The Role of Genetic Testing in the Prevention of Occupational Diseases

The Role of Genetic Testing in thePrevention of Occupational Diseases

April 1983

NTIS order #PB83-233734

Library of Congress Catalog Card Number 83-600526

For sale by the Superintendent of Documents,U.S. Government Printing Office, Washington, D.C. 20402

Foreword

This report examines a technology, genetic testing, that may be useful in reducingoccupational disease, but that also raises concerns about potential misuse. Genetic testingencompasses two major techniques, one (screening) that may be able to identify individualworkers who are genetically at higher risk to disease; and another (monitoring) thatmay serve as an early warning system that exposure to a hazardous agent in the work-place has occurred. Information from these techniques might be used in various preven-tive measures, but some people fear it could result in workers being unfairly excludedfrom jobs.

OTA undertook the study at the request of the House Committee on Science andTechnology. The study examines the technology and its social implications. It evaluatesthe evidence supporting its claimed benefits, the extent of testing, and how the resultshave been used. Social issues, particularly of a legal and ethical nature, are identifiedand discussed. Finally, congressional options for both promotion and control arepresented.

In preparing this report, OTA consulted with members of the project advisory panel,with contractors and special consultants, and with numerous other experts in industry,academia, labor, medicine, law, economics, and ethics. Drafts of the final report werereviewed by the advisory panel chaired by Arthur Bloom and by approximately 32 otherindividuals and groups representing a wide range of disciplines and perspectives. Weare grateful for their many contributions. As with all OTA reports, however, the con-tent is the responsibility of the Office and does not constitute anadvisory panel or the Technology Assessment Board.

endorsement by the

Director

. .Ill

Advisory Panel on Occupational Genetic Testing

Arthur D. Bloom, Panel Chairprofessor of Pediatrics, College of Physicians and Surgeons, Columbia University

Eula Bingham

J

Environmental Health DepartmentUniversity of Cincinnati

Grant BrewenMolecular and Applied Genetics LaboratoryAllied Chemical Corp.

Patricia BufflerSchool of Public HealthUniversity of Texas

Ira CisinSocial Research GroupGeorge Washington University

Burford W. CulpepperMedical DivisionE. I. du Pent de Nemours & Co.

James D. EnglishUnited Steel Workers of America

Neil HoltzmanJohns Hopkins University

Paul KotinDenver, Colo.

Thomas O. McGaritySchool of LawUniversity of Texas at Austin

Rafael MoureOil, Chemical and Atomic Workers Union

Robert F. Murray Jr.Division of Medical GeneticsCollege of MedicineHoward University

Elena NightingaleInstitute of MedicineNational Academy of Sciences

Gilbert OmennDean, School of Public HealthUniversity of Washington

William N. RomRocky Mountain Center for Occupational

and EnvironmentalUniversity of Utah

Stuart SchweitzerDirector, Program in

Policy Analysis

Health

Health Planning and

UCLA School of Public Health

Robert VeatchThe Kennedy Institute of EthicsGeorgetown University

iv

OTA Project Staff—Genetic Testing Assessment

H. David Banta, Assistant Director, OTAHealth and Life Sciences Division

Gretchen Kolsrud, Biobgical Applications Program Manager

Geoffrey M. Karny, Project Director

Nanette Newell, Senior Analyst *

Ann Rose, Senior Analyst

Louise Williams, Senior Analyst

Nina Graybill, Editor

Ted Wagner, Administrative Assistant **

Fatimah Taylor, Administrative Assistant***

Lynne Alexander, Secretary

Marese Miles, Secretary†

Special Contributors

Hellen Gelband, Analyst

Michael Gough, Senior Analyst

Principal Contractors

David Brusick, Litton Bionetics, Inc.Edward Calabrese, University of Massachusetts, AmherstBetty Dabney, Boulder, ColoradoMarc Lappe, University of California, BerkeleyMark A. Rothstein, West Virginia University College of LawCynthia A. Thomas, National Opinion Research CenterJudith L. Wagner, Technology Research Associates

OTA Publishing Staff

John C. Holmes, Publishing Officer

John Bergling Kathie S. Boss Debra M, Datcher Joe HensonDoreen Foster Donna Young

—.-

Contents

Chapter PageGlossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Part I: Introduction to Genetic Testing

1. Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2. Introduction: Occupational Illness and Genetic Testing . . . . . . . . . . . . . . . . . . 23

3. Survey of the Use of Genetic Testing in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . 35

Part II: Underlying Scientific Principles

4. Essentials of Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

5. Principles of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 7

Part 111: An Assessment of the State of the Art

6. Genetic Monitoring in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

7. Genetic Screening for Heritable Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Part IV: Legal, Ethical, and Economic Issues

8. Legal Issues Raised by Genetic Testing in the Workplace . . . . . . . . . . . . . . . 111

9. Application of Ethical Principles to Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

10. Prospects and Problems for the Economic Evaluation of Genetic Testing . . . . . . . . . . 151

Part V: Congressional Issues and Options

11. Issues and Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

Appendixes

A. Survey Design and Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.5

B. Report From the National Opinion Research Center . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

C. Survey Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

D. Background Frequencies for Chromosome Aberrations . . . . . . . . . . . . . . . . . . . . . . . . 227

E. Background Frequencies for Sister Chromatid Exchanges. . . . . . . . . . . . . . . . . . . . . . . . . 231

F. Screening Tests (Available in Hospitals or Medical Centers) for Heritable Traits . . . . . . . . 233

G. Other Contractors and Contributors and Acknowledgments . . . . . . . . . . . . . . . . . . . . , . . 235

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... , . . . . . . . . . . 239

vii

Glossary

Acetylation.–The introduction of one or more acetylgroups into an organic compound.

Allele.--One of several alternate forms of a gene.Amino acid.—Any one of a class of organic chemical

compounds characterized by the presence of anamino group (NHZ) and a carboxyl group (COOH) at-tached to either side of a central carbon atom. Theyare the primary building blocks of proteins; 20 ma-jor types are found.

Anemia.—A condition characterized by a decreasedoxygen-carrying capacity of the red blood cells be-cause of reduced number of cells, too little hemo-globin, or malfunctioning hemoglobin.

Assay.—Any technique that measures a biologicalresponse.

Biologically significant.-An exposure or dose thatcan cause detectable damage or disease.

Carcinogen/carcinogenesis.-An agent that in-duces cancer.

Carrier.—An individual apparently normal, but pos-sessing a single copy of a recessive gene obscuredby a dominant allele; a heterozygote.

Centromere.--A specialized region of a chromosomethat holds the two chromatics together and that isinvolved in directing chromosome movements dur-ing cellular reproduction.

Chromatid.--One of the two daughter strands of aduplicated chromosome that is still joined by a singlecentromere.

Chromosomal aberration.-–An abnormality ofchromosome structure or number.

Chromosomes.—The structures in the cell nucleusthat store and transmit genetic information.

Clastogen.--Chromosome-damaging agent.Codominant.—Alleles are codominant if each is ex-

pressed independent of the presence of the other;the effects of expression are additive.

Cyanosis.—Slightly bluish, grayish, slatelike, or darkpurple discoloration of the skin due to the presenceof abnormal amounts of reduced hemoglobin in theblood.

Cytogenetics.–The study of the relationship of themicroscopic appearance of the chromosomes andtheir behavior to the genotype and phenotype of theindividual.

Deletion.—A chromosomal aberration involving theloss of a portion of a chromosome.

Deoxyribonucleic acid (DNA) .—The geneticmaterial of all cells.

Dominant.–An allele that exerts its phenotypic ef-fect when present either in homozygous or hetero -zygous form.

Des&response. -An increasing biological responsewith increasing dose of a chemical or ionizing radi-ation.

Dosimeter.—Device or methodology for measuringthe dose of a chemical or ionizing radiation to abiological system.

Duplication.—A chromosomal aberration in whicha portion of a chromosome is present more thanonce; may involve whole genes, parts of genes, orseries of genes.

Endpoint.—The particular biological response beingmeasured,

Erythrocyte.--Mature hemoglobin-rich red bloodcell involved in oxygen transport.

Gene.—A unit of heredity. At present, genes are usu-ally equated with units of function, that is, the se-quence of DNA required to code for one polypep-tide chain or one RNA molecule.

Genetic monitoring.—The periodic testing ofworkers to assess damage to their DNA or chromo-somes from exposure to hazardous substances oragents.

Genetic predisposition. -Susceptibility to illnesson the basis of one’s inherited genetic constitutionand triggered by an environmental stress.

Genetic screening.—A one-time test to determinethe presence of particular genetic traits in individ-uals. For this report, the term is limited to thescreening of workers for genetic traits that mightcause them to be at increased risk for occupationaldisease.

Genetic tests. -Those tests that determine a person’sgenetic makeup or that identify changes (damage)in the genetic material of certain cells for the pur-pose of identifying people who may be at risk ofdisease when exposed to hazardous substances.

Genotoxic.—Damaging to the genetic material.Genotype.-The genetic constitution of an organism

(to be distinguished from its physical appearance orphenotype).

Germ cell—The male and female reproductive cells;egg and sperm.

Hemoglobin. -Protein carrier of oxygen found inred blood cells. Composed of two pairs of polypep-tide chains and an iron-containing heme group.

Hemolytic.--Pertinent to the breaking down of redblood cells.

Heterozygous--Having different alleles at a geneticlocus.

Homozygous.–Having indistinguishable alleles at aparticular locus on both chromosomes.

Human leukocyte antigens (HLAs).—A set of im-

ix

munologic proteins found on the surface of all cells;each person’s set is thought to be as unique as fin-gerprints.

Hypoxia.—Result of lack of an adequate amount ofoxygen in inspired air such as occurs at highaltitudes; reduced oxygen content.

Initiation.—The first step in the development ofcancer.

Inversion.-A chromosome rearrangement in whicha central segment produced by two breaks is in-verted prior to repair of the breaks.

In vitro. -Pertaining to experiments done in a cell-free system. The term is sometimes used to includethe growth of cells from multicellular organismsunder cell culture conditions.

In vivo.—Pertaining to experiments done in a systemsuch that the organism remains intact, either at thelevel of the cell (for bacteria) or at the level of thewhole organism (for animals).

Ionizing radiation. —High energy electromagneticradiation, associated with gamma and X-rays, whichis capable of changing the electronic structure ofatoms.

Karyotype.-A chart made from a photograph of thechromosomes in which the homologous pairs arematched and arranged in numerical order from thelongest to the shortest pair.

Leukocyte.–White blood cell.Locus (pl—loci).—The position of a gene on a chro-

mosome.Lymphocyte.-One of the major groups of white

blood cells.Messenger RNA (mRNA).—Type of RNA that car-

ries the transcribed genetic code from the DNA tothe protein-synthesizing enzymes to direct proteinsynthesis.

Mutagen/mutagenesis.--Any substance that dam-ages the genetic material.

Nucleotide base.—Structural unit of nucleic acids.Nucleus.—A relatively large spherical body inside a

cell that contains the chromosomes in their un-coiled, threadlike state.

Oxidation. -Chemical reaction where there is a lossof electrons.

Phenotype.—Appearance or observable nature of anindividual as determined by his or her genotype andthe influence of the environment. Individuals thatappear alike may be genetically different.

ppm.-–parts per million.Predictive value.—The likelihood that a person with

a positive test result has the disease or that a per-

son with a negative result does not have the disease.Also refers to the likelihood that the index or mark-er (chromosome damage) predicts the occurrenceof a disease.

Promotiom--The second step in the development ofcancer.

Protein--A linear array of amino acids joined by pep-tide bonds. In their biologically active states, pro-teins are folded into specific three-dimensionalstructures and function as catalysts in metabolismand to some extent as structural elements of cellsand tissues.

Recessive.–An allele which exerts its phenotypic ef-fect only when present in homozygous form, other-wise being masked by the dominant allele.

Reduction--Chemically, the acceptance of electrons;used as the opposite of oxidaticm.

Relative risk—The ratio of the incidence of diseaseamong exposed persons divided by the same rateamong nonexposed persons.

Reliability.—The ability of the same specimen to givethe same result repeatedly when measured by dif-ferent laboratories or by different individuals in thesame laboratory on several occasions.

Sensitivity.–The ability of a test to identify correctlythose who have a disease.

Serum.—The liquid portion of the blood that carriesthe blood cells.

Somatic cell--All cells of the body except the germcells.

Specificity.--The ability of a test to identify correctlythose who do not have the trait or disease whichis being tested.

Teratogen/teratogenesis. -An agent that inter-feres with embryonic development.

Trait.—A distinguishing feature; a characteristic orproperty of an individual.

Transcription.—In gene function, the complemen-tary copying of the genetic code from DNA to mes-senger RNA.

Translation.—In gene function, decoding the mes-senger RNA into an amino acid sequence in the pro-duction of a protein.

Translocation.—A chromosomal aberration inwhich a portion of one chromosome is attached toanother chromosome; often a reciprocal exchangeof segments between two chromosomes.

Validity.–The extent to which a test will correctlyclassify true susceptible and true nonsusceptible in-dividuals; sensitivity and specificity are componentsof validity.

x

Part I

Introduction to Genetic Testing

Chapter I—Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Chapter 2—Introduction: Occupational Illness and Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . 23Chapter 3—Survey of the Use of Genetic Testing in the Workplace . . . . . . . . . . . . . . . . . . . . . . 35

Chapter I

Executive Summary

Contents

PageOccupational Illness and Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

The Problem of Occupational Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Health Hazards in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6The Use of Genetic Testing for the Prevention of Occupational Disease . . . . . . . . . . . . 7

Theoretical Foundations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Detection of Increased Risk in Individuals or Groups . . . . . . . . . . . . . . . . . . . . . . . . . . 7Potential Benefits and Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Survey of the Use of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9The State of the Art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Genetic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Genetic Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Genetic Testing and the Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Ethics of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Economic Evaluation of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Congressional Issues and Policy Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Issue: What Actions Could Congress Take With Respect to Genetic Testing

in the Workplace? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Issue: How Could Congress Regulate Genetic Testing in the Workplace? . . . . . . . . . . . 16Issue: How Could Congress Foster the Development and Use of This Technology? . . . 18

Chapter 1

Executive Summary

Occupational illness and genetic testing

The problem of occupational illness

Occupational illness cost the U.S. economy over850,000 workdays in 1981. * Diseases and othermedical conditions associated with the workplacerange from minor skin rashes to cancer. Someexperts estimate that exposures to hazardous sub-stances at work may play a role in 5 percent ofall cancers. one substance-asbestos-is at thecenter of litigation over claimed illness that couldresult in insurance payments in the tens of billionsof dollars over the next three or four decades.A large asbestos company has had more than16,500 lawsuits filed against it and, as a result,has filed for reorganization under the BankruptcyAct. Clearly, occupational illness has a serious andfar-reaching impact not only on society as a wholebut also on individuals who face impaired healthand shortened lifespans.

What steps are being taken to mitigate thisproblem? Scientific and industrial response hasvaried: environmental and biological monitoring,engineering controls, personal protection devices,and modified work practices are among the tech-niques used today.

And on the horizon is an emerging technology–genetic testing–that may prove useful in reduc-ing occupational disease, especially disease aris-ing from exposure to two main workplace haz-ards: chemicals and ionizing radiation. That newtechnology—its potential applications and its limi-tations, its current state of development, and itslegal, ethical, and social implications—is the sub-ject of this report.

Genetic testing, as used in the workplace, en-compasses two types of techniques. Geneticscreening involves examining individuals for cer-tain inherited genetic traits. Genetic monitoringinvolves examining individuals periodically for en-

*’I hr nllnlt)f’r of lost w (Irk{id}s ]s t)iisf’(1 (m a sun fw t)y the BLIJ’f’iILI. .01 I .at)OI” stat ist 1[’s \$hl(’h ‘i(’k Il(l\$’lf’(lgf’h t hilt 11)(’ t’igu [’(’ LIJN](’I’St:it(’S

thr dn)ount of ()([l]~):iti{)ll:il illness t)w<iusf’ the sun f~> dof~s not a(l(’-

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vironmentally uced changes in the genetic ma-terial of certain cells in their bodies. The assump-tion underlying both types of procedures is thatthe traits or changes may predispose the individ-uals to occupational diseases. (Changes in thegerm cells--egg and sperm-could result in birthdefects in offspring but such reproductive effectsare not part of this study.)

Although this technology is still in its infancy,it has the potential to play a role in the preven -tion of occupational diseases. It is technologicallyand economically impossible to lower the level ofexposure to hazardous agents to zero. However,if individuals or groups who were predisposedto specific types of occupational illness could beidentified, other preventive measures could bespecifically directed at those persons. This is thepromise of genetic testing. At the same time, how-ever, the technology has potential drawbacks andproblems. For example, the ability of the tech-niques to identify people who are predisposed tooccupational illness has not been demonstrated.In addition, some people are concerned that itsuse could result in workers being unfairly ex-cluded from jobs or in attention being directedaway from efforts to reduce workplace hazards.

While it may be too soon to be able to answermany of the questions raised by genetic testing,it is not too soon for society to begin to considerthem. The technology is developing, and some ma-jor companies have used it to a limited degree,Many more companies have expressed an interestin using it in the future. Moreover, genetic testingis one of a number of technologies that purportto identify people, both in and out of theworkplace, who face an increased risk for disease.Policy decisions made on issues raised by genetictesting are likely to be relevant to the issues raisedby those other technologies. Thus, the Commit-tee on Science and Technology of the House ofRepresentatives requested an assessment of ge-netic testing in the workplace.

5

6 . The Role of Genetic Testing in the Prevention of Occupational Disease

Health hazards in the workplace

While there are many different kinds of hazardous substances or physical agents in the work-place, this report focuses on chemicals and ioniz-ing radiation. It is for these two categories ofhazards that genetic testing has been used andthat some data exist for evaluating the scientificvalidity of such tests.

Virtually all chemicals are hazardous, if a per-son is exposed to a sufficient degree. Chemicalsmay be irritating, toxic, mutagenic, teratogenic,and/or carcinogenic. Moreover, the hazard ofworking with chemicals is compounded by thelikelihood of multiple exposures to one or morechemicals over time. Exposure to more than onechemical may result in a synergistic effect—damage greater than the additive damage of theindividual exposures,

The exact number of hazardous chemicalsfound in the American workplace is unknown.An Environmental Protection Agency (EPA) inven-tory lists more than 55,000 different chemicalsin commerce, most of which are hazardous at suf-ficiently high exposure. Chemicals are found notonly in companies that produce them butthroughout the manufacturing sector, The Na-tional Institute for Occupational Safety and Healthestimated that 8.9 million workers in the manufac-turing sector were exposed to hazardous chemi-cals in 1980.

Photo credit: Off/cc of Technology Assessment

Chemical manufacturing plants sucn as the one shownproduce hazardous chemicals to which

workers may be exposed

Ionizing radiation is energy in the form ofwaves or particles that produce certain chargedparticles in passing through matter. X-rays are awell-known example of ionizing radiation. Thisradiation can harm exposed individuals or theirunborn children, For the exposed individual, theprincipal risk is that he or she may develop can-cer. For unborn children, the principal risks arechildhood leukemia and birth defects.

Occupational exposures to ionizing radiation(above natural background levels) occur in manyfields, such as the health professions, nuclear fuelmining and production, industrial testing, and 1ab-oratory research. Estimates of the number of ex-posed workers have varied from 750,000 by theCommittee on the Biological Effects of IonizingRadiation to 1.1 million by EPA.

Photo credit; Department of Energy

Protective clothing worn by employees in nuclear powergenerating facilities to avoid radiation exposure

Ch. l—Executive Summary ● 7

The use of genetic testing for theprevention of occupational disease

The problem of occupational diseases resultingfrom exposure to chemicals or ionizing radiationcan be addressed in many ways. These includelowering exposure levels through engineeringcontrols, physical and biological monitoring of ex-posure levels, medical screening and monitoringof workers, and individual protective devices.Genetic testing falls within the category of medicalscreening and monitoring.

THEORETICAL FOUNDATIONS

Genetically determined individuality is a fact oflife. People differ not only in such obvious phys-ical characteristics as height, facial features, andskin color, but also in ways that can be deter-mined only in a laboratory, such as by blood typeor types of proteins found in blood serum. Varia-tions in some characteristics or traits result fromthe interaction of many genes; variations in othertraits result from variations in a single gene thatcontrols that trait. The probability of any two peo-ple (except identical twins) being exactly alike isastronomically small.

Genetic variability is also a factor in the differ-ing reactions of people to environmental stresses,which include disease-causing agents such as bac-teria, viruses, and chemicals. For example, somepeople have a deficiency in an enzyme called glu -cose-6-phosphate dehydrogenase (G-6-PD). Theproduction of this enzyme is controlled by a sin-gle gene, and the deficiency is caused by a vari-ant form of the gene. The deficiency usually isharmless. However, if these people take certaindrugs for malaria or eat fava beans, they may suf-fer from acute anemia, due to the destruction oftheir red blood cells. Thus, G-6-PD deficient indi-viduals are at a higher risk of illness than otherpeople when exposed to those environmentalstresses. Some scientists have postulated that peo-ple with G-6-PD deficiency may also be at in-creased risk of disease in workplaces where theyare exposed to chemicals that are similar to theantimalarial drugs.

Many factors besides genetic makeup can causean individual to be predisposed to illness from en-vironmental stresses. Some of these are age, sex,

preexisting illnesses, nutritional status, personalhabits (such as smoking), and prior exposure tothe environmental factors.

prior exposure is particularly important for thepurposes of this report. If the environmental fac-tor is a chemical, it may be in the body at leveIsat which even slight additional amounts couldcause illness. In fact, the prior exposure may al-ready have begun the disease process eventhough the disease may not yet have manifesteditself in overt symptoms.

These considerations lead to the concept in oc-cupational medicine of unequal risk. People whodiffer according to age, sex, medical history, nutri-tional status, lifestyle, genetic makeup, or priorexposure to hazardous agents might differ in theirrisk for future illness when exposed to hazardousagents in the workplace. Some may be at in-creased risk; in other words, they might have ahigher probability than others for developing acondition, illness, or other medically abnormal sta-tus. Theoretically, it should be possible to iden-tify such people if the risk factors could be reli-ably identified and if the factors could be dem-onstrated scientifically to be correlated with anincreased risk of disease. In some cases, however,depending on the disease mechanisms involvedand the state of scientific knowledge, it might bepossible only to identify groups at an increasedrisk of disease. In other words, the group as awhole might have a higher risk compared to othergroups, but it would be impossible to predictwhich individuals in the increased risk groupmight develop the disease. Genetic testing is a col-lection of emerging techniques that may eventual-ly permit the identification of individuals orgroups at increased risk to certain occupationaldiseases.

DETECTION OF INCREASED RISK ININDIVIDUALS OR GROUPS

The term genetic testing applies to several tech-niques used to examine workers for particularinherited genetic traits or environmentally in-duced changes in the genetic material of certaincells on the assumption that the traits or changesmay predispose them to illness. It has been usedby some manufacturing companies and utilitiesfor medical evaluation and by others for research.

8 ● The Role of Genetic Testing in the Prevention of Occupational Disease

There are two inherently different kinds of test-ing, genetic monitoring and genetic screening,whose results can be used in the workplace fordifferent purposes.

Genetic monitoring involves periodically exam-ining a group of workers by collecting blood orother body fluids to assess whether genetic da-mage has occurred in certain cells. This damagemay indicate exposure to a hazardous agent, suchas a carcinogenic chemical or ionizing radiation.It may also indicate the possibility that the ex-posed group will be at an increased risk of de-veloping disease, most likely cancer. The proce-dure focuses on the risk for the exposed groupas a whole because there is no evidence to sug-gest that it could be used to identify which indi-viduals in the group are at increased risk. If thescientific validity of genetic monitoring were fullyestablished, it would have potential as an earlywarning system, by indicating that exposures toknown or suspected carcinogens are too high orthat a previously unsuspected chemical should beviewed as a potential carcinogen,

In contrast, genetic screening, when used in theworkplace, is a one-time testing procedure to de-termine if a person has particular genetic traits,regardless of whether the person has been ex-posed to a hazardous substance. The traits areidentified through laboratory tests on body fluids,usually blood. Some scientists have hypothesizedthat these genetic traits might predispose an in-dividual to adverse health effects in the presenceof particular chemicals. While normally not harm-ful, the traits theoretically may make the individ-ual more susceptible to blood-damaging chemi-cals, pulmonary irritants, oxygen deprivation, orother physical or chemical stresses in the work-place.

