana, and stimulants (113). The abuseof solvents by Hispanic and Native Americans iswidespread in some regions, exceeded only by


Figure 10-6-Classes of Organic Solvents

Allphatic hydrocarbons(Acyclic)

Straight or branched chains ofcarbon and hydrocarbons

AlcoholsContain a single OH group

Halogenated hydrocarbonsA halogen atom has replaced

one or more hydrogenatoms on the hydrocarbon

IfH H H H H H111111

H — C — C — C — C — C — C — H~~~~1~

c l

c l — c — c lH—C–OH

J

cl

n- Hexane Carbon tetrachlorideMethyl alcohol

Cyclic hydrocarbons(cycloparaffins, naphthenes)Ring structure saturated andunsaturated with hydrogen

EstersFormed by interaction of anorganic acid with an alcohol

EthersContain the C–O–C linkage

i’!’7/0

‘–~–c\o–$–~–HIIH H

Ethyl acetateCyclohexane

Ethyl ether

KetonesContain the double bonded

carbonyl group, C = O, with 2hydrocarbon groups on

the carbon

NitrohydrocarbonsContains an NO, group Glycols

Contain double OH groups

Ethyl nitrate

Ethylene glycolAromatic hydrocarbons

Contain a 6-carbon ring

structure with one

hydrogen per carbon bound

by energy from severalresonant forms

Acetone

AldehydesContain the double bonded carbonyl

group, C = O, with onlyone hydrocarbon group on the carbon‘PI

H–c/c”-ckc–H\

c = c /

~~

Acetaldehyde

Benzene

SOURCE: Alliance of American Insurers, Handbook of Organic Industrial Solvents, 6th edition, 1987, pp. 1-20.

298 ● Neurotoxicity: Identfying and Controlling Poisons of the Nervous System

alcohol abuse (l). Such exposures greatly exceedthose encountered in the workplace and can beassociated with severe and irreversible toxicities.

Uptake, Distribution, and Eliminationof Solvents

Solvents may enter the body by inhalation, dermalcontact, or ingestion. The hazards associated withdermal exposure and ingestion can be severe; in fact,numerous fatalities have resulted from exposure tomethanol by these routes. However, because of thevolatility of these chemicals, a major route ofexposure is inhalation. Exposure to the skin isanother important route. For example, immersion ofhands in methylene chloride causes neurologicaldamage (159), and carbon disulfide produces shak-ing of the hands and loss of feeling (89).

The amount of the solvent entering the bodydepends on such factors as route of exposure, theconcentration of the solvent in the air, the volubilityof the solvent in blood, and the amount of physicalwork being performed at the time of exposure. Asedentary worker on a factory floor will absorb lesssolvent than a worker engaged in a vigorous physicaltask because the latter will be inhaling more rapidlyand deeply (thereby moving more solvent to the siteof uptake in the lungs) and more blood will betraveling through the lungs (carrying the solventthroughout the body).

Some solvents tend to be distributed unequallyamong the organs of the body. This is both becausethe volubility of a particular solvent varies withdifferent tissues and because the blood supply totissues varies greatly. Thus, an organ like the brain,with its high fat content and very rich blood supply,achieves high levels of solvents quickly. Given aconstant concentration of solvent in the air, theamount of solvent present in body tissues eventuallyreaches a plateau in each tissue, but the time requiredto achieve that plateau varies among tissues andamong individuals.

At the same time that the body is absorbingsolvents, it is working to eliminate them. If exposureceases or is reduced, the solvent begins to beexhaled, or “blown off. ” Enzymes may change thestructure of the solvent, making it more watersoluble and enabling the kidneys to eliminate it. Themetabolism of solvents can be a two-edged sword,however, since the metabolize may be more toxicthan the parent solvent. Mixtures of solvents or

Photo credit: United Automobile, Aerospace, and Agricultural ImprovmntWinkers of America-UA’VPublic Relations Department

Respirators may be useful in minimizing exposure tosolvent vapors when engineering or work practice controls

are inadequate.

industrial grade solvents may be more toxic thanpure solvents, either because of toxic contaminantsor because of chemical interactions.

Neurological and Behavioral Effects

All solvents are soluble in fat and will at somelevel of exposure produce effects on the centralnervous system (35). For a wide variety of drugs andchemicals, the more soluble the chemical is in brainmembranes, the more potent it is and the longer itacts.

Interest in the effects of solvents on the centralnervous system dates back to the early search foranesthetics, when many agents were examined.Short-term exposures at low toxicity may producemucous membrane irritation, tearing, nasal irrita-


tion, headache, and nausea (35). With repeatedinhalation of high levels of solvents, a state of severenarcosis may be produced; at lower levels, theeffects resemble those of alcohol. There may beinitial euphoria, loquaciousness, and excitement,followed by confusion, dizziness, headache, motorincoordination, ataxia, unconsciousness, and death.These so-called nonspecific narcotic effects ofsolvents are the major reason they are regulated inthe workplace; they can impair work performanceand the ability to avoid hazards (35).

Toxicity studies and health problems in theworkplace have revealed other effects that arespecific to individual solvents or classes of solvents.For example, neuropathies may result from chronicexposure to hexane, methyl-n-butyl ketone, andrelated solvents. This disorder (sometimes referredto as hexacarbon neuropathy) is characterized bynumbness in the hands and feet and may progress tomuscle weakness and lack of coordination (152).Some solvents produce seizures and convulsions onacute exposure, for example, such alkylcycloparaffinsas methylcyclopentane and methylcyclohexane (79,80,129). Indeed, epileptic seizures in the workplacemay be mistakenly attributed to an undiagnosedneurological defect of the worker rather than to achemical exposure.

Adverse effects on the inner ear may also becaused by exposure to solvents. For example,exposure to high levels of alkylbenzenes such astoluene and xylene can damage the inner ear, leadingto high-frequency hearing loss (128,130,133). Dizzi-ness and vertigo have been reported following acuteexposure to a variety of solvents. Exposure may alsoadversely affect various visual functions and thesense of smell (43,94,95).

Some solvents may cause emotional disorders.Carbon disulfide can produce a raging mania and hasbeen associated with increased risk of suicide (92).In 1902, Thomas Oliver described his visits toIndia-rubber factories in London and Manchester,noting “the extremely violent maniacal conditioninto which some of the workers, both female andmale, are known to have been thrown. Some of themhave become the victims of acute insanity, and intheir frenzy have precipitated themselves from thetop rooms of the factory to the ground” (122).

Other disorders associated with exposure tosolvents include sleep disturbances, nightmares, andinsomnia (18,190). Trichloroethylene or its contam-

inants may damage facial nerves and produce facialnumbness (20). Severe brain injuries (chronic enceph-alopathies) have been documented following pro-longed exposures to high levels of solvents, such asduring deliberate self-administration of solvents.This has produced concern about the likelihood ofsuch effects occurring in the workplace. Prolongedexposure to styrene may produce impairments inperceptual speed and accuracy, memory, and cogni-tive performance (60).

The Solvent Syndrome: A Current Controversy

There is considerable evidence that toxic enceph-alopathy may be caused by high-level, prolonged,and repeated exposure to some organic solvents(158). Encephalopathy consists of a wasting of brainmatter, which leads to expansion of the fluid-filledcavities in the brain. The syndrome is associatedwith motor disorders and impaired mental function.Several Scandinavian countries have identified anew disease entity, a toxic encephalopathy follow-ing chronic solvent exposure, and compensate work-ers who develop it at the workplace (52). However,the studies used to document the syndrome’s exis-tence are the subject of controversy (45,58). Amultinational study of workers exposed to solventsis being funded by a consortium of industrial groups(158). In studies of this type, many variables mayobscure the detection of an effect or erroneouslysuggest its existence. These include age, concurrentexposure to other chemicals, excessive alcoholintake, drug abuse, and socioeconomic status. Infact, a recent reanalysis of test data failed to confirman earlier report of a ‘‘chronic painters’ syndrome”with dementia (54). Many studies suffer from nothaving extensive documentation of workplace expo-sure levels. It was having such information onexposure that enabled investigators to do landmarkstudies of carbon disulfide neurotoxicity. Thesestudies revealed differences in suicide rates amongworkers in a rayon factory as a function of workassignment and associated carbon disulfide expo-sure within the plant (92).

Although painters are exposed for long periods oftime to solvents, their exposure is moderate incomparison to that of solvent abusers, who routinelyexpose themselves to very high concentrations. Theinjuries to the nervous system suffered by solventabusers are unequivocal and severe (53,78,1 38,142).A scientific conference recommended directionsthat human and animal research should take (9). The


lack of an animal model inhibits the normal regula-tory process of hazard identification, risk assess-ment, and risk management. Just as prudent regula-tory actions are undertaken to minimize the risk ofcancer in humans when tumors are observed inlaboratory animals, a nervous system injury orbehavioral disorder identified in laboratory animalscould be the basis for regulation to reduce thelikelihood of injury to the human nervous system. Todate, little effort has been devoted to developing ananimal model of the solvent syndrome.

Health Protection

There are several methods for controlling workerexposure to organic solvents, including workerisolation, use of engineering controls, and personalprotective equipment. Proper maintenance proce-dures and education programs are important ingredi-ents of protection programs. OSHA regulationsrequire that workers be informed about the hazardsassociated with the chemicals present in theworkplace (29 CFR 1987 ed. 1910.1200). NIOSHrecommends that employers establish a medicalsurveillance program to evaluate both the acute andchronic effects of exposure to organic solvents andthat workers undergo periodic medical examinations(166). Both physicians and workers should be giveninformation regarding the adverse effects of expo-sure to organic solvents and an estimate of theworker’s potential for exposure to the solvents. Thisinformation should include the results of workplacesampling and a description of protective devices thatthe worker may be required to use (166).

Contaminant Controls, Worker Isolation, andPersonal Protective Equipment

The primary means of preventing contaminationis by applying appropriate engineering controls.These may be necessary to eliminate the potentialfor exposure and to prevent fires and explosions.Achieving an adequate reduction of exposure to asolvent depends on the construction and mainte-nance of the engineering control applied to thesystem, the exposed liquid surface, and the tempera-ture and vapor pressure of the solvent. Closedsystem operations are the most effective method ofminimizing worker exposure. Closed system equip-ment can be used for manufacturing, storing, andprocessing organic solvents. As an alternative,workers can be isolated from the process by beingenclosed in a control booth.

Photo credit: United Automobile, Aerospace, and Agricultural ImplementWorkers of America-UAWPublic Relations Department

Millions of workers come into contact with toxic substancesevery day through inhalation or skin contact, Many of thesubstances are known to be or are potentially neurotoxic.

When a closed system cannot be implemented,exhaust fans can be used to direct vapors away fromworkers and to prevent the contaminated air fromrecirculating in the workplace (166). In addition,personal protective equipment may be necessary(see box 10-G).

Respirators may be needed to minimize exposurewhen engineering or work practice controls areinadequate for this purpose. Respirator may berequired for protection in certain situations such asimplementation of engineering controls, some short-duration maintenance procedures, and emergencies.The use of respiratory protection requires that theplant or company institute a respiratory protectionprogram (166). Direct contact of organic solventswith the skin can be prevented by wearing solvent-resistant gloves, aprons, boots, or entire work suits.Depending on the workplace and on the hazardous


Box 10-G-Engineering Controls v. Personal Protective Devices

The scientific and technical community has generally preferred engineering controls, that is, changes inthe design of the physical environment and equipment used in the workplace, to personal protective devices,such as respirators, because:

● workers are erratic in their use of personal protective devices; such devices are cumbersome and, in the case of respirators, even the most conscientious worker may

have difficulty ensuring an effective seal between face and mask;. personal protective devices themselves require maintenance, such as periodic replacement of air

filters; and● it can be difficult to know when a personal protective device has failed.

The Occupational Safety and Health Act (OSH Act) was designed to decrease worker exposure to toxicsubstances and to provide information to employees about remaining occupational health risks. Maintaininglow levels of toxic substances in the workplace through engineered controls has historically been givenpriority over the use of personal protective devices, except in those cases where it is not feasible to useengineering controls to reach the OSH Act exposure limit. Engineering controls are generally more expensivethan personal protective equipment, and small plants and businesses often cannot afford to make expensivechanges.

The mandate of the Act, however, has been to maintain a safe workplace, regardless of the size of thebusiness. If it is not feasible to institute engineering controls or to engineer down to what the Act determinesto be a safe level of exposure, then personal protective equipment is an acceptable choice. Recent changesin the existing rule on methods of compliance (54 FR 23991) allow respiratory protection to be used in lieuof administrative or engineering controls under the following circumstances (54 FR 23991):

1. during the time necessary to install or implement feasible engineering controls;2. where feasible engineering controls result in only a negligible reduction in exposures;3. during emergencies, recovery operations, unscheduled repairs, shutdowns, and field situations where

there are no utilities for implementing engineering controls;4. operations requiring added protection where there is a failure of normal controls; and5. entries into unknown atmospheres (e.g., entering vessels, tanks, or other confined spaces for

cleaning).In addition to regulatory requirements, there are important ethical arguments about engineering controls

versus personal protective devices. What are the important values at stake? The health, well-being, andautonomy of the worker are obviously important. (Autonomy refers to behaviors that reflect the capacity ofcompetent adult individuals to formulate life plans and make decisions freely, without coercive influences.)

The Act is designed to ensure a safe and healthful workplace by setting exposure levels and establishingstandards on behalf of the worker. One can argue that the option of using personal protective devices givesthe worker a choice in determining the extent of exposure to hazardous substances. Yet it is difficult to imaginewhy a worker would prefer to use a cumbersome device like a respirator rather than have the workplace andequipment engineered to be safer. In situations in which it is not feasible to engineer safe levels of exposure,the use of personal protective devices may be the only option for working safely. On occasion, employeesmay decide to work in an area that requires the use of personal protective equipment in order to gain aparticular type of work experience or to make more money. From an ethical standpoint however,circumstances in which there exists some coercive element are objectionable.

On balance, the interests of the worker seem to be best served by the use of engineering controls thatlower levels of exposure to toxic substances for most workers most of the time. Some employers, however,can and do continue to argue that the greatest good for the greatest number requires at least some reliance onthe use of personal protective devices.



properties of the substance, face shields and safetygoggles may be required.

OSHA Regulations

The principal reason for the enactment of theOccupational Safety and Health Act of 1970 was toprotect workers from occupational safety and healthhazards. To accomplish this goal, OSHA setsminimum standards for working conditions. Haz-ards not mentioned in the standards are covered bythe “general duty clause,” which requires eachemployer to maintain a workplace ‘‘free f romrecognized hazards. ” All work environments mustmeet the regulations and standards set by the law (29CFR 1987 ed. 1900-1910). OSHA has the authorityto conduct inspections, determine compliance withthe standards, and initiate enforcement actionsagainst employers who are not in compliance.

If an inspector documents a violation, it i sreported to the OSHA area director, who theninforms the employer of the citation or proposedpenalty. If the employer disagrees with the action, heor she may contest it by informing the Departmentof Labor within 15 working days of the citation.When notification is received that an action is beingcontested, the Occupational Safety and HealthReview Commission is notified, and this reviewcommission assigns the hearing to an administrativelaw judge. Following the hearing, the judge mayissue an order to affirm, modify, or vacate thecitation or proposed penalty. The order is final after30 days unless the commission reviews the decision.If the employer decides not to contest the citation, heor she must correct the situation that is in violationof the standards. If the employer cannot do so withinthe proposed abatement period, an extension mayberequested. The law provides for fines of up to $1,000for each violation and up to $10,000 if the violationis willful or repeated (29 CFR 1987 ed. 1903).

The PEL Controversy

OSHA recently published a revised standard thatincreased the protection of workers by implementingnew or revised PELs for 428 toxic substances,including a number of organic solvents (53 FR20960-20991). The final standard was published inJanuary 1989. According to the Department ofLabor, the new limits will reduce considerably therisk of illness, including cancer, by using the forceof law to ensure that workers are not exposed atlevels above the new PELs. The final rule was

effective in March 1989, and the start-up date forcompliance with any combination of controls (e.g.,personal protective equipment) was September 1989,whereas compliance with engineering controls isdelayed until December 31, 1992, or in some casesa year later.

The PELs are listed in the so-called Z tables in theOSHA regulations (29 CFR 1910.1000). The recentchanges include revising the PELs, adding short-term exposure limits (STELs) to complement the8-hour time-weighted average (TWA) limits, andwhere necessary designating skin or ceiling limitsfor the substances (54 FR 2332-2403). According tothe Department of Labor:

OSHA has reviewed health, risk and feasibilityevidence for all 428 substances for which changes tothe PEL were considered. In each instance where arevised or new PEL is adopted, OSHA has deter-mined that the new limits substantially reduce asignificant risk of material impairment of health orfunctional capacity among American workers, andthat the new limits are technologically and economi-cally feasible. This determination has been based onfurther review of the material discussed in theProposal, public comments and a detailed review ofthe entire record for this rulemaking (54 FR 2334).

The new rule established lower exposure limitsfor approximately 212 substances already regulatedby OSHA. PELs would be established for the firsttime for another 164 substances. A large number ofthese are established to prevent adverse effects onthe nervous system. According to the Department ofLabor:

. . . Benefits will accrue to approximately 4.5million workers who are currently exposed in excessof the PEL and are expected to include over 55,000occupational illness cases, including almost 24,000lost workdays annually. If not prevented, theseillnesses would eventually result in approximately700 fatalities per year. . . . The annual cost isapproximately $150 per worker protected, and isnever more than a fraction of 1 percent of sales andless than 2 percent of profits (usually substantiallyless) except for a very few segments . . . (54 FR2335).

The approach used to develop the regulations ofthe new PELs has been controversial (54 FR3272-2377). In evaluating the PELs, OSHA used thethreshold limit values (TLVs) published by theAmerican Conference of Governmental IndustrialHygienists (ACGIH) published in 1988 and the

Chapter 10--Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 303

recommended exposure limits (RELs) developed byNIOSH as its starting point. The agency comparedthe PELs to the Z tables and to the TLVs. If the twodiffered, the PEL was evaluated for revision. Theagency first determined if the TLVs and RELs weresimilar. If they were, or if there was no REL, thenOSHA studied the TLVs. If the TLV and RELdiffered significantly, OSHA examined the scien-tific basis of each recommendation and determinedwhich was more appropriate. According to OSHA:

In its review, OSHA determined frost whether thestudies and analysis were valid and of reasonablescientific quality. Second, it determined, based onthe studies, if the published documentation of theREL or TLV would meet OSHA’s legal require-ments for setting a PEL. Thus, OSHA reviewed thestudies to see if there was substantial evidence ofsignificant risk at the existing PEL or, if there was noPEL, at exposures which might exist in theworkplace in the absence of any limit. Third, OSHAreviewed the studies to determine if the new PELwould lead to substantial reduction in significantrisk. If this was so, and if the new PEL was feasible,OSHA proposed the new PEL (54 FR 2372).

The TLVs, RELs, and old and new PELs of someselected solvents are listed in table 10-6.

The final standard has been controversial becauseit represents a substantially different approach toOSHA rule-making. Until this action, OSHA ad-dressed toxic substances individually, a process thatproduced standards for only 24 substances in 17years. In this single rule-making, however, OSHAestablished new exposure limits for 376 toxicsubstances by adopting the TLVs published byACGIH. Industry and several unions expressedconcern that OSHA was delegating its regulatoryauthority to a nongovernment organization and thatin some cases TLVs are not based on recent studies(25,139). The extent of corporate influence on TLVshas also been the subject of debate (25). Someunions contended that ACGIH is dominated byindustry and that OSHA’s action subverts theactivities of NIOSH (139).

NIOSH offers RELs for chemicals followingcareful review of available data and bases itsrecommendations solely on the chemical’s effectson health. However, OSHA, by law, cannot enforcea standard with a recommended exposure limit(REL) that is not technologically or economicallyfeasible. These constraints often prevent OSHAfrom lowering a limit on the basis of health

Table 10-6-Representative Exposure Limitsto Solvents

Measure (ppm)

Solvent R E La T L Vb Old PELC New PELToluene ., . . . . . . . . . . 100 100 200Xylene . . . . . . . . . . . . . . 100 100 100Cresol . . . . . . . . . . . . . . 2.3 5d 5dAcetone . . . . . . . . . . . . 250 750 1,000Styrene . . . . . . . . . . . . . 50 50 100Tetrachloroethylene . . . — 50 100Methyl chloroform . . . . 200 350 350Allyl chloride . . . . . . . . . 1 1 1Furfuryl alcohol . . . . . . 50 10d

50Ethylene dichloride , . . 1 10 50Benzene . . . . . . . . . . . . 0.1 10Carbon disulfide . . . . . . 1 10 d Z.Trichloroethylene . . . . . 25 50 100Chloroform . . . . . . . . . . — 10 50

100100

4750

5025

3501

101

104

502

aREI-s (recommended exposure hmits) are set by the National hIstltute forOccupational Safety and Health.

%LVS (threshold limit values) are set by the American Conference ofGovernmental Industrial Hygiemsts.

CPELS (permissible exposure limits) are set by the Occupational safety andHealth Administration.

dThe ACGIH designation “skin’’(s) refers to the potential contribution Ofexposure by the cutaneous route, including mucous membranesand eyes.

SOURCES: 54 FR 2332-2983; 29 CFR 1987 ad. 1910.1000; R.B. Dick,“Short Duration Exposures to Organic Solvents: The Relatlon-shlp Between Neurobehavioral Test Results and Other indica-tors,” Neurotoxicology and Teratology 10:39-50, 1988; U.S.Department of Health and Human Services, National Institutefor(lccupational Safety and HeaJth, ‘Organic Solvent Neurotoxic-Ity,” Current Intelligence Bulbtin 48:1-39, 1987.

considerations alone, that is, on NIOSH’s recom-mendation.

Public comments submitted to OSHA on the PELproposal were in broad agreement that the PELsneeded updating; however, many thought the projectwas being undertaken hastily and that the publicinterest would not be well served by such a majorprocedural change. Some commentors recommendedthat periodic updates be conducted on a morefrequent and less harried basis.

By using the ACGIH list of TLVs as the basis forits selection, OSHA was able to save a great deal ofthe time it would have taken to address thesechemicals through the usual regulatory procedures.OSHA is constrained to conduct a number ofanalyses by statute or executive order, includingextensive economic analyses. By its own admission,OSHA states that it follows more extensive andelaborate administrative procedures than otherhealth regulatory agencies:

. . . Clearly an improved approach to regulation isneeded to solve this problem in a reasonable timeperiod. OSHA’s traditional approach, which has


permitted on the average less than two major healthregulations per year, is not adequate to address thebacklog of at least 400 chemicals generally recog-nized as needing new or lower exposure limits.OSHA has reviewed the law, Congressional intent,its history, and the recommendations of experts . . .[and has] concluded that this approach has a greaterhealth benefit and will prevent more deaths andvarious deleterious health effects, than could beachieved by allocating the same resources to com-prehensive rulemaking for a small group of sub-stances. . . (54 FR 2370).

The advisability of using the recommended expo-sure standards of a private organization instead ofNIOSH is likely to be a subject of continuingcontroversy in the occupational health arena.


Organic solvents and mixtures of solvents with orwithout other toxic substances are widely used in theworkplace. It is estimated that 9.8 million workerscome into contact with solvents every day throughinhalation or skin contact. Some solvents mayprofoundly affect the nervous system. Acute expo-sure to solvents can affect an individual’s manualdexterity, response speed, coordination, or balance.Chronic exposure may lead to reduced function ofthe peripheral nerves and such adverse neurobehav-ioral effects as fatigue, irritability, loss of memory,sustained changes in personality or mood, anddecreased learning and concentration abilities.

In order to protect workers, OSHA requires thatemployers inform and educate workers about thepotential health risks of the materials to which theyare exposed and adopt work practices that minimizeexposure to hazardous substances. NIOSH recom-mends that employers assess the conditions underwhich workers may be exposed to solvents, developmonitoring programs to evaluate the extent ofexposure, establish medical surveillance for anyadverse health effects, and routinely examine theeffectiveness of the control methods.

OSHA recently updated the permissible exposurelimits for 428 substances, many of them solvents.The new ruling established lower PELs for 212substances already regulated by the agency. PELswere also established for the first time for another168 substances, while existing limits for 25 sub-stances were reaffirmed. This marks the first time in17 years that a new set of exposure standards hasbeen established. The mechanism by which the new

PELs were set, however, is the subject of contro-versy.

For many companies, meeting the new standardsmay require stricter engineering controls or morefrequent use of respirators and other personalprotective devices, or both. OSHA requires compa-nies to educate workers about the hazards of thesubstances to which they are exposed, to institutecontrol methods to prevent exposure, and to formu-late plans or procedures to maintain compliance withthe new rulings.