In sum, genetic screening has the potential todetermine individual susceptibility to certain haz-ardous agents, It may be that, in time, geneticmonitoring also will be able to determine individ-ual susceptibility; however, currently it appearsonly to have potential for assessing a chemical’seffect on an exposed population as a whole, Be-

cause of this distinction, screening could be usedto exclude genetically susceptible individuals fromjobs where they would be exposed to hazardoussubstances, whereas monitoring would most like-ly indicate a need to lower exposure levels for agroup exposed to a previously unknown hazard.

POTENTIAL BENEFITS AND RISKS

Although genetic testing is still in its infancy,its advocates believe that it might be able to playan important role in the prevention of occupa-tional disease. It is technologically and economical-ly impossible to attain a no-risk workplace bylowering the level of exposure to hazardous sub-stances to zero, However, if individuals or groupswho were predisposed to occupational illness be-cause of past exposure to hazardous substancesor particular genetic makeup could be identified,preventive measures could be taken by the com-pany or the workers themselves. In addition tothe obvious and significant benefits from prevent-ing serious illnesses, there could be indirect ben-efits, such as a reduction in the costs associatedwith occupational illness for employers, employ-ees, and society. These costs include medical, in-surance, and legal expenses; time lost from work;and disability or unemployment payments.

The use of this technology, however, raises sev-eral questions. Can the techniques truly predictan association between genetic makeup or geneticdamage and disease? How much of the variationin risk can be attributed to such predisposinggenetic factors and how much to variation in en-vironmental exposure? Since many of the genetictraits sought in screening happen to be distributedunevenly among some races and ethnic groups,could the use of the tests result in discriminationon the basis of race or national origin? How willthe availability of the tests affect the employer’sresponsibility for maintaining a safe workplace?How might these procedures affect efforts to re-duce the level of hazardous substances in theworkplace? If the tests are predictive, to whatdegree should society protect high-risk individualsor groups, at what cost, and who should bear thatcost?

Ch. l—Executive Summary ● 9

Findings

Because genetic testing is an emerging technol-ogy, there is insufficient evidence to assess manyof its potential benefits, risks, and impacts. How-ever, this report does examine the degree towhich it has been used, the current stage of itsdevelopment, expected future developments, andvarious legal, ethical, economic, and policy issuesthat it raises. This examination provides the basisfor a discussion of the broader social issues andthe options for possible congressional action.

Survey of the use of genetic testing

There have been conflicting accounts about theextent of testing and the use of the results. Noneof the accounts examined by OTA was based ona rigorous, scientifically valid survey. Therefore,in order to reduce the confusion and speculationand to provide necessary data for policy analysis,OTA surveyed major U.S. industrial companies,utilities, and unions about their use of this tech-nology.

The survey was conducted for OTA from Feb-ruary 25 to June 8, 1982, by the National opinionResearch Center (NORC), a nonprofit survrey re-search corporation affiliated with the Universityof Chicago. NORC sent confidential questionnairesto the chief executive officers of the 500 largestindustrial companies and 50 largest private utili-ties in the United States and to the presidents of11 major unions representing the largest numberof employees in these companies. Of the 366 (65.2percent) organizations responding, 6 (1.6 percent)were currently using one or more tests, 17 (4.6percent) used-some of the tests in the past 12years, 4 (1.1 percent) anticipated using the testsin the next 5 years, and 55 (15 percent) stated theywould possibly use the tests in the next 5 years.Of the 17 organizations that have tested in thepast 12 years, 5 are currently testing. None of thefour responding unions reported any testing.

For each type of test, companies were askedabout the circumstances under which the testswere done (that is, routinely, for research, or forother reasons) and how employees were selected.Respondents generally tested routinely or for

other unspecified reasons. Testing for sickle celltrait was most often based on ethnicity; for othertypes of tests, employees were selected on thebasis of job category. No organization reportedbasing a genetic test on an employee’s sex.

The 18 respondents who are testing or havetested took various actions based on the results.The most common action reported—by eight or-ganizations —was informing an employee of a po-tential problem. Five organizations transferredemployees. Two companies suggested the employ-ee seek another job, and one changed or discon-tinued a product.

In evaluating the results of the survey, severalcaveats must be considered. The most importantof these are:

Since the questionnaire instructed respond-ents to include any instances of testing, pos -itive responses can include isolated cases aswell as long-term testing programs.The questionnaire was not structured to pro-vide information on the numbers of workerstested.Results of this study are more representativeof the larger companies in this survey thanother groups, since more large companies re-sponded than did small ones.Since approximately one-third of the popula-tion did not respond and the number of orga-nizations testing is very small, any generaliz-ing of these results to the study populationas a whole is not warranted.

The state of the art

This assessment took a two-stage approach toanalyzing the scientific data available on genetictesting. First, the laboratory tests themselves wereevaluated to determine their reliability and validi-ty, Then the available studies were evaluated todetermine if there is a correlation between thegenetic damage or trait in question and an in-creased risk for disease. None of the genetictests evaluated by OTA meets establishedscientific criteria for routine use in an oc-cupational setting. However, there is

10 ● The Role of Genetic Testing in the prevention of Occupational Disease

enough suggestive evidence to merit fur-ther research.

GENETIC MONITORING

The concept of monitoring workplace popula-tions for genetic damage from chemicals or ioniz-ing radiation is well grounded on a theoretical andexperimental base. Ionizing radiation and a widerange of chemicals cause damage to the geneticmaterial in experimental animals and, in somecases, humans. This damage may result in muta-tions, which are changes in the genetic informa-tion. The consequences of increasing the muta-tion rate of a population are not well understood,but mutations have been implicated in several dis-eases, most notably cancer.

There are two major types of genetic monitor-ing methods-the established cytogenetic methodswhich detect major structural changes in chro-mosomes and the newer noncytogenetic methods,which detect damage to the DNA (deoxyribo-nucleic acid). The noncytogenetic methods, forthe most part, are still in experimental stages, buteventually could lead to faster and less expensivemonitoring methods.

The detection of chromosome damage usingcytogenetic techniques is a fairly complex proce-dure. It requires skilled laboratory techniciansand is often labor intensive. But if laboratory var-iables are kept constant, chromosome damage canbe determined reliably.

There are two stages involved in the assessmentof genetic monitoring. The first determineswhether the agent actually causes the geneticdamage in a manner such that increasing dosagesof the agent gives increasing amounts of damage(dose-response). The second stage of the analysisasks whether the observed genetic damage actual-ly will predict an increased risk for disease, Ifgood scientific evidence is available to supportboth stages of the analysis (this is, that the hazard-ous agent causes genetic damage, and that thisdamage predicts an increased risk for disease),then the assumption can be made that the agentcauses disease. OTA found that there are somestudies where a dose-response relationship hasbeen established, but there are few studies show-ing a correlation between genetic damage and anincreased risk for disease.

A large number of studies on workplace popula-tions, using cytogenetic techniques, have beendone, but there are several factors which makethe interpretation of these studies difficult. Invery few cases has the level of exposure of theworkers to the hazard been documented, mak-ing the establishment of a dose-response relation-ship impossible. Also, it is fairly well establishedthat other factors such as age, smoking and drink-ing habits, nutritional status, and the presence ofdisease can cause differences in the level ofchromosomal damage. Because most studies havenot taken these factors into account, there is alarge variability in both exposed and unexposedpopulations. When exposed populations arestudied, rarely is there found more than a twofoldincrease in damage over the average of the unex-posed population. Thus, given the variability ofthe unexposed population, interpretations ofthese studies are difficult. Finally, it is not knownwhether chromosomal changes in blood cells re-flect the presence of chromosomal damage in in-ternal organs.

Studies done on populations exposed to ioniz-ing radiation, including atomic bomb survivorsin Japan, are less equivocal than those for chem-ical exposure, mainly because radiation exposurelevels are more easily documented. The evidencedoes show an increase in chromosomal damagewith increasing dose of radiation. This damage,though, has not been correlated with an increasedrisk for disease with one exception. Extensivestudies on the bomb survivors have shown cleardose-related increases in both chromosomal ab-normalities and various cancers for these popula-tions as a whole. Yet there seems to be no corre-lation between the frequency of chromosomal ab-normalities for a given individual and his or herrisk for cancer.

Currently, genetic monitoring has the potentialfor use as a biological indicator of exposure toworkplace chemicals or ionizing radiation andcould aid in the identification of hazardous agents,The correlation of induced genetic damage withrisk for disease has been shown statistically onlyfor the Japanese population exposed to ionizingradiation from the atomic bombs, For people ex-posed to hazards in the workplace, more infor-mation is needed to elucidate other environmen-

Ch. I—Executive Summary ● 11

tal and genetic factors which may contribute toincreased risk for disease.

GENETIC SCREENING

Differential susceptibility to chemicals has beenpredicted, in part, from differential reactions todrugs, which have been extensively documented.Explicitly defining this genetic differentialsusceptibility is not yet possible given the currentstate of knowledge; however, some data do existon a few genetic traits, implicating them in suscep-tibility differences to certain chemicals. The listprobably represents only a small percentage ofthe genetic traits involved in responses to chem-icals. This report examines the following traits:glucose-6-phosphate dehydrogenase (G-6P-D) defi-ciency, sickle cell trait, alpha and beta thalassemiatrait, NADH dehydrogenase deficiency, serumalpha1-antitrypsin (SAT) deficiency, aryl hydrocar-bon hydroxylase (AHH) inducibility, slow v. fastacetylation, human leukocyte antigens (HLA), car-bon oxidation, diseases of DNA repair, and severalother less well-characterized genetic traits.

OTA found that most tests for identifying thesetraits are accurate and reliable, but only whenapplied to subgroups already suspected of hav-ing the trait at a relatively high prevalence. Be-cause the predictive value of these tests is lowwhen used in the general population, studiesusing these tests could be seriously flawed. In fact,the predictive value of the test, which is basednot only on accuracy but also on the prevalenceof the trait in the population, will only be highwhen the prevalence of the trait is high,

There is some suggestive evidence, from ad-verse drug reactions and illnesses resulting fromexposures to chemicals, that associations may ex-ist between certain traits and risk for disease fromparticular occupational exposures. This report re-viewed occupational studies on several genetictraits and found that the data were not extensiveenough to draw any conclusions on the correla-tion between given genetic traits and risk for dis-ease. On the other hand, the data are suggestiveof these correlations, and research seems indi-cated for attempting to determine these relation-ships.

Genetic testing and the law

Genetic testing raises legal questions related toworkplace safety and employee rights. Althoughthe law generally has not dealt with genetic test-ing, many existing legal principles are directly ap-plicable to the issues raised by this technology.Moreover, employers and unions could negotiatemutually agreeable solutions to the problemsraised by genetic testing. Unions, however, haveno legal duty to bargain over such issues or totake special steps to protect workers who mightbe at increased risk.

The employer has the legal responsibility forworkplace safety. Failure to meet the responsibili-ty can result in costly judgments or civil or crim-inal penalties against the employer. This responsi-bility would not require the employer to use gen-etic testing, even if it were highly predictive offuture illness. If the employer chose to use a high-ly predictive test, it would probably be negligentif it ignored the results and placed employees ina high-risk rather a than low-risk environment.However, recovery of damages by such an em-ployee who developed the predicted illness wouldprobably be barred by the “exclusive remedy”provision of workers’ compensation laws and pos-sibly by the doctrine of assumption of the risk,if the employee had been informed of the risk.If the risk had been concealed from the employee,recovery probably would not be barred underworkers’ compensation laws, and the employerwould face the possibility of punitive damages.

Under the Occupational Safety and Health Actof 1970 (OSH Act), the Secretary of Labor is em-powered to promulgate standards that protect allemployees from toxic substances to the extentthat the standards are directed toward a signifi-cant risk to health and to the extent that they aretechnologically and economically feasible. Thesestandards can, among other things, set maximumexposure levels, require personal protection gear,and require various medical procedures. The fea-sibility requirement may leave some percentageof exposed workers at risk, depending on thecircumstances of the particular hazardoussubstance and industry. Of those workers at risk,


some may be genetically susceptible and othersmay be at increased risk because of geneticdamage. An open question is whether the courtswould allow a standard designed to protect a verysmall number of susceptible individuals or wouldinvalidate it on the grounds that it failed to ad-dress a significant risk because of the smallnumber of workers involved.

The OSH Act and regulations thereunder nei-ther prohibit nor require genetic testing. How-ever, the Secretary of Labor has broad authori-ty to regulate employer medical procedures aslong as the regulation is related to worker healthand meets the feasibility and significant risk re-quirements. Therefore, the Secretary could re-quire genetic testing in its various forms, if thetechniques were shown to be reliable and reason-ably predictive of future illness. The Secretaryalso could regulate the use of genetic testing, butonly to the extent that the regulation was relatedto employee health. The act grants no authorityover rights or conditions of employment per seand no authority to protect applicants for employ-ment from discrimination.

State and Federal laws place few restrictionson how medical exams or testing procedures maybe conducted in the workplace and what the em-ployer does with the resulting information otherthan the requirements that the procedure not benegligently performed and that the employee beinformed of potentially serious health risks. Sub-mission to medical exams, which include varioustests, can be a valid condition of employment. Asa result, employees or applicants would have noright to refuse to participate without jeopardiz-ing their job. Moreover, participation in researchcan be a valid condition of employment. Howmuch the employee needs to be told about theresearch is unclear, except in two cases. If theresearch were federally funded, subjects mustunderstand the risks and other aspects of thestudy and consent to them, A few States requireresearch to be reviewed by special boards inorder to protect the interests of human subjects,and these boards may require informed consent.

With respect to the data generated by genetictesting, there are few requirements regardingconfidentiality except in the State of California.But employees have a right of access to medical

records under Occupational Safety and Health Ad-ministration (OSHA) regulations and unions havea similar right under a recent decision by the Na-tional Labor Relations Board. This access couldhelp prevent abuse of genetic testing. However,those who face the greatest risk of being deniedemployment because of their genetic makeup—job applicants —would not have access to the testresults.

For those applicants or employees who weresubject to some adverse job action because oftheir genetic makeup, Federal and State antidis-crimination statutes may offer some relief.However, they do not deal specifically with ge-netic screening except for a few State statutes thatprohibit employment discrimination on the basisof certain genetic traits, usually sickle cell trait.

Title VII of the Civil Rights Act of 1964 prohibitsdiscrimination in employment based on race, col-or, religion, sex, or national origin, In addition tointentionally discriminatory actions, neutral em-ployment practices that have a disparate impacton a protected group may violate title VII. Sometypes of genetic screening, such as for sickle celltrait, would have a disparate impact; therefore,an adversely affected genetically susceptible em-ployee in one of those classes would have a primafacie case of discrimination. Then, the employerwould have the burden of justifying the screen-ing program by demonstrating its relation to legit-imate job requirements or business needs. It ispresently unclear whether using genetic testingto screen out employees who might become ill inorder to avoid the cost of engineering controlsis a business necessity. Nor is it clear whether theemployee’s capacity to perform the job withouta risk of future illness is a legitimate job require-ment. However, it is clear that any job selectionmethod must be predictive of the characteristicfor which it allegedly selects. Since the ability ofgenetic screening to identify workers at increasedrisk for disease has not been demonstrated, a pro-gram that had a disparate impact on the employ-ment opportunities of the classes protected bytitle VII probably would violate that act.

The Rehabilitation Act of 1973 prohibits em-ployment discrimination against otherwise qual-ified handicapped people by employers who are

Ch. l—Executive Summary ● 1 3

Government contractors or recipients of Federalassistance. Virtually all of the States have similarstatutes, and the State laws usually offer broaderprotection to handicapped people. These statutesoffer a greater potential than title VII for aidingthe employment opportunities of genetically sus-ceptible individuals; however, for those laws tobe applicable, two currently unresolved legalquestions must be settled in favor of the employ-ees. The first is whether or not a particular gen-etic makeup is a handicap. If not, these employeeswould have no rights under these laws. If it is ahandicap, the next question is whether employ-ment may be denied to handicapped individualson the basis of a reasonable probability of futureillness. If the courts were to rule that future riskof illness was not a legitimate area of inquiry foremployers, the Rehabilitation Act and similar stat-utes would prohibit adverse job actions on thebasis of genetic makeup. If risk of illness wererecognized as a legitimate concern, the employerwouId have the burden of showing the geneticscreening techniques were reasonably predictiveof illness. Even if the employer demonstrated this,however, it might have to accommodate the “ge-netically handicapped” employee anyway. Butsuch accommodation probably would not requirethe installation of expensive engineering controlsto lower exposure. *

Ethics of genetic testing

Because genetic testing is relatively new and hasnot been widely used, there is little direct exper-ience on which to make judgments regarding itsuse, Nor are there direct legal precedents. Underthese circumstances, it is appropriate for policy-makers and others involved in decisions concern-ing this technology to look to ethical principlesfor guidance.

Ethics may be defined as the study of moralprinciples governing human action. These prin-ciples, or general prescriptive judgments, createmoral duties that guide action in particular cir-cumstances. Sometimes, however, the principlesconflict in their application and provide no clearguidance. Then, difficult choices must be made.

“()’1’.1 is conducting a study on the use of engineering controlsto enhanre worker safety and health.

Such is the case with genetic testing in the work-place.

Genetic screening and monitoring are not in-herently unethical. The tests are morally justifiedto the extent they enhance worker health in amanner consistent with established ethical princi-ples. Whether or not they are consistent withthese principles will depend on how the tests aredone and how the information is used.

Ethical principles regarding the duties of com-pany medical personnel toward workers are oftenconflicting or not well established. Therefore,they offer little specific guidance about the man-ner in which tests should be conducted with theexception of procedures done for purposes ofmedical research. In cases of research on humans,ethical principles are well established and providefor the rigorous protection of individual rightsand interests.

Ethical principles constrain how the results ofgenetic testing may be used. In the absence of asignificant correlation between genetic endpoints(traits or evidence of damage from exposure) anddisease, it would be unethical for the employerto act adversely to the employee’s interests, suchas by denying him or her a job.

In the hypothetical case of a strong correlationbetween genetic endpoints and disease, the moral-ly correct course of action is significantly lessclear. For screening, the employer might justifyexcluding susceptible workers from certain jobson the grounds of benefiting the employees. onthe other hand, employees might claim that theyhave the right to decide whether to assume therisk. Whether or not genetically susceptible peo-ple are entitled to protection from discriminationor compensation for harm depends on which ofseveral theories of justice is chosen. For monitor-ing, the most ethically feasible course of actionfor an employer would be to inform the workersof adverse findings and to reduce worker expo-sure, Failure to do so would be inflicting harm,and it is unlikely that the group would consentto assuming this risk.

Economic evaluation of genetic testing

Genetic testing in the workplace has potentialbenefits and costs to workers, employers, and so-

14 . The Role of Genetic Testing in the Prevention of occupational Disease

ciety as a whole. The magnitude and distributionamong the sectors of society of these benefits andcosts will help determine the desirability of thisapproach to improving occupational health. Twotechniques of economic evaluation-cost-benefitand cost-effectiveness analysis—are methods forcollecting, organizing, and presenting evidenceabout the benefits and costs of alternative coursesof action so that choices can be better informed.They are systematic approaches to examining thetradeoffs among the different kinds of conse-quences–for example, dollar outlays today v. im-proved levels of health 5 years hence—stemmingfrom a decision.

The usefulness of economic evaluation rests onits ability to improve decisions. Even when eco-nomic analysis is severely limited by uncertain-ties about the magnitude, direction, or value ofcertain consequences, as with genetic testing, it

can still be a useful exercise. The identificationof key areas of uncertainty, for example, can beused to set priorities for further research, Thus,economic evaluation can be used to dissect andexamine alternative strategies in order to under-stand their underlying assumptions and uncer-tainties.

In the case of genetic testing, rigorous economicanalysis of the costs and benefits is not possiblebecause of the lack of knowledge about the asso-ciation between test results and risk of disease,the numbers of people to whom testing could beapplied, and the amount of occupational diseasethat could be prevented, If additional informationbecame available, economic analysis could pro-vide a rough sense of the benefits, burdens, andtradeoffs associated with genetic testing pro-grams.

Congressional issues and policy options

ISSUE: What actions could Congress takewith respect to genetic testing inthe workplace?

OPTIONS:

A. Maintain the status quo,

Congress could choose not to take any actionto stimulate, constrain, or regulate genetic testing.This would allow private parties to continue re-search into the merits of the technology. Con-straints on its use would develop through courtrulings in lawsuits between these parties or bynegotiations between companies and unions. In-terested congressional committees could continuetheir practice of holding oversight hearings toraise the issues for public discussion.

The primary argument supporting this optionwould be the view that congressional actionwould be premature. The technology is not be-ing widely used, and it is primarily in the researchphase of its development. In addition, there areexisting constraints on its potential misuse. Theseinclude the possibility of lawsuits and adversepublicity. Finally, much of the important informa-

tion necessary for legislation is unavailable be-cause it is unknown. For genetic screening tech-niques, this information includes the number ofworkers who might be genetically predisposedto disease, the extent to which they might faceadverse employment actions, the availability ofother employment opportunities, and the cost ofsafeguarding these workers. For genetic monitor-ing techniques, this information includes theirpredictive value, the extent to which they mightbe used, and the costs associated with either usingor not using them.

The arguments against this option relate to howsociety controls an emerging technology. Manypolicy decisions will need to be made with respectto genetic testing, and arguably Congress is a bet-ter forum for doing so than the courts or privateparties. Congress can gather all information andviewpoints and then balance the conflicting in-terests. In addition, while the courts often playa major regulatory role for any technology, theyare limited in their ability to encourage the de-velopment of a technology in a positive manner.However, Congress can do so by providing fundsfor research or other incentives.

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Ch. I—Executive Summary 1 5

B. Stimulate the technology’s development anduse.

Congress could stimulate the technology by pro-viding money for research on the techniques, forepidemiological studies to determine associationsbetween genetic endpoints and disease, and forbasic research on the cause of occupational dis-ease in general, If genetic testing could be devel-oped to the point where the tests are predictiveof an individual’s or group’s increased risk of oc-cupational illness, their use could result in a num-ber of direct and indirect benefits. The principaldirect benefit would be a lower incidence of oc-cupational disease among workers. They andtheir families would be spared some of the pain,cost, and emotional trauma that accompany ill-ness. In addition, employers would save some oftheir direct and indirect costs of occupational dis-ease-employee time lost from work, insurancepremiums, legal fees, and monetary damages as-sessed in lawsuits. Society would benefit throughthe greater health and productivity of its workforce. A major indirect benefit of developing thistechnology might be a greater understanding ofthe causes of occupational disease and disease ingeneral.

The principal argument against this option isthe concern about the potential misuse of thetechnology and about potential adverse impacts.Some of these concerns relate to unfair employ-ment discrimination and attention being directedaway from other ways to address occupationaldiseases. These concerns might be dispelled byregulation to direct the technology’s developmentin socially desirable ways. In fact, if the tests werehighly predictive of future illness, OSHA could re-quire their use and constrain how they wereused, so long as those constraints were shownto enhance worker health and were not directedmerely toward prohibiting unfair employmentpractices.

Another drawback to this option is the fact thatthere is no definitive information on the amountof occupational disease that could be preventedby genetic testing, even if the tests were reliablepredictors of disease. Similarly, there is no infor-mation on what it would cost to develop the teststo the point of clinical usefulness.

C. Prohibit the use of genetic testing in theworkplace.

The principal reason for prohibiting genetictesting in the workplace would be concern overits potential misuse, particularly at its currentstage of development where its ability to predictfuture disease has not been demonstrated. Thispotential for misuse probably would be greaterfor genetic screening than genetic monitoring be-cause the former is targeted toward identifyingindividuals at increased risk while the latterfocuses on groups at increased risk. However,concern exists that employers might use eithertype of test to exclude individuals from jobs. Ex-isting law may offer protection in some circum-stances, but there are many questions to be re-solved. The collective bargaining process couldbe used by unions to negotiate protection forworkers, but the primary focus of bargaining hasbeen economic matters. While health mattershave also been important, little, if any, negotiatinghas occurred with respect to genetic screening.In addition, most of the work force is not union-ized. Moreover, these remedies are not helpfulif a susceptible person does not know why he orshe was denied a job. Finally, while ethical prin-ciples provide guidance for the proper use of thistechnology, it is difficult to know if they are beingfollowed.

The principal drawback to this option is thatit is a drastic solution to the problem of potentialmisuse. Genetic testing does not appear to bewidely used. Law, ethics, and public opinion pro-vide incentives against its misuse. Moreover, ban-ning its use would prevent research that mightdetermine its usefulness in preventing occupa-tional disease or provide basic knowledge aboutoccupational disease.

Another argument in favor of this option wouldbe the claim that an employee’s risk of future ill-ness is not an appropriate factor for job selection,even if screening or monitoring were highly pre-dictive, Employees have no control over their ge-netic makeup and generally have no control overprevious exposures to harmful agents, In addi-tion, their increased risk would not affect theircurrent ability to do the job.


There are at least two counterarguments to theassertion that risk of illness should not be a jobselection factor. First, society accepts the proposi-tion that immutable characteristics can be prop-er criteria for employment selection. Intelligenceis at least an implicit selection criterion for manyprofessional jobs and physical attributes are ex-ceedingly important for jobs ranging from pro-fessional basketball to neurosurgery. Second, thisviewpoint places the autonomy interests of theindividual above the interests of society in lower-ing the costs of occupational illness even whenit may not be feasible to take other steps, suchas lowering exposure,

D. Regulate the technology.

This option represents a judgment that anyrisks presented by the technology can be con-trolled and that the claimed benefits will be ofvalue to society. The option would permit re-search to continue, yet constrain the manner inwhich genetic testing is used, One type of con-straint would be limitations on what job actionsemployers could take on the basis of test results.Another type of constraint would be a require-ment that the tests meet minimum standards ofscientific validity before employment decisionswere made on the basis of the results. Such a stat-ute need not specify detailed standards; it couldadopt a standard such as “reasonably predictiveof future illness” and allow the appropriate agen-cy to provide details.

This option has the advantage of addressing thepotential risks of genetic testing immediately andin a comprehensive manner rather than waitingfor the law to develop on a case-by-case basisthrough the courts. Congress may be uniquelyable to study the problem fully, balance compet-ing interests, and provide comprehensive yet tar-geted solutions.

A possible drawback of this option is that theproblem may not yet be “ripe” for congressionalaction. On the basis of available evidence, genetictesting in the workplace does not appear to bewidespread. Moreover, there is no available evi-dence about: 1) the number of workers who po-tentially could be screened or monitored if thetests were sufficiently predictive, 2) the numberwho might be excluded from jobs, 3) the ease with

which excluded workers could find comparablejobs, and 4) the costs of various regulatoryalternatives.

E. Encourage the development of voluntaryguidelines on the acceptable use of genetictesting.

Congress could request the National Academyof Sciences or a similar body to establish a specialcommission of representatives from industry,labor, academia, and other sectors of society todraft voluntary guidelines for the use of the tests,This would allow the parties most involved tomake the difficult value judgments in balancingcompeting interests and would avoid direct gov-ernmental regulation.

ISSUE: How could Congress regulate ge-netic testing in the workplace?

OPTIONS:

A, Constrain employment actions that may betaken on the basis of genetic testing.

Congress could address many of the concernsraised by genetic testing by regulating how em-ployers may use the results of the tests, even ifthey were highly predictive. The following repre-sent some possible elements of such an approach:1) prohibit job exclusion on the basis of geneticmakeup or genetic damage, 2) prohibit job trans-fers because of genetic makeup or genetic damageunless the transfer were to a comparable job atcomparable pay and benefits, 3) require strict con-fidentiality of medical information, and 4) requirethat employees be told the results of testing andbe given counseling.

This option clearly would protect the interestsof workers, preventing potentially serious con-sequences to individuals who have no controlover the reason for the discrimination. In addi-tion, no difficult judgment would have to be madeas to how predictive the tests should be beforethey are permitted.

There are at least two major disadvantages tothis option. First, it may be too broad, If not care-fully drafted, a statute could reach genetic dis-eases (not traits) that do affect an employee’s cur-rent ability to perform the job safely and effective-

Ch. I—Executive Summary 17

ly. It is generally accepted that inability to per-form a job, even for medical reasons, is a validcriterion for job selection. Second, if workers withcertain traits were in fact predisposed to occupa-tional illnesses and chose to ignore that informa-tion, the additional direct and indirect costs oftheir illnesses eventually would be borne by socie-ty. This would be the case even if employers wererequired to install additional engineering controls,since the costs of those controls would be passedon to society. On the other hand, if excludedworkers were unable to find comparable jobs, so-ciety would bear the costs of lost productivity andpossibly additional unemployment payments. Theanswer to the question of who should bear thecosts associated with genetically predisposed ordamaged individuals will depend not only on eco-nomic analyses but on prevailing political viewsof distributive justice.

B. Prohibit employment decisions on the basis ofgenetic testing unless the employer can demon-strate that the results are reasonably (or sub-stantially) predictive of future illnesses.

This option places the burden on an employerto justify the claimed correlation between testresults and risk of illness. The specific criteria formeeting a necessarily general statutory standardcould be provided by agency regulation and caselaw.

There are several advantages to this option, es-pecially when compared to option A. First, it fo-cuses on the immediate concern of job denial onthe basis of poorly predictive tests, thus protect-ing employees’ interests. Second, it protects em-ployers’ interests in lowering their costs fromoccupational diseases by allowing the exclusionof certain workers when there is a rational, scien-tific basis for doing so. Third, it would allow re-search on the techniques to continue.

The principal drawback of this option is thatit could be a de facto determination without a fullpublic debate that future risk of illness is a prop-er job selection criterion. On the other hand, thereis a substantial lack of the type of information de-sirable for deciding this fundamental issue at thistime.

C. Amend the Rehabilitation Act of 1973 to statethat genetic makeup is a handicap and clarify

whether individuals who are genetically pre-disposed to illness are considered to be “other-wise qualified” within the meaning of that act.

A major advantage of this option would beworking with an existing statute rather than de-vising an entirely new one. Sections 503 and 504of the Rehabilitation Act deal with problems thatconceptually are very similar to those posed bygenetic screening. If applied to genetic screening,the act would require at a minimum that the testsbe reasonably predictive of future illness.

On the other hand, this option would force leg-islative activity into an existing statutory frame-work that may not be completely suited to geneticscreening. The Rehabilitation Act was designedto bring millions of handicapped people into themainstream of American life. Genetic screeninghas not created a problem anywhere near themagnitude of that addressed by the Rehabilita-tion Act. Moreover, section 503 requires employ-ers to take affirmative action to employ the hand-icapped. Congress may not wish to require affirm-ative action to employ people who are genetical-ly predisposed to occupational illness, if that pre-disposition can, in fact, be demonstrated.

D. Require that research on employees be doneaccording to existing Federal regulations de-signed to protect human subjects of research.

The Department of Health and Human Serviceshas promulgated regulations governing federal-ly funded biomedical and behavioral research onhumans. The regulations contain a number ofprovisions designed to protect the interests of theresearch subjects. Requiring private companiesto follow these regulations in research involvinggenetic testing or any other kind of research donein the workplace would mitigate the potential forabuse.

E. Require full disclosure to employees and theirrepresentatives of the nature and purpose ofall medical procedures performed on employ-ees.

Under current law, employees and unions haveaccess to employee medical records, but em-ployers are not required to disclose the natureand purpose of medical procedures and how theresults are used. Required disclosure of this in-


formation to the employee at the time the proce-dure was being performed would be a strong in-centive to employers for self-regulation. If work-ers and their medical advisors had full knowledgeof a company’s medical procedures, they couldtake steps to prevent abuses, through negotiationor legal action. Publicity alone could prevent theworst abuses. This would also protect the auton-omy interests of workers by allowing them to bepart of a decisionmaking process that affects theirhealth and economic interests. Some of the ar-guments against this option would be that it mightbe burdensome and costly for employers and thatit would intrude too much on the professionaljudgment of the occupational medical specialist.

ISSUE: How could Congress foster the de-velopment and use of this technol-ogy?

OPTIONS:

A. Fund research for the development of testswith high reliability and validity.

Genetic variability and differential susceptibilityto toxic chemicals are well-established conceptsin the scientific literature. Currently there aremany genetic screening tests which could be donein a workplace setting to detect potentially suscep-tible individuals. For the most part, these tests areaccurate, reliable, and valid for identifying thegenetic traits in question when applied to sub-groups already suspected of having the trait ata relatively high prevalence; a notable exceptionis the test for aryl hydrocarbon hydroxylase(AHH) inducibility. Research on developing testsfor those traits which are more prevalent in thepopulation should receive higher priority becausethey are more likely to have a high predictive val-ue. The only test covered in this report which fallsinto this category is AHH inducibility.

With respect to genetic monitoring, the notionthat exposure to toxic chemicals and ionizingradiation can cause genetic damage in humansis less well established scientifically than the con-cept of differential susceptibility. However, thereis an overwhelming amount of evidence that thisis true in experimental mammals. Moreover, theimpact of genetic damage on one’s risk for disease,

especially cancer, or on future generations is notknown, yet the current thinking of the scientificcommunity is that increased amounts of geneticdamage is generally deleterious.

Alternatives are needed to the time-consumingcytogenetic tests currently in use. If geneticmonitoring is to be done on a large scale, the avail-ability of automated tests becomes important. Thedevelopment of various noncytogenetic methodscould be useful in this respect. Those that showpromise currently include tests for detection of:mutagens in urine, alkylated hemoglobin, HGPRTmutation in lymphocytes, hemoglobin mutations,chemically damaged DNA bases, and LDH-X var-iants in sperm. For both cytogenetic and noncyto-genetic tests, a better understanding of the fac-tors that contribute to genetic damage in the ab-sence of occupational exposure is needed (that is,a “normal” or baseline response) in order for thetests on exposed populations to be meaningful.

The government agencies which could be in-volved in these studies include the Environmen-tal Protection Agency (EPA), the National Institutefor Occupational Safety and Health (NIOSH), andthe National Institute for Environmental Healthand Safety (NIEHS).

B. Fund epidemiologic studies in occupational set-tings directed by NIOSH or NIEHS.

Data are most lacking concerning the correla-tion of genetic traits or genetic damage to an in-creased risk for disease. Epidemiologic studies inan occupational setting can address this problem.If these studies were to be undertaken, they mustuse good epidemiological practices and documentexposures. Studies should only be undertaken ifthey are likely to yield statistically reliable data.For instance, genetic monitoring studies wouldrequire exposure levels high enough to yield aclear-cut statistical response between exposed andnonexposed groups without having to use exces-sively large numbers of people. Especially impor-tant would be to establish a dose-response rela-tionship. Genetic screening studies would haveto focus on genetic traits which have a significantprevalence in the population (greater than 1 per-cent).

Ch. l—Executive Summary 19

Epidemiologic studies are very costly and diffi-cult to control, especially if they run over longtime periods. Some genetic screening studiescould be done in a short time (1 to 3 years) oncea population with the trait was selected because,presumably, the symptoms of disease resultingfrom exposure would manifest themselves soonafter exposure. These traits include the red bloodcell traits. Most of the other traits reviewed hereare potentially correlated with diseases whichhave a long latent period, such as emphysema andcancer. To correctly assess the exposure infor-mation with the disease endpoint, much longerepidemiologic studies (10 to 30 years) are neces-sary.

For genetic screening, higher priority shouldbe given to studies on traits which have a highprevalence in the population. These include SATdeficiency, AHH inducibility, carbon oxidationability, and the association of particular humanleukocyte antigens with risk for disease.

Epidemiologic studies using genetic monitoringtechniques would have to be long term in orderto determine the association between geneticdamage and cancer. The chemicals chosen forstudy would have to be selected carefully. Manyof the agents discussed in this report are known

already to cause cancer in humans (for example,ionizing radiation, benzene, vinyl chloride), andoccupational exposure to these is very low andpossibly not detectable by the genetic techniquesnow in use.

C. Establish a federal!y funded data bank, directed

by NIOHS, EPA, or NIEHS, to be used in thestud&v of the causes of differential susceptibili-ty to occupational disease.

Because the study of the effects of harmfulagents includes many scientific disciplines, itwould be useful to have the relevant data col-lected in an accessible location. This computerizeddata bank could include not only genetic factorsaffecting toxicity, but developmental, aging, nutri-tional, and lifestyle factors as well. The data bankwould include epidemiologic studies that havebeen or are being done in occupational settings,either governmentally or privately funded (some-what in the same manner as EPA’s Gene-Tox Pro-gram). Those working in the field of genetic tox-icology could draw on the information in the bankin order to design studies and to prevent duplica-tion of effort. The toxicology data would be ofconsiderable value to various regulatory agenciesin their standard setting.

Chapter 2

Introduction: OccupationalIllness and Genetic Testing

Contents

The Problem of Occupational Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Health Hazards in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hazardous Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Ionizing Radiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Control of Occupational Health Hazards.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Theoretical Foundations: Biological Diversity and Differential Susceptibility . . . . . . . . .Detection of Individuals or Groups at Increased Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Potential Benefits and Risks of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Organization and Scope of Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure

Figure No.l.Components of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2324242525272727292930

Page28

chapter 2

Introduction: OccupationalIllness and Genetic Testing

The problem of occupational illness

Occupational illness is a major problem in thiscountry. In a 1981 private sector work force ofapproximately 75.6 million people, there were anestimated 126,000 cases of work-related acute ill-ness, which resulted in more than 850,000 lostworkdays, according to the Bureau of Labor Sta-tistics (2). * Moreover, an estimated 5 percent ofall cancers are believed to be associated with ex-posure to harmful substances in the workplace(17). * * Litigation over illness claimed to haveresulted from one substance alone—asbestos—could result in insurance payments as high as $38billion over the next 35 years, and one majormanufacturer of asbestos, faced with more than16,500 lawsuits, has filed for reorganization underthe Bankruptcy Act (21,22).

The health risks posed by the workplace envi-ronment vary with the industry and the type ofjob but are often associated with exposures toharmful substances or agents. These substancesor agents include minerals, chemicals, and ioniz-ing radiation. This report focuses on an emerg-ing technology, genetic testing, that may be usefulin reducing occupational illness arising from suchexposure, especially to chemicals and ionizingradiation.

*The accorac~ of these figures is subject to much debate amongthe experts ‘1’he ~ureau of I,abor Statistics itself acknowledges thatthe figurm understate the amount of occupational illness becausethey do not adequately rcfle(t chronic diseases and diseases withlong latenr} peri[xis because of problems with detection and recogni-tion (2) ‘1’hry are US(YI hwe simply to prolide the reader with agwreral notion of the magnitude of the problem.

● “F:stimating the amount of cancer associated with occupationalexposures is extremely difficult, and experts often disagree. In thepast, estimtites haie ranged from S to 38 percent In 1981, OTAsuggested that almost all estimates of work-related cancer fit intoa range of 10 ( ~ 5) percent of all cancer (141. Data presented atan international conference on quantification of occupational cancersuggest that the (ITA rstirnate ma}’ ha~e been too high (17). Fivepercent now appears to be the fig;lre acceptable to most experts,although some experts still argue for estimates greater than 20 percfmt I 17,19).

Genetic testing, as used in the workplace, en-compasses two types of techniques. Geneticscreening involves examining individuals for cer-tain inherited genetic traits (9). Genetic monitor-ing involves examining individuals periodically forenvironmentally induced changes in their geneticmaterial. The assumption underlying both typesof procedures is that the traits or changes maypredispose individuals to illness. Although thistechnology is still in its infancy, genetic testingpotentially could play an important role in the pre-vention of occupational diseases. It is technologi-cally and economically impossible to attain a no-risk workplace by lowering the level of exposureto hazardous substances to zero. However, if in-dividuals or groups predisposed to occupationaldiseases could be identified, other preventivemeasures could be specifically directed at thosepersons. This is the promise of genetic testing.At the same time, however, the technology haspotential drawbacks and problems. For example,it could result in workers being unfairly excludedfrom jobs or in attention being directed awayfrom efforts to “clean up” the workplace.

Because genetic testing is still in its infancy,many of its potential impacts—both positive andnegative—at present cannot be precisely defined.Nonetheless, it is not too soon for society to beginto consider how genetic testing may affect us. Inindustry, genetic testing has been little used todate, but an Office of Technology Assessment(OTA) survey has found several companies inter-ested in using it in the future. Thus, this report,requested by the Committee on Science and Tech-nology of the U.S. House of Representatives as anassessment of genetic testing, can provide a foun-dation for future debate as this technology con-tinues to develop.

23


Health hazards in the workplace

Of the many different kinds of hazardous sub-stances or physical agents in the workplace,chemicals and ionizing radiation are the twocategories of hazards for which genetic testinghas been used and for which some data exist forevaluating the scientific validity of that testing.

Hazardous chemicals

Many, but not all, chemicals are hazardous.Chemicals may be irritating, toxic, mutagenic,teratogenic, and/or carcinogenic. They may enterthe body through the skin, the lungs, and the gas-trointestinal tract. Contact with skin can produceirritation and dermatitis. Breathing chemicals cancause irritation or damage to the upper respira-tory tract and the lungs. Contact with some chem-icals through virtually any route may cause can-cer.* Exposure to more than one chemical mayresult in a synergistic effect--diamage greater thanthe combined damage of the individual exposures.The degree of risk posed by a hazardous sub-stance depends on the degree to which a personis exposed to it, and risks can be reduced byreducing exposures,

There are more than 55)000 different chemicalsin commerce (14). The percentage of these thatare hazardous at current exposure levels is un-known. Chemicals are found not only in compan-ies that produce them but throughout the man-ufacturing sector. The National OccupationalHazard Survey (NOHS), conducted by the NationalInstitute of Occupational Safety and Health,estimated that approximately 8.5 million workerswere exposed to chemical hazards in the manu-facturing sector during the years 1972 to 1974(11). Because the manufacturing labor force grewat a 0.7 percent annual rate during the years 1973to 1979, the number of exposed workers in man-ufacturing in 1980 may have totaled 8.9 million(11). According to the Occupational Safety andHealth Administration, exposure to chemicals isthe most important occupational health problembecause of the number of workers involved (13).

● The National Institute of Occupational Safety and Health has pub-lished a list of approximately 2,400 suspected carcinogens (14).

Photo credit: Occupational Safety and Health Administration

Exposure to chemicals in work-related environments overlong periods of time can be hazardous to health

For the individual, the hazard of working withchemicals is compounded by the likelihood ofmultiple exposures. A worker may be exposed tonumerous chemicals at any one time or over along period of employment. Rubber workers, forexample, are exposed to an estimated 3)000 chem-icals (18). The NOHS data indicate that more than280 million chemical exposures* occurred in themanufacturing sector during 1972 to 1974 (18).By 1980, based on growth projections in the num-ber of workers and in the number of chemicals, * *chemical exposures among workers in manufac-turing were estimated to be 361 million. * * *

● NOHS defined “exposure” as “employees’ iidud or potential, director indirect, contact with any chemical and biological agent, or physi-cal and safety condition” (1 1).

* *Data indicate that new chemical substances are generated atthe rate of about 8 percent annually and 5 percent of existingchemicals are discontinued, resulting in an assumed annual growthrate of 3 percent (3,12).

● * ● 47 Fed, Reg. 12092, 12108 (1982).

.

Ch. 2—introduction: Occupational illness ● 2 5

Photo credit’ Occupational Safety and Health Administration

Special clothing protects worker’s skin and respiratorytract from exposure to toxic chemicals

Ionizing radiation

Ionizing radiation is energy in the form ofwaves or particles that produces certain chargedparticles known as ions in passing through mat-ter. It may harm exposed individuals or their un-born children. For the exposed individual, theprincipal risk is that he or she may developcancer. Radiation-induced cancers include leuke-mia and most of the commonly occurring solidcancers. Other possible adverse effects of ioniz-ing radiation include eye cataracts, nonmalignantskin damage, blood disorders, and impaired fer-tility. Unborn children can be harmed in twoways. The first is through radiation-induced ad-verse changes in the genetic material from theirparents, which can be passed on to future genera-tions. The second is by direct in utero exposureswhich can result in birth defects, growth retar-dation, or cancer (4).

Occupational exposures to ionizing radiation oc-cur in many fields. In the health professions, forexample, exposures result from the use of medicaland dental X-rays and radiopharmaceuticals. Inindustry, exposures result from the use of X-raysand gamma rays for flaw detection and other test-ing of materials. In the production and use of nu-clear energy, exposures occur for miners, fuelprocessors, material handlers, and others. Radiumworkers and research laboratory workers oftenare exposed to ionizing radiation.

Estimates vary on the number of workers po-tentially exposed to ionizing radiation. The En-vironmental Protection Agency estimated that 1.1million workers were potentially exposed in 1975(4). * The Committee on the Biological Effects ofIonizing Radiation estimated that approximately7 50 )000 workers each year were potentially ex-posed, based on exposure data for differentgroups in different years between 1969 and 1977(8),

Control of occupational health hazards

To prevent occupational disease, health hazardsmust be recognized, evaluated, and controlled.

● workem exws~ in mining operations were not included in theseestimates; there is little information on exposure of such workerswith the exception of underground uranium miners.


Environmental and biological monitoring, engi-neering controls, personal protective measures,and modified work practices are the techniquesused to accomplish this goal (1). Genetic testingis just one of many techniques that fall into thesegeneral categories, It could complement but prob-ably not replace any of the existing techniques.

Recognition and evaluation of hazardous sub-stances or agents involves identification of poten-tial hazards in the workplace and determinationof the degree of exposure. The two major com-plementary ways to do this are through environ-mental and biological monitoring (1), Environmen-tal monitoring uses various sampling instrumentsor personal monitoring devices to identify haz-ardous substances in the environment and todetermine their concentration (l). Biologicalmonitoring uses biochemical and other tests onbody fluids, tissues, expired air, or human wastesto estimate the amount of a hazardous substanceactually absorbed by a particular worker as wellas its health effects (7). Some genetic testingtechniques are a type of biological monitoring,

Control of hazardous substances and their ef-fects may be accomplished by engineering tech-niques designed to lower or eliminate exposureor by measures designed to protect individualworkers (I). Engineering controls include the sub-stitution of a less harmful material for a hazard-ous one, the alteration of a process to lower the

Photo credit: Occupational Safety and Health Admlnistration

Environmental monitoring

degree of exposure, the isolation or enclosure ofa process to lower the degree of exposure, theuse of exhaust systems, and ventilation with cleanair (l). Measures targeted to individuals includepersonal protection devices such as respiratorsor special clothing and workplace practices suchas job placement in a suitable environment, jobrotation to minimize exposure, and job denial (1).

The use of personal protective measures re-quires the identification of individuals or groupswho can benefit from them. Such identificationis the goal of medical surveillance, a preventiveactivity using preemployment or periodic medicalexaminations both to identify individuals orgroups that may be predisposed to some occupa-tional illnesses and to monitor the health experi-ence of workers exposed to presumably safe lev-els of potentially hazardous substances (7).Genetic testing has potential for use in medicalsurveillance.

Photo credit.’ Occupational Safety and Health Adminlstration

Personal protection mask is utilized to safeguard workersin many occupations where hazardous

substances are present

Ch. Z—Introduction: Occupational Illness and Genetic Testing ● 2 7

Genetic testing

Theoretical foundations: biologicaldiversity and differentialsusceptibility

Genetically determined individuality is a fact oflife. People differ not only in such obviousphysical characteristics as height, facial features,and skin color, but also in ways that can only bedetermined in a laboratory, such as blood typeand types of proteins found in blood plasma. Var-iations in some characteristics or traits result fromthe interaction of many genes; variations amongother traits result from variations in a single genethat controls that trait. On the basis of a meretwo dozen traits that have been extensively stud-ied, some scientists have calculated that the prob-ability of any two people (except identical twins)being exactly alike is roughly 1 in 4 billion (15). *

Genetic variability is also a factor in the dif-ferent reactions of people to environmental fac-tors, including disease-causing agents such as bac-teria, viruses, and chemicals. There is evidencethat some people are at a higher risk than othersof contracting diseases-cancer and heart disease,for example—not only because of environmentalfactors such as diet or smoking, but because oftheir genetic makeup (5,6). In fact, there are a fewcases where a person’s genetic makeup has beenproven to predispose him or her to certain ill-nesses in the presence of some environmental fac-tor. One situation involves a deficiency in the en-zyme glucose-6-phosphate dehydrogenase (G-6-PD).The production of this enzyme is controlled bya single gene; some people have a variant formof that gene that results in a deficiency in the en-zyme. The deficiency generally causes them noharm. However, if they take certain antimalarialdrugs or eat a type of bean known as the favabean, they may suffer from acute anemia (16).Thus, G-6-PD deficient individuals are at a higherrisk of illness than other people when exposedto those environmental stresses.