There is insufficient information available toregulatory agencies to distinguish dangerous sol-vents from ones that are not dangerous. Creativeapproaches are needed to protect workers whileavoiding unnecessary and overly burdensome regu-lations. To fill this need, research programs inacademia, industry, and government will have to beexpanded significantly. If NIOSH is to play animportant future role in the development and analy-sis of information on safe exposure levels forsolvents, then additional resources will be requiredand the Institute will have to make a commitment tofocus more attention on the neurological and behav-ioral effects of solvents. Improvement in the devel-opment of toxicity standards will require a substan-tially closer working relationship between OSHAand NIOSH.


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Appendixes

Appendix A

The Food Additive Approval Process: A Case Study

The primary responsibility of the Food and DrugAdministration (FDA) is to ensure that the food and drugsAmericans consume and the medical devices and cosmet-ics they use are safe. In so doing, it ties not to deny ordelay unnecessarily Americans’ access to new or moreaffordable foods, food additives, and therapeutics. Toillustrate how FDA’s review procedures work, this casestudy discusses the approval process for aspartame, a foodadditive for which questions about possible neurotoxiceffects were raised.

Aspartame, more commonly known as Nutrasweet, isan artificial sweetener that is used by more than 100million people (3). Users include persons with a medicalneed to reduce sugar intake, such as diabetics and obeseindividuals, as well as the general population. Thesweetener is composed of phenylalanine and asparticacid, two naturally occurring amino acids. Aspartame’sextreme sweetness, 180 to 200 times that of sugar, wasdiscovered serendipitously in 1965 by two G.D. SearleCorp. scientists, 8 years before submission of the firstfood additive petition for the compound, After aspar-tame’s approval as an additive, the amount added to foodsincreased substantially each year until 1985, when itappeared to reach a plateau. Approximately 75 percent ofall the aspartame used in the United States is used incarbonated diet beverages. An ongoing dietary survey ofaspartame ingestion undertaken by FDA indicates that 35percent of the population (40 percent of adults) are regularusers of aspartame.

The Application Process

preapplication

The first step in the food additive approval process, aninformal meeting with FDA staff, is optional. The staff ofthe Center for Food Safety and Applied Nutrition(CFSAN) encourage applicants to discuss with them thenature of the compound, available animal toxicity dataand uses for which approval is sought before formallysubmitting a petition. In these meetings, potential prob-lems can be identified, enabling applicants to begin anynecessary research quickly. Although both CFSAN andthe Center for Drugs and Biologics encourage thesemeetings, they occur much more frequently with drug-licensing applications, where problems are often moreevident. G.D. Searle did meet informally with CFSANstaff before submitting its petition in February 1973.

Application

Searle petitioned FDA for permission to marketaspartame as an additive for certain foods (38 FR 5921).Section 409 of the Federal Food, Drug, and Cosmetic Actrequires FDA to evaluate and act on petitions for approval

of food additives. Petitions are evaluated for toxicology,chemistry, probable consumption levels, and potentialenvironmental and health impact. The applicable safetystandard is the “reasonable certainty of no harm, ” and theburden of proof is on the petitioner. This standard is lessstringent than that for new drugs, which must be proven‘‘safe and effective” in human studies.

The Act does not require specific tests to measure theneurotoxic potential of any compound, and FDA gener-ally assumes that adverse neurobehavioral effects willbecome apparent during routine toxicological studies inanimals. However, if neurotoxic potential is suspectedbecause a substance is structurally similar to a knownneurotoxic substance or for any other reason, FDA mayspecifically require a neurotoxicological evaluation. Nor-mally, only animal toxicity (preclinical) studies arerequired for foods and food additives. In contrast, newdrug approval requires that the results from three phasesof human studies be submitted for review.

Review

Following receipt of a petition, FDA personnel identifythe types of reviews appropriate for the particularapplication. Reviews are frequently solicited from FDAstaff in other divisions with relevant expertise.

Every application is reviewed for potential toxicity.The ancient Roman credo “moderation in all things” isthe first principle of toxicology. Virtually every food andchemical in existence can be toxic in excessive quantities;therefore, the first step is to assess the chemical to whichhumans will be exposed and estimate the degree ofexposure. This is done by testing what happens when thefood additive is administered to laboratory-grown mam-malian cell lines and animals and by analyzing thechemistry of the compound, including identifying theadditive and products of its metabolic breakdown andestimating the likely level of human exposure. Thesestudies identify the types of toxicity caused by thecompound and determine the amounts required to pro-duce the toxic effects.

Initially, concerns were raised that aspartame mightlead to significantly higher concentrations of phenylalan-ine in the blood, which could lead to mental retardation inchildren with the genetic disease phenylketonuria (PKU).One in every 50 to 70 Americans carries the gene forPKU, and every year 200 children are born with thisdisease (1 of every 14,000 to 15,000 live births). PKUresults only if a child has two copies of the gene, one fromeach parent. Fortunately, if PKU is identified at birth,mental retardation can be prevented by a diet that isrestricted in phenylalanine. By law, all newborn babies inthe United States must be tested for PKU.

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Approval

Toxicological studies on animal models were deter-mined to be sufficient, and Searle’s petition to addaspartame to some foods was approved on July 26, 1974(39 FR 27317-27319). It was approved for consumer useas a dry sugar substitute in granular and tablet form andfor industry use as an addition to cold breakfast cereals,chewing gum, and dry bases for beverages, instant coffeeand tea, gelatins, puddings, fillings, and nondairy top-pings.

The toxicity research on which approval was basedincluded 2-year feeding studies in rats and dogs as well asa lifetime feeding study in rats first exposed to aspartameas fetuses. Based on these studies, a no observed effectlevel (NOEL), or the largest amount of the additive thatcould be administered without evidence of toxicity inanimals, was established-namely, 2 grams of aspartameper kilogram of body weight. The acceptable daily intakefor humans is somewhat arbitrarily set at 100 times lessthan the NOEL for animals, thus the acceptable dailyintake was set at 50 milligrams of aspartame per kilogramof body weight per day. For a 140-pound man, this is theequivalent of approximately 17 (12-ounce) diet sodas or100 packets of coffee sweetener per day (4). Estimates ofthe probable maximum daily intake (1.3 to 1.7 grams)were sufficiently close to the acceptable daily intake topermit product approval. The petitioner submitted datafrom clinical (human) studies which showed that theapproved levels of aspartame would not elevate concentra-tions of phenylalanine in the blood.

Appeal

Two parties objected to the approval of aspartame ongrounds of questionable safety and, as is their right,requested a hearing before a judge. However, because ofthe scientific controversy surrounding the approval proc-ess, FDA decided instead to convene a Public Board ofInquiry (15). The board, consisting of three expertsappointed by the FDA Commissioner, would hear evi-dence and make a recommendation to the Commissioner,who would then make the final decision. The board wasasked to consider whether aspartame, alone or in combina-tion with glutamate, an amino acid found in monosodiumglutamate (MSG), could contribute to brain damage ormental retardation. In addition, if marketing approvalwere recommended, the board was to suggest appropriatelabeling and use restrictions. In response to an additionalobjection, the board also evaluated evidence that aspar-tame ingestion resulted in cancer in rats. (The Delaneyclause prohibits approval of any food or additive that isshown to be carcinogenic in animals following appropri-ate testing. If carcinogenic potential is demonstrated, theclause mandates that no level of usage for humans can beconsidered reasonably safe.)

Before the Public Board of Inquiry was convened,Searle voluntarily suspended plans to market aspartame,pending the resolution of an additional objection, aquestion about the role of diketopiperazine (DKP, aproduct of the metabolic breakdown of aspartame) in thedevelopment of benign growths in the uterus of femalerats (5). (The eventual conclusion was that DKP did notpromote the development of these benign growths.) Anadditional complication resulted from questions raisedabout the reliability of the animal testing data submittedby the petitioner. As a result, FDA stayed the approval,pending additional review and audit of the animal studies(40 FR 56907). The audit was performed both by the FDAand an independent organization, Universities Associatedfor Research and Education in Pathology. The processtook more than a year and resulted in the conclusion thatthere were no discrepancies sufficiently significant tocompromise the results of the studies.

This conclusion cleared the way for convening thePublic Board of Inquiry in January 1980. The board wascomposed of three distinguished scientists with expertisein neurology, pathology, and nutrition. The role of thisboard, like other FDA advisory committees, was merelyadvisory; its conclusions were not binding on FDA, whichhas statutory responsibility for approval decisions. Solici-tation of outside expert opinion, a regular procedure in theevaluation of drugs and biologics, occurs less often inCFSAN. This is presumably because most of theirdecisions are not controversial. In fact, this board was thefirst external advisory panel convened by CFSAN.

The panel heard 3 days of testimony, including newclinical data, from FDA staff, G.D. Searle staff, andinterested scientists. To the consternation of both FDAand Searle staff, the board’s report was not delivered untilthe fall of 1980. The new clinical data that were presentedallowed the board to establish an estimate of themaximum daily intake of aspartame (34 milligrams) by anaverage-sized man. This step was essential for anevaluation of the toxic potential of aspartame use. Thedata also demonstrated that the ingestion of very largequantities of aspartame, equivalent to 12 liters of aspartame-sweetened beverage in a single sitting, raised phenylalan-ine concentrations in the blood to only slightly abovenormal [from the normal 6 to 12 micromole per deciliterof blood (uM/dl) to 20 uM/dl]. Studies of people withPKU have shown that only sustained, extremely elevatedconcentrations (above 100 uM/dl, or 50 uM/dl forpregnant women) are associated with developmentalbrain damage. This damage can be prevented by re-stricting dietary phenylalanine. Therefore the boardconcluded, and FDA concurred, that aspartame usewould not contribute to the type of brain damageassociated with sustained high levels of phenylalaninein the blood. However, the board did recommend thatall aspartame-containing products carry informational

Appendix A-The Food Additive Approval Process: A Case Study .317

statements to alert people on phenylalanine-restricteddiets.

Additional animal and clinical studies demonstratedthat the products resulting from the metabolic breakdownof aspartame, alone or in combination with other dietarycompounds, including glutamate, had no neurotoxicpotential. Clinical studies of possible toxicity arealmost never required for the approval of foods orfood additives. The aspartame application was unu-sual in that the sponsor voluntarily conducted clinicalstudies and submitted the results to FDA during thereview process. Indeed, ‘‘extensive clinical safety studieswere conducted under the (original) food additive petitionwith the awareness and encouragement of the FDA” invarious populations with metabolic disorders (17). Theresolution of questions of clinical toxicity requires thatclinical studies be carried out, so these would presumablyhave been required by FDA even if they had not beenprovided by the sponsor.

The board also found, however, some questions aboutwhether aspartame caused tumors in rats. This findingwas based on an incidence of brain tumors, equivalent inthe aspartame-treated and control rats, that was higherthan the expected incidence of spontaneous tumors. Thisconclusion would result in automatic disapproval of thefood additive petition, as required by the Delaney clause.FDA disputed the validity of the data and cited widevariations in the literature regarding spontaneous inci-dence of brain tumors in rats, as well as the lack of astatistically significant difference between the treated andcontrol groups.

Final ApprovalA decision on the merits of the aspartame application

was further delayed to allow all interested parties toprepare exceptions to the findings of the board. In earlyMarch 1981, a number of FDA staff members wereselected to serve as advisors to the Commissioner for thispetition. This group’s deliberations were perhaps hurriedby Searle’s intention to file suit in Federal court againstthe FDA for unreasonable delay (18). Searle’s majorconcern was that its period of patent exclusivity was beingsignificantly diminished. In 1982, the Senate passed anamendment to the Orphan Drug Act which extended thepatent life of products that had experienced unusualregulatory delays in approval.

Following evaluation of additional studies on thequestion of whether aspartame induces tumors in rats,FDA issued its final ruling in July 1981, a year after themeeting of the board and 8,5 years after the original filingof the petition (see table A-1). The FDA report concluded

l!!


that there was no evidence that either aspartame or itsbreakdown product, DKP, contributed to the developmentof brain tumors in rats. This avoided the obligatoryinvocation of the Delaney clause,l FDA concluded thatproper handling of foods containing aspartame wouldprevent this breakdown and that the consumption of amishandled product, although possibly unsavory, wouldbe safe.

An additional concern addressed by FDA was thatmethanol, a metabolize of aspartame, might cause adverseeffects. A review of the data revealed that aspartameconsumption resulted in the production of smaller amounts

1~ 1977, ~A, on tie bml~ of ~onv~c~g ~viknm of tie ~Uc~ogeNc po~nti~ of ~~~hfi in rats, ~d attempt~ to ret’n~e sa~~ from the “getlerdly r~gIli~as safe’ list. The resultant public outay caused Congress to .spedlcally exempt saccharin from the requirements of the Delaney clause, but at the same time required thatfoods containing saccharin carry a prominent w arning label (8).


Table A-l-Chronology of the AspartamePetition Process

Date Action

February 1973July 1974April 1975

December 1975

September 1976December 1978June 1979January 1980October 1980January 1981March 1981JUIY 1981

Petition filedPetition approvedSearle voluntarily suspends plans to market a

response to objectionsFDA stay of approval to review and authenti-

cate dataData audit initiatedData found acceptableNotice of public hearingPublic Board of Inquiry coveredBoard report represented to FDADeadline for comments on Board reportFDA advisors to Commissioner selectedPetition approved


of methanol than resulted from eating many fruits andvegetables and that this toxic potential was thereforenegligible. A final concern was that aspartame, eatenalone or in combination with carbohydrates, might alterthe activity of neurotransmitters. A study of infantmonkeys fed large quantities of aspartame or phenylalan-ine continually for 9 months showed that their develop-ment and behavior were normal and that there was noevidence of seizures or irregularities in brain waves (1 1).Therefore, aspartame was finally approved as a foodadditive in July 1981 (46 FR 38285-38308; 40 FR 46394)and for use in carbonated beverages in July 1983 (48 FR31376-31382).

In the case of aspartame, approval was based on amassive amount of data derived from animal andhuman studies. However, the vast majority of foodadditive petitions are approved on the basis of animalstudies alone. It has been repeatedly demonstratedthat the effects of active chemicals in animals are notalways predictive of their effects in humans.

FDA has supported limited research on the develop-ment of neurobehavioral testing methods to assesspotential neurotoxic effects of food additives. Indeed, a1983 article written by FDA staff concludes with thestatement:

Within the general field of toxicological testing, theFDA Bureau of Foods views the development of behav-ioral teratological or neurotoxicological testing as one ofthe most important and urgent areas for future improve-ment. We await with keen interest the creation of testingparadigms that can be recommended for routine meas-urement of the neurotoxic potential of food additivesubstances (5).

Postmarketing Surveillance

Until recently, there was no formal postmarketing, orPhase IV, procedure for evaluating any adverse reactions

to a newly approved food additive; however, aspartame’sapproval agreement of 1981 included the establishment ofa postmarketing survey. The survey had two components:1) a poundage survey, in which sales of aspartame to foodand pharmaceutical industries were reported; and 2) adietary survey, in which actual ingestion of aspartame bya sample population was reported. Partially in response tothe publicity surrounding the approval of aspartame, FDAalso established a passive system of review of consumercomplaints. In 1985, FDA asked the Centers for DiseaseControl (CDC) to evaluate the complaints received. TheCDC concluded, on the basis of interviews conductedwith 517 complainants, that “although it may be thatcertain individuals have an unusual sensitivity to theproduct, these data do not provide evidence for theexistence of serious, widespread, adverse health conse-quences attendant to the use of aspartame” (2).

A more extensive postmarketing reporting system, theAdverse Reaction Monitoring System, was implementedin July 1985 for all food additives as part of FDA’s Planfor Action, Phase I. This monitoring system was strength-ened in December 1985 with the publication of a“Request for Reports of Adverse Food Reactions” in theFDA Drug Bulletin. This announcement requested thatphysicians and other health professionals inform CFSANof any severe, well-documented reactions associated withfoods, food additives, or dietary practices. In the FDAPlan for Action, Phase II, announced in 1987, this systemwas expanded to incorporate data from other governmentagencies, industry, and professional organizations.

Besides monitoring adverse reactions, FDA conductedresearch in the postmarketing period on the safety ofaspartame. A contract was awarded to Battelle MemorialInstitute to evaluate the effects of altered amino acidbalances on rodent brain function, with an emphasis onneurotransmitters. Also, FDA transferred funds to theNational Institute of Environmental Health Sciences inFebruary 1987 for study of the impact of amino acidimbalances on seizure thresholds and neurobehavioralfunction in rodents. This study is still under way, butpreliminary results demonstrate that large doses ofaspartame do not affect the sensory or motor functions,learning and memory, or seizure induction in rats (19).Another interagency agreement transferred funds to theFederal Aviation Administration to study the effects ofaspartame on the performance of airplane pilots on anumber of complex laboratory-based tests of physical andmental function.

Claims of Adverse Effects

Despite the preclinical evidence of safety, there havebeen numerous consumer complaints alleging that aspar-tame use resulted insignificant medical problems, includ-ing seizures, severe headaches, tremors, insomnia, dizzi-ness, panic attacks, and moodiness. Many of the patients’

Appendix A-The Food Additive Approval Process: A Case Study ● 319

symptoms were reportedly reversed when use of as-partame was discontinued. In many of the anecdotalreports there may have been contributing factors, such asexcessive dieting, fluid intake, and caffeine consumption.One study (partially supported by the Nutrasweet Co.) ofpeople who claimed to get headaches following ingestionof aspartame demonstrated no difference in their head-aches when they ingested aspartame or a placebo (12).However, another placebo-controlled study (in a verysmall number of patients) found that there was anassociation between aspartame ingestion and migrainesfor some patients (7). To date, these are the onlycontrolled studies of the effects of aspartame on peoplewho claim to be sensitive to it, A recent review of researchon aspartame was conducted by the Nutrasweet Co.,which concluded that ‘‘available evidence confirms that,other than in individuals with homozygous phenylketon-uria, who must consider aspartame as an additional sourceof phenykdanine, aspartame is a remarkably safe foodadditive” (l).

It is plausible that there may be a small portion of thepopulation that is vulnerable to neurological side-effectsfollowing consumption of aspartame. Other “restaurantsyndromes” afflicting subpopulations with unusual sen-sitivity include susceptibility to caffeine, MSG, red wine,and chocolate (13).

The Council on Scientific Affairs of the AmericanMedical Association, in a report based on members’expertise and the scientific literature, concluded in 1985that “Available evidence suggests that consumption ofaspartame is safe except by individuals with homozygousphenylketonuria or other individuals needing to controltheir aspartame intake” (2). Similarly, in his November3, 1987, statement to the Senate Committee on Labor andHuman Resources, the FDA Commissioner expressed hisconfidence that no serious, reproducible adverse reactionscan be associated with aspartame use. He added thatwidespread use of aspartame and the publicity regardingpossible adverse effects would have guaranteed theiridentification had they existed (16). Nonetheless, hecommitted the FDA to continue the postmarketingmonitoring of aspartame and to maintain close communi-cation with aspartame’s critics. He agreed that somepeople may be exquisitely sensitive to aspartame and thatsome people are allergic to the compound. FDA has theauthority to remove substances from approved lists on thebasis of new information (5). This occurred in 1970, whencyclamate was removed from the “generally recognizedas safe” list.


Because of the continuing dispute about aspartame’ssafety (9), FDA’s approval procedures have been thesubject of careful scrutiny. The General AccountingOffice and others have concluded that FDA acted entirely

properly and according to established policy during theaspartame approval process, but it is not clear whether theestablished procedures are optimal, striking the bestbalance between consumer dietary wishes and publichealth. Critics argue that the procedures are only mini-mally sufficient and that products which have not beenadequately tested are entering the marketplace.

Some of the safety questions emerged as a result ofpostmarketing passive surveillance, an activity that isoptional for food additives but mandatory for drugs. Infact, this distinction between food additives and drugs isitself arbitrary. The acting director of the Bureau of Drugsrecommended in an FDA memorandum (which was notissued) that ‘‘safety evaluations of proposed new sugarsubstitutes be conducted as Phase I studies under theInvestigational New Drug (IND) Regulations” (15),Postmarketing monitoring is nearly impossible unless thepresence of additives is clearly noted on the food package.Some critics argue that, even when there are unsubstanti-ated anecdotal reports of toxicity due to ingestion of afood additive, people who feel they are vulnerable to thesetoxic effects have a right to know the identity and quantityof the suspect additive, This would allow concernedindividuals to monitor their intake and would facilitate thereporting of adverse effects. Clearly, consumers cannotreport an adverse effect if they are not aware of what theyhave ingested. This view is supported by some investiga-tors who contend that ingestion of quantities exceedingthe acceptable daily intake is possible in some individuals(such as children) and that increasing rates of con-sumption could lead to more frequent ingestions exceed-ing the acceptable daily intake (6,10). On the other hand,the Nutrasweet Co., although not opposing the labeling ofall food ingredients, would not agree that sufficientscientific evidence of possible toxicity exists to warrantsingling out aspartame for obligatory labeling (14).

The value of postmarketing surveillance for identifica-tion of neurotoxic effects has been demonstrated severaltimes with new drugs; therefore, many persons argue thatestablishment of postmarketing surveillance-at least apassive system—should be required for all new products.Because of the difficulty of identifying and quantifyingsubtle neurological damage and because of the differencesbetween the nervous systems of humans and otheranimals, an optimal approval process would requireclinical studies.

Appendix A References1.

2.

Butchko, H. H., and Kotsonis, F. N., “Aspartame:Review of Recent Research,” Comments in Toxicol-ogy, 1988.Council on Scientific Affairs, American MedicalAssociation, “Aspartame, Review of Safety Issues,”Journal of the American Medical Association 254:40@401, 1985.


3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

Dews, P. B., “Summary Report of an InternationalAspartame Workshop,” Food and Chemical Toxi-cology 25:549-552, 1987.Franz, M., “Is It Safe To Consume AspartameDuring Pregnancy? A Review,” The Diabetes Edu-cator 12:145-147, 1986.Hattan, D. G., Henry, S.H., Montgomery, S.B., et al.,“Role of the Food and Drug Administration inRegulation of Neuroeffective Food Additives,” Nutri-tion and the Brain, R.J. Wurtman and J.J. Wurtman(eds.) (New York, NY: Raven Press, 1983).Janssen, P.J.C.M., and van der Heijden, C. A., “As-Partame: Review of Recent Environmental andObservational Data,” Toxicology 50:1-26, 1988.Koehler, S. M., and Glares, A., “The Effect ofAspartame on Migraine Headache,” Headache 28:10-13, 1988.Lecos, C., ‘ ‘The Sweet and Sour History of Saccharin

Cyclamate , . . Aspartame,” FDA Consumer15(4):8, 1981.Maher, T. J,, and Wurtman, R. J., “Possible Neurol-ogic Effects of Aspartame, a Widely Used FoodAdditive,” Environmental Health Perspectives 75:53-57, 1987.Partridge, W. M., “Potential Effects of the DipeptideSweetener Aspartame on the Brain,” Nutrition andthe Brain, R.J, Wurtman and J,J. Wurtman (eds.)(New York, NY: Raven Press, 1983), pp. 199-241.Reynolds, W.A., Bauman, A. F., Stegink, L. D., et al.,“Developmental Assessment of Infant MacaquesReceiving Dietary Aspartame or Phenylalanine,”Aspartame, L.D. Stegink and L.J. Filer, Jr. (eds.)(New York, NY: Marcel Dekker Press, 1984), pp.405-423.Schiffinan, S. S., Buckley, C. E., III, Sampson, H. A.,et al., ‘‘Aspartame and Susceptibility to Headache, ’New England Journal of Medicine 317:1181-1185,1987.

13.

14.

15.

16.

17.

8.

9.

Settipane, G. A., “The Restaurant Syndrome,” NewEngland and Regional Allergy Proceedings 8;39-46,1987.

Shapiro, R. B., “Statement of Robert B. Shapiro,Chairman of the Board and Chief Executive Officeof the Nutrasweet Company, Before the Committeeon Labor and Human Resources, ’ NutrasweetHealth and Safety Concerns, U.S. Senate hearing100-567 (Washington, DC: U.S. Government Print-ing Office, 1988), pp. 412-423.

U.S. Congress, General Accounting Office, Food andDrug Administration: Food Additive Approval Proc-ess Followed for Aspartame, report to the HonorableHoward M. Metzenbaum, GAO/HRD-87-46 (Wash-ington, DC: 1987), p. 38.U.S. Congress, Senate, Nutrasweet Health andSafety Concerns, hearings before the Committee onLabor and Human Resources, hearing 100-567 (Wash-ington, DC: U.S. Government Printing Office, 1988),p. 227.

U.S. Department of Health and Human Services,Public Health Service, Food and Drug Administra-tion, FDA Medical Review of Clinical Safety Studies,FAP No. 3A2885, Aug. 20, 1973,U.S. Department of Health and Human Services,Public Health Service, Food and Drug Administrat-ion, internal memorandum from the Acting Associ-ate Commissioner for Health Affairs to the Commis-sioner, Apr. 24, 1981.Young, F. E., “Statement of Frank E. Young, Com-missioner, Food and Drug Administration, Beforethe Committee on Labor and Human Resources,”Nutrasweet-Health and Safety Concerns, U.S. Sen-ate hearing 100-567 (Washington, DC: U.S. Govern-ment Printing Office, 1988), pp. 74-77.