‘Another approach to the question of human variability is to lookat the number of nucleotides in the human ,genome, which is aboutlog . on this basis, the chances of two people being exactly alikeis 1 in 1 ()’~ (109 X 1()’).

Many factors besides genetic makeup can causean individual to be predisposed to illness triggeredby environmental factors. Among these are age,sex, nutritional status, lifestyle, and prior ex-posure to the environmental factors.

Prior exposure is particularly important for thepurposes of this report. If the environmental fac-tor is a chemical, it may be in the body at levelswhere only slight additional amounts could causeillness. In fact, the prior exposure may alreadyhave begun the disease process even though thedisease itself may not appear for many years.

These considerations lead to the concept in oc-cupational medicine of unequal risk. Individualsor groups that may be predisposed to illness havebeen called, among other terms, “hypersuscepti-ble,” ‘(high -risk,” and “sensitive.” These terms oftenhave been used interchangeably but also havebeen defined by different experts in differentways.

This report uses the terms “increased risk, ” “ge-netically predisposed)” and “susceptible. ” Whenapplied to individuals or groups, the terms “in-creased risk” or “susceptible” refer to a higherprobability than average of developing a condi-tion, illness, or other abnormal status. In the con-text of genetic testing, this increased risk mayresult from either inherited genetic traits or pre-vious exposure to environmental insult. The term‘(genetically predisposed” refers to the situationwhere one or more of an individual’s inheritedgenetic traits may cause him or her to be at anincreased risk of illness when exposed to someenvironmental stresses.

Detection of individuals or groupsat increased risk

Genetic testing, as used in this report, appliesto several techniques used to examine workersfor particular inherited genetic traits or environ-mentally induced changes in their genetic materialon the assumption that the traits or changes maypredispose them to illness. It has been used bysome manufacturing companies and utilities inboth medical practice and research. There are


two inherently different kinds of testing, geneticmonitoring and genetic screening (fig, 1).

Genetic monitoring is done to assess whetheror not genetic damage has occurred in certaincells of an individual as a result of exposure tohazardous chemicals or ionizing radiation. Moni-toring can also be done over a period of time tolook for responses to variations in exposure. Thus,it can be used to measure genetic changes in cer-tain cells from before exposure through variouslevels of exposure. Monitoring can be done in oneof two ways. Cytogenetic techniques look fordamage to the gross structure of chromosomes,the cellular structures that contain the geneticmaterial, deoxyribonucleic acid (DNA). Noncyto-genetic techniques look for damage to the actualmolecular structure of DNA. For the most part,these latter techniques are still in a developmen-tal stage.

Genetic monitoring involves examining bloodand other body fluids for evidence of geneticdamage to cells from chemicals or ionizing radia-tion. This damage may indicate exposure to a haz-ardous agent and the possibility that the groupso exposed will be at an increased risk of develop-ing diseases, particularly cancer. Thus, this pro-cedure has potential as an early warning system,by indicating that exposures to known or sus-pected carcinogens are too high or that a previ-ously unsuspected chemical should be viewed asa potential carcinogen.

SOURCE: Office of Technology Assessment

In contrast, genetic screening is a one-time test-ing process to determine the presence of parti-cular genetic traits, regardless of whether the per-son has been exposed to a hazardous substance(9). Some genetic traits appear to predispose anindividual to adverse health effects in the pres-ence of a particular chemical. while normally notharmful, the traits may make the individual sus-ceptible to hemolytic chemicals, pulmonary irri-tants, oxygen deprivation, or other physical orchemical stresses in the workplace. For example,two scientists proposed in 1963 that workers inthe chemical industry be tested for G-6-PD defi-ciency on the grounds that 37 chemicals or fam-ilies of chemicals may cause such employees todevelop anemia (20). Most screening tests requirethat blood be drawn for laboratory tests.

In sum, screening is used to determine indivi-dual susceptibility, whereas monitoring may beable to assess a chemical’s effect on an exposedpopulation in order to determine if that popula-tion is at increased risk. Because of this distinc-tion, one use of screening could be to excludegenetically susceptible individuals from jobswhere they would be exposed to hazardous sub-stances, whereas monitoring would most likelyindicate a need to lower exposure levels for agroup identified to be at increased risk.

Genetic monitoring must be subjected to twoprincipal technical questions: Are the techniquesused to assess genetic damage reliable and valid?Is there an association between positive test re-sults and an increased risk of disease? Similarly,the reliability and validity of screening tests areimportant technical questions, but the key ques-tion here is whether or not there is an associa-tion between the genetically determined trait andany increased susceptibility of that individual toharm from particular chemicals.

When used as described here, screening andmonitoring are forms of medical practice. Theycan also be used in medical research. It is impor-tant to distinguish between medical practice andmedical research because different legal and eth-ical principles can govern each, depending on thesituation. The term “practice” generally refers tomedical interventions that are designed solely toenhance the well-being of an individual and thathave a reasonable expectation of success, The

Ch. 2—introduction: Occupational Illness and Genetic Testing ● 2 9

purpose of medical practice is to provide diagno- in the form of theories, principles, and statementssis, preventive treatment, or therapy to individ- of relationships (10). Medical research is oftenuals. Research, on the other hand, refers to an done to determine the value of new techniquesactivity designed to test a hypothesis so that con- for medical practice. It generally does not enhanceelusions may be drawn. Its purpose is to contrib- the well-being of the individual, and, in fact, mayute to a general body of knowledge, expressed have some risks associated with it.

Potential benefits and risks of genetic testing

Advocates of genetic testing believe it might beable to play an important role in the preventionof occupational disease. By identifying workerswho may be at increased risk of disease becauseof past or potential exposure to hazardous sub-stances, additional preventive measures could betaken by the company or the workers themselves.In addition to the obvious and significant benefitsof preventing serious illness, there could be in-direct benefits, such as a reduction in the costsassociated with occupational disease for employ-ers, employees, and society. These costs includemedical, insurance, and legal expenses; time lostfrom work; and disability or unemployment pay-ments,

The use of this emerging technology, however,raises several questions. Are the techniques suf -

Organization and scope of

This report attempts to assess the potentialrisks, benefits, and effects of genetic testing. PartI discusses the extent of testing on the basis ofa survey of major companies and unions con-ducted by OTA. Part H explains the underlyingscientific principles. Part III assesses the currentstate of the technology and expected future de-velopments. It addresses the question of whetherthe technology in fact could play a role in reduc-ing occupational disease. Part IV analyzes thelegal, ethical, and economic issues raised by thistechnology. It considers whether genetic testingis compatible with law or established ethical prin-ciples and how the costs and benefits of the tech-nology could be assessed. Part V integrates thefindings of the previous parts into a discussion

ficiently developed so as to predict reliably anassociation between either genetic damage or aperson’s genetic makeup and disease? Since manyof the genetic traits sought in screening are founddisproportionately among some races and ethnicgroups, could the use of the tests result in dis-crimination on the basis of race, sex, or nationalorigin? How will the availability of the tests af-fect the employer’s responsibility for maintain-ing a safe workplace? How might these proce-dures affect efforts to reduce the level of hazard-ous substances in the workplace? If the tests areshown to be effective, to what degree should soc-iety protect high-risk individuals or groups, atwhat cost, and who should bear that cost?

report

of issues and policy options for possible congres-sional action.

The report does not consider certain aspectsof genetic testing. Hazards to offspring are notaddressed; the report considers only the risk tothe workers themselves. The report also does notassess many of the claimed risks of the wide-spread use of this technology. Because genetictesting is an emerging technology, little evidenceexists concerning its potential impacts. Finally, itwas not within the scope of this study to assesswhether occupational exposures to hazardoussubstances are at “safe” levels and whether othertechnologies might be more appropriate for pre-venting occupational diseases.


Chapter 2 references

1. Anton, Thomas J., Occupational Safety and Healthhfanagement (New York: McGraw Hill, 1979), pp.143-156.

2. Bureau of Labor Statistics, Department of Labor,Occupational Injuries and Illnesses in the UnitedStates Qv Indust[v, 1981, Bulletin 2164, January1983.

3, Environmental Protection Agency, EconomicAna[vsis of Proposed Hazard Warning Regulations,prepared for the Office of Pesticides and ToxicSubstances, Office of Regulatory Analysis undercontract No. 68-01-5924, September 1980.

4. Environmental Protection Agency, Proposed Fed-eral Radiation Protection Guidance for Occupa-tional Exposure: Background Report, Office of Ra-diation Programs, Criteria and Standards Division,Report No. EPA-520 4-81-003, Jan. 16, 1981.

5. Harsanyi, Z., and Hutton, R., Genetic Prophecy:Beovond the Double HeZix, (New York: Rawson,Wade Publishers, Inc., 1981).

6. Institute of Medicine, Genetic Influences onResponses to the Environment (Washington, D. C.:National Academy Press, 1981).

7. Monroe, Carl B, ‘(The Role of Biological Monitor-ing in Medical and Environmental Surveillance, ”in Chemical Hazards in the Workplace: Measure-ment and Control, Gangadhar Choudhary (cd.)(Washington, D. C.: American Chemical Society,1981), p. 223.

8. National Academy of Sciences, Committee on theBiological Effects of Ionizing Radiation, The Effectson Populations of Exposures to Low Levels of Ioniz -in,g Radiation, table III-23 (Washington, D. C.: 1980).

9. National Academy of Sciences, Genetic Screening:Programs, Principles, and Research (Washington,D. C.: 1975).

10. National Commission for the Protection of HumanSubjects of Biomedical and Behavioral Research,The Belmont Report: Ethical Principles andGuidelines for the Protection of Human Subjectsof Research (Washington, D. C.: 1978) DHEW pub-lication No. (OS) 78-0012, p. 2.

11. National Institute for Occupational Safety andHealth, Centers for Disease Control, “Proposed

Hazard Communication Standard, ” 47 Fed. Reg.12092, 12108 (1982), citing, U.S. Department ofHealth, Education, and Welfare, Public HealthService, National Occupational Hazard Survey,DHEW (NIOSH) publication No. 78-114, 1977, p.792.

12. Occupational Safety and Health Adminstration, Of -fice of Regulatory Analysis, Draft Regulatory Im-pact Analysis and Regulatordy Flexibility Analysisof the Hazard Communication Proposal, March1982, p. 11-21, citing Kearney, A. T., Inc.

13. Occupational Safety and Health Administration,Field Operations Manual, pp. xiii - 2.

14. Office of Technology Assessment, U.S. Congress.Assessment of Technologies for DeterminingCancer Risks From the Environment, OTA-H-138,June 1981.

15. Omenn, G., “Predictive Identification of Hyper-susceptible Individuals, ” Journal of OccupationalMedicine, 24:369, May 1982.

16. Omenn, G., and Motulsky, A., “Eco-Genetics: Genet-ic Variation in Susceptibility to EnvironmentalAgents, ” in Genetic issues in Public Health andMedicine, B. Cohen (cd.) (Springfield, Ill.: CharlesC. Thomas, 1978).

17. Pete, R., and Schneiderman, M., Banbuqv Report9: Quantification of Occupational Cancer (NewYork: Cold Spring Harbor Laboratory, 1981).

18. Ruttenberg, R., and Hudgins, R., Occupational Safe-tuy and Health in the Chemicaf Industry (New York:Council on Economic Priorities, 1981), p. 25.

19. Schwartz, J., and Epstein, S., “Problems in Assess-ing Risk From Occupational and Environmental Ex-posures to Carcinogens,” in Quantification of Oc-cupational Cancer, 1981, pp. 559-576.

20. Stokinger, H,, and Mountain, J., “Test of Hyper-susceptibility to Hemolytic Chemicals, ” Arch. En-viron. Health, vol. 6, 1963, p. 57.

21. Wall Street Journal, “Asbestos Lawsuits Spur WarAmong Insurers, With Billions at Stake, ” June 14,1982, p. 1.

22. Washington Post, “Conglomerate Facing AsbestosLawsuits Files for Bankruptcy, ” Aug. 27, 1982, p.A-1,

Chapter 3

Survey of the Use of GeneticTesting in the workplace

Contents

PagePurpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Overall Rates obtesting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Types of Testing: Genetic Screening and Cytogenetic Monitoring . . . . . . . . . . . . . . . . . . 34Actions Taken as a Result of Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Generalizability of the Survey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Comments on Survey. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38Caveats .. .. .. .. ... ... ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Conclusions . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. ... ... ......O .. .. .. . . $ . . . . . . . . . . . . 39Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

List of Tables

Table No.l.Frequency of Response to Survey by 6/8/82 By Type of Response . . . . . . . . . . . . . . . .2.2x 2 Contingency Table for Organizations Engaged in Genetic Testing . . . . . . . . . . .3. Distribution of Organizations By Type, Indicating Current, Past, and/or Future Use

of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4. Frequency of Current, Past, and/or Future Use of Genetic Testing, By Type. . . . . . .5. Distribution of Companies by Classification, Indicating Current, Past, and/or

Future Use of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6.Genetic Testing Ever Conducted By Purpose and Type of Test . . . . . . . . . . . . . . . . . .7.Genetic Testing Ever Conducted By Criteria and Type of Test. . . . . . . . . . . . . . . . . . .8.Genetic Testing Ever Conducted By Reasons for and Type of Testing . . . . . . . . . . . .9. Genetic Testing Ever Conducted By Criteria for Test Selection and Type obtesting

10.Distribution of Type obtesting By Status of Tester. . . . . . . . . . . . . . . . . . . . . . . . . . . .11. Actions Taken by Respondents That Have Ever Used Genetic Testing . . . . . . . . . . . .

Page3434

3535

35363636373738

—

Chapter 3

Survey of the Use of GeneticTesting in the workplace

There have been conflicting accounts of the ex-tent of genetic testing and the use of its results.In testimony given before Congress in the fall of1981, the corporate medical director of a largechemical company stated that except for sicklecell trait tests, his company “ . . . is not conduct-ing genetic screening of its employees, and I amnot aware of any other company which is” (2).However, a series of articles in the New YorkTimes in February 1980 alleged a widespread cor-porate practice of such testing on Americanworkers (3). Furthermore, a May 1981 survey ofeast coast industrial physicians indicated thatpreemployment, preplacement, and periodic test-

Purpose

The survey was

●

ing for sickle cell anemia, hemoglobin disease, andglucose 6-phosphate dehydrogenase (G-6-PD) defi-ciency was being conducted in some large eastcoast companies (l).

None of these or other accounts examined byOTA has been based on a rigorous, scientificallyvalid assessment of the use of genetic testing.Therefore, in an attempt to dispel the confusionand speculation and to provide necessary data forpolicy analysis, OTA surveyed major U.S. indus-trial companies, utilities, and unions about theiruse of this technology.

designed to determine: ● which tests were used and under whatcircumstances:

the frequency of past, present, and an-●

ticipated genetic screening and cytogenetic●

monitoring * in the workplace and whetherthey had been conducted on a routine,

how the results of the tests were used; andthe criteria against which tests have beenmeasured to determine acceptability for use.

special, or research basis; The survey did not attempt to establish thenumber of workers involved in these tests: that

“The questionnaire used the term biochemical genetic testing torefer to genetir screening and the term cytogymetic testing to referto cytngfmetir monitoring

Study design

The survey was conducted for OTA fromFebruary 25 to June 8, 1982, by the National Opin-ion Research Center (NORC), a nonprofit surveyresearch corporation affiliated with the Univer-sity of Chicago. NORC sent confidential question-naires to the chief executive officers of the 500largest U.S. industrial companies, * the chief ex-ecutive officers of the 50 largest private utility

information would have required a much moreextensive effort.

companies, * * and the presidents of the 11 ma-jor unions that represent the largest numbers ofemployees in those companies.** * For further in-formation on the study design and other aspectsof survey methodology, see appendix A, TheNORC report to OTA on the survey is in appen-dix B.

● *Identified by Fortune hfagazim? List C; Forrune, ~rol. 10S, No.9, Nla}’ 4, 1981.

* Identified by Fortune 500 listing of [ 1.S, mmpaoi[?s engaged in * * ‘Identifiecl inmanl]fa(’t l]ring(nlilling: I’orfunr, \’ol. 103 , No, 9, Nla} 4, 1 9 8 1 . Association (19791

Dirt? rtory of National Llnions and F,mployeesh~r the Cl S. Department of Lahor.

33


Table 1 .—Frequency of Response to Survey by 6/8/82By Type of Response (based on 561 organizations)

By the June 8, 1982, cutoff date, 366 organiza-tions had answered the questionnaire, a 65.2 per- Type of response Number Percent

cent response rate, and 26 organizations had spe- Participated . . . . . . . . . . . . . . . . . . . 366 65.2%cifically declined to do so, a 4.6 percent refusal Refused to participate: . . . . . . . . . 4.60/o

Policy not to reply to surveys .rate. Those who declined generally gave either (:;

Not interested, no time. . . . . . . (3)no reason for refusal or the reason of corporate Object to methodology . . . . . . . (1)

policy not to respond to surveys. (See table 1.) Phone refusal—no reason . . . . (12)Unknown . . . . . . . . . . . . . . . . . . . . . 169 30.1%

Total . . . . . . . . . . . . . . . . . . . . . . . 561SOURCE: National Opinion Research Center, survey conducted for OTA, 1982,

Results

Overall rates of testing

Of the 366 organizations responding, 6 (1,6 per-cent) were currently conducting genetic testing, *17 (4.6 percent) used some of the tests in the past12 years, 4 (1,1 percent) anticipated using the testsin the next 5 years, and 55 (15 percent) stated theywould possibly use the tests in the next 5 years.Most of these organizations are in manufactur-ing/mining (particularly chemicals) or are utilitycompanies. Of those organizations that havetested in the past 12 years, five are currentlydoing so, (See table 2.) Because the questionnaireinstructed respondents to include any instanceof testing, positive responses can include isolatedinstances of testing as well as long-term testingprograms. Among the six companies currentlytesting, two are in the chemical industry, two areutilities, and two are in the electronics industry.Half of those that tested in the past are chemicalcompanies. Of the four organizations that antici-pate the use of genetic testing, two are conduct-ing testing at present, one has done so in the past,and one has never had such a program. None ofthe four responding unions reported any testing.These results are set forth in more detail in tables3, 4, and 5.

Types of testing: genetic screening andcytogenetic monitoring

Organizations that reported some geneticscreening were asked whether they had evertested employees for genetic traits associated

● Genetic screening and/or cytogenetic monitoring

Table 2.—2 x 2 Contingency Table forOrganizations Engaged in Genetic Testing

(past testers by current testers)

Past testers

Yes No Total

Current Yes 5 1 6testers No 12 348 360

Total 17 349 366SOURCE: National Oplnlon Research Center, survey conducted for OTA, 1982.

with: (A) any red blood cell and serum disorders,(B) liver detoxification systems, (C) immune systemmarkers, or (D) heterozygous chromosomal insta-bilities. For each of the four broad categories Athrough D, the questionnaire listed several exam-ples. Of those who have ever tested, 14 of the or-ganizations had tested in category A, 3 in categoryB, 5 in category C, and none in category D. Orga-nizations that have used red blood cell and serumdisorder tests, category A, often used more thanone type of test. The most frequently used testin this category was that for sickle cell trait, forwhich 10 organizations have tested. The G-6-PDand serum alpha-1 antitrypsin deficiency testswere the second most frequently used. (See table6 for a summary of the frequency of individualgenetic screening tests.)

For each test, companies were asked about thecircumstances under which the tests were done(that is, routinely, for research, or for other rea-sons) and the type of employee tested. Respond-ents generally said they tested routinely or forunspecified reasons. (See table 6.) Employees mostoften were selected on the basis of ethnicity andrace for sickle cell trait testing and on the basis

Ch. 3—Survey of the Use of Genetic Testing in the Workplace ● 35

Table 3.—Distribution of Organizations By Type, Indicating Current, Past, and/or Future Use ofGenetic Testing (based on 366 responses)

Testing

Current Past Future

Organization type (number of respondents) Yes No/NA a Yes No/NA a Yes/Poss. No/NA a

Manufacturing/mining companies (322). . . . . . . . . 4 318 16 306 49 273Private utility companies (31) . . . . . . . . . . . . . . . . . 2 29 1 30 9 22Unions (5) . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . 0 5 0 5 0 5Unknown (8) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 8 0 8 1 7

Total (366). , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 360 17 349 59 307(1.6%) (4.6%) (16.1 0/0)

aA combination response Further breakdown is fmposslble stnce the category (current, past, future) is a summary of responses to two questions dealtng with geneticscreen i n g and cytogenet!c mon Itori ng In the case of No/NA, most responses were No, for Yes/Poss , most responses were possibly. See table 4 for further breakdown

SOURCE National Opinion Research Center, survey conducted for OTA, 1982

Table 4.—Frequency of Current, Past, and/or Future Use of Genetic Testing, By Type (based on 366 responses)

Testing

Current Past Future

Type of test Yes No N/A Yes No N/A Yes Poss. No N/A

Genetic screening . . . . . . . . . . 5 350 11 12 342 12 1 53 292 20Cytogenetic monitoring . . . . . . 2 354 10 6 348 12 3 49 294 20SOURCE National Oplnlon Research Center, survey conducted for OTA, 1982

Table 5.— Distribution of Companies by Classification,a Indicating Current, Past,and/or Future Use of Genetic Testing (based on 366 responses)

Genetic testing

Current Past FutureMain industrial classification

(number of respondents) Yes No/NA b Yes No/NA b Yes/Poss. No/NA b

Chemical (37) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 35 8 29 11 26Utilities (33) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 31 1 32 10 23Petroleum (18) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 18 0 18 4 14Pharmaceuticals (9) . . . . . . . . . . . . . . . . . . . . . . . . . 0 9 0 9 3 6Rubbers/plastics (4) . . . . . . . . . . . . . . . . . . . . . . . . . 0 4 0 4 3 1Metals (16) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 16 0 16 2 14Others (249) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2C 247 8 241 26 223

Total (366) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 349 307(1 .6%) (4.&o) (16.1%)

~Main industrial classification based on the first listed response of respondent to question concerning the major Industrial classification of their companyA combination response. Further breakdown Impossible since the category (current, past, future) is a summary of two questions” 1) genetic screening, 2) cytogenetlcmonitoring. In the case of No/NA, most responses were No; for Yes/Poss. most responses were possibly. See table 4 for further breakdown

cBoth of t~ese companies report electronics as their main industrial classification

SOURCE National Optn!on Research Center, survey conducted for OTA, 1982.

of job category for other types of tests. No orga-nization reported basing a genetic screening teston an employee’s sex. (See table 7.)

Of the organizations that reported cytogeneticmonitoring, four had tested for chromosomalaberrations and two for sister chromatid ex-changes (SCE). None reported having tested for

mutations by assaying either deoxyribonucleicacid (DNA) or enzymes. Most frequently, noreason was given for chromosomal aberrationtesting. The two companies that did SCE testingsaid it was for research purposes. (See table 6.)Job category was the only employee-relatedcharacteristic used to determine who would betested. (See table 7.)

36 ● The Role of Genetic Testing in the prevention of Occupation/ Disease

Table 6.—Genetic Testing Evera Conducted By Purpose and Type of Test (based on 18 responses)

Genetic screening Cytogenetic monitoring

Unspecified Unspecifiedred blood immune Sister

Methemoglobin cell/serum Unspecified system Chromosomal chromatidPurpose Sickle cell G-6-PD SAT reductase disorder liver detox markers aberrations exchanges

Routine ., . 5 3 1 0 1 1 4 1 0Research , . 1 0 2 1 2 1 0 1 2Other ... , . 6 2 2 1 2 1 3 3 0

Totalnumber ofrespondentsutilizingtest b . . . . 10 4 4 1 3 3 5 4 2

aln the past 12 years.bSince categories above are not mutually exclusive, total can be Iesslmore than sum of categories.SOURCE: National Opinion Research Center, survey conducted for OTA, 1982.

Table 7.—Genetic Testing Evera Conducted By Criteria and Type of Test (based on 18 responses)

Genetic screening Cytogenetic monitoring

Unspecified Unspecified -

red blood immune SisterMethemoglobin cell/serum Unspecified system Chromosomal chromatid

Criteria Sickle cell G-6-PD SAT reductase disorder liver detox markers aberrations exchanges

J o b c a t e g o r y 1 2 2 0 2 1 2 1E thn ic i ty / race 7 0 0 0 0 0 : o 0Sex . . . . . . . . 0 0 0 0 0 0 0 0 0

Totalnumber ofrespondentsutilizingtest b . . . . . 10 4 4 1 3 2 4 4 2

~ln the past 12 years.Since categories above are not mutually exclusive, total can be less/more than sum of categories,

SOURCE: National Opinion Research Center, survey conducted for OTA, 1982,

Recipients were asked about the factors con-sidered in the decision to implement testing andthe criteria employed in selecting specific tests.Data from epidemiological studies, data from an-imal studies, and other reasons such as employeeprotection were the highest ranked factors in-volved in decisions to implement genetic testingfor both genetic screening and cytogenetic mon-itoring. (See table 8.) The predictive value of a test,its specificity, scientific consensus, and other fac-tors such as research findings were the factorscited most frequently as criteria for selecting aspecific genetic test. These responses were similarfor both genetic screening and cytogenetic mon-itoring. (See table 9.)

The types of testing carried out by currenttesters were compared with those of past testers.For genetic screening, current testers are using

Table 8.—Genetic Testing Evera ConductedBy Reasons for and Type of Testing

(based on 18 responses)

Type of testing

Reasons for deciding to Genetic Cytogeneticimplement testing screening monitoring

Data epidemiologic studies 6 2Data animal studies . . . . . . 4 2Legal consequences of not

testing . . . . . . . . . . . . . . . . 3 0Union employee initiative . 3 0Cost-benefit analysis . . . . . 2 0Other b . . . . . . . . . . . . . . . . . . 4 3~ln the past 12 years.

Includes reasons related to protecting employees, research findings.

SOURCE: National Opinion Research Center, survey conducted for OTA, 1982.

a slightly greater variety of tests (tests for redblood cell and serum disorders, liver detoxifica-tion systems, and immune system markers) than

Ch. 3—Survey of the Use of Genetic Testing in the Workplace ● 3 7

Table 9.–Genetic Testing Evera Conducted ByCriteria for Test Selection and Type of Testing

(based on 18 responses)

Type of testing

Genetic CytogeneticCriteria b screening monitoring

Predictive value of testc . . . 5 1Specificity of testd . . . . . . . 5 1Scientific concensus . . . . . 4 2Sensitivity of teste . . . . . . . 3 0Cost of test . . . . . . . . . . . . . 2 0Other f . . . . . . . . . . . . . . . . . . 4 3~ln the past 12 years.

A respondent may have based its selection for a test on one or more of theabove criteria

cpredictive value of test the l~kellhood that the disease status of the ind~vidual

wi I I be correctly Identified by the test; i e., a disease-free individual will havenegative test result, a diseased indiwdual will have positive test result

‘Specificity of test: ability of test to correctly identify individuals without disease:Sensltlwty of test” ability of test to correctly identify individuals with diseaseIncludes research findings (general).


past testers and at a slightly higher proportionof usage. of the six current testers, five are testingfor red blood cell and serum disorders, three forliver detoxification systems, and two for immunesystems markers. Eight of twelve past testers hadtested for red blood cell and serum disorders,none had tested for liver detoxification systems,and two had tested for immune system markers.In fact, however, because of the small numbersinvolved, the only notable difference between cur-rent and past testers may be the current use oftests for liver detoxification systems. In any event,testing for red blood cell and serum disorderscontinues to be the most frequently used test. (Seetable 10. )

A different pattern of use emerges for cytoge-netic monitoring, Of the six current testers, oneis testing for chromosomal aberrations and oneis testing for sister chromatid exchanges, For the12 past testers, 3 tested for chromosomal aberra-tions and 1 tested for sister chromatid exchanges.This may reflect the change in the state of theart concerning the science of sister chromatid ex-changes. (See table 10.) In any event, the numberof tests remain small and caution is advised ininterpreting these data.

Actions taken as a result of testing

Responses concerning the way in which the re-sults of genetic screening or cytogenetic monitor-ing were used varied greatly, ranging from ac-tions involving an employee to changing or discon-tinuing a product. Of the 18 companies that re-ported taking some action, 8 reported that theyhad informed an employee of a potential prob-lem. Five respondents reported transferring the“at-risk” employee. Two suggested that the em-ployee seek another job as a result of testing. Onediscontinued or changed a product, The completelist of actions taken appears in table 11.

Generalizability of the survey

Can the results of this survey be generalizedto the population of Fortune 500 companies, largeutility companies, and major unions? An answerto this involves two additional questions: Are theresponses equally distributed among the groups

Table 10.—Distribution of Type of Testing By Status of Tester (based on 18 responses)

Status of tester

Current N-6 Past N-12

Percent PercentType of testing Yes No/NA using Yes No/NA using Total

Genetic screening:Red blood cell and serum disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . 5Liver detoxification systems ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Immune system markers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Heterozygous chromosomal instabilities . . . . . . . . . . . . . . . . . . . . . . . 0

Cytogenetic monitoring:Chromosomal aberrations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Sister chromatid exchange. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Mutations by assaying DNA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Mutations by assaying enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1 830/o 83 50 ”/0 o4 33% 26 0% o

5 17 ”/0 35 17“/06 0% :6 0% o5 17 ”/0 o

4 670/o 1812 O O /o 1810 1OO/o 1812 0% 18

9 250/o 1811 80/0 1812 O O /o 1812 0% 1812 O O /o 18



Table 11 .—Actions Taken by Respondents That HaveEvera Used Genetic Testing (based on 18 responses)

Number ofType of actionb companiesInformed employee of a potential problem 8Transferred employee . . . . . . . . . . . . . . . . . . 5Personal protection device . . . . . . . . . . . . . . 3Other action . . . . . . . . . . . . . . . . . . . . . . . . . . 3Suggested employee seek other job . . . . . 2Installed engineering control . . . . . . . . . . . . 2Implemented research program . . . . . . . . . . 1Discontinued/changed product . . . . . . . . . . 1~ln the past 12 years.

A respondent may have taken more than one action

SOURCE: National Opinion Research Center, survey conducted for OTA, 1982.

represented in the survey? Are characteristics ofthe respondents different from the nonrespond -ents? These two questions are discussed in turn.

By the close of the survey, a discrepancy in re-sponse rate among the groups represented in thesurvey became apparent. The large corporationshad the highest response rates: 68 percent forutilities and 61.5 percent for the top 200 com-panies in the Fortune 500 listing; the unions andsmall corporations had the lowest response rates:36.4 percent for unions and 44 percent amongthe bottom 300 companies in the Fortune 500 list-ing. (See app. A.) The variation in response pat-tern was most probably due to the followup ef-forts that focused on the top 100 companies ofthe Fortune 500 listing and organizations in se-lected industrial classifications such as utilities.Thus, the results of this survey may be more ap-plicable to the larger manufacturing/mining andutility companies than to smaller manufactur-ing/mining companies and unions.

Analysis of selected characteristics of respond-ents compared with nonrespondents is limited tothe Fortune 500 companies. Respondents andnonrespondents were compared on the follow-ing characteristics: geographic location, size oforganization, and type of industry. Rates ofresponse and nonresponse did not differ greatlygeographically. (See app. A.)

For size of company, however, the rate of non-responses did differ widely from the rate of re-sponses. For example, 53 percent of the nonre-spondents were in the smallest companies, com-pared with 32 percent of the respondents. Again,

because larger companies were used in followupefforts, the response rates may reflect these ef-forts. (See app. A.)

Rate of nonresponse did not vary greatly fromrate of response with respect to industry classi-fication. Eleven industries had a slightly higherrate of response than predicted. Of these indus-tries, five (chemicals, petroleum refining, rubberand plastic products, metal manufacturing, andpharmaceuticals) were the key industries selectedfor followup activities and the rates from the re-maining six (glass/concrete, electronics, measur-ing equipment, motor vehicles, aerospace, and of-fice equipment) may be explained by such factorsas the effect of followup based on size of com-pany or chance. (See app, A.)

Thus, the results of the survey may be morerepresentative of the larger manufacturing/min-ing corporations and private utility companies asidentified in Fortune magazine listings; however,the respondents do not appear to differ greatlyfrom the nonrespondents in geographic locationor type of company.

Comments on survey

Respondents were encouraged to write explan-atory notes or other comments on the question-naires and on the post cards. Thirty-one respond-ents did so. (See app. C for complete text of com-ments,) Three current testers sent in comments.Two of these respondents said testing was beingdone for reasons of health evaluation—preplace -ment and/or routine monitoring; one respondentsaid that such testing should not be interpretedto mean a large-scale testing program or a prob-lem exists.

Comments were received from two companiesthat had tested in the past, Both respondents re-ferred to testing for sickle cell trait, one at therequest of the State health department, and theother at the request of the employer for employ-ees of child-bearing age as part of the company’spreventive medical program.

Seven organizations that anticipate future test-ing but that have not conducted any testing todate provided comments. The comments ranged

Ch. 3—Survey of the Use of Genetic Testing in the Workplace 39

from addressing animal research to questionnaireimprovement to any future testing being depend-ent on ‘(practical utility. ”

Comments received from 19 organizations thathave never tested or that do not plan to test inthe future focused on three major points. Thefirst was the genetic testing was not relevant tothe products or processes to which their workerswere exposed. The second was that these testswere not sufficiently developed for use. The thirdpoint was that the organization was satisfied withits current conventional industrial hygiene prac-tice and standard medical surveillance of itsworkers.

Caveats

In evaluating the results of the survey, severalcaveats must be considered. First, since thequestionnaire instructed respondents to includeany instances of testing, positive responses caninclude isolated cases as well as long-term testingprograms. Second, the questionnaire was notstructured to provide information on the number

of workers tested. Positive responses indicate onlythe existence of testing, not its extent. Third, sinceapproximately one-third of the population did notrespond and the number of organizations testingis very small, any generalizing of these results tothe study population as a whole is not warranted.Fourth, the level of effort employed in completingeach questionnaire is unknown. For example,holding companies which have autonomously op-erating subsidiaries may or may not have includedthe activities of those subsidiaries in their re-sponses. Fifth, a limitation of an anonymous ques-tionnaire is that respondents cannot be contactedabout missing information or unclear responses.Approximately 3 percent of the respondents failedto answer every item in the core questions. Eightreturned questionnaires did not provide enoughinformation to allow the respondents to be clas-sified as a Fortune 500 company or as a utility.Sixth, the use of post cards for followup has pit-falls: respondents may return post cards but notquestionnaires or vice versa; NORC received 293post cards and 366 questionnaires. This may haveresulted in duplication of information or mini-mized the effect of followup.

Conclusions

The survey of major U.S. industrial companies,utilities, and unions has shown that genetic testingcurrently is being used by a few companies, thatits use has declined in the past 12 years, but thatit may be used by many more companies in thefuture. The responses cannot be generalized tothe survey population or to all U.S. companies andlabor unions. However, it is clear that 17 organiza-tions have used genetic testing in the past 12years, 5 of the 17 and 1 other currently are do-ing so, and 59 organizations have expressed aninterest in using these tests. None of these orga-nizations is a union. The extent of testing by theseorganizations is unknown.

Further, of the 18 companies that have everconducted genetic testing in the past 12 years,more companies have conducted genetic screen-ing (17 companies) than cytogenetic monitoring(8 companies). Tests for sickle cell trait were the

most frequently used type of genetic screeningand tests for chromosomal aberrations were themost frequently used type of cytogenetic monitor-ing. Research was the least frequently mentionedpurpose for testing. Respondents generally testedroutinely or for other unspecified reasons. Thetype of employee chosen for testing was basedmost often on ethnicity and race for sickle celltrait testing, and job category for other types oftests. Sex was never stated as a criterion used indetermining the test of choice. Actions taken onthe results of the tests ranged from informing theemployee of a potential problem (eight companies)to discontinuing or changing the product (onecompany).

Data from epidemiological and animal studieswere the most frequently cited factors in the deci-sion to implement testing of those companies thattested. A cost-benefit analysis was the least impor-

,2,_”, q ,, — ~ J — . .


tant factor. The predictive value and specificity while research findings were most important inof a test were the most important criteria in the the selection of the specific cytogenetic monitor-selection of the specific genetic screening test, ing test.


1. Compton, A., “Company Practices in Protecting Pent de Nemours & Co., testimony before Subcom-Minority Workers, ” paper presented at The Na- mittee on Investigations and Oversight of thetional Conference on Occupational Health and House Committee on Science and Technology, Oct.Issues Affecting Minority Workers, sponsored by 14 and 15, 1981.the National Institute of Occupational Safety and 3. Severe, R., ‘(Screening of Blacks by DuPontHealth, July 6-8, 1981. Sharpens Debate on Gene Tests)” The New York

2. Karrh, B. W., Corporate Medical Director, E. I. du Times, Feb. 4, 1980.

Part II

Underlying Scientific Principles

Chapter 4—Essentials of Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Chapter 5—Principles of Genetic Testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Chapter 4

Essentials of Genetics

Contents

PageChromosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ... ... ... ....$ . . . . . . . . . . . . . . 45DNA) Genes) and Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Genetic Variability in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49Mutation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Single Gene Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Mutations, Chromosomes, and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52Body Fluids Used in Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

List of Figures

Figure No. Page2.A Chromosome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453.Normal Human Male Karyotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464. Sister Chromatic Exchanges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475.The Structure of DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486.Mechanism of Gene Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Chapter 4

Essentials of Genetics

The role of genes in disease is still not fullyunderstood. Many diseases--cancer and heart dis-ease, for example—appear to have some geneticinfluence. These genetic variations may be in-herited or may arise from environmental sources.In other cases, it is hypothesized that a personwith inherited types of gene variations may suf-fer harmful effects when exposed to hazardoussubstances.

The occupational studies assessed in Part 111 ofthis report rely on genetic analyses. An under-standing of genetics—the basic structure andfunction of genes and their connection with dis-ease—will enable the reader to comprehend morereadily the report’s interpretation of those studies.This chapter, therefore, attempts to provide anintroduction to the complex subject of genetics.

Chromosomes

In higher organisms, the nucleus of each cellcontains the genetic material DNA (deoxyribo-nucleic acid), which directs all the functions ofthe cell such as metabolism and growth. The DNAin its normal state in the nucleus is joined withproteins to form a set of complicated structurescalled chromosomes. Each human cell contains46 chromosomes, half derived from the motherand half from the father. These 23 pairs of chro-mosomes mean that all genetic material is repre-sented twice in each cell. One of the twenty-threepairs is a pair of sex chromosomes. Females havetwo X chromosomes and males have one X andone Y. When the cell is in a resting stage, all thechromosomes are tangled and difficult to distin-guish; just prior to cell division, however, thechromosomes condense and replicate to appearin a light microscope as dual structures, eachchromosome consisting of two identical chroma-tics (fig. 2). These two sister chromatics are heldtogether by a central constriction, the centro-mere. At cell division, the sister chromatics arepulled apart at the centromere, and one chroma-tid goes to each of the two daughter cells, thusensuring a full complement of DNA in each cell.

Each of the 23 pairs of chromosomes is a uniquesize and shape, permitting the chromosomes tobe distinguished from one another, In addition,various staining treatments have been developedthat reveal, for each chromosome, a characteristic

Figure 2.— A Chromosome

Sisterchromatids

Chromat\


sequence of “bands” composed of alternately darkand light staining regions. From the combinationof size, shape, and banding patterns, the 46 chro-mosomes from a single cell can be arranged intoa systematic picture called a karyotype (fig. 3).Chromosomal abnormalities, which alter the

45


Figure 3.—Normal Human Male Karyotype

1 2 3 4 5

A B

6 7 8 9 10 11 12

14

c

D

19 20

F

SOURCE” Cytogenetics Laboratory, The Johns Hopkins University

banding patterns or size or shape, can be detectedusing this technique.

The study of cytogenetics compares the appear-ance of the chromosomes in the karyotypes toidentifiable traits in the individual. Several chro-mosomal abnormalities have been identified, andthey fall into two classes: a change in the numberof chromosomes and a change in the chromosomestructure. Changes in the number of chromo-somes occur during germ cell (egg or sperm) for-mation and are detected in the offspring. For ex-ample, Down’s syndrome is a result of an extrachromosome 21 in all cells. Although it is possi-ble for the number of chromosomes to changein somatic cells (all cells other than germ cells)by a mistake made during cell division, these cellsare usually nonviable; thus, this type of changewill not be discussed further.

E

G X Y

Chromosomal aberrations, or changes in chro-mosome structure, can occur spontaneously orcan be caused by chemicals or ionizing radiation.They are important because, whatever their ori-gin, they can be replicated and passed on to suc-ceeding generations of somatic cells. How chem-icals or ionizing radiation causes these aberrationsis not well understood.

Everyone has some chromosomal aberrationsin his or her somatic cells. In lymphocytes (whiteblood cells) grown under laboratory conditions,roughly 2 out of every 100 cells contain at leastone structurally abnormal chromosome. Similarlevels of aberrations have been seen in prepara-tions of bone marrow cells and fibroblasts (con-nective tissue cells) and presumably are presentto some extent in every kind of somatic cell (seeapp. D). These “background” or “spontaneous”

Ch. 4—Essentials of Genetics . 47

chromosomal aberrations are thought to be theconsequence either of failure to repair rarereplication errors or of postreplication chromatidexchanges, which may be a normal part of thecell cycle. However, an increase in the numberof aberrations may imply the existence of certainrare chromosomal instability diseases (discussedbelow) or exposure to clastogens (chromosome-damaging agents) in the environment. In the lat-ter case, such an increase may serve as a methodfor monitoring exposure to harmful agents.

Another type of chromosomal change is a sisterchromatid exchange (SCE). SCEs are exchangesof apparently equivalent sections of the sisterchromatics of the same chromosome (fig. 4). Thisphenomenon, which can be seen only under spe-

cial laboratory conditions, occurs at a muchhigher frequency than do chromosomal aberra-tions, with most reported background frequen-cies being in the range of 5 to 15 SCEs per cell(see app. E). * The biological or genetic significanceof SCEs is unknown. While the presence of SCEsin a cell is not necessarily indicative of damageto that cell, some empirical evidence suggests arelationship between SCEs and agents whichdamage DNA (7). The detection of SCEs thus isseen as another way to monitor damage to chro-mosomes. A major exception is that SCEs are notusually induced by ionizing radiation (3).

● ’I’hese higher background frequencies are thought to be due tothe laboratory procedures necessary for ~’isualization of S(’ES.

Figure 4.—Sister Chromatid Exchanges


DNA, genes, and proteins

The genetic information contained within thefamiliar DNA double helix (fig. 5) is completelydefined by the linear order of four chemical com-pounds known as nucleotide bases, adenine (A),guanine (G), cytosine (C), and thymine (T). Thesebases, attached to the double strands of the helix,interact in a specific fashion to form the rungsof the DNA ladder: A’s can pair only with T’s, andG’s only with C’s. Therefore, the two sides of theladder are not identical but are “complementary.”The chemical nature of the complementary basepairing is vital to the function of DNA. The pair-ing is specific, which ensures that the genetic in-formation will be maintained, but not very strong,so that sections of the helix can “unzip” to exposethe bases, thus making the genetic informationavailable for use,

An ordered sequence of a few thousand nucleo-tide bases is the unit of heredity known as the

gene. A gene has regulatory signals at either endspecifying its beginning and end. The signalsthemselves are a series of nucleotide bases, usu-ally on the order of 10 to 100 bases long. For themost part, one gene contains the information forthe synthesis of one protein. Thus, the four bases,A, G, T, and C, depending on their order, con-tain the information for the synthesis of proteins.The genetic code is the same for all organisms,The difference between organisms, therefore, isnot the inherent chemical nature of the geneticmaterial, but the different sequences of nucleo-tide bases.

The DNA present in every cell of every livingorganism has the capacity to direct the functionsof that cell. Gene expression is the way in whichthe genetic directions in any particular cell aredecoded and processed into the final functioningproduct, usually a protein (fig. 6). In the first step,

Figure 5.— The Structure of DNA

r Base pairs

A schematic diagram of the DNA double helix. A three-dimensional representation of the DNA double helix.

The DNA molecule is a double helix composed of two chains. The sugar-phosphate backbones twist around the out-side, with the paired bases on the inside serving to hold the chains together.SOURCE” Office of Technology Assessment

. .

Ch. 4—Essentials of Genetics ● 4 9

Figure 6. —Mechanism of Gene Expression

Transcr ip t ion

mRNA released andtransported out of

nucleus

Protein

called transcription, the DNA double helix is local-ly unzipped, in the region of the gene of interest,and the intermediate product, messenger RNA(mRNA), a single-stranded, linear sequence ofnucleotide bases chemically very similar to DNA,is synthesized. The transcription process dictatesthe synthesis of mRNA that is complementary tothe section of unzipped DNA. The second step istranslation. The mRNA, after release from theDNA, becomes associated with the protein-synthe-sizing machinery of the cell, and the sequence ofnucleotide bases in the mRNA is decoded andtranslated into a protein. The protein goes on toperform its particular function, and when theprotein is no longer needed, the protein and themRNA coding for that protein are degraded. Thismechanism allows a cell to “fine tune” the quan-tity of its proteins while keeping its DNA in a verystable and intact form.

Proteins actually perform the necessary func-tions of the cell. By far the most diverse groupare the enzymes, or the proteins that catalyze allbiological reactions. Another group, the structuralproteins, are found, for instance, in cell mem-branes. Other proteins, such as hormones, haveregulatory functions; still others have highlyspecialized functions —for example, hemoglobincarries oxygen from the lungs to the rest of thetissues.

SOURCE Office of Technology Assessment.

Genetic variability in humans

Because all humans need to perform the same are called alleles. It is the variation in these alleleslife-supporting tasks, they all have genes that code that forms the basis for diversity within species.for the same types of proteins. But for any givenprotein, there may be many variants, some “nor- Variants have been discovered for many humanreal” and some deleterious. This means that the genes. For example, of the 319 possible detectablegenes that code for these variants are also slight- variants of beta-globin, 104 had been observedly different. These forms of the same basic gene by 1976. More than 80 different variants of glu-

50 The Role of Genetic Testing in the Prevention of Occupational Disease

cose-6-phosphate-dehydrogenase (G-6-PD) havebeen identified, and some of these differ in theirmetabolic and clinical effects.

Although most variants are rare, a few occurwith frequencies of at least 2 percent. The prod-ucts of such variable alleles include beta-S globin(which produces a sickling of red blood cells), theA- G-6-PD allele, blood groups, and histocompati-bility substances. One study estimated that for the“average” gene coding for an enzyme, approx-imately 6 percent of individuals will be easilydetected as carrying a variant gene. Other vari-ants, which are not so readily detectable, probablyoccur more frequently. Thus, it may be that fora given gene, 20 percent of the population mightpossess two variant alleles. If this is true, the pros-pects for detecting individuals with susceptibility-conferring genotypes by mass screening seemhigh.

At first glance, it would appear unlikely thatgenes conferring susceptibility to chemical orphysical agents in the workplace could gain highfrequency; they should have been selectedagainst. This is not necessarily the case.

The frequency of an allele will decrease overthe course of generations if the individuals whopossess it have, as a result, lower reproductivefitness (that is, die before having children or havechildren who die before reproductive age). How-ever, those who possess alleles whose only harm-ful effect results from workplace exposures maybe well into the reproductive phase of their livesbefore their first exposure. If, in addition, a la-tent period occurs between exposure and harm-ful effect, as is the case for most cancers, thoseindividuals may have completed their reproduc-tion before the disease appears, Thus, the allelewould not reduce reproductive fitness. Suchalleles could attain high frequency by randomgenetic drift or by an advantage that they con-

fer to the reproductively active members of thepopulation or that they conferred in an earlierevolutionary setting. For example, the hemoglobinalleles (such as sickle cell) gained in frequencybecause of the protection they conferred againstmalaria.

On the other hand, in situations where the harm-ful effect of an allele only occasionally manifestsitself during the reproductive phase, some indi-viduals with that allele would have their repro-ductive years shortened, Therefore, the averagereproductive fitness of those possessing the allelewould be slightly less than those lacking it. Overmany generations, even a small decrease in re-productive fitness would diminish the frequen-cy of the allele and, in the absence of other ef-fects, result in its eventual disappearance. Thus,there may not be very many alleles present todaywith high frequency whose harmful effects areusually manifested later in life.

Harmful reactions to newly invented chemicalsalso may occur frequently simply because mostindividuals lack genetically determined mecha-nisms for detoxifying them or repairing thedamage they cause. It remains to be determinedwhether biological detoxification methods havealready evolved for many chemicals that causedisability today. If they have not, only rare indi-viduals may be able to cope with those chemicals.Thus, the susceptibility-conferring alleles thenwould be the predominant types.