Appendix B

Workshop on Federal Interagency Coordination ofNeurotoxicity Research and Regulatory Programs

Federally sponsored activities in neurotoxicology arediverse and highly decentralized. They involve more than15 different institutes, centers, and independent agencies,such as the Environmental Protection Agency (EPA) andthe Consumer Product Safety Commission (CPSC), aswell as agencies in several departments, including theDepartment of Health and Human Services (DHHS), theDepartment of Energy (DOE), the Department of Labor,and the Department of Defense (DoD). Coordination ofneurotoxicity research and regulatory activities tends tobe informal within agencies and more formal but lessextensively developed between agencies. Notable excep-tions at the interagency level have included the coordinat-ing efforts of at least two Federal organizations-theInteragency Regulatory Liaison Group and, within DHHS,the Committee to Coordinate Environmental Health andRelated Programs.

Results of research into the mechanisms of neurotoxic-ity must be made available rapidly to risk assessors andother officials at regulatory agencies. This need ismagnified by current budgetary constraints, which pro-vide a considerable impetus for improving coordinationof Federal research and regulatory activities. Improvedcoordination of Federal neurotoxicological research couldwell benefit not only the regulatory sector, but alsoindustry and consumers.

With such considerations in mind, representatives frommore than a dozen Federal organizations were convenedon May 23-24, 1989, at a workshop, ‘Federal InteragencyCoordination of Neurotoxicity Research and RegulatoryPrograms,” sponsored jointly by the congressional Officeof Technology Assessment (OTA) and EPA (l).

Overview of Federal NeurotoxicologyResearch Programs

Federal research in neurotoxicology spans the spec-trum from basic to targeted. Coordination of Federalresearch and regulatory programs in neurotoxicologyvaries widely—with informal communication being thedominant means, particularly among basic researchers.Much of the data developed in Federal programs-butcertainly not all of it—is being made accessible bypublication, through on-line computer networks, or both.However, some information, including a great deal of datadeveloped in the private sector and furnished to Federalregulatory agencies to support drug, pesticide, and otherproduct marketing applications, is often unavailableexcept through cumbersome means, such as requests viathe Freedom of Information Act. Still other data submit-ted to Federal agencies by companies in the private sectorare considered proprietary and therefore confidential. The

following section provides a brief overview of Federalresearch and regulatory activities in this area.

Department of Health and Human Services

The responsibility for overseeing neurotoxicology-related activities within DHHS falls to the Office of theAssistant Secretary for Health. The Committee to Coordi-nate Environmental Health and Related Programs oper-ates within that office.

National Institutes of HealthSeveral Institutes within the National Institutes of

Health (NIH) sponsor a great deal, perhaps the majority,of the U.S. basic research effort in neurotoxicology. MostNIH research is investigator-initiated, and the dataproduced are published in the scientific literature. Theprincipal Institutes with such programs are the NationalInstitute on Neurological Disorders and Stroke (NINDS),the National Institute of Environmental Health Sciences(NIEHS), the National Institute on Aging (NIA), and therecently created National Institute on Deafness and otherCommunication Disorders (NIDCD). These Institutessupport a broad range of basic studies of the nervoussystem, including development of model systems for theetiology of neurological diseases, particularly chronicdegenerative conditions.

Neurotoxicological research within NINDS is dividedinto two areas of interest: exogenously applied andendogenously occurring neurotoxic agents, The action ofsynthetic neurotoxicants may cause damage that mimicsneurodegenerative diseases. For instance, the syntheticcompound MPTP, sometimes formed during the illicitsynthesis of a meperidine-like drug, destroys dopamine-producing cells of the central nervous system, making thedrug a powerful tool for studying Parkinson’s disease.Among endogenous toxins, the reactive forms of oxygenthat can damage membranes through lipid peroxidationare now being studied as possible mediators of damagewhen cell protective mechanisms go awry.

NIEHS, which supports the most targeted of the severalNIH-sponsored neurotoxicity research programs, is nowtaking a “broader look” at toxicology than it did whencarcinogen testing dominated its activities. The Instituteconducts and supports research to identify environmentalagents that may cause adverse reproductive, neurological,and other effects on human health in addition to cancer.NIEHS oversees a substantial extramural grants programin the neurotoxicology field.

The National Toxicology Program within NIEHSconducts tests of selected chemicals, including suspectedneurotoxic agents, and develops databases on them.

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Although the selection of chemicals for testing receives agreat deal of attention, the program ‘ ‘shouldn’t be drivenpurely by the [chemical] nomination-based process,’ saidone NIEHS official. Compounds are selected on the basesof extent of human exposure, quantity produced, ade-quacy of existing toxicological data, and regulatory andresearch agency concerns regarding potential adverseeffects.

Although NIEHS, EPA, and the National Institute forOccupational Safety and Health (NIOSH) have overlap-ping research interests and can use similar research andtesting technologies, there is little direct formal interac-tion between the agencies, according to an official fromNIEHS. The executive committee that oversees theprogram is composed of directors or administrators fromNIEHS, the National Cancer Institute, NIOSH, theAgency for Toxic Substances and Disease Registry(ATSDR), the Food and Drug Administration (FDA),CPSC, EPA, and the Occupational Safety and HealthAdministration; the program is reviewed by nongovern-ment scientists.

Because of its mandate, NIA supports researchersinvestigating the “special vulnerability of the agingnervous system to toxins, ‘‘ noted an official from NIA. Aswith programs in NINDS, the emphasis is on “the basicneurobiology of the problem. ” The Institute also spon-sors epidemiological studies to identify populations withchronic exposures to toxic substances, such as agingresidents of rural areas, who maybe exposed to pesticides.


The National Institute on Drug Abuse (NIDA), whichis part of the Alcohol, Drug Abuse, and Mental HealthAdministration (ADAMHA), sponsors research to studythe neurotoxicological effects of addictive drugs as wellas drugs being developed to treat or prevent drug abuse.Researchers at NIDA are trying to determine what areasof the brain are affected by such drugs and whether theireffects are reversible. FDA and NIDA have an inter-agency agreement to develop and validate methods ofassessing the neurotoxic actions of drugs that are cur-rently being prescribed or considered for treatment ofneuropsychiatric disorders. NIDA researchers are alsoseeking avenues for coordinating some of their effortswith officials of the Drug Enforcement Agency, but that“gap is difficult to bridge,’ according to an official fromNIDA. Cooperative agreements with other Federal agen-cies to develop and validate neurotoxicity screening testsand a neurotoxicity database should become priorityactivities, noted another NIDA official.

The National Institute of Mental Health (NIMH),another agency within ADAMHA, also sponsors researchon therapeutic agents that can exert neurotoxic effects on

brain function. NIMH researchers are helping to developa neurophysiological battery of tests for evaluating centralnervous system impairment, particularly among patientswith AIDS. Because NIMH and NIDA interact closelywith the pharmaceutical industry, some neurotoxicologydata they obtain may be kept confidential because it isconsidered proprietary information.

Centers for Disease ControlThe Centers for Disease Control (CDC) act as a sentinel

protecting the public health. Currently, CDC is updatingits regulations for setting lead safety standards and thus isreexamining the concentrations in the blood at which thispotent neurotoxic agent exerts adverse effects.

NIOSH studies a broad range of products through bothintramural and extramural programs. Specifically, NIOSHconsiders substances to which individuals may be ex-posed in the workplace, including field studies offarmworkers and others exposed to pesticides. In addi-tion, Institute researchers conduct studies using variousanimal models. The primary concern of the NIOSHintramural program is methods assessment.

NIOSH is participating in the National Health andNutrition Survey, which is organized under the auspicesof the National Center for Health Statistics. During thecourse of this study, about 6,000 people will be giventhree tests from the neurobehavioral evaluation system inorder to develop baseline data to assess future exposuresto neurotoxic agents. NIOSH is also participating with theInternational Program on Chemical Safety and the WorldHealth Organization (WHO) invalidation of a neurobehav-ioral screening battery for rodents.

Agency for Toxic Substances andDisease Registry

Under Superfund auspices, ATSDR carries out appliedresearch on health effects of exposures to hazardoussubstances, including neurotoxic agents. ATSDR is“looking at data gaps,” according to an official of theAgency. By law, the Agency must make a list of the 200most toxic substances found at Superfund sites and helpdetermine which of them maybe toxic in general as wellas neurotoxic. Officials also expect to develop a standardbattery of tests that could be used not only for broadtesting of the population, but also for workers and otherindividuals at Superfund sites who might be exposed tomixtures of neurotoxic agents. In December 1988, theATSDR cosponsored the Third International Symposiumon Neurobehavioral Methods in Occupational and Envi-ronmental Health with WHO and the Pan AmericanHealth Organization. Discussions at the symposium havehelped ATSDR officials develop a list of scientificpriorities.

Appendix B-Workshop on Federal Interagency Coordination of Neurotoxicity Research and Regulatory Programs .323

Food and Drug AdministrationFDA evaluates the adverse effects of drugs on the

nervous system through its general toxicological evalua-tions. Such testing is designed not only to detect drugswith adverse effects on the central nervous system, butalso to evaluate psychoactive drugs, which generally actdirectly on the nervous system. Before a drug is approvedfor marketing, general toxicity is evaluated by a battery ofstudies, ranging from short-term acute tests in severalspecies by different routes of administration to chronicdosing studies in two species exposed at three dose levelsfor up to 2 years. Behavior in test animals is monitoredperiodically, and abnormalities are recorded. Mating,fertility, developmental abnormalities, maternal behavior,and survival are among the endpoints that are evaluated.However, officials of some agencies voiced concern thatFDA’s general toxicological testing approach may misssome neurotoxicological effects. Many neurotoxicolo-gists believe that specific neurotoxicological testing isnecessary to detect some adverse effects.

Elsewhere in FDA, officials are concerned aboutpesticides, contaminants, and additives in the food supplyand how they may affect individuals of different ages, onvarious diets, or with other risk factors. In addition, theNational Center for Toxicological Research is developingmodels and trying to enhance current risk assessmentmethods in general, as it begins to examine neurotoxicagents specifically.

Department of Energy

DOE sponsors a relatively small program to study toxicchemicals. The Department is also interested in centralnervous system disorders such as Alzheimer’s disease.DOE researchers typically are interested in the underlyingmechanisms of such diseases. Historically, their effortshave led to the development of complex instruments forexamining central nervous system functions. DOE hasalso conducted evaluations of Federal agency carcinogenrisk assessment procedures—an exercise that could provehelpful as many agencies try to develop consistent riskassessment procedures for analyzing neurotoxic sub-stances.

Environmental Protection AgencyEPA faces a broad mandate under several statutes in

regulating neurotoxic agents. Throughout the Agency,officials are refining risk assessment methods. Otherefforts focus more directly on neurotoxic substances. Forinstance, the Agency maintains files on hundreds ofpesticides, many of which are neurotoxic. EPA sponsorsa sizable research program within the Office of Researchand Development, which focuses on development ofmethods and applied research questions, including hazardidentification and characterization.

EPA is currently revising and adapting guidelines foranimal tests to screen organophosphorous pesticides forneurotoxic activity. The Agency has found evidence thatpesticide residues in foods cause neurotoxic effects inchildren, and the identification and characterization ofneurotoxic pesticides is a high priority for EPA officials.An EPA Scientific Advisory Panel recommended thatroutine testing of pesticides include observation for signsof neurobehavioral abnormality and neuropathology.

Under Superfund legislation, EPA officials are cooper-ating with their counterparts at ATSDR to study chemicalmixtures at toxic waste sites, where individuals may beexposed to complex mixtures of chemicals that might actsynergistically on the nervous system.

In 1986, EPA established an intra-agency work groupto look at substances that act as reproductive anddevelopmental toxicants. Testing guidelines for developmental neurotoxicity are now being drafted. According toEPA scientists, animal models have consistently proveduseful for predicting human response to neurotoxicagents.

Consumer Product Safety CommissionCPSC is beginning to develop neurotoxicity guidelines

for manufacturers. The Commission program is directedat developing new regulations for products such as paintthinners and art materials that may have neurotoxicologi-cal effects under certain conditions of use. Appropriatelabeling to warn of hazards, advise against hazardous usesor exposures, and provide first-aid instruction is requiredunder statutes administered by CPSC.

Although the Commission develops guidelines andregulations rather than conducting research, staff mem-bers are identifying areas where scientific research wouldhelp them better fulfill their mandate. Development of testmethods for identifying toxicants that cause neurologicaldamage after chronic low-level exposures, identificationof key species differences to aid in extrapolating animaltest results to appropriate endpoints in humans, anddevelopment of a better understanding of the relationshipbetween high- and low-dose neurotoxic effects areresearch areas of particular interest to CPSC officials.

Department of LaborAlthough charged with setting neurotoxicity health and

safety standards, the Occupational Safety and HealthAdministration (OSHA) conducts no research of its own.Instead, scientists at NIOSH and elsewhere supply OSHAwith information needed to promulgate health standards.For example, to help in regulating neurotoxic agents,OSHA officials would like to see research conducted onsubclinical effects of neurotoxic substances and at whatexposure levels such effects remain reversible. OSHAwould also like Federal agencies to standardize means for


conducting risk assessments, develop quantitative meth-ods for expressing subtle behavioral changes, devisesimple tests to measure toxic effects on individualworkers, and publish a standardized list of neurotoxicsubstances.

OSHA health standards become legal documentsintended to ensure that employees not suffer “materialimpairment of health or functional capacity, ’ which thecourts interpret to include subclinical effects. Thus, insetting standards, OSHA can act to prevent relatively mildand reversible forms of potentially serious diseases, suchas those caused by a particular neurotoxic substance.“Material impairment” can also mean workplace expo-sures to chemicals that cause temporary narcosis, whichcan lead to accidents and injuries. The courts give OSHAconsiderable latitude in determining “significant risk”and the consequences of resetting exposure limits toparticular chemicals.

Department of Defense

DoD has carried out extensive testing of protectivedrugs designed to counteract neurotoxic chemical agents.Its current program involves 26 laboratories, includingsupport of research at laboratories within NIDA. Toevaluate such drugs, DoD has developed a four-partprocedure for extrapolating their effects to human per-formance in real-world situations, noted an official fromDoD. DoD has developed sophisticated performanceevaluation test batteries, risk identification procedures, acomputer-based task-analysis procedure, and a real-worldcontingency analysis package, which provides informa-tion about the use and potential neurotoxic effects ofantidotes for chemical warfare agents.

Workshop Discussion Groups

Identifying Testing NeedsAlthough there are processes prescribed by the Na-

tional Testing Program (within ATSDR) and by theInteragency Testing Committee for nominating chemicalsfor neurotoxicity testing and evaluation, the discussiongroup concluded that the processes need revising. A majordifficulty in conducting evaluations that lead to achemical’s nomination is the inadequate number ofpeople with expertise in neurotoxicology. Having moreappropriately trained experts would also help in educatingregulators who select chemicals for such testing. Thenotion that neurotoxicity is a valid endpoint for evaluatingchemicals needs general reinforcement.

Moreover, the scientific criteria for defining neurotox-icity, setting priorities, and selecting chemicals, includingstructure-activity relationships and comparisons of chem-icals and chemical classes, also should be reevaluated andstrengthened. For example, the volume of production andlikely extent of human exposure to a particular chemical

could be taken into account when deciding whether itshould be nominated for testing, an official from NIEHSnoted.

Thus, establishment of an independent advisory groupof experienced individuals to better define neurotoxicity,to evaluate the nomination process, to review chemicalsgoing through it, and to act as an information “resource”seems warranted, the discussion group concluded. Ifestablished, such an advisory group would not “supplant’ the regulatory agency, but would help ‘sanction”the decisions the agency makes, an EPA official said.

A battery of standardized human neurotoxicity tests isneeded, particularly for use in evaluating the effects ofenvironmental exposures to potentially hazardous agents.Because several test batteries, such as the field perform-ance battery used by DoD as well as another test batterydeveloped by NIOSH, have been developed for testinghumans exposed to suspected neurotoxic substances, itmay be possible to adapt existing procedures into a morebroadly applicable test battery.

‘‘If you’re going to do a particular test, at what level doyou consider that some adverse health effect has oc-curred?” asked an official from ATSDR. “What you’dlike is not only some tests, but indications for when to usethem. . . .The whole idea. . . is to get the biggest bang forthe Federal buck. ” In that context the lack of resourcesfor funding research and testing of suspected neurotoxicsubstances is a critical “rate-limiting” step.

Development and Use of StandardizedNeurotoxicity Tests

Many neurotoxicity tests are now in use. The discus-sion group agreed that representatives from variousagencies could form a coordinating group to compare thespecific tests each agency is using and to evaluatestrategies for developing new tests.

Some effort to coordinate research involving animaland human neurotoxicity testing is also needed. Improvedefforts to obtain relevant information, such as pharmaco-kinetic data about a chemical’s behavior in a particularspecies, are part of this overall task, an FDA official said.

Despite differences in statutory authority, other agen-cies besides EPA need to acknowledge critical arenas,such as developmental neurotoxicity, for evaluatingchemicals and drugs, noted an official from EPA.However, any effort to move toward uniformity in testingbecomes challenging because so much depends on theregulatory context in which a particular test will be used.EPA, for example, is expected to set and observestandards for tests that are mandated under severallegislative acts—particularly the Toxic Substances Con-trol Act-that are unique to the Agency. Working underquite different legislative mandates, NIDA and FDA have

Appendix B-Workshop on Federal Interagency Coordination of Neurotoxicity Research and Regulatory Programs ● 325

developed specific, highly sophisticated tests for particu-lar categories of neuropharmacological agents. Whateverthe tests being performed, noted another EPA official, theinterpretation of results is “very dependent on theexpertise of your reviewers, ” For example, withoutadequate training in neuropathology, agency reviewersmight overlook telltale signs of neurotoxicity in aparticular animal model test.

A practical consideration arising from mission andstatutory differences among regulatory agencies is thatthe costs of testing commodity chemicals, for instance,rather than drugs ‘‘can very often not be supported by theanticipated market, ’ an EPA official pointed out. None-theless, sharing of adequately reviewed informationamong agencies could help individual agencies in makingdecisions about neurotoxic substances to fulfill theirparticular legislative mandates. Whether test methodsshould be standardized or merely codified remains anunresolved issue.

Coordination of Federal Research Programs

Neurotoxicity research is defined broadly because thedefinition is driven by individual investigators as well aslegislatively mandated regulatory agencies. Existing mech-anisms for coordinating such research, particularly itsmore basic components, are largely informal and oftenfragmented. The discussion group did not reach aconsensus on whether a central coordinating mechanismwould be useful or desirable.

In particular, several representatives of the basicresearch community thought that such a committee mightbe viewed as an advocacy body trying to obtain a largershare of resources for conducting neurotoxicity researchinstead of studies in other areas. Thus, their misgivingsabout a formal neurotoxicity research coordinating bodyare based on an underlying fear that a central committeemight interfere with research freedom “through budgetleverage. ’

In addition, noted an official from NIH, although otherFederal activities involving neurotoxicity may well bene-fit from coordination, research “would be the leastimportant to coordinate. . . .We’re trying to solve anonproblem. ” Informal exchanges of information nowensure that research interests and opportunities are sharedfairly freely between various Institutes within NIH, hesaid. Moreover, that exchange of information occursoutside the formal budget process. Sometimes it involvesefforts to minimize overlap, but it also permits a degree ofresearch ‘redundancy’ —i.e., overlapping or even repeti-tive research by different investigators. (Such redun-dancy, when it occurs, is usually justified as a vital part ofthe self-correcting, confirmatory aspect of basic research.)There are plenty of “knowledge gaps” in the neuro-

science, he said. “Instead of feeling redundant, we’reworking to fill the knowledge gaps. ”

Representatives from agencies that are purely regula-tory or that also conduct research to support theirregulatory responsibilities see a need for more deliberateefforts to coordinate research. “We need to identify gapsin the research database available to the regulatoryagencies, ” said an official from EPA. “We need. . .totransfer information [when] trying to develop researchstrategies, added another EPA representative, “Wewant to test their validity with other agencies. ”

Historically, basic research findings have had anenormous impact on setting neurotoxicity-related regula-tions, The current effort within CDC, for instance, toreevaluate safe blood levels for lead “arose from basicresearch findings about lead’s neurotoxicity, ’ an EPAofficial pointed out. “How can we [convey] basicinformation about how the nervous system responds tovarious insults . . . to [officials] to protect public health?”He and many other participants at the workshop agreedthat such information could be evaluated and dissemi-nated more effectively than current mechanisms allow.They also agreed that, by making basic researchers moreaware of the scientific challenges facing regulatoryagencies, the nature of some research undertakings maychange in valuable ways. “We want NIH aware ofproblems facing regulatory agencies ., , to see if it cangive a different emphasis to basic research,” an EPAofficial noted.

Coordination of Testing andMonitoring Programs

Several Federal agencies, including, EPA, OSHA,NIOSH, FDA, and CPSC, have both passive and activeneurotoxicity monitoring capabilities and interests. Datadeveloped during the conduct of such activities typicallyare stored by the agencies, Members of the discussiongroup concluded that sharing such information amongagencies would be useful-as would identifying keycontact people at each agency and making agency-specific databases compatible with one another.

The handling of data is seen as a challenge. Agenciesnow have different criteria for evaluating such data. EPA,for example, stringently reviews data before enteringthem into the Integrated Risk Information System, anAgency official noted. “These data have status. [As] anagency policy. . . .1 would have to ask what status otherkinds of shared data would have. ’ The expected uses fora “centralized database. , . to a large extent might dictatewhat kind of data you would put in it” another EPAofficial said.

Officials face serious questions in evaluating neurotox-icity test schemes. The development and validation ofnew tests and test batteries are a central challenge.


Moreover, there is no agreed-on basis for moving from atier-one to a tier-two battery of tests. A concise definitionof “significant biological effect” is needed, as areconsistent strategies for using test data when conductingrisk assessments, The exchange of information, some-times at the early stage of description in grant applica-tions, might expedite development of useful procedures.In the same vein, it would be useful to track whatcompounds are being tested by which agencies so thatinterested parties could be kept informed about the statusof particular suspect neurotoxic agents, even during theearliest stages of examination. Similarly, it would beuseful to reexamine past neurotoxicology data, in part togain a greater understanding of what test endpoints haveproved particularly reliable.

Coordination of Risk Assessmentand Regulatory Programs

Of the regulatory agencies represented at the workshop,EPA apparently has the most stringent guidelines for riskassessment. This stringency is dictated in part by EPA’sneed for consistency throughout its diverse programs andacross its regional offices. For example, engineers atSuperfund sites may be called on to make $20-milliondecisions, pointed out an EPA representative, In suchcircumstances, guidance and consistency are essential—to support the on-site decision if it is subsequentlychallenged in court.

Although other regulatory agencies may not have suchformal guidelines, they often have special offices foraddressing risk assessment, scientific, and policy issues.OSHA, for instance, has promulgated guidelines forcarcinogens, according to an agency official. However,developing those guidelines “was time-consuming andnot an effective process, ’ this same official noted, addingthat having consistent practices across agencies seemsmore important than publishing specific guidelines.Informally, many agencies follow a process outlined inthe National Research Council document Risk Assess-ment in the Federal Government: Managing the Process(2). It distinguishes between risk assessment, which isconsidered principally a scientific evaluation process, andrisk management, which involves political, economic,and other considerations, Efforts to coordinate neurotox-icity risk assessment ought to emphasize “science and. . .risk assessment and not . . . risk management” an EPAofficial recommended.

“I don’t think you can make that kind of cleandistinction,’ another discussion group participant re-sponded. “I don’t think you can live with that kind ofartificial situation. . . it’s the sort of thing that gets us intotrouble. And, noted another participant, “There is abasic political premise that is involved in that separationdecision. If it works well for an agency under a set of

circumstances, great. But I don’t think it’s universallyclear that is the way to proceed. ”

The discussion group considered whether universalguidelines for conducting risk assessments might exertuntoward effects, such as restricting scientific judgmentsand, ultimately, impeding regulatory actions. “Standard-ized guidelines tend to stagnate the discipline,” said anofficial from DOE. “Formalizing them too soon is notgood. The important part of risk assessment is [holding]a social dialogue, focusing on a problem, and stimulatingresearch.” However, an official from EPA responded,“What you say is very nice if the agency doesn’t have alawsuit accusing [it] of not making a regulatory deci-s i o n .

There was general agreement that careful thought mustbe exercised lest risk assessment concepts be introducedtoo early. Nonetheless, some principles of risk assessmentmay be applicable to neurotoxicity data from all regula-tory agencies. Moreover, research issues common tomost, if not all, regulatory agencies can be addressed in acoordinated fashion. “Looking at common researchissues could certainly be a marked advantage,’ thediscussion group agreed. However, concern was voicedthat other agencies feel “their input into what EPA isdoing in risk assessment is. . . retrospective.” Thus, thereis a need for them to have input earlier in the process soas to have greater impact.