Even when a genetically determined detoxifica-tion mechanism has evolved, it might protectagainst an acute effect of the chemical (and con-sequently confer a reproductive advantage), butthe mechanism itself might cause a change in thechemical that increases the chance of a latentharmful effect. If the latency period exceeds thereproductive period, this long-term effect wouldnot have a selective disadvantage.


Mutation

A mutation is a heritable change in the sequenceof nucleotide bases. * A mutation can be an inser-tion or deletion of a base or a base change. A basechange is usually caused by a mispairing reactionduring DNA replication which effectively changesone base pair to the other one. For instance, ifa modified A mispairs with a C, the C will cor-rectly pair with a G during replication and willhave effectively converted an A-T base pair to aG-C base pair in one of the daughter cells.

Mutations normally occur at a low rate and, in-deed, are the raw material for the evolutionaryprocess. They can occur in spaces between genesand thus be neutral, or they can occur withingenes. Occasionally an intragene mutation willcause the gene to encode a protein that is betteradapted to its function, but most mutations withingenes are deleterious (l). Mutations within genesare well documented in humans. In fact, at least

‘Some of the (hromosomal ahf’rrations discussed a!)o\e are ac-

tually mutations, t)ut for simplicity, thr Llse of “mutation’ in thisreport mill refer to nucle{)tidr hase changes ~ihereas “chromosomalaberration” will refer [o ~ros~ structural rhangm iisihle in the lightmicroscope

Single gene traits

A genetic trait is any detectable condition thatis known to be inherited. The easiest case to studygenetically is a trait specified by a single gene. Ex-amples include sickle cell anemia and Tay-Sachsdisease. Suppose a hypothetical single gene traitB determines the normal condition and the rare-ly occurring allele b results in an observable defi-ciency. Because there are pairs of each chromo-some, a normal individual will be either BB (both

1,000 human diseases are known to be geneticin origin (5), and many more are thought to havea significant genetic contribution.

Induced mutations can be caused by genotox-ic (gene-damaging) chemicals or ionizing radiation.Mispairing of nucleotide bases during DNA rep-lication can be caused by chemical modificationof bases or by the incorporation of compoundsthat look like bases. Some compounds insert them-selves between base pairs, distort the helix, andthus cause additions or deletions of nucleotidebases during DNA replication. Radiation isthought to cause mutations by damaging thestructure of the nucleotide base or the backboneof the DNA helix.

DNA damage that can lead to mutations canoften be repaired. A mismatched base pair orchemically modified base will distort the doublehelix and alert cellular repair mechanisms. Thedamaged section of the DNA strand can be ex-cised and new DNA synthesized using the otherstrand as a template. It is important for DNA tobe repaired prior to replication because mis-matched bases become fixed during replication.

chromosomes of the pair have the B allele) or Bb(one chromosome has the B allele and the otherhas the b allele). An afflicted individual will bebb (both chromosomes of the pair have the ballele). When both chromosomes carry the sameallele, the trait is homozygous (that is, BB or bb);when the two chromosomes carry different al-leles, as in the Bb individual, the trait isheterozygous. In a heterozygous trait where only

52 The Role of Genetic Testing in the Prevention of Occupation/ Disease

one allele appears to be contributing to the ob-servable condition (in this case, B), that allele issaid to be dominant. The allele (b) that is maskedby the dominant allele is recessive. Only whenboth chromosomes of a pair carry the recessiveallele will the deficiency be detected. A hetero-zygote for the trait is called a carrier.

The actual genetic constitution of a trait (or anindividual) is the genotype, In the case of BB andbb individuals, the genotype is reflected in the ob-served trait, or phenotype. In general, a specificphenotype associated with the heterozygous gen-otype is not observed. In this simple case, becauseB is dominant, the phenotype of the heterozygoteis the same as the homozygote (BB). In addition,the phenotype reflects the interaction of the gen-otype with the environment,

Occasionally, a heterozygous trait is expressedat an intermediate level, that is, neither allele isfully dominant or recessive. In these cases the al-leles are said to be codominant, and the observedphenotypes reflect both homozygous and heter-ozygous genotypes.

The deficient phenotype (from genotype bb)may be expressed by various symptoms, but itis the result of a single protein deficiency. Theresult may be due, for example, to a nonfunctionalstructural protein, the lack of a protein or hor-mone, or a deficient metabolic enzyme. Moreover,there are many traits whose phenotypic expres-sion is the result of several gene products work-ing together. An example of a polygenic trait isa person’s height,

Mutations } chromosomes, and cancer

Both mutations and chromosomal aberrationsare thought to play a role in the set of diseasesknown as cancer. Many (about 90 percent) of thechemicals known to cause cancer (carcinogens)in animals are also known to cause mutations inin vitro tests (6). In fact, chemicals being testedfor their potential carcinogenic effects are firstscreened for their ability to cause mutations. Onetheory of carcinogenesis postulates that one ormore mutations causes a cell to reproduce outof control and, subsequently, form a tumor.Strongly supporting a mutational origin of manycancers is the fact that they arise from a singlesomatic cell; that is, the cancer genotype, oncepresent, is stable and passed on to daughter cellsduring tumor growth.

Most cancer cells have abnormal karyotypes;there are frequently changes in chromosomenumber, and more recently, it has been shownthat there are an unusually high number of chro-mosomal aberrations. It is not known whetherthese abnormalities are a cause or an effect ofthe malignant state, but several inherited dis-eases, * in which there is an increased aberration

*Bloom’s syndrome, ataxia telangiectasia, Fanconi’s anemia, andxeroderma pigmentosum.

frequency, are associated with an increased riskfor developing cancer (9). These single generecessive diseases are thought to be due to defi-ciencies in DNA repair processes, and the chro-mosomes of afflicted individuals are much moresusceptible to breakage caused by radiation andchemicals. Clearly, these chromosomal instabilitiesprecede any malignancy, because these individ-uals also have many aberrant cells that are notmalignant. Still, some types of cancer (for exam-ple, myelocytic leukemia) correlate with specificchromosomal abnormalities.

One hypothesis holds that mutations and/orchromosomal aberrations are precancerousevents, but, as yet, there is very little definitivescientific evidence to support this. A recent reporthas shown that the gene presumably responsiblefor one type of human bladder cancer differsfrom its normal counterpart by a single basemutation (10).

A conspicuous feature of carcinogenesis is thegenerally long period of time that elapses betweenthe initial exposure to the carcinogen and theappearance of the disease. Why this time courseis so long is unknown, but based on extensiveanimal experimentation, carcinogenesis can beseparated into two distinct steps, initiation and

--—.


promotion. Evidence has accumulated to suggestthat initiation may be nothing more than muta-genesis, the most powerful initiators being themost potent mutagens. However, initiation aloneapparently is not enough to produce the disease;promotion is also necessary. * The nature of pro-motion is still obscure. Various agents or physicalinsults (for example, wounding) can act as pro-moters, often a long time after initiation. Thefeature all promoters have in common is that theyprovoke increased cell multiplication of initiatedcells; generally, they do not affect noninitiatedcells. How rapid cell proliferation in the presenceof a mutation could lead to a malignant state isunknown. At any rate, both genetic and environ-mental factors can influence whether one devel-ops cancer, but the elucidation of these factorshas not yet been achieved (6).

If cancer indeed has one or more genetic com-ponents, individuals who have the “wrong” com-binations of genes may be genetically more sus-ceptible to cancer. Several gene products thatcould be involved in determining one’s inheritedpredisposition to cancer are genes for DNA repair,immune function, and carcinogen metabolism.

Certain complex pathways of DNA repair arebeginning to be understood in higher animals. Ifdamaged DNA is repaired in such a way that thenucleotide base is the same as the old, no perma-nent change has taken place. On the other hand,if mistakes are made during DNA repair due todeficiencies in the repair enzymes, the new basesequence will be different from the original one,and, by definition, a mutation will now exist.Hence, this deficient repair may play an intimaterole in the mechanism of formation of some kinds

● Som[? agents, known as “complete carcinogens ,“ ran act as hthi n i t ia to rs and p r o m o t e r s .

of mutations, Individuals who have deficient path-ways of DNA repair might then be more suscep-tible to cancer.

Immune deficiencies, or the inability to fight dis-ease, also might predispose one to cancer. If ini-tiation is the result of a somatic cell mutation, thenpotential cancer cells would continually beformed in our bodies at a low frequency. An effi-cient immune system would recognize these can-cer cells as “foreign” and kill them. Hence, re-duced immune function may increase the risk forcancer. Indeed, many chemical carcinogens arealso immunosuppressants, and this has been spec-ulated to be part of their carcinogenic mechanism.Organ transplant patients who receive massivedoses of immunosuppressants are at increasedrisk for developing cancer later (8).

Finally, genetic differences in the ability to me-tabolize chemical agents to carcinogens may beinvolved in determining an individual’s predisposi-tion to cancer. Many chemicals alone are notharmful, but in mammals a metabolic activationby complex enzymatic systems can occur to forman active carcinogenic compound. However, thereare also enzyme systems that deactivate poten-tial carcinogens by forming compounds that aresafely eliminated from the body.

Hence, a person who is deficient in DNA repairor cellular immune function or who has higherlevels of the activation enzymes or lower levelsof the deactivation enzymes may be more suscep-tible to chemically induced cancer than someonewho is competent in DNA repair or immune func-tion or who does not activate specific chemicalsto carcinogens very well or who efficientlyeliminates potential carcinogens by deactivation.Because each of these critical functions may showa wide spectrum of activity, cancer susceptibili-ty may be quite variable as well (2,4).

Body fluids used in genetic testing

The detection of genetic traits or abnormalities eral sources of body fluids are available, but usual-in humans presents special problems because ly blood, urine, and feces have been used intests for these factors must be noninvasive, that genetic tests. Because they are waste material andis, they must use easily obtainable material. Sev - do not participate in the normal functions of the


body, urine and feces have limited application ingenetic testing. Their current use is as sourcesof material for the detection of mutagens. Theassumption is that the presence of mutagens inwaste material indicates that those mutagens alsowere present in body tissues.

Only blood serves as an easily obtainable sourceof body fluid and cells for genetic tests, and, again,an assumption is made that blood reflects eventshappening in the other parts of the body. An argu-ment against this assumption is the fact thatchemicals act in tissue-specific manners. On theother hand, in experimental situations with ani-mals, it has been found that blood cells do reflectexposure levels. In addition, because blood is soeasy to obtain, much of the research on geneticmutations in humans has been done on blood pro-teins.

Blood can be divided into two components: cellsand serum, the fluid in which they float. Serumcan be assayed for three types of compounds: pro-teins normally found in serum such as clottingfactors, protein degraders, and antibodies; pro-

Chapter 4 references1.

2.

3.

4.

5.

6.

teins from liver cells, some of which are impor-tant in carcinogen metabolism; and mutagens.

The two types of blood cells, red and white, canbe used to detect genetic traits or abnormalities.Red blood cells, or erythrocytes, have both en-zymatic functions and an oxygen-carrying func-tion, handled by the protein complex called he-moglobin. Because the red cells are so easily ob-tained, a great deal is known about both the nor-mal and genetic variants of erythrocyte proteins,In addition, hemoglobin is probably the easiestprotein in the body to isolate in large quantities.For these reasons, tests to identify genetic orchemical variants of hemoglobin have been usedto detect the presence of mutagens and are in-cluded in this assessment.

White blood cells, or leukocytes, are a hetero-geneous set of cells involved primarily in the im-mune functions. A subset of these cells, the lym-phocytes, are the cells most often used to detectmutagenic activity. It is the lymphocytes that areassayed for chromosomal aberrations and SCEs.Many other biochemical tests to detect mutagen-esis also use lymphocytes.

Crow, J. F., “How We]] Can We Assess GeneticRisk? Not Very,” Lauriston S. Taylor Lectures inRadiation Protection and Measurement, LectureNo. 5. (Washington, D, C.: National Council on Radi- 7<

ation Protection and Measurements, 1981).Harris, C. C., et al., “Individual Differences inCancer Susceptibility, ” Ann. Int. Med. 92:809-825,1980. 8.Latt, S. A., et al., “Sister Chromatid Exchanges: AReport of the Gene-Tox Program)” Mutat. Res. 87: 9.17-62, 1981.Marks, P. A., “Genetically Determined Susceptibili-

Technologies for Determining Cancer Risks Fromthe Environment (Washington, D.C.: U.S. Govern-ment Printing Office, OTA-H-138, June 1981).Perry, P., and Evans, H. J., “Cytological Detectionof Mutagen-Carcinogen Exposure by Sister Chro-matid Exchange, ” Nature (London) 258:121-125,1975.Siskind, G. W. (cd.), Immune Repression andCancer (New York: Grune & Stratton, 1975).Swift, M., et al., “Reassessment of Cancer Predis-position of Fanconi Anemia Heterozygotes, ” JNCZ65:863-867, 1980.

ty to Cancer,” g~ood 58:415-419, 1981. 10. Taparowsky, E., et al., “Activation of the T24 Blad -McKusick, V., ‘( Mendelian Inheritance in Man” der Carcinoma Transforming Gene is Linked to(Baltimore: Johns Hopkins University Press, 6th a Single Amino Acid Change, ” Nature (London)cd., 1982). 300:762-765, 1982.Office of Technology Assessment, US. Congress,

Chapter 5

Principles of Genetic Testing

Contents

P a g e ,Validity) Reliability, and Predictive Value.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57Relative Risk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59OTA’s Assessment of Occupational Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

List of Tables

Table Page12. Calculation of Predictive Value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5913. Influence of Genotype Frequency on the predictive Value of Screening Tests.. . . . . 5914. Influence of Genotype Frequency and Relative Risks on the Proportion of Workers

at Risk for Harmful Reactions Who Will Have Positive Screening Test Results . . . . . 60

Figure

Figure Page7. Example of a Hypothetical G-6-PD Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Chapter 5

Principles of Genetic Testing

Genetic testing of employee populations is abasic method for identifying individuals or groupswith particular inherited traits or evidence of ge-netic damage in certain cells who may be at in-creased risk for disease. It is the application oftests to a group of apparently well persons inorder to identify those who have a high probabili-ty of developing a disease so that prevention orearly treatment is possible. Genetic testing in-volves laboratory examination of body fluids suchas blood to determine the presence of inheritedtraits or changes in chromosomes or deoxyri-bonucleic acid (DNA). It includes both geneticscreening and genetic monitoring. Each usesspecific laboratory tests but the goals of each areslightly different.

A genetic screening test is a one-time procedureused in occupational settings to identify individ-uals with certain inherited traits. Some scientistshave hypothesized that these traits may cause theindividual to be at increased risk for certain oc-cupational diseases when exposed to hazardouschemicals (1). Because these inherited traits donot change, a single test for them is sufficient.

Genetic monitoring periodically examines in-duced genetic damage in certain cells of workers.Some scientists believe that certain types ofgenetic damage may indicate exposure to hazar-dous agents and may be associated with an in-creased risk for certain diseases, in particularcancer, The laboratory tests search for endpointsdifferent from those used in genetic screening,

and the procedures are applied initially to deter-mine a baseline of genetic damage prior to ex-posure and then periodically to determinechanges in that damage. Changes in certain ge-netic characteristics of the population may indi-cate that the population is at an increased riskfor disease.

Before a rational decision can be made on thevalue of any genetic screening or monitoring pro-gram in the workplace, two questions must beanswered. The first is: “Does the test being em-ployed reliably identify either the genetic trait ortype of damage in question?” The answer to thisquestion requires an assessment of the particularlaboratory techniques used to identify genetictraits or genetic damage from exposure to haz-ards. Only after achieving a positive answer tothis question can the following question be asked:“Does this particular trait or damage cause theindividual or population to be at increased riskfor disease?” The answer to this question involvesassessing the conclusions of epidemiologic stud-ies regarding the association between these ge-netic factors and disease. Available scientific evi-dence indicates that the first question can be an-swered in some cases; the answer to the secondone awaits significantly more research. In ascer-taining whether the test identifies either a genetictrait or damage, the tests must be subjected toscientifically recognized analytical criteria: valid-ity, reliability, predictive value, and relative risk(6).

Validity, reliability, and predictive value

The validity of genetic testing—i.e., the proba- ance) and biological (i.e., the influence of otherbility that a test will correctly classify true sus- genetic as well as environmental factors).ceptible (“positive”) and true nonsusceptible (“neg-ative”) individuals—should be evaluated before the From the distribution of the test results in thosetest is placed into routine use. Few tests are 100 for whom the presence or absence of a geneticpercent valid. The reasons are both methodology - endpoint (trait or genetic damage) has been con-cal (i.e., the inherent variability in test perform- firmed, the validity of the test at different cutoff

57


points can be determined (fig. 7). Two separate,independent characteristics are subsumed undervalidity; each depends on the cutoff point that isselected. These are:

●

●

sensitivity, or true positive ratio—the fre-quency with which the test will be positivewhen the genotype in question is present;andspecificity, or true negative ratio—the fre-quency with which the test will be negativewhen the genotype in question is absent. Anideal test would be 100 percent sensitive and100 percent specific. In actual practice thisdoes not occur.

Sensitivity and specificity are usually inverselyrelated. That is, one usually achieves high sensi-tivity at the expense of low specificity and viceversa. This can be demonstrated by examininga hypothetical situation to determine the cutoffpoint for a screening test (fig. 7).

The selection of the actual cutoff point dependson the objective of the screening or monitoringtest. If the objective is to identify all individualswith the abnormal genotype or genetic damage,cutpoint A would be selected. As the figure shows,such a cutpoint will pick up all true positives, butit will also result in many false positives. If nofollowup test is planned in the routine operation

of a screening program, this cutoff point wouldmislabel many people as affected who are not.With cutoff point B, no individuals would be false-ly labeled as affected, but some affected individ-uals would be falsely labeled as unaffected. Meth-ods of determining the cutpoint that minimizecosts of mislabeling or that maximize the infor-mation to be gained from the screening tests areavailable (5,7),

In addition to validity, reliability under condi-tions of routine use must also be demonstrated.That is, tests of the same specimen must repeated-ly give the same result whether performed by sev-eral different laboratories or by the same labo-ratory on several occasions.

predictive value is related to sensitivity, speci-ficity, and the prevalence of the trait or geneticdamage in the population. When the prevalenceof a particular trait or genetic damage is low inthe population, even a highly specific test will givea relatively large number of false positives be-cause many persons being tested will not havethe endpoint. The likelihood that an individualwith a positive test has the disease, and vice versafor a negative test result, is the predictive valueof the test. The importance of prevalence for thepredictive value of a test can be seen in the follow-ing example. Table 12 presents hypothetical data

Figure 7.—Example of a Hypothetical G-6-PD Distribution


Ch. 5—Principles of Genetic Testing ● 5 9

Table 12.—Calculation of Predictive Valuea

Number with Number withpositive test negative test Total

Genotype present . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990 1,000Genotype absent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990 98,010 99,000

Totals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,980 98,020 100,000

Predictive value of a positive test result = 9 9 0 = 0 . 5 0

1,98098,010 = 0.9999Predictive value of a negative test result = —98,020

sensitivity, specificity = O 99.SOURCE: N A Holtzman, “Principles of Screening Applied to Testing for Genetic Susceptibilities to Harm From Workplace Exposure,” prepared for OTA, September 1982

for calculating the predictive value of a positivetest result for a genotype frequency of 1 percent(1,000/100,000) (2). Even where the sensitivity andspecificity are arbitrarily set high, 0.99, the posi-tive predictive value is only 50 percent. Thismeans that the test correctly measures the resultonly half the time; in the case of genetic screen-ing, half of the workers with positive test resultswould, in fact, not have the predisposing geno-type. Followup testing would have to be a partof a screening or monitoring program in orderto detect the false positives or false negatives.

Table 13 shows the influence of selected fre-quencies when a cutpoint for the screening test

is used that yields both a specificity and a sen-sitivity of 0.99. The predictive value of the positivetest will vary between O and 0.92 percent as thefrequency of the genotype varies between 1 and10,000 per 100)000 (0.001 to 10 percent) peoplescreened. The chance that a person with a nega-tive test result does not have the genotype is alsoshown. Note that all the predictive values for anegative test result in the table are very close to1.0. A genotype frequency (prevalence) of approx-imately 50 percent (not shown) is needed beforethe predictive value of a negative test rises to 0.99(3,6).

Table 13.—lnfluence of Genotype Frequency on the Predictive Value of Screening Testsa

Frequency of the genotype (per 100,000)1 10 100 1,000 10,000

Predictive value of a positive test result . . . . . . . . . . . . . . . . . . 0 0.01 0.09 0.50 0.92Predictive value of a negative test result . . . . . . . . . . . . . . . . . . 1 1 1 1 1%ensitivlty, specif~clty =0 99.SOURCE: N. A. Holtzman, “Principles of Screening Applied to Testing for Genetic Susceptibilities to Harm From Workplace Exposures,” prepared for OTA, September 1982,

Relative risk

The proportion of workers likely to contracta disease depends not only on the previously men-tioned variables (reliability, validity, frequency ofthe genotype), but on the relative risk for thedisease imposed by the genetic trait or damage.Information for calculating relative risk* can be

● Relati\re risk is the ratio of the incidence of disease among ex-posed persons divided by the same rate among nonexposed per-sons.

collected in two ways. In the prospective ap-proach, all individuals comprising the populationexposed to the agent would be tested for the gen-otype and followed for a set period of time todetermine the incidence of harmful effects inthose with the specific genotype and in thosewithout it. Alternatively, a retrospective studycould be used to compare the frequency of thegenotype among workers who developed the


harmful reaction to the frequency in workerswho did not. (Note: The latter approach wouldyield a risk ratio which is a close approximationto the relative risk measure.)

Table 14 shows the influence of relative riskand genotype frequency on the proportion ofworkers at risk for harm from exposure dis-covered by a test whose sensitivity and specifici-ty are set equal to 0.99 (3). For example, with agenotype frequency of 1,000/100,000(1 percent),those with the genotype must be 100 times morelikely to suffer adverse reactions before thescreening test will discover half of those who willsuffer harm. In addition, in this table and the twopreceding tables, sensitivity and specificity levels

Table 14.-lnfluence of Genotype Frequency andRelative Riska on the Proportion of Workers at Risk

for Harmful Reactions Who Will Have PositiveScreening Test Resultsb

Frequency of Relative riskgenotype (per 100,000) 5 10 50 100

Proportion of at-risk workersdiscovered by screening

1 0.01 0.01 0.01 0.0110” : : : : : : : : : : : : : : : : 0.01 0.01 0.01 0.02100 . . . . . . . . . . . . . . . 0.01 0.02 0.06 0.101,000 . . . . . . . . . . . . . . 0.06 0.10 0.34 0.5010,000 . . . . . . . . . . . . . 0.36 0,53 0.64 0.91‘Relative risk = incidence of adverse reaction in

those with the susceptible genotypeincidence of adverse reaction Inthose without the susceptible genotype

bSensitivlty, specificity set at = 0.99SOURCE: N, A. Holtzman, “Principles of Screening Applied to Testing for Genetic

Susceptibilities to Harm From Workplace Exposures,” prepared forOTA, September 1982.

have been set at 0.99 in order to elucidate theother components. In actual studies sensitivityand specificity are never as high. Thus, the abili-ty to detect predisposing factors is further com-promised.

From this discussion, it is clear that attentionmust be paid to validity, reliability, predictivevalue, and relative risk or screening and monitor-ing in the workplace may turn out to be costlyand of little benefit. The less frequent the geneticendpoint being tested, the less likely that the per-son with a positive test result will truly have thattrait or damage. Unless testing of high validity isrestricted to conditions in which the frequencyof the trait or damage is high, a significant num-ber of false positives and false negatives can beexpected. False positives increase the social, eco-nomic, and psychological costs of screening; falsenegatives reduce the health benefits, When thefrequency of the endpoint is high, however, low-ering exposure for the entire work force may bethe most effective way of reducing disability. Ifa genetic screening program were instituted, apopulation that would ensure a relatively high fre-quency (greater than 1 percent) of the trait of in-terest should be chosen, One way to increase thefrequency in a population is to select a subgroupthat is expected to have a higher frequency of thetrait than the general population. A monitoringprogram should be instituted only when bacterialand animal tests have proven that the chemicalin question is mutagenic or carcinogenic. More-over, worksite sampling should establish that thehazardous agent is present in areas where work-ers would be significantly exposed.

OTA’s assessment of occupational studies

The correlation of a test endpoint (for exam-ple, chromosomal damage) with the later occur-rence of disease is difficult to ascertain becausethe possibility remains that adverse consequencesfrom exposure will not occur in all of those withthe predisposing condition; other genetic or en-vironmental factors (for example, smoking) maybe necessary for the development of the diseaseor may contribute differently in different indi-

viduals. Because an illness may have multiplecauses, it may also occur in workers without thepredisposing condition. Thus, genetic tests mayidentify only a proportion of the workers whowill develop adverse reactions,

Part III of this report contains OTA’s assessmentof relevant monitoring and screening studies con-ducted on human populations. The following cri-

Ch. 5—Principles of Genetic Testing . 61

teria were applied to determine whether the ●

studies were based on sound methodological ap-proaches (4):

• Is the observed association consistent? That●

is, has the same association been observedin similar studies?

●

● Is the association specific? Was there a mixof exposure levels or grouping of individualssuch that the precise nature of the effect ofexposure is difficult to ascertain?

● Is the strength of the association strong? Isit strong enough to indicate a causal relation-ship between exposure and disease?

Is there a dose-response relationship? Doesit appear that higher exposure levels are as-sociated with higher prevalence of thedisease?Is there a biological mechanism to explain theassociation?Was the study designed so that the assump-tions of statistical methodology were met?Has the sample been properly drawn?

Chapter 5 references ___

1. Buffler, P., manuscript of Presentation to the Amer-ican Council of Governmental and Industrial Hygien-ists Conference on the Sensitive Worker, Tucson,Ariz., November 1981.

2. Galen, R. S., and Gambino, S. R., Beuvond Abrrnalituv 5(New York: John Wiley, 1975).

3. Holtzman, N. A., “Principles of Screening Applied 6.

Chromatid Exchange,” Mutat. Iles. 99:373-382, 1982,Elsevier Press, International Commission for pro-tection Against Environmental Mutagens and Car-cinogens, ICPEMC Working Paper 5/2.McNeil, B. J., et al., iVetv Eng). J. Med. 293:211-215,1975.National Academy of Sciences (NAS), Genetic Screen-

to Testing for Genetic Susceptibilities to Harm From kg: Programs, Principles and Research, CommitteeWorkplace Exposure, ” prepared for OTA, Septem- for the Study of Inborn Errors of Metabolism (Wash-ber 1982. ington, D. C.: NAS, 1975).

4. Hook, E. B., “Epidemiologic and Design Aspects of 7. Weinstein, M, C., and Feinberg, H. t’., Clinical De-Studies of Somatic Chromosome Breakage and Sister cision Ana@sis (Philadelphia: W. B. Saunders, 1980).

Part III

An Assessment of theState of the Art

Chapter 6-Genetic Monitoring in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Chapter 7-Genetic Screening for Heritable Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

.—— — .——

Chapter 6

Genetic Monitoringin the workplace

Contents

Cytogenetic Monitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Associations Between Chromosomal Aberrations and Disease . . . . . . . . . . . . . . . . . . . . .Correlation Between Chromosomal Aberrations, SCEs, and Carcinogenicity . . . . . . . . .Chromosomal Studies on Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Studies on Unexposed Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Studies on Atomic Bomb Survivors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Occupational Studies on Ionizing Radiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Occupational Studies on Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Occupational Studies on Benzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ... .....Occupational Studies on Epichlorohydrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Occupational Studies on Ethylene Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Occupational Studies on Lead, Cadmium, and Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . .Occupational Studies on Vinyl Chloride Monomer . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Priorities for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Noncytogenetic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Survey of Monitoring Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Mutagens in Body Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Somatic Cell Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Germ Cell Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Priorities for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

List of Tables

Table No.15. Summary of Noncytogenetic Monitoring Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . .16. A Summary of Noncytogenetic Methods Used in Human Monitoring . . . . . . . . . . . . .

Page6768676970707171727272727374747575757779798080

Page7680

Chapter 6

Genetic Monitoring in the workplace

Although humans have been exposed to chem-icals and radiation for thousands of generations,the numbers and amounts of these potentiallyhazardous agents in the environment have in-creased dramatically since the industrial revolu-tion. Moreover, certain occupational groups areexposed to these substances over many years atmuch higher concentrations than is the generalpopulation.

While the contribution of toxic chemicals andionizing radiation to the human genetic burdenhas not been directly shown, some of these agentsdo cause mutations and chromosomal damage inlaboratory animals. Geneticists are concerned thatexposures to new mutagenic agents could in-crease the number of gene mutations in thehuman population and hence the incidence of dis-ease. Because of the increasing chances for ex-posure to harmful agents, it is desirable to developtests that identify the mutagenic and clastogenic(chromosome-damaging) potential of chemicalsand ionizing radiation. When hazards are iden-tified, prevention programs can he consideredthat will reduce exposures to the hazards. In ad-dition, genetic tests may be useful to monitorhuman populations for exposure.

Ideally, an occupational monitoring techniquewould provide early, reliable, and quantitative in-formation regarding “biologically significant”exposure * to hazardous agents. Once a biological-

““1’he ciefinitlon of’ hiolr~gl(allj signifi(’ant ” exposure is a difficult011(1, and there IS hj no means a concurrence of opinion amonghealttl (art’ pr[)f[~ssionals I t normallj ref(~rs to an [~xposure Imelt h a t can (’aust> detwtdhle dtirnage or- dis(>ase

ly significant level of exposure has been estab-lished, intervention measures to eliminate or sig-nificantly reduce worker exposure and preventuntoward biological effects could be imple-mented.

Genetic monitoring in the workplace involvesthe periodic testing of employees to assess damageto their deoxyribonucleic acid (DNA) or chromo-somes from exposure to hazardous agents. Cur-rently, genetic monitoring techniques are mostuseful for identifying or monitoring exposure toa chemical that causes genetic damage. The ob-jective of these techniques ultimately is to predictrisk of disease due to genetic damage.

There are two types of techniques covered inthis assessment. The first type, cytogenetic tech-niques, looks for gross changes in chromosomalstructure. These techniques, including tests forchromosomal aberrations and sister chromatidexchange (SCE), represent the currently usedmethods for monitoring for genetic damage.Other monitoring techniques that also look fordamage to the genetic material have been pro-posed for human populations. These newer non-cytogenetic techniques may offer advantages insensitivity, cost, and performance time over thecytogenetic methods, often because of automa-tion, but most of them have had little actual ap-plication in human monitoring programs at thepresent time. This chapter reviews the occupa-tional studies done to date, first examining theuse of cytogenetic monitoring and then noncy-togenetic monitoring.

Cytogenetic monitoring

The empirical association between chromo- SCEs may be used as possible biological dosi-somal damage and mutagenic/carcinogenic agents meters (measures of exposure) for human ex-established from animal studies implies that posure to these agents. There are three naturalchemically induced chromosomal aberrations and extensions of this dosimeter hypothesis. One is

67


the idea that studies using cytogenetic endpoints*may be used to identify human carcinogens ormutagens. * * The second is that these studiesmight identify populations at risk for cancer andother diseases as a result of exposure to theseclastogens. Last, the studies may identify individ-uals in those populations who, because of a defectin DNA repair mechanisms, may be particularlypredisposed to chromosomal damage. In theworkplace, the goals of such studies would be todetermine acceptably safe levels for occupationalexposure to chemicals and radiation (that is, thoselevels associated with minimal, or acceptable, riskof disease) for the average population and to insu-late susceptible individuals from the chemical.

This section examines the appropriateness ofchromosomal endpoints to detect occupational ex-posures to chemicals and radiation. This criticalreview of the literature seeks to determinewhether chromosomal endpoints can be used asa measure of occupational exposures and whetherthe results of cytogenetic monitoring are a predic-tor of risk for disease for either groups or in-dividuals. The discussion is limited to studies thatare pertinent to adult somatic effects resultingfrom occupational exposures.

Associations between chromosomalaberrations and disease

Many diseases are thought to involve somaticcell genetic defects. Interference with immunefunction, manifested as autoimmune disease, al-lergy, or increased susceptibility to infectiousagents, may involve somatic cell genetic changes.Hence, induced chromosomal aberrations mayprove to be related to these clinical states. How-ever, there are no studies, either in animals orin man, that address the possible association be-tween induced chromosomal aberrations or SCEsand immune function,

. —‘The term endpoint refers to the biological response to exposure

being monitored. In this section, two endpoints are discussed, chro-mosomal aberrations and SCEs.

● *Studies would not be done primarily to investigate this issue,but results identifying human carcinogens or mutagens could derivefrom cytogenetic studies investigating risk for disease. The iden-tification of mutagens and carcinogens is done with animals andextrapolated to humans; cytogenetic studies would either verify theanimal data or refute the extrapolation.

Photo credit: National Institutes of Health

Cytogenetics involves the examination of chromosomesunder a microscope

other diseases of the blood/lymph system, suchas aplastic anemia and multiple myeloma, alsomay be the result of somatic cell genetic changes.Because cytogenetic monitoring usually utilizesblood lymphocytes as the chromosomal source,cytogenetics may prove useful in predictingwhether individuals exposed to high levels ofclastogens may be candidates for these blood celldiseases, but this association is only speculative.

Cancer is the disease most commonly hypothe-sized to be associated with induced chromosomalaberrations, undoubtedly because of the largeanimal literature linking carcinogens with chro-mosomal aberrations. Additionally, many typesof human cancer cells contain specific chromo-somal aberrations (31,34,63,76,93,99,141). Chro-mosomal aberrations have been found for bothlymphoproliferative disorders, such as leukemia,

Ch. 6—Genetic Monitoring in the Workplace ● 6 9

and solid tumors. The strength of the associationbetween the specific aberration and the presenceof cancer varies from one cancer to another. Atone extreme, the Philadelphia chromosome (atranslocation from the long arm of chromosome#22 most often to the long arm terminus of chro-mosome #9) correlates highly with chronic mye-logenous leukemia, with 85 to 95 percent of pa-tients having this marker chromosome in theiraffected cells. On the other hand, in the case ofa pair of identical twins, each carrying the specificdeletion associated with Wilms tumor, only oneof the twins developed the disease (76). Thus, evenwhen specific chromosomal markers are involved,other nongenetic factors can play a role in thedevelopment of cancer.

Correlation between chromosomalaberrations, SCEs, and carcinogenicity

The extensive literature on animal studies thatuse chromosomal endpoints has recently been ap-praised and reviewed by the U.S. EnvironmentalProtection Agency’s (EPA) Gene-Tox Programcommittees (80, 113). The Gene-Tox committee formammalian in vivo and in vitro cytogenetic assays(chromosomal aberrations) reviewed 177 paperspublished through October 1978 using severalsomatic cell systems (113). For one or another ofthese systems, 150 chemicals were reviewed.

According to the Gene-Tox findings for chro-mosomal aberrations and SCEs, the data base forchemicals that have been adequately studied inanimal or in in vitro systems is quite limited, andthe number of the chemicals for which carcino-genicity is known is even more limited. In addi-tion, the carcinogenicity data were generated inseparate studies from the chromosomal data andare not directly comparable. But within theserestrictions, it would appear that the inductionof chromosomal aberrations and SCEs by chem-ical agents are reasonable indicators of car-cinogenicity, with the former possibly being thebetter predictor. However, for both endpoints,examples exist of chemicals that cause chromo-somal damage but not cancer, and vice versa. Inorder to relate genotoxicity more closely tohumans, the Gene-Tox review recommended hu-man cells as being suitable for in vitro studies.

The review is still is progress, and EPA has yetto issue any recommendations on the predictivevalue of any of the techniques.

A recent review by Gebhart (57) summarizesthe world’s literature concerning the agreementbetween chromosomal aberrations and SCEs.Gebhart found a 30 percent disagreement be-tween these two endpoints where the same chem-ical had been evaluated for aberrations and SCEsboth in vitro and in vivo. This indicates that thefundamental way in which a particular chemicalinteracts with the DNA to produce SCEs may bedifferent from the mechanism that produceschromosomal aberrations.

Chromosomal studies on groups

This section provides a comprehensive reviewof occupational studies using chromosomal end-points. Many of the studies fall short of ideal. Forinstance, confounding factors, such as cigarettesmoking, were not always determined, and somestudies examined populations too small to pro-duce reliable results. In general, more recentstudies are better designed and executed. How-ever, rather than discard the evidence of the olderstudies, the strengths and weaknesses of all thestudies are reviewed, and overall conclusions aredrawn.

The review covers studies addressing the nor-mal range of values for chromosomal endpoints,studies on the chromosomal endpoints and healthstatus of atomic bomb survivors exposed to ioniz-ing radiation, and occupational studies on thechromosomal endpoints of workers exposed toionizing radiation and specific chemicals.

For the occupational studies, the following ques-tions were asked:

●

●

●

Was there substantial evidence of an increasein the endpoint that could be associated withexposure to a specific agent? was there adose response? Were chronic as well as acuteexposures monitored?Was there evidence to link any of these end-points with increased risk for disease?Are these tests sufficiently sensitive to per-mit detection of effects at current occupa-tional exposures?

70 . The Role of Genetic Testing in the Prevention of Occupation/ Disease

• For each of the agents discussed in detail, isthere evidence that cytogenetic endpoints candetect susceptible individuals?

STUDIES ON UNEXPOSED POPULATIONS

Several large studies have examined the rangeof chromosomal aberration and SCE frequenciesand the variables affecting them in unexposedpopulations (13,15,28,29,35,59,71,79,86,88,90,95,100). Seasonal variations, age, sex, smoking,and alcohol effects have been reported, althoughnot consistently for every study. From these stud-ies, it is apparent that background frequenciesfor chromosomal aberrations and SCEs may fluc-tuate greatly. The background frequencies re-ported in several studies are shown in appendixD for chromosomal aberrations and in appendixE for SCEs. Comparison of findings from studieswith varied laboratory methodology is difficultbut useful to the extent that it conveys a senseof possible variability for these endpoints.

The range of reported frequencies per cell forindividual aberrations found was:

● chromatid breaks: 0.11 to 6.72 percent,. chromosome breaks: 0.1 to 3.0 percent,● exchange aberrations: O to 0.34 percent,● cells containing any aberration: 0.2 to 8.5 per-

cent, and● SCEs: 5.8 to 16.2 per cell.

These wide variations suggest that the rangeof “normal” values for chromosomal endpointsmay be dependent on the particular laboratorymethodology. Certainly the fortyfold differencesseen for background values of chromosomal aber-rations are much greater than those reported inindividual studies between occupationally ex-posed and unexposed groups.

STUDIES ON ATOMIC BOMB SURVIVORS

Since the end of World War II, the Japanesesurvivors of the atomic bombs and their offspringhave been extensively monitored by the AtomicBomb Casualty Commission, recently redesig-nated the Radiation Effects Research Foundation,for residual and latent biological effects, Thesestudies have been a joint effort between eminentJapanese and American scientists and are ongo-

ing (102). Refinements are still being made indosimetry estimates and epidemiology.

This Japanese population has been observed tohave an increased risk for many types of cancer(14). Leukemias were the first evident cancers,with incidence peaking 7 to 8 years after ex-posure, The incidence of all leukemias for thispopulation has subsided with time, but it is notclear if the risk for leukemias has declined tobackground values.

With the decline of leukemias, the onset ofother types of cancer has become apparent. Todate there is a clearly increased risk for cancersof the thyroid, female breast, and lung. Excessstomach and salivary gland cancers are suspectedbut not yet confirmed. In contrast to the leu-kemias, the time of onset for breast cancer in ex-posed populations has not been earlier thanwould be predicted on the basis of studies inunexposed populations. Rather, breast cancer hasappeared at a higher, dose-related frequency atthe age when it usually occurs. All of thesecancers have shown a dose dependence for radia-tion, but the shape of the dose-response curvesdiffers with different cancers. These differencesin patterns of cancer incidence are consistentwith the widely held opinion that the mechanismsof radiation-induced cancers are complex andperhaps different from one cancer to another.

In conjunction with these morbidity and mor-tality studies, extensive cytogenetic investigationson these survivors have revealed a dose-depend-ent increase in chromosomal aberrations (14).These cytogenetic studies have been possiblebecause some of the chromosomal abnormalitiesinduced by ionizing radiation are very long lived.The frequencies of these aberrations seen in theatomic bomb survivors are very high comparedto the aberration frequencies found in occupa-tional exposures, even in individuals receivingsmall doses (less than 1 rad * ). The reason for thisis unknown.

The ongoing epidemiological studies on thesesame individuals provide an unparalleled oppor-tunity to examine directly the relationship be-

*A ~a~ is a measure of absorbed dose of ionizing radiation,

Ch. 6—Genetic Monitoring in the Workplace . 71

tween chromosomal aberrations and cancer. Inan extensive study reported by King, et al. (75),where chromosomal aberrations, malignancy, andother clinical findings were tracked for individ-uals in the Hiroshima population, the tentativeconclusion was that such correlations do not exist.

with populations or groups, however, the stud-ies on the Japanese clearly demonstrate a relation-ship between estimated radiation dose and cer-tain cancers and between radiation dose andchromosomal aberrations. But for individuals, ele-vated frequencies of chromosomal aberrationsare not reliable predictors for risk of cancer orother somatic cell diseases. Thus, even these ex -tensive studies do not provide evidence that radia-tion-induced chromosomal aberrations mean thatindividuals with these aberrations will necessarilydevelop cancer.

Several points should be borne in mind in re-lating these studies to the ionizing radiationstudies discussed below. First, the Japanesestudies reported quite high frequencies for rareaberrations, even in groups receiving less than1 rad. Second, because of the manner in whichthe studies were designed, little or no cytogenet-ic information is available on the group receiv-ing exposures between 1 and 100 rads. This groupis probably the most comparable, in terms ofequivalent genotoxic dose, to groups receiving oc-cupational exposures to radiation. Thus, becauseof the different types of chromosomal aberrationsinvolved and, because of probably larger radia-tion doses in the exposed Japanese populations,it is difficult to relate the significance of these find-ings to occupational studies. Finally, the Japanesestudies deal with the effects of a single, large,acute dose of radiation. In the majority of occupa-tional situations, the effects of chronic lowerdoses of radiation may not be so easily detected.

OCCUPATIONAL STUDIES ON ION1ZING RADIATION

If chromosomal aberrations induced by radia-tion are indicative of some health risks, albeit fora group, then occupational cytogenetic studies onworkers exposed to chronic lower doses of radia-tion may be of some value in setting acceptablestandards for occupational exposure to radiation.Several occupational studies have been done onuranium miners, workers in a plutonium process-

ing facility, and nuclear powerplant workers(17,20,21,22,23,46,89,98). Every study reviewedhas shown that increases in chromosomal aber-rations are associated with occupational ex-posures to ionizing radiation. If these aberrationsare as stable as those in the Japanese, they wouldnot necessarily indicate recent exposures undercurrent occupational exposure standards, butrather accumulated exposure over several years..

From these studies, it is not clear if the chro-mosomal aberration endpoint is sensitive enoughto detect chronic exposures within the currentoccupational exposure standard of 5 reins* peryear. occupational groups would have to bestudied at low-level chronic exposures to deter-mine if individuals exposed to the current occupa-tional standard have increased frequencies ofaberrations.

OCCUPATIONAL STUDIES ON ARSENIC

Arsenic is a ubiquitous element that can occurin several chemical forms, some of which havecommercial uses as fungicides, insecticides, andherbicides. It also has been used for medicinalpurposes, for instance, in the treatment of ail-ments ranging from asthma to psoriasis and syph-ilis. When arsenic is eaten or inhaled, about 50percent of the dose is absorbed. Of the absorbeddose, roughly half is excreted within 2 days. Theremainder is eliminated more slowly, and a frac-tion can accumulate in the body, where it isdistributed in many different tissues (85). Arsenicis classified as a human carcinogen (72). Severaltypes of cancers have been associated with oc-cupational exposure to arsenic in smelters, in thechemical industry, and in gold mining (103).

Both chromosomal aberrations and SCEs havebeen reported to be elevated in individuals ex-posed to arsenic, with SCEs possibly being themore sensitive indicator (26,97,1 10). Chromo-somal effects of arsenic exposure are long livedand possibly reflect cumulative exposure. It is notclear if chromosomal endpoints can detect low-level chronic exposure to arsenic, because the ex-posures in the studies reviewed here were rela-tively high. The one study on arsenic in an oc-

‘~ rem is a raci multiplied b> a number that takrs into accountI}lf’ potential darnage<’ausing abilit} of a particular t~pe of ionizingradiation in a biological sl’stem.

,)— , .; – 27 - r,


cupational setting (97) is not sufficient to permita decision on the suitability of cytogenetic end-points for measuring exposure.

OCCUPATIONAL STUDIES ON BENZENE

Benzene is a constituent of fossil fuels and alsois a major industrial and laboratory chemical. Asa result, a substantial number of people arechronically exposed to benzene at work, andmany more receive transient exposures outsidethe workplace, for instance, while pumping gas-oline. As with arsenic, benzene is classified as ahuman carcinogen (72), with an excess of leu-kemias, particularly erythroleukemia, associatedwith high exposures (73,134), Benzene is also apotent blood cell poison, with manifestations in-cluding pancytopenia (reduction of all blood ele-ments) and aplastic anemia, The current occupa-tional exposure standard for benzene in theUnited States is 10 parts per million (ppm), a time-weighted average for 8 hours.

Benzene is one of the most widely studied chem-icals in occupational cytogenetics. Several studiesconsistently have shown that exposure to highdoses of benzene (greater than 40 ppm) is asso-ciated with chromosomal aberrations, eventhough frequencies are low in comparison withradiation-induced effects (52,53,54)111)112,131)132,136). The aberrations appear to be stable foryears and most likely reflect cumulative ratherthan recent exposure. Whether exposure to ben-zene within the current occupational standard of10 ppm induces chromosomal aberrations has yetto be determined.

OCCUPATIONAL STUDIES ON EPICHLOROHYDRIN

Epichlorohydrin is a highly reactive major in-dustrial chemical that has been extensivelystudied for genotoxic activity (126). It is mutagenicin microorganisms, causes chromosomal aberra-tions in mouse bone marrow, and induces chro-mosomal aberrations in human lymphocytes invitro (126). Epichlorohydrin causes nasal tumorsin rats by the inhalation route at levels higherthan 10 ppm (N. Nelson, unpublished study). Onestudy has indicated a slight, but not statisticallysignificant, excess in respiratory cancers amongworkers exposed to this chemical (45), and IARC

(72) found that it “could not be classified asto . . . carcinogenicity for humans.”

The only adequate cytogenetic study on epi-chlorohydrin (127) showed that occupational ex-posure to the chemical may be associated withlow frequencies of chromosomal aberrations. Nostudies have been done linking chromosomalaberrations with risk for disease in a populationexposed to epichlorohydrin.

OCCUPATIONAL STUDIES OF ETHYLENE OXIDE

Ethylene oxide is an extremely reactive chem-ical whose commercial uses are primarily as asterilizer of medical products and as a chemicalintermediate. Ethylene oxide has been shown tocause leukemias in rats by the inhalation routeat doses higher than 33 ppm (58). It can inducechromosomal aberrations in vitro and mutationsin tester micro-organisms (46). Because of ethy-lene oxide’s volatility, there is a high potential foroccupational exposure in situations where it is notproperly contained. The current OccupationalSafety and Health Administration’s (OSHA) oc-cupational exposure standard is so ppm, time-weighted average. Two reports (.57,68) suggest anincrease in leukemia among workers exposed tothis chemical.

Three published studies associate present levelsof ethylene oxide found in the workplace withchromosomal aberrations and possibly SCEs(56, 109, 130). However, frequencies for these end-points were low. Two additional studies on ethy-lene oxide (S. Galloway and A. Carrano, personalcommunication) are now being conducted. Pre-liminary reports on a study being conducted atthree Johnson & Johnson plants indicate a con-sistent dose-response for both chromosomal aber-ration and SCE endpoints. Statistically significantincreases in cytogenetic aberrations were seeneven in a plant where exposures range from 1to 10 ppm. No effects were found at less than 1ppm (32, 101).