“Rather than adopt [guidelines] uniformly, we maywant to see how a particular agency’s guidelines work out. . . and then learn from each other’s mistakes andsuccesses, ” suggested an official from FDA. “EPA andFDA may start at the same point trying to detectneurotoxic drugs or environmental agents, Later on, theFDA decision on setting a neurotoxic threshold for a drugwill be different from [the standard] EPA sets for anenvironmental agent. ”

The group was divided over how risk assessmentprocedures for evaluating suspected carcinogens stand upagainst procedures for evaluating putative neurotoxicsubstances. “In some ways, we know more in the area ofneurotoxicity, ’ an EPA official argued. “We know aboutvariety, reversibility, as much or more about mecha-nisms. . . . [In neurotoxicity] somehow we are able toaccept a certain level of risk. . . .It’s not that cancer riskassessment is more developed, [but] we put an arbitrarystructure on [it] largely in response to a political need. ”Added an official from FDA, “The key is that we arebetter able to set a safe limit for a neurotoxicant than. . .for carcinogens.’

Sometimes the “politics of the situation require us tosay, ‘We don’t know enough about what we’re doinghere’,’ said another EPA official. However, both EPAand FDA “have a long empirical track record of dealing

Appendix B Workshop on Federal Interagency Coordination of Neurotoxicity Research and RegulatoryProgr~ ● 327

with neurotoxic agents, of establishing safe levels. . . .Sowe shouldn’t confuse ourselves.

Such considerations also have an impact on “riskcommunication’ ‘—that is, notifying individuals of therisk posed by particular substances. “That whole area isunder great scrutiny within the cognitive psychologycommunity, ” noted a participant. Research “to explain acomplex concept” and efforts to “develop a speciallanguage” could help in getting the public to understandrisks more clearly.

Models for Coordinating FederalNeurotoxicity Efforts

There are several models for coordinating interagencyneurotoxicity activities. The Interagency Regulatory Liai-son Group was established more than a decade ago andseemed to work well until it became too difficult tomanage, according to a DOE official. Moreover, with achange in administrations came a change in activitiesamong regulatory agencies and a decreased emphasis oncoordination among them.

Within DHHS, the Committee to Coordinate Environ-mental Health and Related Programs (CCEHRP) couldcoordinate neurotoxicity activities. The committee “isauthorized to establish subcommittees and could readilyaccommodate interests in neurotoxicity among DHHSagencies with liaisons to agencies outside the Department.CCEHRP has a policy board and counsel that areresearch- and program-directed, according to a represen-tative from DHHS. CCEHRP is also integrated vertically,meaning its membership includes researchers who workat the bench as well as high-level managers.

Historically, the Office of Science and TechnologyPolicy (OSTP) within the Office of the President hasfunctioned as an organizing body for cooperative activi-ties to establish risk assessment principles for carcino-gens. The OSTP Chemical Carcinogens Documentpublished in the Federal Register on March 14, 1985, iswidely accepted as a model achievement. Moreover, withOSTP leadership, representatives from academia, indus-try, and the Federal Government can work together in

developing acceptable policies. A risk in calling on OSTPto undertake Federal coordination of neurotoxicity activi-ties is that the issue could become too political. Thus,some workshop participants argued that the coordinationof neurotoxicity activities to fulfill research and dataneeds might prove more workable if organized from “thebottom up. ” Once successful, agency officials then arebetter positioned to convince management of particularpolicy options to implement.

ProposalToward the close of the workshop, participants agreed

that an “Interagency Working Group on Neurotoxicol-ogy ” should be formed.1 The proposed working group,which would be dedicated to improving the Federalresponse to human health issues related to neurotoxicol-ogy, would include members from all Federal agenciesand organizations having research, regulatory, or otherpertinent interests in neurotoxicology. Such a forum forexchanging information could help minimize duplicationof efforts. The working group could also help ensure thatnegative as well as positive findings are shared byindividuals interested in neurotoxicology.

Although workshop participants limited their proposalto a sketch of what such an interagency working groupshould undertake, they did outline key areas where sucha body could fill gaps and help to coordinate otherwiseisolated efforts in research, testing, monitoring, riskassessment, regulation, and other areas. The workinggroup also might develop a “conceptual framework. . .toidentify long-range needs related to neurotoxicology, ”suggested an official from EPA. It might also “encouragethe Library of Medicine to participate in the establishmentof a neurotoxicology database.”

1.

2.

Appendix B ReferencesThis summary of the OTA/EPA workshop was pre-pared by Jeffrey Fox under contract No. L3-2630.O.National Research Council, Risk Assessment in theFederal Government: Managing the Process (Wash-ington, DC: National Academy Press, 1983).

l~&t. 26,1989, knmew~ch~g~ to the Interagency committee on Neurotoxicology (l~N). ~ committee is adrninisteredthrough the Neurotoxicology Divisionof EPA’s Health Effects Research Laboratmy in Research Triangle Park, NC.


Federal Interagency Coordination of NeurotoxicityResearch and Regulatory Programs

Sponsored by the Office of Technology Assessmentand the U.S. Environmental Protection Agency

Lawrence W. Reiter, Workshop ChairU.S. Environmental Protection Agency, Washington, D.C.

John S. Andrews, Jr.Agency for Toxic Substances and Disease RegistryAtlanta, GA

Timothy M. Barry*U.S. Environmental Protection AgencyWashington, DC

James R. BeanU.S. Department of EnergyWashington, DC

Robert BiersnerNational Institute for Occupational Safety and HealthCincinnati, OH

Suzanne BinderCenters for Disease ControlAtlanta, GA

William K. BoyesU.S. Environmental Protection AgencyResearch Triangle Park, NC

Margarita CollantesConsumer Product Safety CommissionBethesda, MD

Joseph F. ContreraU.S. Food and Drug AdministrationRockville, MD

Miriam DavisU.S. Department of Health and Human ServicesWashington, DC

Errol B. de SouzaNational Institute on Drug AbuseBaltimore, MD

Sandra EberlyConsumer Product Safety CommissionWashington, DC

Lynda ErinoffNational Institute on Drug AbuseRockville, MD

David G. HattanU.S. Food and Drug AdministrationWashington, DC

Frederick HeggeWalter Reed Institute of ResearchSilver Spring, MD

Stephen KennedyNational Institute of Mental HealthRockville, MD

Zaven S. KhachaturianNational Institute on AgingBethesda, MD

Carole A. KimmelU.S. Environmental Protection AgencyWashington, DC

Annette KirshnerNational Institute of Environmental Health SciencesResearch Triangle Park, NC

Stephen H. KoslowNational Institute of Mental HealthRockville, MD

Carl M. LeventhalNational Institute of Neurological Disorders and StrokeBethesda, MD

Tina LevineU.S. Environmental Protection AgencyWashington, DC

Robert C. MacPhailU.S. Environmental Protection AgencyResearch Triangle Park, NC

Craig McCormack*U.S. Environmental Protection AgencyWashington, DC

Suzanne McMasterU.S. Environmental Protection AgencyWashington, DC

*Organizing Committee

AppendixB-Workshop on Federal Interagency Coordination of Neurotoxicity Research and Regulatoryprograrns ● 329

Lakshmi C. MishraConsumer Product Safety CommissionBethesda, MD

Lawrence S. RosensteinU.S. Environmental Protection AgencyWashington, DC

Bernard A. SchwetzNational Institute of Environmental Health SciencesResearch Triangle Park, NC

William SetteU.S. Environmental Protection AgencyWashington, DC

Imogene Sevin-RodgersU.S. Department of LaborWashington, DC

William SlikkerNational Center for Toxicological ResearchJefferson, AR

Thomas J. SobotkaU.S. Food and Drug AdministrationWashington, DC

Letitia TahanU.S. Environmental Protection AgencyWashington, DC

Hugh A. TilsonU.S. Environmental Protection AgencyResearch Triangle Park, NC

Judith WeissingerU.S. Food and Drug AdministrationRockville, MD

Harold ZenickU.S. Environmental Protection AgencyWashington, DC

OTA Staff

Roger HerdmanGretchen KolsrudMark SchaeferTimothy CondonPeter AndrewsJoyce Ann BrentleyBlair WardenburgGladys White

Appendix C

Decade of the Brain

Public Law 101-58, 101st Congress,Joint Resolution

Whereas it is estimated that 50 million Americans areaffected each year by disorders and disabilities thatinvolve the brain, including the major mental illnesses;inherited and degenerative diseases; stroke; epilepsy;addictive disorders; injury resulting from prenatal events,environmental neurotoxins, and trauma; and speech,language, hearing, and other cognitive disorders;

Whereas it is estimated that treatment, rehabilitationand related costs of disorders and disabilities that affectthe brain represents a total economic burden of $305billion annually;

Whereas the people of the Nation should be aware ofthe exciting research advances on the brain and of theavailability of effective treatment of disorders and disabil-ities that affect the brain;

Whereas a technological revolution occurring in thebrain sciences, resulting in such procedures as positronemission tomography and magnetic resonance imaging,permits clinical researches to observe the living brainnoninvasively and in exquisite detail, to define brainsystems that are implicated in specific disorders anddisabilities, to study complex neuropeptides and behavioras well as to begin to learn about the complex structuresunderlying memory;

Whereas scientific information on the brain is amassingat an enormous rate, and the field of computer andinformation sciences has reached a level of sophisticationsufficient to handle neuroscience data in a manner thatwould be maximally useful to both basic researches andclinicians dealing with brain function and dysfunction;

Whereas advances in mathematics, physics, computa-tional science, and brain imaging technologies have madepossible the initiation of significant work in imaging brainfunction and pathology, modeling neural networks andsimulating their dynamic interactions;

Whereas comprehending the reality of the nervoussystem is still on the frontier of technological innovationrequiring a comprehensive effort to decipher how individ-ual neurons, by their collective action, give rise to humanintelligence;

Whereas fundamental discoveries at the molecular andcellular levels of the organization of the brain areclarifying the role of the brain in translating neurophysio-logic events into behavior, thought, and emotion;

Whereas molecular biology and molecular geneticshave yielded strategies effective in preventing severalforms of severe mental retardation and are contributing to

promising breakthroughs in the study of inheritableneurological disorders, such as Huntington’s disease, andmental disorders, such as affective illnesses;

Whereas the capacity to map the biochemical circuitryof neurotransmitters and neuromodulators will permit therational design of potent medications possessing minimaladverse effects that will act on the discrete neurochemicaldeficits associated with such disorders as Parkinson’sdisease, schizophrenia and Alzheimer’s disease;

Whereas the incidence of necrologic, psychiatric,psychological, and cognitive disorders and disabilitiesexperienced by older persons will increase in the future asthe number of older persons increases;

Whereas studies of the brain and central nervoussystem will contribute not only to the relief of necrologic,psychiatric, psychological, and cognitive, disorders, butalso to the management of fertility and infertility,cardiovascular disease, infectious and parasitic diseases,developmental disabilities and immunologic disorders, aswell as to an understanding of behavioral factors thatunderlie the leading preventable causes of death in thisNation;

Whereas the central nervous and immune systems areboth signaling systems which serve the entire organism,are direct connections between the nervous and immunesystem, and whereas studies of the modulatory effects ofeach system on the other will enhance our understandingof diseases as diverse as the major psychiatric disorders,acquired immune deficiency syndrome, and autoimmunedisorders;

Whereas recent discoveries have led to fundamentalinsights as to why people abuse drugs, how abused drugsaffect brain function leading to addiction, and how someof these drugs cause permanent brain damage;

Whereas studies of the brain will contribute to thedevelopment of new treatments that will curtail thecraving for drugs, break the addictive effects of drugs,prevent the brain-mediated “high” caused by certainabused drugs, and lessen the damage done to thedeveloping minds of babies, who are the innocent victimsof drug abuse;

Whereas treatment for persons with head injury,developmental disabilities, speech, hearing, and othercognitive functions is increasing in availability andeffectiveness;

Whereas the study of the brain involves the multidisci-plinary efforts of scientist, from such diverse areas asphysiology, biochemistry, psychology, psychiatry, mo-lecular biology, anatomy, medicine, genetics, and manyothers working together toward the common goals of

-330-

Appendix C--Decade of the Brain ● 331

better understanding the structure of the brain and how itaffects our development health, and behavior;

Whereas the Nobel Prize for Medicine of Physiologyhas been awarded to 15 neuroscientist within the past 25years, an achievement that underscores the excitementand productivity of the study of the brain and centralnervous system and its potential for contributing to thehealth of humanity;

Whereas the people of the Nation should be concernedwith research into disorders and disabilities that affect thebrain, and should recognize prevention and treatment ofsuch disorders and disabilities as a health priority;

Whereas the declaration of the Decade of the Brain willfocus needed government attention on research, treat-ment and rehabilitation in this area: Now, therefore, be it

Resolved by the Senate and House of Representatives ofthe United States of America in Congress Assembled,That the decade beginning January 1, 1990, hereby isdesignated the “Decade of the Brain,” and the Presidentof the United States is authorized and requested to issuea proclamation calling upon all public officials and thepeople of the United States to observe such decade withappropriate programs and activities.

Approved July 25, 1989.

LEGISLATIVE HISTORY-H.J. Res. 174 (S. J. Res. 173):CONGRESSIONAL RECORD, vol. 135 (1989):

June 29, considered and passed House.July 13, considered and passed Senate.

Appendix D

Acknowledgments

OTA would like to thank the members of the advisory panel who commented on drafts of this report the contractorswho provided material for this assessment, and the many individuals and organizations that supplied information for thestudy. In addition, OTA acknowledges the following individuals for their review of drafts of this report.

Jacqueline AgnewThe Johns Hopkins University

W. Kent AngerOregon Health Sciences University

Thomas E. AndersonGeneral Motors Research Laboratories

Zoltan AnnauThe Johns Hopkins University

Arnold AspelinU.S. Environmental Protection Agency

Isaiah BakerAmerican University

James R. BeanJefferson, MD

John F. Beary, IIIPharmaceutical Manufacturers Association

Charles E. BeckerUniversity of California

Robert J. BiersnerNational Institute for Occupational Safety and Health

Michael BolgerU.S. Food and Drug Administration

William K. BoyesU.S. Environmental Protection Agency

Peter BreysseUniversity of Washington

Brian BroxupBio-Research Laboratory, Ltd.

Harriett H. ButchkoThe NutraSweet Co.

Daniel M. ByrdDistilled Spirits Council of the United States, Inc.

James W. CaldwellU.S. Environmental Protection Agency

Margarita CollantesU.S. Consumer Product Safety Commission

Joseph ContreraU.S. Food and Drug Administration

Jacqueline CourteauHampshire Research Associates, Inc.

Wayne DaughtreyExxon Biomedical Sciences, Inc.

J. Michael DavisU.S. Environmental Protection Agency

Miriam DavisU.S. Department of Health and Human Services

John A. DellingerSan Antonio, TX

Robert T. DrewAmerican Petroleum Institute

Cynthia DriscollE.I. du Pent de Nemours & Co.

Alan DucatmanMassachusetts Institute of Technology

Robert S. DyerU.S. Environmental Protection Agency

David EckermanUniversity of North Carolina

Rob EliasU.S. Environmental Protection Agency

Lynda ErinoffNational Institute on Drug Abuse

Hugh L. EvansNew York University Medical Center

Henry FalkCenters for Disease Control

Robert G. FeldmanBoston University School of Medicine

W. Scott FergusonNational Agricultural Chemical Association

Shayne C. GadSearle Research& Development

Paul GarvinAmoco Corp.

Carl GiannettaU.S. Food and Drug Administration

Frank P. GradColumbia University Law School

Sidney GreenU.S. Food and Drug Administration

-332-

Appendix D-Acknowledgments ● 333

Richard A. GriesemerNational Institute of Environmental Health Sciences

Michael HansenInstitute for Consumer Policy Research

David G. HattanU.S. Food and Drug Administration

Carol J. HenryILSI Risk Science Institute

Karen HoffmanNational Institute of Environmental Health Sciences

Anne K. HollanderThe Conservation Foundation

Pony HoppinThe Conservation Foundation

Ken HudnellU.S. Environmental Protection Agency

Karl JensenU.S. Environmental Protection Agency

Barry L. JohnsonAgency for Toxic Substances and Disease Registry

E. Marshall JohnsonJefferson Medical College

David L. KarmolCan Manufacturers Institute

Carole A. KimmelU.S. Environmental Protection Agency

Philip J. LandriganThe Mount Sinai Medical Center

Robert F. Lee, HU.S. Environmental Protection Agency

Richard LetZMount Sinai School of Medicine

Carl LeventhalNational Institutes of Health

Ronnie LevinU.S. Environmental Protection Agency

Tina E. LevineU.S. Environmental Protection Agency

David E. LilienfeldMount Sinai School of Medicine

David C. LoganMobil Corp.

Robert C. MacPhailU.S. Environmental Research Laboratory

Richard B. MailmanUniversity of North Carolina School of Medicine

Sandra MarquardtGreenpeace USA

John F. McCarthyNational Agricultural Chemicals Association

Barbara McElgunnAssociation for Children and Adults with Learning

Disabilities

John A. McLachlanNational Institute of Environmental Health Sciences

Donald E. McMillanUniversity of Arkansas

Rita B. MessingUniversity of Minnesota

Lakshmi MishraU.S. Consumer Product Safety Commission

Charles P. MitchellCenter for Science in the Public Interest

Ira H. MonossonAmerican College of Occupational Medicine

Virginia C. MoserNSI Technology Services

Warren R. MuirHampshire Research Associates, Inc.

Douglas L. MurrayTexas Center for Policy Studies

Robert A. NealVanderbilt University School of Medicine

Herbert L. NeedlemanUniversity of Pittsburgh

Dorothy NelkinNew York University

David A. OttoU.S. Environmental Protection Agency

Howard G. PasterTimmons & Co., Inc.

George H. PauliU.S. Food and Drug Administration

Nancy N. RagsdaleU.S. Department of Agriculture

Imogene Sevin-RodgersU.S. Environmental Protection Agency

Allen RubyOffice of Technology Assessment


Roger W. RussellUniversity of California, Los Angeles

Eldon P. SavageColorado State University

Robert A. ScalaExxon Biomedical Sciences, Inc.

James L. SchardeinInternational Research & Development Corp.

Herbert H. SchaumburgAlbert Einstein College of Medicine

Brenda SeidmanKarch & Associates, Inc.

William SetteU.S. Environmental Protection Agency

Ellen SilbergeldEnvironmental Defense Fund

William SlikkerU.S. Food and Drug Administration

Thomas J. SobotkaU.S. Food and Drug Administration

Judith P. SwazeyAcadia Institute

Letitia TahanU.S. Environmental Protection Agency

Hugh A. TilsonNational Institute of Environmental Health Sciences

Daniel C. VanderMeerNational Institute of Environmental Health Sciences

Charles V. VorheesChildren’s Hospital Research Foundation

Andrea A. WargoAgency for Toxic Substances and Disease Registry

David E. WeillU.S. Environmental Protection Agency

Judith WeissingerU.S. Food and Drug Administration

Ellen WidessTexas Department of Agriculture

Valerie A. WilkFarmworker Justice Fund

Ronald WoodNew York University Medical Center

Michael J. WrightUnited Steelworkers of America

Richard J. WurtmanMassachusetts Institute of Technology

Charles XintarasAgency for Toxic Substances and Disease Registry

Ralph YodaikenOccupational Safety and Health Administration

John S. YoungHampshire Research Associates, Inc.

Appendix E

List of Contractor Documents

For this report, OTA commissioned six papers on various topics in neurotoxicology. The manuscriptsof all but one of these contract documents(*) are available from the National Technical Information Service,5285 Port Royal Road, Springfield, VA 22161, telephone (703) 487-4650.

“Neurotoxic Pesticides and the Farmworker,” E. Widess, 1988.“The Federal Regulatory Response to the Problem of Neurotoxicity,” J.B. Corteau, J.S, Young, and

W. Muir, Hampshire Research Associates, Inc., 1988.“International Neurotoxicity Research: Current Activities and Future Directions,” Z. Annau, 1988.“Assessing Human Risks Posed by Neurotoxic Substances,” Environ Corp., 1988.“Economic Considerations in Regulating Neurotoxic Substances,” G. Provenzano, 1989.*“ Neurotoxicity Research-Current Activities and Future Directions,” R. Wood, 1988.

-335-

Appendix F

Glossary of Terms and List of Acronyms

Glossary of Terms

Acceptable daily intake (ADI): See reference dose.Acetylcholine: See neurotransmitter.Acetylcholinesterase: An enzyme that catalyzes the

breakdown of the neurotransmitter acetylcholine. Seeneurotransmitter.

Action level: The point at which steps must be taken toreduce the concentration of a toxic substance in or onfood, air, or water. An action level is based on the samecriteria as a tolerance, but the action level is temporary,until a tolerance level can be set and is not legallybinding. Compare tolerance level.

Active ingredient (of a pesticide): The component of achemical compound that produces the desired biochemi-cal effect; specifically, the pesticide itself. Compareinert ingredient.

Acute exposure: See duration of exposure, frequency ofexposure.

Administrative controls: Methods of reducing workerexposures to occupational hazards through administra-tive arrangements. For example, rotating a workerfrom areas of high exposures to areas of low exposuresreduces that worker’s average exposure level.

Axon: The long extension, or process, of the neuron alongwhich nerve impulses travel.

Axonopathy: Degeneration of axons. In central-peripheral distal axonopathy, degeneration usuallybegins at the end of the axon and proceeds toward thecell body (the cell body itself is not affected). Incentral-distal axonopathy, a less common form, degen-eration of the spinal cord, but not the peripheralnervous system, occurs, Compare neuronopathy, neu-ropathy.

Biotransformation: The biochemical processes by whicha foreign substance is altered or metabolized by thebody (e.g., by the action of enzymes). Althoughbiotransformation usually results in less toxic com-pounds, it can result in more toxic compounds.

Blood-brain barrier: A layer of tightly juxtaposed cellsin blood vessel walls that protects much of the centralnervous system by selectively filtering out somesubstances while allowing others to pass from theblood into the brain,

Carbamate: A synthetic organic insecticide. As pesti-cides, carbamates are reversible inhibitors of cholinest-erase.

Carcinogen: A substance that causes cancer.Cell body: The relatively compact portion of the neuron

that contains the nucleus. Compare process.Cell culture: Growth in the laboratory of cells isolated

from multicellular organisms. Although the cellsproliferate, they do not organize into tissue. See purecell culture, mixed cell culture, cell line, and clonedcells.

Cell line: A group of malignant cells derived from aprimary culture at the time of first subculture; anestablished cell line has the potential for indefinitesubculture in vitro.

Central nervous system: One of the two major divisionsof the nervous system, made up of the brain and spinalcord. Compare peripheral nervous system.

Cerebellum: The part of the brain involved in coordina-tion of muscles and the maintenance of equilibrium.

Cerebrum: The portion of the brain responsible forconscious mental processes.

Cholinesterase inhibition: See acetylcholinesterase.Chronic exposure: See duration of exposure, frequency

of exposure.Classical neurotransmitter: See neurotransmitter.Clinical test: Experimental use (as of drugs) on humans.Cloned cells: Asexually produced cells, all of them

genetically identical to the original cell.Commodity chemical: A compound produced by several

companies. Compare specialty chemical.Consent decree: A legally binding mutual agreement

between EPA and the manufacturer of a chemicalunder which the manufacturer will conduct EPA-specified tests and EPA will not require further testing,

Cost-benefit analysis: A determination of whether thecosts of regulating a toxic substance exceed thebenefits in reducing risk to health or the environment.Both costs and benefits are measured in monetaryunits. Compare risk-benefit analysis, cost-eelective-ness analysis. See risk.

Cost-effectiveness analysis: A determination of whetherthe costs of regulating a toxic substance exceed theeffectiveness in reducing risks to health or the environ-ment. Costs are measured in monetary units, effective-ness in natural units such as years of life saved,incidence of disease averted, and days of work lossavoided. Compare cost-benefit analysis. See risk.

Dementia: Loss of intellectual function.Demyelination: Destruction of the myelin sheath of a

nerve. See myelin sheath.Dendrite: Any of the branched extensions, or processes,

of the neuron along which nerve impulses traveltoward the cell body.

Developmental neurotoxicity tests: Studies of the off-spring of animals exposed to toxic substances duringpregnancy and lactation in order to determine thenature and extent of structural or functional damage tothe nervous system of the offspring.

Differentiation: The process of cells and tissues acquir-ing distinct characteristics during development.

Discounting: Relating costs or benefits that occur atdifferent times to a common basis.

Dopamine: See neurotransmitter.

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Appendix F--Glossary of Terms and List of Acronyms ● 337

Dosage: The amount, frequency, and number of dosesadministered in a test.

Dose: The amount of a substance absorbed in a unitvolume or in an individual. Dose rate is the dosedelivered per unit of time.

Dose-response: The quantitative relationship betweenexposure to a substance, usually expressed as a dose,and the extent of toxic injury or disease.

Duration of exposure: The length of time a person or testanimal is exposed to a chemical. Duration of exposureis divided into four categories: acute (exposure to achemical for less than 24 hours), subacute (exposurefor 1 month or less), subchronic (exposure for 1 to 3months), and chronic (exposure for more than 3months). See frequency of exposure.

Economic efficiency: The ‘state in which the greatestdirect and indirect gains (benefits) are derived from theresources expended (costs) to achieve a stated objec-tive. Compare net efficiency.

Efficiency: See economic efficiency.Electromyography, EMG: Recording and measuring

the electrical activity of muscles by means of anelectromyograph. Electromyography is used in testingthe effects of neurotoxic substances on humans.

Electroneurography, ENG: Recording and measuringthe electrical signals generated by nerves by means ofan electromyograph. Electroneurography is used intesting the effects of neurotoxic substances on humans.

Electrophysiology: Measuring and recording the electri-cal activity of the brain or nerve cells by means ofelectrodes.

Encephalopathy: Degeneration of the brain.Endpoint: The disease, conditions, or adverse effect

resulting from exposure to a toxic substance (e.g.,memory loss, paralysis, dizziness, anxiety).

Engineering controls: Methods of controlling workerexposure by modifying the source or reducing theamount of contaminants released into the workplace.These include process design and modification, equip-ment design, enclosure and isolation, and ventilation.

Environmental hypothesis: The theory that exposure totoxic substances contributes significantly to neurologi-cal disorders such as Parkinson’s disease, Alzheimer’sdisease, and amyotrophic lateral sclerosis (LouGehrig’s disease).

Epidemiology: The study of the distribution of diseasesand their precursors in human populations.

Evoked potentials, sensory evoked potentials (EPs):Electrical signals generated by the nervous system inresponse to a stimulus, whether auditory (brainstemauditory evoked responses, BAERs), visual (visualevoked potentials, VEPs, which include flash evokedpotentials, PEPs, and pattern reversal evoked poten-tials, PREPs), or somatosensory (somatosensory evokedpotentials, SEPs). EPs can be measured and themeasurements used to identify which senses are

affected by neurotoxic substances and how they areaffected. See electrophysiology.

Explant culture: Tissue taken from its original site andplaced in an artificial medium for growth.

Experimental use permit (EUP): An application to EPAby a manufacturer for permission to conduct fieldtestson a pesticide.

Exposure: The accidental or intentional contact of aperson or animal with a substance, specifically a toxicsubstance. Exposure is measured by the amount of thesubstance involved (dose), how often and for how longcontact took place (frequency and duration of expo-sure), and the means through which contact occurred(route of exposure). See dose, duration of exposure,frequency of exposure, route of exposure.

Frequency of exposure: The number of times a person ortest animal is exposed to a chemical. Acute exposures

“are generally single exposures, whereas subacute,subchronic, and chronic exposures are repeated expo-sures. See duration of exposure.

Functional observational battery (FOB): A collectionof noninvasive tests to evaluate sensory, motor, andautonomic dysfunction in test animals exposed tosubstances or whose nervous systems have beendamaged, FOBS are generally used to screen forneurotoxic substances. See screening test.

Ganglion: A collection of nerve cells outside the brain orspinal cord.

Glia, glial cells: The second basic cell type of the nervoussystem. Glia perform support functions for neurons:namely, nutrition, insulation (through the productionof myelin), and structural support. Compare neuron.

Hazard: The likelihood that a pesticide will causeimmediate or short-term adverse effects or injuryunder ordinary circumstances of use.

Hen test: An observational assay in which the observerranks the animals’ motor ability.

Hydrophilic: Having an affinity for water; that is, solublein water. These substances may also be termedlipophobic, or insoluble in lipids.

Hydrophobic: Insoluble in water; these substances mayalso be termed lipophilic.

Inert ingredient (of a pesticide): The solvent or “inac-tive” solid that dilutes or carries a pesticide; inertingredients are so called because they have no effect onthe targeted pest, not because they are inherentlyinactive. An inert ingredient as defined by EPA can, insome cases, cause adverse effects on human health.

Inorganic: Matter generally not containing carbon (i.e.,not animal or plant matter). Compare organic.

Integrated pest management (IPM): A system forcontrolling pests in which pesticides are used inconjunction with biological controls (natural predatorsand parasites, disease-causing microorganisms, phero-mones, pest-resistant plants) and cultural controls(crop rotation, removal of pest-harboring crop residues


after harvest).Investigational new drug (IND): Application to FDA by

a manufacturer for permission to conduct clinical trialson a drug.

In vitro test: Experiment using cells, tissues, or explantsgrown in a nutritive medium as a model system intoxicity testing rather than using living animals orhuman beings. Toxicity is assessed by adding a testsubstance to the culture and observing any changesthat occur. See cell culture, tissue culture, explantculture.

In vivo: Literally, in the living; pertaining to a biologicalprocess or reaction taking place in a living cell ororganism.

Latent effect: A reaction to a toxic substance that is notimmediately evident but that appears later in life; alsoreferred to as a silent effect.

Lipids: Fat-like substances that are an important constitu-ent of cell structure; the nervous system is composedof high concentrations of lipids.

Lipophilic: Having an affinity for lipids; that is, solublein fat-like material, These substances may also betermed hydrophobic, or insoluble in water. Many toxicsubstances are lipophilic, making them especiallydangerous to the nervous system. See lipids.

Margin of exposure: See margin of safety.Margin of safety: Division of the NOEL or NOAEL by

the current, desired, or most feasible human exposurelevel. See NOEL, NOAEL.

Maximum allowable concentration (MAC): The limiton atmospheric contaminants in manned spacecraft formissions of up to 7 days; set by the NationalAeronautics and Space Administration.

Maximum contaminant level (MCL): An enforceablestandard set by EPA for pollutants in drinking water,to be set as close as possible to the maximumcontaminant level goals. See maximum contaminantlevel goals, recommended maximum contaminantlevel.

Maximum contaminant level goal (MCLG): Nonen-forceable goal set by EPA for pollutants in drinkingwater. MCLGs for carcinogenic pollutants are set atzero; goals for noncarcinogenic pollutants are set byestablishing the lowest dose at which harmful effectscan be observed, compensating for uncertainties, andcalculating predicted human exposure from food andair. See maximum contaminant level.

Me-too registration: A practice by which subsequentproducts that are identical to an initial, registeredproduct can be registered without undergoing regula-tory tests.

Mixed cell culture: A culture of more than one type ofcell.

Mixed neuropathy: Degeneration of both sensory andmotor neurons.

Motor activity tests: Observation and evaluation of the

movements of test animals after acute or subchronicexposures to a substance; used as a screen forneurotoxic substances. See screening test.

Motor neuron: See neuron.Mutagenic: Causing increases in the mutation of genes.Myelin: A fatty substance (of which the myelin sheath

surrounding axons is made) that acts as an electricalinsulator to speed the conduction of nerve impulses.Myelin is formed in the peripheral nervous system bySchwann cells and in the central nervous system byglial cells.

Myelin sheath: Concentric layers of myelin surroundingthe axons of some neurons. The myelin sheath speedsthe conduction of electrical impulses.

Myopathy: Degeneration of muscle fiber.Narcosis: Nonspecific, reversible depression of central

nervous system function, marked by stupor or uncon-sciousness and produced by drugs.

National primary drinking water regulations (NPDWRs):Enforceable standards for contaminants in drinkingwater set by EPA that include maximum contaminantlevels or required treatment techniques, or both. Seemaximum contaminant level.

Net efficiency: The difference between direct benefits anddirect costs, generally in regard to regulation.

Neuromuscular junction: The site at which chemical orelectrical information is transmitted from a nerve cellto muscle fiber. Compare synapse.

Neuron, nerve cell: The basic functional unit of thenervous system. The neuron is typically composed ofa relatively compact cell body containing the nucleus,several short radiating processes (dendrites), and onelong process (the axon) with branches along its lengthand at its end. Information in the form of electricalimpulses travels from the cell body along theseprocesses to other cells. Sensory neurons send infor-mation to the brain and spinal cord; motor neuronssend instructions to the muscles. See axon, dendrite.

Neuronopathy: A primary damage to the nerve cell bodywhich results in a rapid, but secondary, degeneration ofnerve processes.

Neuropathological tests: Postmortem examination oftest animals in order to determine changes in thestructure and function of the nervous system as a resultof exposure to a toxic substance. These tests may beused to screen for toxic substances. See screening test.

Neuropathy: Degeneration of nerve cells; a generaldescription for any disease of the peripheral or centralnervous system.

Neuropeptide: See neurotransmitter.Neurophysiological tests: Techniques for measuring the

electrical signals, or evoked potentials, of chargedions; the measured potentials reflect the functioning ofthe neuron or neurons that generated them. Seeelectrophysiology, evoked potentials.

Neurotoxic esterase (NTE) assay: A procedure for

Appendix F--Glossary of Terms and List of Acronyms ● 339

measuring the inhibition of the enzyme NTE in thebrain or spinal cord of hens exposed to organo-phosphates. The test can be used to determine thedelayed effects of acute and subchronic exposures toorganophosphates. See organophosphates.

Neurotoxicant, neurotoxic substance: A chemical thatadversely affects the nervous system.

Neurotoxicity, neurotoxic effect: An adverse change inthe structure or function of the nervous systemfollowing exposure to a toxic substance.

Neurotoxicology: Study of the effects of toxic chemicalson the nervous system, including the modes by whichneurotoxic substances enter the body, the effects thesesubstances have on the nervous system, the biochemi-cal and physiological mechanisms through which theeffects occur, the prevention of damage to the nervoussystem, and the treatment of neurological and psychi-atric disorders caused by exposure.

Neurotransmitter: Specialized chemical messenger syn-thesized and secreted by neurons to convey informa-tion from one nerve cell to another (serotonin, norep-inephrine, dopamine) or from a nerve cell to musclefiber (acetylcholine). Neurotransmitters act on thereceptors of other cells: classical neurotransmitters(e.g., the four mentioned above) typically interact withreceptors of adjacent cells; neuropeptides (e.g., theendorphins and vasopressin) may transmit messages toreceptors on distant cells. See receptor.

New drug application (NDA): Submission of evidence,including results of clinical trials, to FDA by amanufacturer that a drug is both safe and effective.Approval of the NDA is required before the drug canbe marketed. Compare investigational new drug.

NOAEL, no observed adverse effect level: That dosebelow which no adverse effect is observed. CompareNOEL.

No-effect levels: See NOEL, NOAEL, threshold.NOEL, no observed effect level: That dose below which

no effect of any sort is observed. Compare NOAEL,threshold.

Norepinephrine: See neurotransmitter.No-threshold: The situation in which any dose greater

than zero increases risk. Compare threshold.Oligodendrocyte: A type of glial cell that appears to play

a role in myelin formation in the central nervoussystem. Compare Schwann cell. See glia.

Opportunity cost: The value of alternative endeavorsthat might have been undertaken with the resourcesused for the particular endeavor chosen.

Organ culture: A type of tissue culture in which a wholeorgan is maintained in vitro.

Organic: Matter containing carbon (i.e., animal or plantmatter). Compare inorganic.

Organic farming, organic production: Farming withoutthe use of or with limited use of chemical pesticides orfertilizers.

Organic solvents: Generic name for a group of simpleorganic liquids that are volatile (that is, in the presenceof air they change from liquids to gases) and thereforeare easily inhaled.

Organoleptic: Stimulating any of the organs of sensationor susceptible to a sensory stimulus.

Organophosphates, organophosphorous pesticides: Aclass of pesticides with neurotoxic properties; organo-phosphates have also been used as nerve gases.

Organotypic culture: A type of primary tissue culture inwhich the structure of the original organ is maintainedin vitro. This method is useful in neurotoxicity studiesbecause the connections and spatial relations betweenneurons and glia can be maintained.

Pattern of exposure: The dose, duration, frequency, androute of exposure; used in risk assessment. See dose,duration of exposure, frequency of exposure, route ofexposure.

Peripheral nervous system: One of the two majordivisions of the nervous system, made up of the nervesconnecting the spinal cord and sensory organs, glands,blood vessels, and muscles. Compare central nervoussystem.

Permissible exposure limit (PEL): The maximum expo-sure to a given chemical that an industrial worker isallowed during an 8-hour workday and 40-hourworkweek, set by the Occupational Safety and HealthAdministration. Compare reentry interval.

Personal protective equipment: Equipment and cloth-ing designed to control hazards: it includes hard hats,safety shoes, protective eyewear, and various types ofrespirators.

Pesticide: A generic term referring to toxic substancesdeveloped to control pests; it includes insecticides,fungicides, rodenticides, and herbicides.

Potentiation: The process through which a nontoxicsubstance increases the toxicity of another substance.

Preclinical test: Experimental testing (as of drugs) onanimals.

Presumption of risk: The probability that an existinghazard, combined with the potential for human expo-sure to it, creates risk. Compare risk assessment.

Primary culture: Cell, tissue, or organ culture initiateddirectly from an organism rather than from anotherculture. Compare explant culture.

Prior informed consent (with respect to pesticides):Agreement on the part of one government to import apesticide banned or severely restricted by anothergovernment in full knowledge of the reasons for thatban or restriction.

Processes, nerve processes: Extensions of the neuron,whether axons or dendrites, along which nerve im-pulses travel. Compare cell body.

Receptor: Sensory neuron terminal; also, a molecule inthe cell membrane that recognizes and combines witha specific chemical substance, such as a neurotransmit-


ter. See neurotransmitter.Recommended exposure limit (REL): Standard for

maximum exposure of industrial workers to toxicsubstances, set by the National Institute for Occupa-tional Safety and Health. Compare permissible expo-sure limit, threshold limit value.

Recommended maximum contaminant level (RMCL):Nonenforceable goals set by EPA for pollutants indrinking water; renamed maximum contaminant levelgoal. See maximum contaminant level goal, maximumcontaminant level.

Red Book: Guidelines for toxicological testing of directfood additives and color additives used in food underthe Federal Food, Drug, and Cosmetic Act publishedby the Center for Food Safety and Applied Nutrition ofFDA,

Reentry interval: The time that must elapse betweenapplication of a pesticide and the return of agriculturalworkers to the treated area without special protection.

Reference dose (RfD): A term used to characterize riskand derived by applying safety factors to NOELs orNOAELs. If human exposure to a substance is belowthe RfD, no risk is assumed to exist; if exposureexceeds the RfD, risk is assumed to exist. The termmay be used interchangeably with acceptable dailyintake, although EPA uses the term RFD. See NOEL,NOAEL.

Reuptake: Process by which neurotransmitters and theirmetabolizes are recycled.

Right-to-know laws: State and local laws requiringcompanies to inform workers and communities of thechemical names and hazards of their products.

Risk: The probability of injury, disease, or death forpersons or groups of persons undertaking certainactivities or exposed to hazardous substances. Risk issometimes expressed numerically (as a fraction) andsometimes qualitatively (e.g., high, moderate, or low).

Risk assessment: The analytical process by which thenature and magnitude of risk are identified. Four stepsmake up a complete risk assessment: hazard identifica-tion, dose-response assessment, exposure assessmentand risk characterization. Compare risk management,presumption of risk. See risk, exposure, dose-response.

Risk-benefit analysis: A determination of whether therisks to health and the environment of using a chemicalor drug exceed the economic benefits that accrue fromits use. In the case of pesticides, benefits are measuredin terms of the monetary value of crop yields; in thecase of drugs, benefits are measured in terms oftherapeutic efficacy.

Risk management: The process of determining whetheror how much to reduce risk through regulatory action.Decisions depend on data from risk assessments andmay also depend on political, social, ethical, eco-nomic, and technological factors.

Route of exposure: The means by which a person oranimal comes into contact with a chemical: namely,intravenous (injected into the bloodstream), inhalation(through the lungs), oral (through ingestion), anddermal (through the skin).

Safety factor: Division of the NOEL or NOAEL andsucceeding measures by a factor, typically 10, to yielda reference dose; used interchangeably with uncer-tainty factor. Safety factors account for uncertainties inthe extrapolation of data from, for example, short- tolong-term exposures, and animals to humans.

Scaling factor: Weighting disparate measures of healthoutcomes for cost-effectiveness analysis on the basisof value judgments concerning their relative worth.

Schedule-controlled operant behavior (SCOB): A testin which an experimental animal’s response to astimulus is reinforced on a predetermined schedule inorder to produce a predictable pattern of behavior.SCOB is used to evaluate the effects of acute or chronicexposure to toxic substances on the rate and pattern ofthe animal’s responses.

Schwann cell: A glial cell in the peripheral nervoussystem that produces myelin for the myelin sheath.Compare oligodendrocyte.

Screening test: Broad-based initial test of a chemicaldesigned to detect adverse health effects. Screeningcan help determine what further tests should beperformed to evaluate a substance’s toxicity.

Sensitivity analysis: Deliberately varying the uncertain-ties in an assessment in order to examine their effectson the decision taken.

Sensory neuron: See neuron.Serotonin: See neurotransmitter.Silent effect: See latent effect.Specialty chemical: A compound produced by only one

company. Compare commodity chemical.Structure-activity relationship: The relationship be-

tween a chemical’s structure and the biochemicalchanges it induces.

Subchronic exposure: See duration of exposure, fre-quency of exposure.

Synapse: The site at which chemical or electricalinformation is transmitted from one nerve cell toanother, typically by a neurotransmitter. Compareneuromuscular junction. See neurotransmitter.

Synaptic cleft: A narrow gap between two adjacentneurons into which neurotransmitters are secreted. Seeneurotransmitter.

Synergism: The state in which the combined adverseeffects of a chemical exceed the sum of the effects ofeach chemical acting alone.

Teratogenic: Producing defects in the developing em-bryo. (A substance that causes physical defects in theoffspring.)

Test rule: A statement written by EPA of what chemicalor chemicals in a compound must be tested by the

Appendix F-Glossary of Terms and List of Acronyms . 341

manufacturer and how they are to be tested. Test rulesare written under the Toxic Substances Control Actwhen it can be shown both that inadequate data on theeffects of a compound exist and that testing is requiredto obtain such data.

Threshold: The highest dosage at which no effect isobserved. Compare no-threshold.

Threshold limit value (TLV): That concentration (byvolume in air) of a hazardous substance to which themajority of industrial workers may be repeatedlyexposed every day without adverse effects; set by theAmerican Conference of Governmental IndustrialHygienists. Compare reference dose.

Tiered testing: A strategy for identifying the toxicologi-cal effects of a substance by proceeding from generaltoxicity tests to progressively more specific andsophisticated tests.

Time-weighted average: An average over a given(working) period of a person’s exposure, as deter-mined by sampling at given times during the period.

Tissue culture: The maintenance or growth of tissue,organs, or cells in vitro. Tissue culture can besubdivided into cell culture and organ culture. See cellculture, organ culture.

Tolerance level: The maximum permissible concentra-tion of a toxic substance in or on food, water, or air, asset by a regulatory agency. Compare action level.

Toxicology: The study of adverse effects of natural orsynthetic chemicals on living organisms.

Uncertainties: Questions involved in risk assessment,ranging from fundamental questions (e.g., How usefulare animals as predictors of toxicity in humans?) tospecific questions arising from incomplete or imper-fect data on a particular substance (e.g., Do responsesdiffer with route of exposure? What exposures arelikely for various populations?).

Uncertainty factor: See safety factor.

List of Acronyms

ACGIH —American Conference of GovernmentalIndustrial Hygienists

ADAMHA —Alcohol, Drug Abuse, and Mental HealthAdministration

ADI —acceptable daily intakeAETT —acetylethyl tetramethyl tetralinALS —amyotrophic lateral sclerosisATSDR —Agency for Toxic Substances and Disease

RegistryAZT —azidothymidineBAER —brainstem auditory evoked responseBHC —benzene hexachlorideBHMH —Lucel-7BPI —Bureau of Plant Industry (Philippines)CAA -Clean Air ActCAP -Consumers Association of Penang

(Malaysia)

CBICDCCEHCERCLA

CFSAN

CIITCOHbCPDACPSACPSCCSACSPICWADBCPDHHS

DOEEDBEECEEGEMGENGEPEPAEPNEUPFAO

FDAFEA

FEPFFDCAFHSAFICFIFRA

FIOHFLTFMSHAFOBFPA

FWPCAGAOGFAPHCHHHANES

HUD

INDIPMIRIS

-confidential business information-Centers for Disease Control—Center for Environmental Health-Comprehensive Environmental Response,

Compensation, and Liability Act—Center for Food Safety and Applied

Nutrition (FDA)—Chemical Industry Institute of Toxicology-carboxyhemoglobin-central-peripheral distal axonopathy—Consumer Product Safety Act—Consumer Product Safety Commission—Controlled Substances Act—Center for Science in the Public Interest—Clean Water Act-dibromochloropropane—Department of Health and Human

Services—Department of Energy--ethylene dibromide—European Economic Community-electroencephalograph-electromyography-electroneurography-evoked potential—Environmental Protection Agency-ethyl-p-nitrophenyl phosphonothionate—Experimental Use Permit—Food and Agriculture Organization

(United Nations)—Food and Drug Administration—Federal Environmental Agency (West

Germany)—flash evoked potential—Federal Food, Drug, and Cosmetic Act—Federal Hazardous Substances Act—Fogerty International Center—Federal Insecticide, Fungicide, and

Rodenticide Act—Finland Institute of Occupational Health—fenvalerate—Federal Mine Safety and Health Act—functional observational battery—Fertilizer and Pesticide Authority

(Philippines)—Federal Water Pollution Control Act—General Accounting Office—glial fibrillary acidic protein—hexachlorocyclohexane—Hispanic Health and Nutrition

Examination Survey—Department of Housing and Urban

Development—investigational new drug—integrated pest management—Integrated Risk Information System


ITCLBPPPA

LMIN

MAMACMCLMCLGMCPAMNAF

MnBKMNDMOEMOSMPRSA

MSHAMPTP

MTBENAPARE

NASNASA

NBSNBTNCHSNCTBNCTR

NDANFPANHANES

NHLBINIANIAAA

NIAID

MDANIEHS

NIGMS

NIMHNINCDS

—Interagency Testing Committee—had-Based Paint Poisoning Prevention

Act—Laboratory of Molecular and Integrative

Neuroscience (NIEHS)—motor activity—maximum allowable concentration—maximum contaminant level—maximum contaminant level goal—2-methyl-4-chlorophenoxyacetic acid—Ministry of Nutrition, Agriculture, and

Forest (West Germany)—methyl-n-butyl ketone—motor neuron disease—margin of exposure—margin of safety—Marine Protection, Research, and

Sanctuaries Act—Mine Safety and Health Administration—l-methyl-4-phenyl- 1,2,3,6-

tetrahydropyridine—methyl-tert-butyl ether—National Association for Perinatal

Addiction Research and Education—National Academy of Sciences—National Aeronautics and Space

Administration—National Bureau of Standards—Neurobehavioral Toxicology Team—National Center for Health Statistics—Neurobehavioral Core Test Battery—National Center for Toxicological

Research—new drug application—National Food Processors Association—National Health and Nutrition

Examination Survey—National Heart, Lung, and Blood Institute—National Institute on Aging—National Institute on Alcohol Abuse and

Aging—National Institute of Allergy and

Infectious Diseases—National Institute on Drug Abuse—National Institute of Environmental

Health Sciences—National Institute of General Medical

Sciences—National Institutes of Health—National Institute of Mental Health—National Institute of Neurological and

Communicative Disorders and Stroke

NIOSH

NLMNOAELNOELNPDWR

NRCNRDCNTDNTENTPOECD

OPPOSH ActOSHA

OTAOTSPANPCBPCPPDDPPELPICPMNPPPAPREPRCRARELRfDRMCLRQSAPSARA

SCOBSDWASEPSMSASNURSTELTDMTLV

TRITSCATWAUSDAUSDJWHO

—National Institute for Occupational Safetyand Health

—National Library of Medicine—no observed adverse effect level—no observed effect level—national primary drinking water

regulations—National Research Council—Natural Resources Defense Council—Neurotoxicology Division (EPA)—neurotoxic esterase assay—National Toxicology Program-Organization for Economic Cooperation

and Development-Office of Pesticide programs (EPA)-Occupational Safety and Health Act-Occupational Safety and Health

Administration-Office of Technology Assessment-Office of Toxic Substances (EPA)—Pesticide Action Network—polychlorinated biphenyl—phencyclidine; pentachlorophenoldiisodecyl phenyl phosphite—permissible exposure limit—prior informed consent—premanufacture notice—Poison Prevention Packaging Act—pattern reversal evoked potentials—Resource Conservation and Recovery Act—recommended exposure limit—reference dose—recommended maximum contaminant level—reportable quantity—Science Advisory Panel—Superfund Amendments and

Reauthorization Act—schedule-controlled operant behavior—Safe Drinking Water Act—somatosensory evoked potential—Standard Metropolitan Statistical Area—significant new use rule—short-term exposure limit—triadimeform—threshold limit value—triphenyltin—Toxics Release Inventory—Toxic Substances Control Act—time-weighted average limit—U.S. Department of Agriculture—U.S. Department of Justice—World Health Organization

Index

abused drugsaddiction, 6, 52,74, 75designer drugs, 51effects on nervous system, 6,9, 51–53, 71health costs of, 20,53,232psychoactive drugs, 6, 10,27,44,50withdrawal from, 74see also specific drugs

academic researchcooperative agreements with government, 94factors influencing directions of, 92-94

acetaldehyde, 297acetone, 14, 136,296, 297,303acetylcholine, 26, 66, 109, 124,294, 336acetylcholinesterase, 11,50,74,84,187,203, 289,290-292,336acetylethyl tetramethyl tetralin (AETT)

exposure route, 108incidents of poisoning, 47, 54neurological effects of, 54

acrylamide, 73, 120neurotoxicity testing, 166, 175regulation for neurotoxicity, 178risk assessment approaches, 150, 151,216research on neurotoxicity, 258

acrylates, 175acrylonitrile, 203

neurotoxicity testing, 166, 173OSHA health standards, 185

action levels for contaminants in foods, 164, 241–242, 336“Adam,” 51Administrative Procedure Act, 162age/aging

and exposure to neurotoxic substances, 269as a factor in animal studies, 107nervous system effects of, 8, 15, 54, 67, 152and neurobehavioral tests, 126and toxicity of chemicals, 15, 63, 152see also children; elderly

Agency for Toxic Substances and Disease Registry, 135–136research activities of, 9, 11, 89, 188, 271, 322

Agent Orange, 295Agricultural Pesticide Institute of the Philippines, 252air pollutants

hazardous, defined, 181lead, 273–274, 276,281standards for, 181, 182, 185see also Clean Air Act

Alar, 291Alaskan Marine Mammal Tissue Archival Project, 133alcohol and alcohol abuse, 4,44, 115

axonopathic effects, 73effects on fetus, 70, 124research on, 9, 11thiamine deficiency and toxicity of, 71

Alcohol, Drug Abuse, and Mental Health Administration(ADAMHA), research

-i

activities of, 33, 81, 88, 322aldicarb, 47, 173,251aldrin, 250,252,292allyl chloride, 303aluminum, 48

and Alzheimer’s disease, 54-55oxide, 14, 136

Alzheimer’s diseaseeffects on hippocampus, 71environmental cause, 3, 6, 54-55, 70, 72research on, 259

American Academy of Pediatrics, 189American Conference of Governmental Industrial Hygienists,

28, 151, 185, 186,203,302-303American National Standards Institute, 185ammonia, 14, 136amphetamines, 74amyotrophic lateral sclerosis

characteristics of, 54environmental cause, 3, 6, 54-55, 70, 72incidence of, 54, 55research on, 259

anencephaly, 70anilines and substituted anilines, 179animal tests, 13

accuracy and reliability, 106, 115advantages and limitations of, 105, 106, 111, 112, 114, 116,

120-121, 136, 137alternatives to, 121–125; see also in vitro neurotoxicity testsof BHMH, 55–56biochemical markers, 117choice of animals, 106-107, 109-110, 121, 152in combination with in vitro tests, 13, 122, 124cost factors, 106-107, 110, 222–225, 226227cross-species comparisons, 115–1 16, 121, 148design, 105, 106-109,222developmental neurotoxicology, 110, 111, 114-116, 137,

165-166, 178dosing regimen, 107, 110, 147-148comparability with human testing, 115EPA guidelines, 110evaluating chemicals for neurotoxicity, 109-110extent and duration of exposure, 108, 222, 225, 226extrapolation to humans, 18,82, 105, 121, 147, 148, 149, 153,

204of food additives, 52functional observational battery, 110,11 1–1 12,136,137,178,

224-225,226hazard identification with, 147housing conditions, 108-109innovation impacts of, 226-227longitudinal, 107of MDMA, 51–52motor activity, 110, 11 1–1 14, 136, 137, 178,224-225, 226Motron Electronic Mobility Meter, 113multispecies, 107

-343-


neuropathological examination, 110, 111, 114, 136, 137, 178,224-225,226

neurophysiology techniques, 118–121neurotoxic esterase assay, 111, 136-137, 178nutritional status of animals, 108observational methods, 112–1 13for organophosphorous pesticides, 110, 117-118quality assurance in, 222-223route of exposure, 108, 121, 222, 225schedule-controlled operant behavior, 110, 111, 116–1 17,

136, 137, 178,224-225temperature of environment, 109tiered approach, 109-110types of, 110-121validation of, 109

antagonism, 65antibiotics, 45, 70, 123, 125anticancer drugs, 51, 73antipsychotic drugs, 44, 50Apiol (with TOCP), incidents of poisoning, 47Argentina

research on neurotoxicity, 258use of banned pesticides in, 239

arsenic, 133, 182, 183, 185aryl phosphates, 179asbestos, 176, 180, 182aspartame, 166, 198

application process, 315–318claims of adverse effects, 18, 318–319postmarketing surveillance, 318

aspartate, 71Association of People for Practical Life Education, 252astrocytes, 117attentional disorders, 70, 229, 273auditory system

substances affecting, 49, 119, 131, 135,272testing of, 119

Australia, use of banned pesticides in, 239axonopathy

causative agents, 73–74defined, 67,336

axons, 72development of, 67effects of toxic substances on, 67, 69, 73, 295functions of, 65-66,336

azidothymidine, 167

barium, 183Basic Document on Regulations of Registration, Marketing and

Control of Agricultural Chemicals for Countries ofCentral America, 253-254

Bayley Scales of Infant Development, Mental DevelopmentIndex, 155

behavioral effects, 70Collaborative Behavioral Teratology Study, 115defined in TSCA, 174duration of exposure and, 70EPA research on, 82examples of, 46of lead, 46, 229–230, 272, 273of organic solvents, 298–299of pesticide poisoning, 285

research needs on, 154tests for, see neurobehavioral testssee also operant behavior

behavioral teratology, 70, 114-116Belgium, regulatory policies in, 246-247Benton Visual Retention Test, 127benzene, 14, 135, 136, 182,297,303beryllium, 182BHC, 252BHMH, incidents of poisoning, 47,55-56biochemical markers, 11,82, 84, 117biological monitoring, 133-134blood-brain barrier

drug passage through, 66-67fetal, 70structure and function, 336, 66-67, 73

blood vessels, neurotoxic substances acting on, 74,76botulinum toxin, 45Bourdon Wiersma Vigilance Test, 127brain

aging, and structure of, 15, 67, 152congressional resolution on Decade of the Brain, 330–331development of, 67opioid receptors, 74regional differences in sensitivity to toxic substances, 68structure and function, 66

brain damagefrom abused drugs, 51,70from lead, 271from mercury, 131from pesticides, 291

brainstem auditory evoked responses, 119, 128Brazil, pesticide misuse in, 251buckthorn (Karwinskia humboldtiana), 74B-bungarotoxin, 124Bureau of Community Environmental Management, 277n-butyl alcohol, 14, 136

cadmium, 48, 68, 74monitoring of, 133, 134research on, 257

California Birth Defects Prevention Act of 1984,289-290camphechlor, 250Canada

human tissue monitoring, 132regulatory policies and practices in, 245research on neurotoxicity, 258

carbamate insecticides, 26,49,74, 175,287, 289–291, 293,295,336

carbon disulfideexposure limits for, 187, 303neurological effects of, 73, 108, 298, 299poisoning incidents, 256releases, 14, 136

carbon monoxideair quality standards, 181, 182central nervous system effects, 181, 187poisoning, 64,69, 181research on neurotoxicity, 258

carbon tetrachloride, 297carbonyl sulfide, 14, 136carcinogenicity, 56

Index ● 345

cassava (Manihot esculenta), 55cell cultures

defined, 123,336mixed, 338monolayer, 124muscle cells, 124retinal neurons, 124

cell lines, 124, 125, 336Center for Environmental Health, research activities of, 90-91Center for Science in the Public Interest, 192Centers for Disease Control

acceptable levels for lead, 271human monitoring program, 133lead poisoning prevention program, 277research activities of, 9, 11, 12, 81, 322

central distal axonopathy, 74central nervous system, 336

degeneration, 72depression of activity, 108lead effects on, 272pesticide effects on, 284-285structure, 66

central-peripheral distal axonopathy, 67, 73–74cerebellum, 67, 70, 72, 336cerebral palsy, 49cerebrum, 70, 336charitable organizations, research by, 97Chemical Industry Institute of Toxicology, 123-124Chemical Specialties Manufacturing Association, 220chemicals

commercial, see industrial chemicalsconsumer, 17diversity of new products, 227high production, high exposure, 17, 178-179, 195, 197,202,

204,227licensing and registration of, 174-180, 197,202low production, low exposure, 178,227-228neurotoxic, classes of, 175neurotoxicity tests and innovation in, 227–228new v, existing, consistency of regulation, 17, 18, 196-198patent protection, 226premanufacture notices, 17, 174-176, 194, 196, 197, 201-

202,219-220,227,247priorities for testing, 178reporting of harmful effects of, 180, 197significant new use rule, 174subject to neurotoxicity evaluation under TSCA, 179, 202testing of, 174-175, 232see also neurotoxic substances; organic solvents; and specific

chemicalschemoreceptors, 65children

lead poisoning in, 7,8,46,70,72-73,181, 229,267,268-271,273,275,278

mental disorders in, 8, 45, 70, 73number exposed to lead, 269, 271pesticide risks to, 25,283,284,293,295vulnerability to neurotoxic substances, 8, 45, 267, 268, 283

chlordane, 238–239, 250, 252, 292chlordecone, incidents of poisoning, 47, 50, 293chlordimeform, 120, 250chlorine, 14, 136

chlorofluorocarbons, neurotoxicity testing, 166chloroform, 14, 136, 303chloroquine, 124chlorphenoxy herbicides, 294-295cholinesterase inhibitors, see acetylcholinesterase; organophos-

phorous pesticideschromium, 133Clean Air Act, 135

1970 amendments, 180amendments proposed, 26, 182, 280cost-benefit analysis under, 216definition of hazardous air pollutant, 181lead regulation under, 273regulatory authority, 23, 160, 162risk assessment approach, 160standard setting under, 180-182toxic substances regulated by, 160

Clean Water Act, 26regulatory authority, 16, 23, 160risk assessment approach, 160standard setting under, 180, 182–183, 187toxic substances regulated by, 160

clioquinol, incidents of poisoning, 47, 74cocaine, 9, 44, 115

effects on nervous system, 6, 52, 74-75fetal effects of, 10,53,70,74

Codex Alimentarius Commission, 242cognitive effects

of carbon monoxide poisoning, 181detection of, 70examples of, 46of lead poisoning, 44, 70, 181, 269,273of pesticide poisoning, 285

Cognitive Scanner, 128Colombia, use of banned pesticides in, 239,243Color Additive Amendments of 1960, 165color additives, see food and color additivesComprehensive Drug Abuse Prevention and Control Act, 188Comprehensive Environmental Response, Compensation, and

Liability Act (CERCLA), 26, 198control measures under, 187–188, 280-281regulatory authority, 16, 23, 161risk assessment approach, 161toxic substances regulated by, 161,280-281see also Superfund Amendments and Reauthorization Act

computer-based testing, 127–128, 137confidentiality, trade secret protection and testing, 19, 25, 176,

202,218,226,288Consumer Product Safety Act (CPSA), 172

regulatory authority, 16, 160reporting requirements for adverse effects, 204risk assessment approach, 160standard setting under, 180, 184toxic substances regulated by, 160

Consumer Product Safety Commission (CPSC), 176in vitro testing by, 122policy issues and options for, 31regulatory authority of, 160, 161, 184, 190, 191, 268research activities of, 323risk assessment applications, 150standard setting by, 184, 276

Consumers Association of Penang, 252


control-oriented measuresunder CERCLA, 187–188under Controlled Substances Act, 188economic incentives, 161features of laws, 159, 161under bad-Based Paint Poisoning Prevention Act, 189–191under Marine Protection, Research, and Sanctuaries Act,

188-189under Poison Prevention Packaging Act, 189–191regulatory approach, 16, 159under Resource Conservation and Recovery Act, 191

Controlled Substances Actcontrol measures under, 187, 188regulatory authority, 16, 161risk assessment approach, 161toxic substances regulated by, 161

cosmeticsantidandruff shampoos, 108color additives in, 165dermal exposure to toxic substances, 108fragrances, 108incidents of neurobehavioral toxicity, 54licensing and registration of, 168regulation of, 54testing, 17,28, 52,54, 168, 196

cost-benefit analysiscompeting interests in, 56costs defined, 214, 215defined, 336economic principles of, 221effect on environmental policymaking, 220-221Executive Order 12291 requirements, 212,214-216,220,231under FIFRA, 216, 286health costs in, 228–230knowledge requirements for estimating benefits, 228for lead, 216net efficiency, 215, 338risk reduction, measures of, 215in standard setting, 181under TSCA, 216unit of value in, 221

cost-effectiveness analysis, 214,220, 221,336Costa Rica regulatory issues in, 253-254costs of testing

in animal studies, 20, 106-107, 110, 111, 112, 116, 222–225drug and pesticide development and, 225–227estimates of, 20, 224-225,231fees, 223financial determinants, 106,223-224general and administrative rates, 223in vitro methodologies, 122and innovation, 217–218, 225–228labor rates, 222,223-224laboratory automation and, 116,223laboratory capabilities and, 223overhead rates, 223personnel, 223protocol and, 222quality assurance, 222-223reregistration of pesticides, 241scientific determinants, 222–223under TSCA, 217

unit test costs, 217 n.10Council on Environmental Quality, 177cresols, 179, 303cumene, 179cutaneous receptors, 65cyanide, 55cycad, 54, 74cyclamates, 166cyclohexane, 179,297cyclohexanone, 179

2,4-D, 183,294,295DDT, 50,72, 134,250,252,255,292deltramethrin, 251dementia, 229,259,299,336dendrites, 72

development of, 67functions of, 65-66, 336

Department of Agriculturemonitoring programs, 135regulatory authority of, 160, 161, 171, 241, 242research activities, 9, 11, 81, 92

Department of Commerce, 177Department of Defense, research activities of, 90,324Department of Energy, research activities of, 9, 11,81,91,323Department of Health and Human Services, 8,45

human research regulations, 130neurotoxicology -related activities, 321

Department of Housing and Urban Development, 276Department of Justice, regulatory authority of, 161, 188Department of Labor, research activities of, 323–324Deprenyl, 6,72designer drugs, 51detoxification systems, in humans, 44,45,64developing counties

famine in, 243,245imports of pesticides, 237, 242manufacture of banned or restricted pesticides in, 243, 253,

255pesticide misuse in, 50,239,248-249,253poisonings and deaths from pesticides in, 250-251,260,283regulatory issues in, 21–22, 237–238, 248–256, 2260screening test for, 126susceptibility to neurotoxicity in, 71use of pesticides, 250, 260see also specific countries

developmental neurotoxicity, 110, 111animal tests for, 13, 114–1 16, 137, 165-166, 247–248, 336biochemical markers, 117of pesticides, 172testing guidelines, 153, 165–166, 178, 179, 192,248

di-tert-butylphenyl phosphite, 1661,2-dibromo-3-chloropropane, 185,250dichloromethane, 14, 1361,2-dichloropropane, 179dichloropropene, incidents of poisoning, 47dichlorvos, 173dieldrin, 250,252,292N,N-diethyl-m-toluamide, 172diethylene glycol butyl ethers, testing guidelines, 115, 179diisodecyl phenyl phosphite, 179Dimecron, 284

Index ● 347

dioxin, 180,294diphenylhydantoin, 115diphtheria toxin, 74Dominican Republic, use of banned pesticides in, 239domoic acid, incidents of poisoning, 47dopamine, 66,72,336

depletion of, 6, 109effects of cocaine on, 52,74

doseacceptable daily intake, 148, 336behaviorally effective, 116defined, 337extrapolation from high to low, 148, 154, 200reference (RfD), 116, 148–149, 150, 153, 340regimen in animal tests, 107, 110threshold, 14, 147, 151, 153, 162, 185,203,341and toxicity, 6, 44, 70, 108, 150, 283, 290see also no observed adverse effect levels; no observed effect

levelsdose-response assessment

from automated motor activity measures, 113defined, 63,337extrapolation of doses, 147issues in, 107, 153–154methods, 111, 118, 147–148NOAEL versus NOEL, 147-148, 153in risk assessment, 147–148safety factors, 147, 148, 149, 153–154, 155thresholds and RfD approach, 153, 155

Down’s syndrome, 71doxorubicin, 73drinking water

hazardous wastes in, 198lead in, 216,230,269,277-279regulations to control contaminants, 183–184, 216, 277–279from water coolers, 279,280

Drug Price Competition and Patent Restoration Act, 226drugs

axonopathy from, 73color additives in, 165development, 219,225-226,231-232neurotoxic potential, 43neurotoxicity testing and innovation in, 226-227passage through blood-brain barrier, 67see also abused drugs; therapeutic drugs; and specific drugs

economic issues, 56analysis of regulations, 213–221, 230benefits of regulating neurotoxic substances, 20, 228-231,

232cost-benefit analyses, 20,211, 214-215,220-221, 337cost-effectiveness analyses, 214-215, 220, 221, 337in design of animal experiments, 106, 222–223economic efficiency, 56, 214-216innovation incentives and disincentives, 20, 218–220, 225–

228market prices and profitability and costs of regulation,

217-218opportunity costs, 221, 228regulatory analyses, 20,211, 214-215,218 n.11, 220-221regulatory impact analyses, 211, 214, 231risk assessments, 211, 231

risk-benefit analyses, 20, 211, 216-217, 218 n.11, 340in standard setting, 199see also costs of testing; health costs of neurotoxicity; risk

assessment“ecstasy,” 9, 51Ecuador

pesticide import problems, 243regulatory issues in, 255–256

educationof health-care professionals, 97-100of research scientists, 97, 259of workers, 30, 287

Egg Products Inspection Act, 241,242elderly, vulnerability to neurotoxic substances, 8, 45electroencephalograph, 119electromyography, 128, 337electroneurography, 128, 337electrophysiological testing, 82, 337

electroencephalograph, 119macroelectrode, 118rnicroelectrode, 118multiunit electrode, 118of muscle cells, 124

encephalitis, 74encephalopathy, 74, 181, 337endorphin, 66, 74endpoints, 337

for emission standards for hazardous air pollutants, 182in risk assessment, 15, 149, 150, 151, 152, 153for toxicity testing, 109, 116, 125, 150, 152, 178for water quality criteria, 182-183

endrin, 47, 183, 250, 255, 292enkephalin, 66, 74environmental hypothesis, 54-55, 70, 72, 337Environmental Protection Agency (EPA), 56, 177

Clean Air Scientific Advisory Committee, 271coordination of regulatory efforts within, 191–192, 198core test battery, 13,20, 23–24, 110-111, 114, 137, 152, 178,

179,224,231,287definition of neurotoxicity, 44developmental neurotoxicology workshop, 115economic assessment of regulations, 213, 218health advisories, 183-184impact analysis of regulations, 220-221Integrated Risk Information System, 198labeling criteria, 172monitoring activities, 132, 133Neurotoxicology Division, 81–84Office of Drinking Water, 183Office of Environment Criteria and Assessment, 187Office of Mobile Sources, 182Office of Pesticide Programs, 110, 135, 170-172, 191-192,

203,216,287Office of Program Planning and Evaluation, 198Office of Solid Waste Management, 198Office of Toxic Substances, 110,152,174,176,177, 191-194,

197, 198,200,201,216Office of Water Regulations and Standards, 182pesticides registered with, 49policy issues and options relevant to, 23-27,31-32policy on neurotoxicity testing, 178regulatory authority of, 15–16, 26, 23, 160-162, 164,


170-177,179-182,187, 189,197,212,227 n. 16,241,267research activities, 9, 11, 31–32, 81–84, 323Risk Assessment Forum, 11risk assessment guidelines, 116, 146, 150, 192, 216Science Advisory Board, 81,82,84Scientific Advisory Panel, 110-111, 115, 173,288standard setting, 180-183testing guidelines, 13,110-112,114-118, 136,137, 177–179,

191-193,200,201,222, 287Tolerance Assessment System, 135Toxics Release Inventory, 3,43, 122, 134-136, 195

epidemiological studies, 337advantages and limitations of, 125, 128computer-based neurobehavioral tests for, 127geographical isolates of neurological conditions, 259hazard identification with, 147industry-government cooperation on, 96international activities in, 259need for, 55, 154occupational, 129–120of pesticide poisoning, 285, 295specimen banking for, 132

erythrosin, 166ethanol, see alcohol and alcohol abuseethical issues

exports of toxic substances, 56-57, 243, 245, 261human testing and monitoring, 125, 130, 136manufacturers’ duty to follow products to consumers, 249

Ethiopialathyrism in, 55research on grass pea neurotoxicity, 259

ethyl acetate, 297ethyl ether, 297ethyl nitrate, 297ethyl parathion, 250, 251ethyl toluenes, 179ethylene, 14, 136ethylene dibromide, 250ethylene dichloride, 303ethylene glycol, 297ethylene oxide, 185ethyl-p-nitrophenyl phosphonothionate, 203

risk assessment approaches, 150, 151, 173European Economic Community, testing guidelines, 115evoked potentials, 337

brainstem auditory, 119flash, 119pattern reversal, 119somatosensory, 118–1 19, 120-121visual, 119–120

excitotoxicity, 71Executive Order 12264, control of exports of hazardous

substances, 57, 240-241, 260Executive Order 12291

cost-benefit analyses under, 212, 215–216, 220inflation considerations in, 217 n.9requirements of, 213–214

exports of toxic substancesconsent requirements, 240Executive Order 12264,57,240-241famine as justification for, 243,245,261international effects of U.S. practices, 21–22, 242–245

labeling violations, 242–243notification requirements, 22, 239–240, 247, 261, 339pesticides, 56-57,237, 241–245, 249–250, 261repackaging problems, 243testing requirements, 240U.S. laws, 239-241,261

exposure to neurotoxic substancesacute, 26, 108, 111, 114, 116, 125, 148, 222, 224,272, 292,

294,296,336additive effects, 44in animal tests, 107–108assessment of, 132, 148; see also Monitoring of toxic

substanceschronic, 26,44, 114, 116, 125; 148, 152,222,224,256,257,

272,291,294,296,336defined, 337dermal, 107, 108,292-293,294-295, 296,298extent and duration, 4,44,67-68,73, 107, 108,125, 133,148,

152,222,337human studies of, 128-131inhalation, 107, 108, 269, 292,293, 296, 298margin of (MOE), 149oral, 107, 269, 292, 298OSHA limits for mercury, 131pattern of, 148, 178, 339prevention of, 130-131risk to humans, 43routes of, 6, 63, 64, 107–108, 121, 125, 131, 148, 222, 224,

231,269,283,290,293, 298,340subacute, 108subchronic, 108, 111, 114, 148, 149, 340see also dose; occupational exposures; and specific

substancesEysenck Personality Inventory, 127

famine, and pesticide use, 243,245,253,261Faroe Islands, 259Federal Emergency Planning and Community Right-to-Know

Act of 1986, 13, 134Federal Environmental Pesticide Control Act, 170,213Federal Food, Drug, and Cosmetic Act (FFDCA), 56, 172,213

1962 amendments, 217,219amendments proposed, 168color additive regulation, 164-166cosmetics regulation, 17, 168Delaney clause, 17, 195drug review and regulatory process, 16, 29, 51, 166-169,

221-222economic balancing provisions of, 212environmental contaminants of food, 163–164food additive regulation, 52, 164-166licensing and registration under, 27,29, 161, 163–169notification requirements, 218pesticide residue standards, 164,241regulatory authority, 16, 160, 213reporting requirements for adverse reactions, 167,203risk assessment approach, 160risk-benefit analysis under, 216tolerance setting, 216toxic substances regulated by, 160

Federal Hazardous Substances Act, 172definition of hazardous substance, 184

Index 349

regulatory authority, 16, 160risk assessment approach, 160standard setting under, 180, 184toxic substances regulated by, 160, 190

Federal Insecticide Act, 168Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA),

56, 172,2131972 amendments, 170,219,285-2861988 amendments, 18, 171, 192, 197,217, 287,288amendments proposed, 24, 26coordination of TSCA neurotoxicity evaluations with, 191–

192definition of pesticide, 281-282economic balancing provisions of, 212,216, 286export controls, 21–22, 239, 240,261extent of testing under, 17, 18, 24, 203, 221–222, 287generic testing guidelines, 115, 136, 171, 192licensing and registration under, 17, 16, 29, 161, 169-173,

194, 199,201,203,204new pesticide registration, 17, 164, 170-171, 194notification requirements, 218, 238, 240pesticide residues in food, 241protection of workers under, 285-287regulatory authority, 16, 23, 26, 160reregistration of existing pesticides, 17, 171–173, 286, 287risk assessment approach, 160risk-benefit analysis under, 216, 286Science Advisory Panel, 192tolerance setting, 27, 164toxic substances regulated by, 160

Federal Interagency Hazardous Substances Export Policy TaskForce, 57

Federal Meat Inspection Act, 241,242Federal Mine Safety and Health Act

regulatory authority, 16, 161risk assessment approach, 161standard setting under, 180, 185, 186toxic substances regulated by, 161

Federal Republic of Germanyhuman tissue monitoring, 132neurotoxicity testing approach, 24regulatory policies in, 22, 245–246, 260,261researcher mining, 259

Federal Water Pollution Control Actregulatory authority, 16, 23, 160risk assessment approach, 160standard setting under, 180, 182–183toxic substances regulated by, 160

Federation of American Societies for Experimental Biology,testing recommendations of, 114, 193

fenvalerate, 113fetuses

alcohol effects, 70, 124antibiotic effects, 70cocaine effects, 9, 10, 52, 53, 70, 74lead effects, 272nervous system development, 67mercury poisoning, 49, 152steroid effects, 70therapeutic drug effects, 51,73vulnerability to neurotoxic substances, 8, 45, 49, 70, 269

Finland, Institute of Occupational Health neurotoxicity test, 126

flash evoked potentials, 119, 128food

action levels for contaminants in, 164adulterants, 241imports, 239, 241–242, 250lead in, 274-275pesticide residues in, 241-242,250,260regulation of environmental contaminants of, 163–164

Food Additives Amendment of 1954, 164food and color additives

adverse effects claims, 318appeals of decisions, 31&317application, 315approval process, 315–3 19lead in, 275licensing and registration process, 52, 164-166postmarketing surveillance, 318preapplication, 315regulation of, 17, 52, 161, 195, 204review, 203, 315testing for neurotoxicity, 18,27,52, 166, 199,204

Food and Drug Administration (FDA), 56analytical methods for pesticide detection, 50Center for Biologics Evaluation and Research, 167Center for Drug Evaluation and Research, 167,168, 198,201Center for Food Safety and Applied Nutrition, 12, 165-166,

192–194color additive regulation, 192–194cosmetic regulation, 54drug review and regulatory process, 51, 199economic assessment of regulations, 213food additive regulation, 52, 192-194interpretation of safety, 165monitoring system for adverse drug reactions, 29, 168, 169,

198neurotoxicity testing by, 27, 166policy options for, 27-28,33-34Priority-Based Assessment of Food Additives Program, 198Red Book for food and color additives, 27–28, 166-167,

192-194,340regulatory authority of, 15–16, 54, 160, 161, 163–167, 171,

188,200,241-242,267research activities of, 9, 12, 33–34, 81, 88-89, 122, 323risk assessment applications, 150testing guidelines, 27, 51, 167–168, 192–194, 199-200,204Total Diet Study, 135

Food and Drugs Act of 1906, 163Food Safety Amendments of 1989, 168France

regulatory policies in, 247, 259research on neurotoxicity, 258

Freon 12, 166Freon 113, 14, 136fufuryl alcohol, 303fumigants, neurotoxic, 293-294functional observational battery

advantages and limitations, 11 1–112costs of, 20, 224-225, 226, 231defined, 337in EPA core test battery, 13, 111, 136, 204EPA guidelines for, 110, 111, 178FDA approach, 193


OECD guidelines, 194fungicides, mercury, 48,257

Galecron, 250Gammalin 20,252ganglion, 124, 337General Accounting Office, 220Generally regarded as safe (GRAS) compounds, 27Ghana

Lake Ghana pesticide poisoning incident, 252regulatory issues in, 248

Ginger-Jake syndrome, 47,69glial cells

development of, 67effects of toxic substances on, 67function of, 65, 124,337,339neurotoxic substances acting on, 74

glial fibrillary acidic protein (GFAP) radioimmunoassay, 117Global Environment Monitoring System, 134glue-sniffing, 48; see also inhalant abuseglutamate, 71, 124glycol ethers

releases of, 14, 136toxicity of, 175testing of, 115, 135

grass pea, 55,259Guam ALS-Parkinson’s dementia, 54,70,74,259

Halcion, FDA monitoring of adverse reactions to, 29, 169hazard identification, 147, 152, 154hazardous wastes

defined, 187, 191in drinking water, 198registry of persons exposed to, 135–136

health-care professionalseducation of, 97-1OOsee also nurses; industrial hygienists; physicians

health costs of neurotoxicitydementia, 229of drug abuse, 20, 53exposure to lead, 20, 229–230mental disorders and nervous system diseases, 229personal health-care expenditures, 20-21,229

health effects“adverse” defined, 7, 4445, 115–1 16, 145, 162, 167, 170,

212,228delayed, 50,54,70, 107, 117, 118, 151-152, 155, 194“harmful,” 145, 147nutritional status and, 70, 72reversibility of, 15,46, 69, 71, 107, 108, 151, 152, 290secondary, 45, 72

health status, and neurotoxicity, 8,70-71, 108,290heavy metals

assessment of effects of, 119, 124effects on nervous system, 74monitoring of, 135research on, 256, 258toxicity of, 46, 71; see also specific metals

hen test, see neurotoxic esterase assayheptachlor, 238,250,292heroin, 6,9,44,72,74hexachlorobenzene

effect on nervous system, 74incidents of poisoning, 47

hexachlorocyclohexane, 250hexachlorophene, 45n-hexane, 73, 124, 297, 299

incidents of poisoning, 47neurotoxicity testing, 179regulation of, 184risk assessment approaches, 150, 151

2,5-hexanediol, 124hippocampus

functions and structure of, 68,71PCP effects on, 71trimethyltin damage to, 68, 74

Hispanic Health and Nutrition Examination Survey, 132Honduras, pesticide-contaminated exports, 238-239Human Nutrition Information Service, 135human testing and studies, 105,336

computerized techniques, 13, 127–128, 137confidentiality, 130consent and disclosure requirements, 130examiner-subject interaction, 128-129exposure studies, 128–131, 256extrapolation of results to other populations, 147, 153of food additives, 52Institutional Review Boards, 130for lead exposure, 270legal and ethical considerations, 12, 125, 130limitations of, 147neurobehavioral, 13, 125–126, 137neurophysiological techniques, 13, 128, 137selection of study populations, 105, 129of therapeutic drugs, 52types of, 125-128, 137workplace research, 129see also epidemiological studies

hydrocarbons, 182hydrochloric acid, 14, 136hydroquinone, 179

imidazoles, 175imports

and “circle of poison,” 22,57,238,250,260,261controls in developing countries, 250-255see also exports of toxic substances

in vitro tests, 338advantages and limitations of, 12–13, 56, 105, 118, 122,

124-125, 136application to neurotoxicity testing, 122, 123–124cell lines, 124costs of, 122development of, 11, 12-13, 84, 122, 137primary cultures, 123-124screening with, 13, 110validation of, 123–124see also tissue culture, 122, 123

incinerator ashexports of, 240lead in, 268,279-280

IndiaBhopal accident, 243grain surpluses, 243

Index ● 351

regulatory activities in, 253research on neurotoxicity, 258

Indonesia, pesticide misuse in, 251industrial chemicals

axonopathy from, 73incidents of poisoning, 47,48-49licensing and registration of, 16,161,174-180,195,196, 204;

see also Toxic Substances Control Actneurotoxic potential, 3,43, 48,259see also chemicals; organic solvents; and specific chemicals

industrial hygienists, education of, 99industrial research, 12

by consumer product industry, 95government-industry consortia, 96industry consortia 96by pesticide industry, 94by pharmaceutical industry, 95

industrialized countriesimports of contaminated food, 238regulatory policies in, 245–248, 260see also specific countries

inert ingredients, neurotoxicity evaluations, 24,288inhalant abuse, 48, 49, 296, 299-300innovation

chemical R&D, 219–220, 227–228costs of neurotoxicity testing and, 225–228drug R&D, 219,225-226input measures, 219output measures, 219pesticide R&D, 219,226-227regulation and incentives for, 20, 218–220

integrated pest management, 243, 290, 291, 295, 337Inter-American Institute for Cooperation on Agriculture, 253-

254interaction of toxic substances

additive effects, 44, 64antagonism, 65drugs, 8-9,29,45, 169potentiation, 65synergistic effects, 64, 65sources of complex mixtures, 65

Interagency Testing Committee, 177–178, 202Interagency Working Group on Neurotoxicology, 19International Code of Conduct on the Distribution and Use of

Pesticides, 242,243,249-251,253-256International Group of National Associations of Manufacturers

of Agrochemical Products, 243, 255international issues, 21, 56-57

effects of U.S. export practices, 242–245monitoring of toxic substances, 132, 134neurotoxicological research, 256-260pesticide residues in domestic and imported food, 241-242regulatory activities, 21–22, 115, 237–256regulatory issues in developing countries, 248–256regulatory policies in other industrialized countries, 245–248testing guidelines, 191U.S. export laws, 239-241U.S. regulation of neurotoxic substances, 239-245see also developing countries; exports of toxic substances;

importsInternational Neurotoxicology Association, 256,258International Program on Chemical Safety, 242

International Rice Research Institute, 252-253ion channels, 7, 66, 72, 118, 295Iraq, mercury poisoning in, 47,48,49,243,257isopropanol, 179Italy

research on neurotoxicity, 258, 259researcher training, 259

Japanhuman tissue monitoring, 132mercury poisoning in Minamata Bay, 47,48,247, 257regulatory policies in, 247–248, 259research on neurotoxicity, 258, 259

kainic acid, 124Kenya, regulatory issues in, 256Kepone, incidents of poisoning, 47,50,293Kuhnburg Figure Matching Test, 127

labeling, 29,44, 169, 171of cosmetics, 28effectiveness of regulatory requirements, 172of exported pesticides, 171, 172, 240, 242–243, 247, 248,

253-255of hazardous substances, 184, 187, 247, 248incidents of poisoning resulting from violations of, 242–243with pictograms, 243–244WHO requirements, 249

latent effects, 50,54, 70, 107acute delayed neurotoxicity, 118defined, 338of organophosphates, 117–1 18, 194, 199,204,284,290-291,

295and risk assessment, 15, 151–152, 155subchronic delayed neurotoxicity, 118

lathyrism, 55lead

in air, 273–274, 276, 281cost-benefit analyses, 20, 216, 230-231,232in drinking water, 8,216, 221,230,231,267,269, 277–279,

281effects on human body, 229–230, 271–273estimates of exposure, nationally, 230Federal regulation of, 8,46, 182, 183in food, 267, 269, 274-275, 281in gasoline, 216,221,230,231,257, 267,269, 273–274, 275,

281health benefits of reducing neurotoxic effects in children, 231,

232in incinerator ash, 279–280levels of exposure, 270-271,274,281MCLs, 183monitoring programs, 133, 134neurological effects of, 6,8,46,56,72-73,74, 150, 162, 181,

185occupational exposures, 269,276OSHA health standards, 185in paint, 8, 184, 189–191, 257, 267–269, 276-277PELs, 276in pesticides, 274regulatory activity, 211,213, 267, 273–281research on toxicity, 256-257, 258, 259


risk assessment approaches, 150, 151routes of exposure, 269screening method for humans, 270sites of accumulation in the body, 64in soil, 269, 280-281sources of exposure, 8, 267,46, 267–269, 273standard setting, 181–181, 184, 189, 276, 277, 281threshold for, 162,267,270-271,281water quality standards, 183, 281see also lead poisoning

Gad-Based Paint Poisoning Prevention Act (LBPPPA)amendments, 189, 190control measures under, 187, 189–191, 276-277, 280regulatory authority, 16, 161risk assessment approach, 161toxic substances regulated by, 161

Lead Industries Association, Inc., 162, 182 n.8lead poisoning, 45, 115

case studies, 267–281chelation treatment, 271–272in children, 7, 8,46,70, 72–73, 155, 181, 184,229,260,267,

268–271, 273,275,276,281cognitive development and, 7, 8, 44,46, 70, 73, 155, 273costs of, 229–230duration of exposure and, 44,270-271economic status and, 271historical perspective on, 268incidents of, 47mortality from, 271–272prevalence of, 267,268prevention of, 8, 189-190,277,278,280, 281research on, 260sources of, 256-157

learning disorders, 46,70, 181,230,283,293tests of, 193

legal issueschallenges to EPA standard-setting authority, 162in human testing and monitoring, 130labeling requirements, 172

legislationdiversity of, 159,211,213export, 237–241interpreting language of, 162key features of laws regulating toxic substances, 160-161major statutes, 23; see also specific statutessee also control-oriented measures; licensing and registration;

regulations and regulatory issues; standards and standardsetting

leptophos, incidents of poisoning, 47levodopa, 72licensing and registration

application and review processes, 161, 163chemicals, 161, 174-180of color additives, 164-166of cosmetics, 168of drugs and biologics, 29, 161, 166-169environmental contaminants of food, 163–164features of laws, 159-160under Federal Food, Drug, and Cosmetic Act, 29, 161,

163-169, 194,218under Federal Insecticide, Fungicide, and Rodenticide Act,

161, 168, 170-173, 194,218

of food additives, 161, 164-166implementation of, 159neurotoxicity testing for, 161, 163of pesticides, 164, 161, 170-173regulatory approach, 16, 159risk-benefit analyses, 216under Toxic Substances Control Act, 173-180, 194

lindane, 183,250,252,292lipophilicity of chemicals, 44,64,298,338locus ceruleus, 67Lou Gehrig’s disease, 54,70LSD, 51,74Lucel-7, 47, 55–56, 73

malathion, 251, 284Malaysia, regulatory issues in, 250-252manganese, 47, 48, 257manganese madness, 48mania, 71margin of safety, 338

EPA interpretation, 180–181risk assessment approaches, 149, 162

marijuana, 10, 53Marine Protection, Research, and Sanctuaries Act (MPRSA)

control measures under, 187, 188–189regulatory authority, 16, 23, 161risk assessment approach, 161toxic substances regulated by, 161

Maternal and Child Health Services Block Grant, 277,280maximum contaminant levels (MCLs) and maximum

contaminant level goals (MCLGs), 183, 198, 278-279,338

MDMA, effects on nervous system, 9, 51–52mental disorders

in children 45, 70costs of, 20, 229exacerbation of, 71retardation, 70, 73, 272

meperidine, 51, 1062-mercaptobenzothiazole, 179mercury

delayed effects of, 152effects on nervous system, 72, 74emission standards, 182incidents of poisoning, 45, 4649, 131, 247, 257MCLs, 183monitoring programs, 133ocean dumping restrictions, 189OSHA exposure limit, 131research on toxicity, 257routes of exposure, 131symptoms of exposure, 48, 49, 131testing for, 124and water quality standards, 183

mescaline, 74methadone, 115methanol, 14, 136, 186-187, 203methomyl, 284methoxychlor, 183methyl alcohol, 296, 297methyl bromide, 255, 294methyl chloride, 166

Index ● 353

methyl chloroform, 303methyl ethyl ketone, 14, 136methyl ethyl ketoxime, 179methyl tin, 166methyl-n-butyl ketone, 299

incidents of poisoning, 47, 49releases of, 14, 136route of exposure to, 108

2-methyl-4-chlorophenoxyacetic acid, 294methyl-tert-butyl ether, 179methylcyclohexane, 299methylcyclopentane, 299methylene chloride, 296, 298methylmercury, 15, 48,49, 115, 152, 243, 257, 258mevinphos, 284Mexico

pesticide import problems, 243regulatory issues in, 254-255research on neurotoxicity, 258

MicroTox System, 128Milan Automated Neurobehavioral System, 127Minamata Bay, Japan, methylmercury poisoning, 47,48,247Mine Safety and Health Administration, 161, 185Minerals Management Service, 133Mira Test, 127mirex, 292monitoring toxic substances

adequacy of regulatory structure determined through, 203–204

animal tissues, 132biological programs, 13, 132, 133-134, 137for cholinesterase inhibition, 84,287,289coordination of programs, 325–326FDA postmarked system for adverse drug reactions, 28, 29,

168, 169, 198in human tissues, 132, 137legal and ethical considerations, 130mechanisms, 13, 203–204need for, 13, 30, 289neurophysiological techniques, 128occupational exposures, 13, 30, 131, 133pesticides, 132, 133, 134, 135,241,242,251-255, 289,296purpose of, 133specimen banking, 132–133, 137worker safety programs, 131see also Toxics Release Inventory

monoamine oxidase inhibitor, 6, 72monohalomethanes, 123–124mood and personality, effects of neurotoxic substances on, 46,

230,283,285morphine, 74mortality

abused drugs, 51, 52mercury poisoning, 47, 48, 49motor neuron disease, 54Parkinson’s disease, 3, 54,55from pesticide poisoning, 250,251,283,285

motor activityanimal tests of, 13, 20, 110, 111-114, 116, 118, 136, 178,

224-225,226,231,338defined, 111-112effects of neurotoxic substances on, 46-50, 53,72, 109, 117,

118, 123, 131,271as an indicator of neurotoxicity, 112, 116, 194mechanical recording of, 113observational analysis, 112–113sensory systems and, 70specificity of measures, 114see also screening

motor neuron disease, 54, 55motor neurons, 66, 70, 74MPTP

animal model for experiments, 106effects on nervous system, 51, 54incidents of poisoning, 47, 70and Parkinson’s disease, 6, 51, 54, 72

multiple sclerosis, 70, 120, 259myelin/myelin sheath

aging and, 67assessment of effects of neurotoxic substances on, 124destruction of, 336effects of toxic substances on, 67function of, 65,66,338neurotoxic substances acting on, 74

myelinopathy, 67

National Academy of Sciences, 8,45proposed study by, 27risk assessment recommendations, 146-147testing recommendations of, 114, 116

National Aeronautics and Space Administration, researchactivities of, 9, 11,92

National Agricultural Chemicals Association, 255National Ambient Air Quality Standards, 180-181National Association for Perinatal Addiction Research and

Education, 10,53National Bureau of Standards, monitoring activities, 132National Cancer Institute, 86, 177National Center for Education in Maternal and Child Health, 277National Center for Health Statistics

HHANES, 132NHANES II, 132,230 n.19NHANES III, 132-133

National Center for Toxicological ResearchCollaborative Behavioral Teratology Study, 115research activities of, 12, 88--89,

National Consumer Health Information and Health PromotionAct, 190

National Emissions Standards for Hazardous Air Pollutants,181, 182

National Environmental Specimen Bank, 132National Food Processors Association, 282National Health and Nutrition Examination Surveys

II, 132,230 n,19III, 132–133

National Human Adipose Tissue Survey, 133National Institute on Aging, research activities, 86National Institute of Child Health and Human Development,

research activities, 86-87National Institute on Drug Abuse, 9,53

developmental neurotoxicology workshop, 115research activities of, 87-88

National Institute of Environmental Health Sciences, 11,85,177National Institute of Mental Health, research activities, 88


National Institute of Neurological Disorders and Stroke,research activities, 11, 84–85

National Institute for Occupational Safety and Health (NIOSH),45,56, 177

Educational Resource Centers, 99-100protective measures recommended by, 30,296research activities of, 12, 34-35, 89–90standard setting by, 28, 185, 186, 198–199testing recommendations, 126

National Institutes of Health (NIH)policy issues and options, 32-33research activities, 9, 11, 32–33, 81, 84-87, 122, 321–322see also specific institutes and programs

National Library of Medicine, research activities, 87National Oceanic and Atmospheric Administration, tissue

monitoring program, 133National Primary Drinking Water Regulations, 183, 191, 278,

338National Research Council, 146-147National Residue Program, 135National Science Foundation, 177National Status and Trends Program for Marine Environment

Quality, 133National Toxicology Program

in vitro test development, 122research activities, 22, 85–86, 259, 261

Nationwide Food Consumption Survey, 135Natural Resources Defense Council, 282naturally occurring toxic substances

in algae, see saxitoxinin buckthorn, 73–74cassava, 55cycad, 54, 74drought-resistant grass pea, 55effects of, 54-55in puffer fish, see tetrodotoxinscorpion toxin, 72

neostriatum, 68nerve gas, 50, 74nervous system

adult-stage modifications, 67changes with aging, 8, 67development of, 8,67diseases, 54, 229; see also specific diseaseseffects of toxic substances on, 67–71; see also symptoms of

toxicityimmune system interaction with, 71functional changes due to toxic substances, 69–70lesions, 172pesticide effects on, 283-285structural changes due to toxic substances, 67-69, 267structure, 43, 65-67vulnerability to toxic substances, 4, 5, 8, 44see also central nervous system; peripheral nervous system;

and other specific elements of the nervous systemNetherlands, pesticide regulation, 249neural tube, 67, 70neuritic plaques, 67Neurobehavioral Evaluation System, 127neurobehavioral tests

advantages and limitations of, 116, 128in animals, 82, 112, 116-117, 171

in combination with NTE, 118computer-based, 127–128environmental factors in, 126examiner factors in, 126Finland Institute of Occupational Health approach, 126, 127in humans, 70, 125–126, 137observational, 112psychological testing, 126reproducibility of, 128selection of techniques, 125–126subject factors in, 126World Health Organization approach, 126-127

neuroblastoma C-1300 cell lines, 124neurofibrillary tangles, 67neuromuscular disorders, exacerbation of, 70neuromuscular junction, 66, 124, 338neuronal membrane, 72neuronal potentials, 118neurons, 124, 338

anoxia, 67degeneration, 54,72,203,338development of, 67effects of toxic substances on, 9, 67electrical properties, 118loss of, 67,68,74, 107neurotoxic substances acting on, 72–74regeneration, 44, 67retinal, 124structure, 5, 65, 72

neuropathiesdefined, 67delayed, 204from industrial chemicals, 49, 108mixed, 70, 338peripheral, 181from pesticides, 291–292

neuropathological examinationof animals, 13, 110, 111, 114, 116, 118, 136, 172, 178, 194,

224-225in combination with NTE, 118costs of, 20, 224-225, 231defined, 338electrophysiological testing with, 119evaluation of PMN assessment accuracy with, 204FDA policy on, 194with glial fibrillary acidic protein radioimmunoassay, 117with operant behavior studies, 116sensitivity of, 193

neurophysiologica1 tests, 338advantages of, 13, 128, 137in animals, 118–121, 137brainstem auditory evoked responses, 119, 128electromyography and electroneurography, 128EPA research on, 82in humans, 70, 128, 137somatosensory evoked potentials, 120-121, 128visual evoked potentials, 119-120, 128

neurotoxic esterase assay (NTE), 111, 117–1 18, 13&137, 178,194,339

neurotoxic substances, 339absorption, distribution, biotransformation, and excretion, 64,

108

Index .355

additive effects, 44, 64, 65behavioral effects, 70benefits of regulating, 228-230,232classes of, 71–76, 175classification criteria, 175detectors of, 199determinants of toxicity, 7,63effects on nervous system, 12, 67–71; see also symptoms of

neurotoxicityevaluation in animals, 109–110export policy, 57health costs of, 228–230; see also specific conditionsincidents of poisoning, 47 (table)lipophilicity of, 44,64multiple, interaction of, 64-65number of, 3, 4, 43releases by industry, 135susceptibility to, 70-71see also abused drugs; chemicals; industrial chemicals;

pesticides; therapeutic drugs; and specific substancesneurotoxicology

defined, 63,339developmental, in animals, 114-116fundamentals, 63–76principles, 63-65see also health effects

neurotransmittersaging and, 67classical, 66, 336depletion of, 109effects of abused drugs on, 51, 52, 74, 74functions of, 65,66,339hippocampal, 71inhibition of, 6, 7, 67neuropeptides, 66, 74see also specific neurotransmitters

nicotine, 74nitrogen oxides, 181, 182, 258no observed adverse effect levels (NOAELs), 106, 146

defined, 147, 339in dose-response assessment, 147–148, 153in risk assessment, 147–149, 150–151in standard setting, 187techniques to determine, 114, 115, 118, 147

no observed effect levels (NOELs)defined, 147, 339in dose-response assessment, 147–148, 153

norepinephrine, 66, 74, 109notification of unreasonable risk, 218nurses, education of, 98–99nutritional status, and toxicity, 70, 71, 108, 269

occupational exposures, 148administrative controls, 336to carbon disulfide, 256epidemiological studies, 26, 128–129ethical issues, 130, 131at fabric production plant, 47, 49Hopewell, Virginia, chemical plant workers, 50,293incidence of disease from, 125to lead, 257, 269,276mercury removal from thermometers, 131

monitoring, 13, 133, 289to organic solvents, 30, 257, 296-304to pesticides, 45, 50, 267, 281–285, 289, 293, 294; see also

pesticide poisoningsat plastic manufacturing plant, 47, 55–56prevention of, 130-131,267,336regulation of, 16; see also Occupational Safety and Health Actresearch on, 256vulnerability of workers, 9

Occupational Safety and Health Act, 56exposure limit for mercury, 131general duty clause, 302MCL for lead in air, 278protection of farmworkers under, 26,250-252,267,284,285,

288–289regulatory authority, 16, 161reporting requirements for adverse effects, 204risk assessment approach, 161standard setting under, 16, 28, 180, 185–187, 195, 267, 276toxic substances regulated by, 161

Occupational Safety and Health Administration (OSHA), 177adequacy of efforts of, 28, 30economic analysis requirements, 303enforcement of regulations, 30, 276Hazard Communication Right-to-Know Standard, 285permissible exposure limits, 185-187, 199,203,302-304policy issues and options for, 28-30regulatory authority of, 15–16, 28, 161, 185, 302risk assessment applications, 150, 151, 216

occupational safety and health programs, 130octadecyl phosphite, 166Office of Management and Budget, 11,84, 159, 162,214,231oleylamine, 179Omnibus Budget Reconciliation Act, 277operant behavior

defined, 116schedule-controlled tests, 13, 110, 111, 116-117, 136, 137,

178, 192, 224–225, 231,340optic neuritis, 120, 272organ cultures, defined, 123, 339organic farming, 291organic solvents, 6, 339

classes of, 296, 297effects of, 30, 119, 267, 296, 298-300encephalopathy from, 299–300inhalant abuse, 296labeling of, 184occupational exposures, 30, 257, 296-304OSHA regulations, 267,302-303PELs, 302–304protection of workers from, 267,296,300-302research on toxicity of, 256-259, 260risk from, 48route of exposure to, 108, 296, 298testing for, 119, 126uptake, distribution, and elimination of, 298volume of production in U. S., 296see also specific solvents

Organochlorine insecticides, 49, 292–294organoleptic effects, 182-183, 339organophosphites, 166organophosphorous pesticides, 292–293, 339


action on nervous system, 26, 50, 74,290animal tests for, 13, 106-107, 110, 117–1 18, 136-137, 171,

194,290delayed effects, 117-118, 194, 199,204,284,290-291, 295duration of exposure and toxicity, 44,67, 107effects on nervous system, 6, 26, 49-50, 67, 73, 107, 117,

290-292,294,295ethyl-p-nitrophenyl phosphonothionate, 150, 151extent of testing of, 18, 171, 199, 204in vitro tests of, 124incidents of toxicity, 47,69, 284; see also pesticide poisoninglist of, by level of toxicity, 292-293monitoring of exposures to, 134, 289reentry intervals for farmworkers, 287research needs on, 26, 284study design for, 178

organotin, 47, 74, 257ozone, 181

paintfumes, toxicity of, 4,44,296lead in, 8, 184, 189-191,257,267-269, 276-277

Papua New Guinea, pesticide import violations, 243,251paralytic shellfish poisoning, 72paraquat, 250,251parathion, 255,284,288Parkinson’s disease

environmental cause, 3, 54-55, 70, 108mortality, 3, 55MPTP as cause of, 3,51,54,72research on, 259

particulate matter, 181, 182pattern reversal evoked potentials, 119, 120, 128pentachlorophenol, 250People’s Republic of China research on neurotoxicity, 22,258,

260perhexilline maleate, 74peripheral nervous system

damage from pesticides, 291-292function tests, 178structure, 66, 339vulnerability of, 73

permissible exposure limits (PELs), 28,30, 185-187, 199,203,276,296,302-304,339

personality effects, see mood and personalitypest control, new approaches, 243,290,295,337Pesticide Action Network, Dirty Dozen Campaign, 249-250pesticide poisoning

and accidents, 285Agent Orange, 295of agricultural workers, 45, 50,267, 282–285, 288,289,294,

295Bhopal, India, accident, 243case studies of, 281–296in children, 283, 284, 293chlordecone (Kepone) in Hopewell, Virginia 47, 50, 293container recycling and, 251deaths from, 250,251,283,285,290, 294,295in developing countries, 250, 260diagnosis of, 50,289dose and, 283,290-292,294effects on nervous system, 6, 26, 49–50, 67, 73, 107, 117,

283-285,290-295epidemiological studies of, 285,295exposure route and, 283, 292–293labeling violations and, 242-243,251Lake Volta, Ghana, incident, 252major incidents of, 47 (table)mercury fungicides, 47-49from methyl bromide, 294from misuse in developing countries, 50,239,248-249,251,

252,253monitoring of, 251–256, 289, 296from organochlorines, 293from organophosphates, 47,50,69,284,290-292prevalence of, 248-249,252,283,284, 295prevention of, 26,28,30,250-252,267, 284,286-289,295recovery periods, 284, 290reentry intervals and, 288repackaging and, 243, 247,248, 251reporting of illnesses related to, 50, 283, 289,295

pesticides, 339active ingredients, 336in adipose tissue, 133, 292–293advertising, 251, 255–256alternatives to use of, 243,290-291,295banned, restricted, or unregistered, 21-22,173,237-238,240,

242, 249-250, 252, 253, 255, 261, 283, 288, 290,292–295; see also Exports

Belgian regulatory policies, 246-247Canadian regulatory policies, 245cancellation/suspension of registration, 173chlorphenoxy herbicides, 294-295cholinesterase inhibitors, 290-292data call-ins, 172, 173,203defined, 49,281-282detection of residues, 50development, 225-226, 231–232in developing countries, regulatory issues, 248-256, 260; see

also exports of toxic substances; and specific countriesdioxin contamination of, 294Experimental Use Permit, 170-171,337exports of, 56-57, 237, 241–245Federal Republic of Germany regulatory policies, 245–246fishing with, 252fumigants, 293-294inert ingredients, neurotoxicity evaluations, 24, 288innovation in, and neurotoxicity testing, 226-227International Code of Conduct on the Distribution and Use of

Pesticides, 242,243international effects of U.S. export practices, 242–245Japanese regulatory policies, 247-248labeling, 171, 172,240,242-243,247, 248,253-255market size worldwide, 237MCLs for, 183me-too registration, 240, 253,255,338monitoring of, 132, 133, 134, 135, 241, 242, 251, 253–255,

289neurotoxic, 43, 172, 183, 290-295notification requirements, 22, 239–240, 247, 261, 290, 339occupational exposures to, 281–283organochlorine, 292–293prior informed consent, 249,339protective clothing, 250,283,287-289

index ● 357

pyrethroids, 72,295reentry intervals for farmworkers, 284, 286-288, 290, 295–

296,340registered, 3,43,49, 195,237registration of new compounds, 17, 161, 170-171, 197, 199,

216,241,287-288,295regulation of (Federal), 16, 17, 56, 164, 170-173, 204,

285-289reregistration of existing compounds, 17, 171–173, 197, 241,

286,287research on neurotoxicity, 256, 257–258, 295residues in domestic and imported food, 241–242, 251, 282resistance of pests to, 243risk standards, 25, 168, 241risk-benefit analysis, 216, 217,296safety information, 287safety, measure of, 221–222special review of, 173, 197, 216state regulation of, 289–290testing for neurotoxicity, 17,18,115,119,170-173, 191–192,

194, 199,204,287,295Tolerance Assessment System, 135tolerances, 27, 164, 168, 171,216, 241,247, 254, 341use annually, 282, 295WHO toxicity classification, 249, 254see also carbamate insecticides; organophosphorous

pesticidesphencyclidine, 9,52,71phenylene diamines (unsubstituted), 179Philippines

pesticide problems in, 251regulatory issues in, 252–253

phosalone, 284Phosdrin, ,242,284phosphamidon, 284phosphines, 175Phosvel, incidents of poisoning, 47photoreceptor cells, 124physicians, education of, 98Poison Prevention Packaging Act (PPPA)

control measures under, 187, 190-191regulatory authority, 16, 161risk assessment approach, 161standard setting under, 180toxic substances regulated by, 161

policy issues and optionsfor ADAMHA, 33adequacy of regulatory framework, 23–31adequacy of research framework, 31–35confidential business information, 25cosmetics testing, 28for CPSC, 31education and training of research and health-care

professionals, 36education of workers and public, 37–38for EPA, 23-27,31-32for FDA, 27-28,33-34interagency coordination of research and regulatory

p r o g r a m s , 3 5 - 3 6international regulatory and research programs, 38-40Material Safety Data Sheets, 30monitoring of adverse health effects, 28, 30

neurotoxicity testing requirements, 24-25, 27–28for NIH, 32-33for NIOSH, 34-35for OSHA, 28,30protection of agricultural workers, 26,28,30statutory scope of neurotoxicity regulation, 26-27

polyaromatic hydrocarbons, 133polychlorinated biphenyls (PCBs), 115, 180

incidents of poisoning, 47, 247monitoring of, 133, 134research on, 258

potentiation, 65,339Poultry Products Inspection Act, 241,242premanufacture notices, 17, 174-176, 194, 196, 197,201-202,

219-220,227,247prevention of exposure

adequacy of measures, 28, 30, 288, 289educational programs, 30, 130engineering controls, 13, 30, 267, 276,296, 300, 301, 337to lead, 8, 189–190, 277, 278,281medical controls, 130-131, 300to organic solvents, 30, 296, 300-302to pesticides, 26,250-252,267,284, 285–290, 295,340protective clothing and devices, 30, 250, 267, 283, 286,

288-289,295,296,300-302, 339reentry levels for farmworkers, 284,286, 288, 290, 295, 340state programs, 289–290training in handling of pesticides, 252,255,290in workplace, 130–131, 300-302, 336see also monitoring toxic substances

propylene, 14, 136protective clothing and devices, 30, 250, 267, 283, 286,

288-289,295,296,300-302, 339psilocybin, 74psycho organic syndrome, 296psychoactive drugs, 6, 10,27,44,50psychological testing, 126psychosis, 71Public Health Service Act, 167Purkinje cells, 67pyramidal cells, 68pyrethroid pesticides, 72,295pyridine derivatives, 175

quaternary ammonium compounds, 175quinone, 179

radionuclides, 182rat glioma C-6 cell lines, 124reentry levels for farmworkers, 284, 286, 288, 290, 295, 340reference dose (RfD), 116, 148-149, 150, 153, 340registration, see licensing and registrationregulations and regulatory issues

adequacy of regulatory framework, 201–203administration of laws, 56, 160-161; see also specific

agenciesapplication and notification procedures, 159; see also

licensing and registrationin behavioral teratology, 115consistency of protection, 17, 19, 194-196, 199-200consistency of requirements, 16-17, 194coordination and cooperation among agencies, 19, 176, 194,


198-199,200-201,205, 326-327costs of compliance, 20, 201, 211, 215, 217–218, 220, 230diversity of, 159economic benefits of, 228–230economic impacts of, 213–215economic incentives, 161effectiveness of regulatory programs, 203–204, 205,274,281endpoint basis for, 56expected and detected neurotoxicity, 201–203expenditures by government, 215export laws, 239–241general toxicological considerations in, 194-199of human research, 130impact analyses, 211 n.1, 214, 220, 231of industrial chemicals, 56in industrialized countries, 245–248international regulatory activities, 21–22, 115, 237–256labeling, 172for lead, 46, 273–281measurements of effectiveness, 201minimal data set, value of, 201neurological considerations in, 18–19, 178, 199-201, 204new initiatives, 191–194new v, existing chemicals, 18, 196-198nonregulatory factors affecting implementation, 159, 161,

162for pesticides, 241-242,286-290redundancy of effort among agencies, 198risk assessment approaches, 146, 150–151State regulation of lead, 277, 278State regulation of pesticides, 289-290statutory authority, 56; see also legislation; and specific

statutestolerance setting, 164see also cost-benefit analysis; economic issues

regulatory analyses, 20, 211, 218 n.11institutionalization of, 215, 230utility in regulatory policymaking, 220-221

regulatory impact analyses (RIAs), 211 n.1, 214, 216, 231reporting of harmful effects, 180, 197

CPSA requirements, 204FFDCA requirements, 167,203OSH Act requirements, 204pesticide poisoning, 50,283,289,295of therapeutic drugs, 18, 167, 203

researchacademic activities, 92–94, 256–259adequacy of Federal programs, 31–35, 81by charitable organizations, 97under Clean Air Act, 180comparison of U.S. and foreign programs, 259coordination of Federal programs, 200, 325development of methodologies, 81,259Federal activities, 9, 11–12, 81–92, 321–324; see also specific

agenciesfunding, 9, 11-12, 81, 82-84,259industry activities, 12, 94-95, 256-259interactions among, government, academia, and industry, 96,

256-259international efforts, 22, 256–260, 261journals, 22,256leadership roles by foreign governments, 260

needs, 3, 11,26,55,76, 137, 154--155, 259–260, 295pathological changes related to functional impairment, 154resources, 259trends internationally, 21,258-259,261workplace, 129; see also occupational exposuressee also academic research; epidemiological studies;

industrial researchresearch scientists, education of, 12, 97, 259Resource Conservation and Recovery Act (RCRA), 135, 176

control measures under, 187, 189–191export controls, 239, 240regulatory authority, 16, 23, 161risk assessment approach, 161toxic substances regulated by, 161

Restoril, 29, 169risk

acceptable, 13, 145, 146, 164, 196, 340characterization of, 148–149defined, 13and economic benefit, 216-217expression of, 13, 145individual v. societal, 154, 155negligible, 168public perceptions of, 145-146and stringency of evaluation process, 17, 195–196unreasonable, 212, 241vulnerable populations, 8–9, 45zero, 153, 168, 339

risk assessmentfor acrylamide exposures, 150, 151,216approaches for neurotoxic substances, 56, 150-154, 160-161carcinogen approach, 15, 149, 150, 151, 152, 153characterization of risk, 56, 105, 106, 148–149, 150, 154; see

also testingcomponents of, 145, 231controversial issues in, 14-15, 146coordination of programs, 326-327defined, 13, 145,211,340dose-response relationship, 147–148, 153–154EPA guidelines, 116, 146, 150, 192exposure assessment, 148hazard identification, 147, 148, 152, 154Integrated Risk Information System, 198and latent adverse effects, 15, 151-152, 155limitations of current approaches, 106, 151-152MOS/MOE approaches, 149, 162, 181regulatory approaches, 17, 25, 146, 150–151, 160-161safety factors, 148–149, 153–154uncertainty in, 149, 153, 154, 340, 341

risk-benefit analysis, 211, 216-217, 218 n.11, 286, 296, 340risk management

defined, 13, 145,211,340process of, 145, 149-150purpose of, 149risk balancing approach, 149–150risk only approach, 149technological control approach, 150

Rorschach Inkblot Test, 127

Safe Drinking Water Act (SDWA), 261986 amendments, 183cost-benefit analysis under, 216

Index ● 359

regulatory authority, 16, 23, 160risk assessment approach, 160standard setting under, 180, 183–184, 278toxic substances regulated by, 160

Santa Ana Dexterity Test, 127saxitoxin, 72Scandinavian counties

neurotoxicological research, 22, 256-259, 260,261regulatory policies in, 260, 261researcher training, 259

schedule-controlled operant behavior (SCOB) tests, 13, 110,111, 116-117, 136, 137, 178, 192,224-225,231,340

scorpion toxin, 72screening, 154, 340

adequacy of, for chemicals, 17developmental neurotoxicity, 116computer-assisted, 82, 175in EPA core test battery, 111FDA policy on, 194with functional observational battery, 82, 111, 112, 193with in vitro tests, 13, 110, 136for lead exposure, 270,277,278,280,281with motor activity test, 82, 193of pesticides, 199, 204structure-activity relationships, 18, 175, 194, 203, 340WHO Neurobehavioral Core Test Battery, 126-127

selecron, 251Senegal, pesticide import violations, 243,251sensory systems

effects of neurotoxic substances on, 46, 51–52, 272evoked potentials, 118–1 19, 128, 337functions of, 66and motor functions, 70neuron losses, 74

serotonin, 66effects of abused drugs on, 9, 51–52, 74

short-term exposure limits, 302significant new use rule, 174silicon, and Alzheimer’s disease, 54–55silver, 133soil, lead in, 269, 280-281solvents, see organic solventssomatosensory evoked potentials, 119, 120–121, 128South Korea, pesticide import problems, 243Soviet Union, neurotoxicity research, 22,258,260specimen banking

domestic and international programs, 132-133nonhuman tissues, 133

spina bifida, 70spinal cord

clioquinol effects on, 74damage from pesticides, 291-292degeneration, 55development of, 67functions, 66

standards and standard settingaction levels for contaminants in foods, 164, 241–242, 336air quality, 180-181for airborne contaminants, 181, 182, 185carcinogenicity -based, 185challenges to EPA authority, 162, 182 n.8under Clean Air Act, 180-182

under Clean Water Act, 182–183under Consumer Product Safety Act, 184cost-benefit analysis, 181drinking water, 183-184economic considerations in, 199emissions, 181, 182exposure probability and, 195features of laws, 159, 160-161under Federal Hazardous Substances Act, 184under Federal Mine Safety and Health Act, 185under Federal Water Pollution Control Act, 182–183hazard communication, 187by international groups, 242for lead, 271,276,278-279litigation over validity of, 276margin of safety in, 180-181, 338maximum contaminant levels and maximum contaminant

level goals, 183, 198,278-279,338neurotoxicity considered in, 162under Occupational Safety and Health Act, 185–187for packaging, 190permissible daily intakes, 189permissible exposure limits, 28,30, 185-187, 199,203,276,

296,302-304,339for pesticide residues, 164recommended exposure limits, 199, 302–303, 340reentry intervals for farmworkers, 284, 286-288, 340regulatory approach, 16, 159, 180regulatory impact analysis, 181reportable quantities, 187under Safe Drinking Water Act, 183–184, 191threshold limit values, 151, 185, 186, 199,203,341and toxicity testing requirements, 180water quality, 182see also regulations and regulatory issues; and specific

statutessteroids, 70stroke research, 259structure-activity relationships, 17, 18, 25, 175, 194, 203, 340styrene, 14, 136, 258, 299, 303substance P, 66substantial nigra, 6, 67, 72Sudan, pesticide poisoning in, 251sudden infant death syndrome, 10,53sulfur oxides, 181sulfuric acid, 14, 136sulfuryl fluoride, 120Superfund Amendments and Reauthorization Act, 135

confidentiality under, 176health effects contemplated by, 188regulatory authority, 161research authorized by, 188risk assessment approach, 161toxic substances regulated by, 161, 198

Swedenhuman tissue monitoring, 132Performance Evaluation System, 127

synapse, 66, 70chemical communication at, 66defined, 340measurement of function at endings, 118, 124

synaptic cleft, 66, 340


synergism, 64, 65, 340

2,4,5-T, 250,294,2952,4,5-TP, 183tardive dyskinesia, 6, 44TCDD, 294Telone II, incidents of poisoning, 47temik, 251temperature, and toxicity, 109testing

accuracy of PMN assessments, 204computerized/automated techniques, 112–1 13confidentiality issues in, 19, 176, 202, 218, 226consent decrees for, 177, 197, 201, 202, 336coordination of programs, 325–326of cosmetics, 52, 54, 168, 196criteria, 152cross-species comparisons, 115-116current extent of, 12, 16,43, 52, 55, 56, 76, 151, 211design, factors considered in, 105-109, 178, 199-200in developing countries, 251–252disincentives to, 174-175, 176economic impacts of, 218; see also Costs of testingendpoints, 109, 116, 125, 150, 152, 178EPA guidelines, 110-112, 114-118, 136, 137, 191-193of exports, 240extrapolation of results to other populations, 147, 153FDA requirements, 163, 165-167, 192-194, 199FIFRA guidelines, 115flexibility in, 193,200of food additives, 52, 192–194in industrialized countries (other than U.S.), 245, 246,

247-248and innovation in drugs and pesticides, 226-227interpretation of safety, 165laboratory automation, 223laboratory capabilities, 223limitations of current tests, 122, 151-152needs, identification of, 324options for changes in requirements for, 24-25personnel, 223protocol requirements, 222quality assurance, 222-223reliability and sensitivity, 26, 115, 152, 191, 193research on new methods, 81–84standardization of, 324-325statutory authority for, 159stringency of, 17, 195–196tiered approach, 18, 109-110, 154, 193,200, 341triggers for, 24validation, 109, 111, 123–124, 168WHO objectives, 106see also animal tests; in vitro tests; human testing and studies;

risk assessment; screeningtetrachloroethylene, 14, 136tetraethyl lead, incidents of poisoning, 47, 303tetrodotoxin, 45, 72Texas Agricultural Hazard Communication Law, 290Thailand, pesticide misuse in, 243,251thalidomide, 73thallium

effects on nervous system, 74

incidents of poisoning, 47testing of, 124toxicity, 48water quality standards, 183

therapeutic drugs and biologicsadverse effects of, 29, 45, 50-51, 167–169for animals, 166, 167benefits assessment, 216benzodiazepine hypnotics, 29, 169efficacy and effectiveness, 217interactions, 8, 29, 45, 169investigational new drugs, 167–168, 203, 338labeling, 29, 169licensing and registration of, 18, 29, 161, 166-169monitoring reactions to, 29, 168, 169neuroeffective substances, 168neurotoxic potential, 3, 45new drug applications, 166, 167, 188, 339packaging information on adverse effects, 28R&D studies, 219reporting of adverse reactions, 18, 167, 203research on neurotoxicity, 258risk assessment, 146, 151, 153risk-benefit analysis, 217safety, measure of, 221–222seizure medication, 44standard for approval, 166-167testing of, 17, 18, 26,29, 105, 115, 166-168, 169, 199,204see also specific drugs

thiamine deficiency, 71thiocarbamates, 172threshold limit values, 151, 185, 186, 199,203,341,302-303time-weighted average limits, 302tin, 133tissue culture

antibiotics added to, 123applications in neurotoxicology, 122defined, 122,340embryo, 123–124expenditures for development of methods, 122explants, 124, 337organotypic, 124, 339see also Cell culture; Organ culture

TOCP, incidents of poisoning, 47tolerance levels

for contaminants in foods, 164enforcement of, 241–242lead in canned evaporated milk, 274-275for pesticides residues, 27, 164, 171,216,239,241recommended approach, 27

toluene, 14, 119, 136, 183, 296,299, 303Total Diet Study, 135toxaphene, 183, 250, 255,292toxic substances

general considerations in regulation of, 194-199see also neurotoxic substances

Toxic Substances Control Act (TSCA), 56, 110confidential business information under, 19, 25, 176, 202,

218,226consent decrees, 17, 177, 179, 197, 201, 202, 336coordination of FIFRA neurotoxicity evaluations with, 191–

192

Index . 361

economic balancing provisions of, 212, 216, 217–218existing chemicals, 175, 177–180export controls, 21–22, 239–240, 261extent of testing under, 17, 18-19, 24-25, 201–202, 204licensing and registration under, 16, 161, 173-180, 194, 195,

197new chemicals, 174-175notification requirement, 218, 239–240premanufacture notices, 17, 174-176, 194, 196, 197, 201-

202,203-204,215,219-220, 227regulatory authority, 16, 20, 160, 213risk assessment approach, 160, 196significant new use rule, 174substances regulated by, 160test guidelines, 150, 191, 199, 224test rules, 17, 82, 197, 178, 179, 215, 217, 222, 340–341

Toxics Release Inventory, 13, 14, 17,43, 122, 134-136, 197triadimefon, 113triazophos, 292tributyl phosphorotrithioates, 1731,l,l-rnchloroethane

releases of, 14, 136testing of, 115, 135, 179

trichloroethylene, 14, 136,299, 3032,4,5 -trichlorophenoxypropionic acid, 294triethylene glycol monomethyl ethers, testing guidelines, 115,

179trimethyl benzenes, 179trihalomethanes, 183trimethyltin

biochemical markers for, 117poisoning, 6,44,68,74

triorthocresyl phosphate, 47, 69triphenyltin, 113Tris phosphite, 166

United Kingdomregulatory policies in, 248

research on neurotoxicity, 21, 256,258, 259, 261United Nations

Food and Agriculture Organization, 135,242,243, 249–251,253-256

OECD toxicity testing guidelines, 191, 194urea-formaldehyde resins, 179U.S. Public Health Service, 189

vasopressin, 66vincristine, 73vinyl chloride, 182visual evoked potentials, 119-120visual systems

impairment of, 26, 48, 49, 51, 55, 72, 74, 131, 135, 181substances affecting, 48, 49, 51, 55,72, 74, 119testing of, 119

vitamins, toxicity, 6, 44, 74

Walsh-Healy Act, 185, 186water quality standards, 182–183Wechsler Adult Intelligence Scale, 127Wechsler Memory Scale, 127World Health Organization, 22, 135,242,255

acceptable levels of lead, 271childhood lead intoxication study, 257, 261epidemiological study of dementia, 259objectives of neurotoxicology testing, 106Neurobehavioral Core Test Battery, 126-128organic solvent studies, 257pesticide toxicity classification, 249,254specimen banking program, 133testing recommendations of, 114, 115, 116, 150

X-irradiation, 115xylene, 14, 136, 299, 303

zinc pyridinethionine, 108Zolone, 284

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