OCCUPATIONAL STUDIES ON LEAD,CADMIUM, AND ZINC

Lead, cadmium, and zinc tend to occur togetherin mineral deposits in nature and, therefore, inoccupational exposures. High exposures to leador cadmium can produce both acute symptoms

— —. —

Ch. 6—Genetic Monitoring in the Workplace . 73

of poisoning and chronic effects. Lead poisoninginvolves nerve degeneration, interference withsome metabolic processes, and, in its severestform, mental retardation. Lead acetate is car-cinogenic in rats, but has been negative for chro-mosomal aberrations and SCEs in vitro (80,113).Cadmium has been shown to cause birth defectsand cancer in rodents, and there is some evidencefor human carcinogenicity (72). Occupational ex-posure to cadmium has been associated at leasttentatively with lung and prostate cancers (36).Both cadmium and lead tend to accumulate in thebody with chronic exposure, a point which maybe important in interpreting the occupationalstudies on these agents because damage may re-flect a cumulative exposure.

Zinc, unlike lead and cadmium, is necessary forthe function of some of the enzymes involved inDNA replication and repair, and it is possible that

Photo credit Occupation/ Safety and Healfh Administration

Cytogenetic monitoring has been explored as a possibletechnique for monitoring worker exposure to lead

cadmium and lead, when present in highamounts, can replace zinc in these enzymes. Ifthis happened, the enzymatic activity would begreatly reduced.

Many conflicting findings exist in the literatureaddressing occupational exposure to lead, cad-mium, and zinc (16)25,37,38,39 )50,51)69)89, 104,105,120, 132). Increased frequencies of chromo-somal aberrations and correlations with bloodlead values have been reported often enough toprovide some credibility to the correlations, butmany good studies have failed to find such rela-tionships. Perhaps one reason for such discrepan-cies is the diversity of occupational exposuresstudied. Different work situations could have en-tailed quite different kinds of exposures withrespect to the specific compounds in the workenvironment and possibly to different primaryroutes of exposure. The relationship between thethree elements and chromosomal aberrationsclearly is complex and awaits further elucidation.

OCCUPATIONAL STUDIES ON VINYLCHLORIDE MONOMER

Vinyl chloride monomer is a major industrialchemical used to make polyvinyl chloride plastics.It is mutagenic for tester micro-organisms andcauses chromosomal aberrations in rats treatedwith 1,500 ppm by the inhalation route, a veryhigh level (7). Vinyl chloride is a human car-cinogen (72) and has been implicated in severaltypes of cancer (103).

Elevation of chromosomal aberrations to rela-tively high levels by occupational exposure toviny I chloride is consistent and well documented(5,8,41,49,55,62,74,77,1 14,1 18,129). The chromo-somal aberration endpoint seems to be more sen-sitive than the SCE endpoint to vinyl chloride ex-posure. In contrast to the aberrations seen withbenzene, arsenic, and ionizing radiation, the aber-rations associated with vinyl chloride exposureare short lived, disappearing over days or weeks.The mechanism for this difference is unknown.Chromosomal aberrations, in this case, could beused to document recent exposure but not nec-essarily cumulative exposure. Elevations in chro-mosomal aberration frequencies have not beendetected when documented exposures have beenless than 5 ppm. (The OSHA standard states that


the vinyl chloride level shall not exceed 1 ppmduring any 15-minute period). Thus, chromo-somal aberrations and SCEs do not seem to besensitive enough to detect chronic low-level ex-posures to vinyl chloride for the number of cellsusually scored (200 or fewer) per individual.

Conclusions

Elevated chromosomal endpoints are associatedwith occupational exposures to ionizing radiationand may be associated with exposure to somechemicals (arsenic, benzene, and vinyl chloride),particularly where long- lived aberrations (arsenicand benzene) are involved. The nature and lon-gevity of the aberrations vary from one agent toanother. For some chemicals such as benzene, theaberrations may persist for years. In these in-stances, the aberrations would indicate a cumula-tive exposure. For others, such as vinyl chloridemonomer, the aberrations disappear quickly afterreduction of exposure, and the cytogenetic testscould monitor exposure only over short time peri-ods. It is not known whether cytogenetic monitor-ing will detect chronic low-level exposure. Hence,the appropriateness of chromosomal endpointsfor occupational monitoring needs to be deter-mined on a case-by-case basis for each chemical.In addition, a monitoring program should onlybe instituted when bacterial and animal tests haveproved that the chemical in question is mutagenicor carcinogenic,

No occupational studies directly relate positivefindings for any chromosomal endpoint with in-creased risk for any disease. Therefore, theclinical significance of a positive occupationalcytogenetic study is unknown; nor is it knownwhether cytogenetic monitoring can be used todetermine “safe” levels of exposure.

Retrospective cytogenetic studies done in con-junction with morbidity and mortality studies onpopulations of survivors of the atomic bomb at-tacks in Japan have found both high frequenciesof stable chromosomal aberrations, particularlycomplex aberrations, and increased risk of can-cer. On the other hand, there is no known cor-relation between an individual’s chromosomalaberrations and his or her risk for cancer.

Cytogenetic monitoring, or any other test basedon a single endpoint, may never be sufficient topredict health risks for an individual (with thepossible exception of the Philadelphia chromo-some) ) because the causes of cancer and otherchronic diseases are complex and multifactorial,with some genetic and some environmental com-ponents. As more is understood about the molecu-lar basis of each disease, an appropriate batteryof tests may be designed with a variety of end-points, each reflecting some aspect of the poten-tial causes, Given the present information, anysingle endpoint, such as chromosomal aberrationsor SCEs, may have some predictive value for agroup, Even findings about groups with increasedchromosomal damage require epidemiologicalstudies on the populations to determine if in-creased risk for disease accompany the damage.

More research is needed to identify any rela-tionships between chromosomal aberrations,SCEs, and disease in populations. At the presenttime, genetic monitoring may be most useful fordetecting exposure to harmful agents. The mostpressing questions yet to be answered concern-ing the use of monitoring in the workplace are:What is the biological significance of small eleva-tions of aberrations or SCEs? Is there consisten-cy between a given frequency of aberrations orSCEs induced by different agents and risk for dis-ease?

Priorities for future research

Additional occupational cytogenetics studies areneeded, combined with epidemiological investiga-tions, to define further the meaning of inducedchromosomal aberrations and SCEs, There is alsoa need to develop faster and easier tests for oc-cupational genetic monitoring. Discussions withscientists involved in this work led to the follow-ing

●

●

suggestions for future research:

There is a need to standardize the laboratoryconditions for cytogenetic tests.The best method of categorizing chromo-somal damage for analysis has not been de-termined. Perhaps more comprehensive andcritical analysis of results already availablecould contribute to the understanding of

.


both the effects of confounding variables andthe biological mechanisms involved in the in-duction of chromosomal aberrations andSCEs. It maybe worthwhile to single out thepercentage of cells with large numbers ofSCEs and to display the chromosomal aber-rations of each category for each individualin a study, including a distinction betweenthe percentage of cells with aberrations andthe percentage of aberrations per ceil.

• New cgytogenetic tests that are less labor in-tensive and that possibly could be automatedare essential if cytogenetic testing is to be con-ducted on a large scale. Manual scoring, suchas is done now, is so labor intensive and time-consuming that most cytogenetics laborator-ies in the United States are now working atcapacity. Test scorers require several yearsof training to reach the point of consistentscoring. The use of a fluorescent-activatedcell sorter has been studied as a possiblemeans of automating chromosomal analysis,but this technique has intrinsic insensitivitiesand has not successfully been used to detectlow frequencies of aberrations in humanchromosomes (107,140).

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Noncytogenetic monitoring –

Further research needs to be done on in vitrosensitivity of human lymphocytes to chem-icals encountered in the workplace. This ap-proach could eventually have some value inpredicting human clastogens as well as in-dividual sensitivities to clastogens.The variables influencing baseline (normal)frequencies of chromosome] aberrations andSCEs need to he elucidated.There apparently has not been a prospectivestudy done that looks for the association be-tween chromosomal aberrations and risk forsomatic disease in the same individual. Thereis a critical need for such studies, where indi-viduals with no previous occupational radia-tion or chemical exposure are tracked, withconcurrent comparisons. The National Insti-tute for occupational Safety and Health hasdeveloped protocols for studies on radiation-exposed workers, but has yet to begin them.Any study addressing biological effects ofcurrent occupational exposure standards forradiation or chemicals should examine someindividuals whose entire occupational historyhas been under the current standards.

Because of the need for inexpensive and rapidtests to monitor human exposure to mutagens,many tests originally developed to screen chem-icals for mutagenic activity have been modifiedto identify human exposure to mutagens. * All ofthese tests, either directly or indirectly, identifythe presence of mutagens or DNA damage result-ing from the presence of mutagens. Most of thesedevelopments are recent and, for the most part,have not been used for routine human monitor-ing.

——“The extensive literature on animal studies using noncytogenet -

ic endpoints for mutagenicity}’ or carcinogenecity has recently beenreviewed and evaluated by EPA’s Gene-Tox program (61). klost ofthe papers have yet to be published, but two reviews ha\’e beenpublished on specific mutation analysis in Chinese hamster cells( 1970). Both of these papers state that the correlation betweenmutagenicity in this t~’pe of assa}’ and animal carcinogenicit~r is high

Survey of monitoring methods

Virtually none of the tests described in table 15has as yet been established as a reliable techniquefor monitoring human populations. The only testapplied to population monitoring on more thana single trial basis has been the analysis of urinefor mutagens. A few of the remaining tests havebeen used in human pilot studies, but thesestudies were for baseline analysis and not actualmonitoring,

MUTAGENS IN BODY FLUIDS

The assumption is made that the presence ofmutagens in body fluids represents a genetichazard. Mutagenic activity in these fluids can beshown by using the rapid screening tests devel-oped for bacterial or in vitro cell culture systems.


Table 15.—Summary of Noncytogenetic Monitoring Techniques

Test type Descr ipt ion

Mutagens in body fluids:1. Urine2. Feces3. Blood

Somatic cell damage:1. Binding of mutagens to hemoglobin2. Specific mutation analysis in lymphocytes3. Unscheduled DNA synthesis in lymphocytes4. Hemoglobin gene mutations

5. Chemically damaged DNA bases6. Lymphocyte transformation

Germ cell (sperm) damage:1. YFF test2. LDH-X variants

Body fluids used as test materials in bacterial orin vitro cell culture mutagenicity assays.

Alkylation of the hemoglobin proteinTechnique that measures gene mutatationTechnique that measures DNA damageImmunological technique that measures gene

mutationTechnique that measures DNA damageTechnique that probably measures gene mutation

Detection of abnormal number of chromosomesImmunological technique that measures genemutation

SOURCE Office of Technology Assessment

Since blood and urine are routinely collected inmedical examinations, these types of tests couldbe integrated into a medical monitoring program.

A number of studies have been performed withbody fluids, primarily urine, from humans pre-sumably exposed to mutagens in their occupationor exposed to mutagens in the course of medicaltreatments (82,83,123,124). Lifestyle factors suchas cigarette smoking also have been studied (2,133,139). It is anticipated that urine analysis in-creasingly will be used for human epidemiologicalstudies, both because it successfully identifiesmutagens and because this test probably can beautomated. Less commonly used tests of fecalsources and blood are not expected to be usefulin general screening because of inherent technicalproblems.

Analysis of urine for the presence of muta-gens.–The use of urine collected from humansas a test material is readily applicable to humanmonitoring situations for the following reasons(18):

● Studies have demonstrated that mutagenicactivity can be detected in the urine of indi-viduals exposed to various therapeutic drugsand industrial chemicals and of individualswith specific lifestyles or occupational experi-ences.

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●

Collection of urine samples is easy and canbe obtained from both males and females ona regular schedule.Both mutagenic and chemical analysis can beperformed simultaneously from a single col-lection of urine.Urine samples can be tested for the presenceof mutagens not only in bacterial cells butalso in mammalian cells.The costs and performance time associatedwith this approach are amenable to large-scale sampling studies.

There are also drawbacks to the use of this testin occupational settings. For example, only recentexposures can be measured. Moreover, the pres-ence of mutagens in urine has not been translatedinto a known risk to the individual. Presence ofmutagens in the urine can be considered evidenceof exposure to a mutagenic chemical or to a chem-ical that forms mutagenic metabolizes which areeventually excreted. However, excretion of muta-gens may be a protective process. In fact, theabsence of mutagens in the urine could be inter-preted as evidence that the mutagens are boundto cellular molecules (thus potentially causingdamage) and are not available for urinary excre-tion. Consequently, knowledge of the metabolicfate of the suspected mutagens is critical to theproper interpretation of this monitoring tech-nique. Moreover, there may be many confound-

Ch 6—Genetic Monitoring in the Workplace 77

Analysis of blood serum for the presence ofmutagens.—There are only two reports on bloodserum analysis for mutagenicity (40,82). Becauseof the difficulty of obtaining large quantities ofserum, it is doubtful that serum analysis will con-tribute to the array of human monitoring tech-niques unless the detection tests could be mademore sensitive.

Photo credit: National Institutes of Health

Noncytogenetic monitoring involves the use ofbiochemical tests

ing variables in urine analysis. For instance, theurine of cigarette smokers has been shown to con-tain mutagens (139).

Analysis of feces fez” the presence of muta-

gens.–Because cancer of the colon is a majorcause of cancer mortality in Western countries,the incidence of the disease has been associatedwith diet (12,96, 103). Examination of human fecesfor mutagens is gaining some attention followinga report (24) that showed that feces from individ-uals on typical Western diets contain high levelsof mutagens. Consequently, analysis of humanfecal samples might represent a monitoring ap-proach for examining the relationship of dietaryfactors to specific types of cancer. Because oftechnical difficulties, such as concentration of thefeces, the use of this procedure in occupationalsettings currently is limited.

SOMATIC CELL DAMAGE

Binding of mutagens to hemoglobin. — T h epossibilities for using hemoglobin from red bloodcells as a biological dosimeter have been exploredby Ehrenberg and coworkers in a series of ex-periments on mice using alkylating agents (43,106,121). The assay is designed to measure alky-lated amino acids in hemoglobin from exposed in-dividuals. This phenomenon is not a genetic alter-ation, but protein alkylation strongly implies con-current alkylation of DNA, a presumed first stepin the production of mutations. The assay seems.to work well for several alkylating agents. It canbe used as a dosimeter, that is, it gives a positivedose-response curve, and it is a measure of accu-mulated damage over a period of a few months.This latter point is important because many othertests have to be done within a day or two ofexposure.

The accumulation of alkylated groups in hemo-globin and the relatively large amounts of hemo-globin that can be isolated from one blood sam-ple and analyzed, together with the availabilityof sensitive chemical and analytical techniques,make it feasible to determine small quantities ofalkylated amino acids formed as a consequenceof exposure to mutagens in the environment. Forthe most part, however, the procedures havebeen used only for mice injected with knownmutagens. In the single report on the practicalapplication of these procedures to human moni-toring, Ehrenburg (42) showed that hemoglobinmolecules were alkylated in workers exposed toethylene oxide,

Before these techniques can be used in routinemonitoring, more extensive validation studies areneeded to standardize protocols, evaluate repro-ducibility, and determine intrinsic individual


variability. Once these factors are established, theprocedure might have wide applications for spe-cific chemical classes.

Specific mutation analysis in lymphocytes. —Theproduction of the enzyme hypoxanthine-guaninephosphoribosyltransferase (HGPRT) in humans iscontrolled by the hpt gene located on the X-chro-mosome (65). Cultured cells in which hpt hasmutated are easily detected because of theirresistance to normally poisonous guanine analogs,such as 6-thioguanine (TG). Thus, cells lackingHGRPT can be selected and grown by exposingthem to one of these analogs in the culture me-dium. The frequency of TG-resistant (presumedmutant) cells in the peripheral blood lymphocytesof normal persons is very low (128), but the fre-quency increases among cancer patients beingtreated with known mutagens (4,128). Althoughthe technique has been hampered by high back-ground levels, recent modifications appear tohave resolved some of these problems (3).

Although no studies have been undertaken, itis speculated that the detection of TG-resistantcells that arise in vivo could play a role in occupa-tional monitoring. This technique could providea sensitive assay for the induction of genetic muta-tions in human somatic cells. An increase in thepercentage of TG-resistant cells in individuals ex-posed to toxic agents in the workplace might indi-cate exposure to a mutagen.

Unscheduled DNA synthesis in lymphocytes. —The damage to DNA by chemicals or radiation isoften repaired by cellular mechanisms that re-move the damaged area and replace it with newnucleotides (33,116), A test that measures thisDNA repair, referred to as unscheduled DNA syn-thesis (UDS), has been suggested as a good in-dicator of exposure of chromosomes to mutagenicagents since the amount of DNA repair inducedshould be proportional to the amount of DNAdamaged. In fact, reported data with human lym-phocytes suggest that UDS is associated withmutation and chromosomal aberrations (108).

This assay also can be used to identify agentsthat inhibit DNA repair. Chemicals capable of in-ducing DNA damage while simultaneously inhibit-ing DNA repair may be especially hazardous.Results of a preliminary study of workers exposed

to ethylene oxide show increases in both chro-mosomal aberrations and suppression of DNA re-pair synthesis (109).

There have been few UDS studies on lympho-cytes in vivo. Limited studies of normal humanlymphocytes (108) and lymphocytes from exposedhumans (109) indicate that sex, age, and bloodpressure may affect both background and chem-ically induced levels of UDS.

At present it appears that this assay can bestbe used to study the nature of tissue specificityof chemical DNA damage. For instance, com-pounds that cause stomach cancer may induceUDS in stomach tissue but not in liver tissue. Onthe other hand, it may not be a very good assayfor mutagenesis because it is a measure of DNArepair, not damage, and repair may not correlatewith genotoxicity.

Hemoglobin gene mutations. —Hemoglobin pro-teins can be altered by single gene mutations, andspecific antibodies prepared against altered hemo-globin proteins can be used to detect these rarevariants. Normal individuals generate the rarevariants at a rate of about one variant per 10 mil-lion red blood cells. If the specific antibodies arelinked to a fluorescent molecule, an automated,fluorescent-activated cell sorter can detect theserare cells with high sensitivity and specificity (92),Presumably, individuals exposed to mutagenswould have an increased rate of production ofthe variants. This method could provide an excel-lent tool for evaluating human populations sinceit can be conducted objectively, quantitatively,and economically. Some preliminary pilot studies,using blood samples from individuals on cancerchemotherapy drugs or radiation therapy, foundthat the frequencies of abnormal hemoglobinwere within the normal range but statisticallyhigher than the frequencies for the correspond-ing controls (Omenn, personal communication).

Detection of chemically damaged DNA bases. —The detection of chemically damaged DNA basesis a direct measure of binding of a chemical toDNA. This binding can interfere with accurateDNA base pairing, thus causing mutations dur-ing DNA replication. Several detection methodshave been described recently (1)64,66)138). Allthese methods are extremely sensitive and some,


depending on the chemical, can detect as few asone event per cell. This level is in the rangenecessary for a test to be predictive for chroniclow-level exposure.

There are limitations to the study of chemical-ly damaged bases. It is a measure of an early eventand a base change may not result in a mutation.For instance, the mutated bases could be repairedprior to cellular DNA synthesis and be of no con-sequence at all. It also is not known how persist-ent the damaged bases are. For instance, in mon-itoring a population, it is necessary to know whento collect samples and then whether the damagedbases found are a result of recent or prior ex-posure.

The detection of damaged DNA bases hasmoved beyond the laboratory. A prospective epi-demiological study was begun recently on cokeoven workers; the researchers are using specificantibodies to detect benzo(a)pyrene bound toDNA bases (137).

Lymphocyte transformation assay. —Severalreports (30)60) 117) suggest that mammalian cellsexposed to mutagenic chemicals in vitro exhibitan enhanced susceptibility to transformation, acondition that has many similarities to tumor cells.It is possible that a modification of this transfor-mation assay could be used to monitor exposureto harmful chemicals. The lymphocytes from ex-posed individuals are grown in culture under con-ditions that select for transformation. Presum-ably, increased exposure will -yield more trans-formed cells.

GERM CELL DAMAGE

Studies on germ cells have focused exclusivelyon sperm. The advantage of monitoring sperm,aside from the ease of obtaining viable cells, isthat studies using sperm have tested about 10times the number of chemicals that have beentested using any other cell type. Whether tox-icological studies of sperm will reflect the genet-ic status of somatic cells is unknown, but, assum-ing that they will, two assays show promise inan occupational setting.

YFF’ test. —The YFF test purports to identify anextra Y chromosome. Sperm with increased flu-orescence under a microscope in the presence

of quiniline dye are scored as having more thanone Y chromosome. They are abnormal and pre-sumably arise due to abnormal chromosome seg-regation during cell division. Yet it has not beenshown conclusively that the increased fluores-cence is not due to a change in the fluorescencepattern of the other chromosomes. Thus, thischange may be an important indicator of expo-sure to chemicals, but cannot be taken as a resultof abnormal segregation. This sperm assay, be-cause of its relative experimental ease, might bemost useful in determining priorities for longerterm studies of chemical agents.

LDH-X variants. —The principle on which thisassay is based is the same as that of the test formutant hemoglobin. Lactate dehydrogenase-X(LDH-X) is a protein found on the tail of spermand is detectable by specific antibodies (27). Ex-periments with rats and mice have shown thatLDH-X mutants are detectable with different anti-bodies (10,11). Presumably, LDH-X variants couldbe detected with a battery of different monospe-cific antibodies. One experiment with miceshowed a linear relationship between increaseddose of mutagen and increased mutant LDH-Xmolecules (9).

The presence of LDH-X mutants presumablywill reveal whether an individual is sensitive to

an environmental mutagen in an analogous fash-ion to the hemoglobin gene mutation assay. Asin that assay, the method could be automated byusing fluorescent-labeled antibodies and afluorescent-activated cell sorter. The human LDH-X mutants need much better characterization,however, before this assay will find applicabilityin a routine monitoring situation (H. Mailing, per-sonal communication).

Conclusions

At present, there is not enough research ex-perience using humans for most noncytogenetictechniques to determine accurately their useful-ness in workplace monitoring situations. Thedetection of mutagens in urine is the only assaythat has been used with human subjects oftenenough to show that spurious results will not begenerated. The other techniques will require con-siderably more development to be considered of


value as monitoring techniques. The most obvious accurately low levels of the abnormality beingdeficiency in these tests is the lack of the avail- assayed, the likely prospects for automation, andability of the normal baseline response. Without low cost. Six of the tests discussed in this sectiona good estimate of the range of responses in unex - potentially have these necessary characteristics,posed humans, the data from test populations will and their development could lead to better work-be difficult to interpret. Table 16 summarizes all place monitoring. These tests include the detec-of the human studies that used noncytogenetic tion of:methods.

●

●

Priorities for future research ●

Several of the noncytogenetic techniques may●

have potential for use in human monitoring. The●

characteristics necessary for a good workplace●

monitoring technique include the ability to detect

mutagens in urine,alkylated hemoglobin,a specific mutation (HGPRT) in lymphocytes,hemoglobin mutations,chemically damaged DNA bases, andLDH-X variants in sperm.

Table 16.—A Summary of Noncytogenetic Methods Usedin Human Monitoring

Technique Population monitored Reference

1. Mutagens in body fluidsA. Urine

B. Blood

C. Fecal

2. Somatic cell damageA. Hemoglobin alkylationB. Specific mutations in

lymphocytesC. Unscheduled DNA

synthesisD. Hemoglobin gene

mutationsE. Chemically damaged

Rubber industry workersCoke plant workers (smokers v.

nonsmokers)Nurses administering cytostatic drugsChemical workers in ink and solvent plantsPatients receiving cancer therapeutic drugs

Patients receiving drugsCigarette smokers v. nonsmokersPersons dosed with anantiparasitic drug which has mutagenicand carcinogenic activity

Comparison of humans with different dietsand geographical origin

Workers exposed to ethylene oxideCancer patients treated with chemo-

therapeutic drugsFactory workers exposed to ethylene oxide

Cancer patients treated with chemo-therapeutic drugs

Coke oven workers exposed to ben-zo(a)pyrene

Falck, et al. (47)Moeller and Dybing (94)

Falck, et al. (48)Mazzoll (91)Siebert and Simon (123,124)Legator, et al. (82,83,84)Speck, et al. (125)Wang, et al. (135)Roxe, et al. (1 19)Legator, et al. (81)Yamasaki and Ames (139)Legator, et al. (82)Dobias (40)

Ehrich, et al. (44)Reddy, et al. (115)Kunhleln, et al, (78)

Ehrenberg (42)Strauss and Albertini (128)Albertini and Allen (4)Pero, et al. (109)

Mendelssohn, et al. (92)

Weinstein and Perera (137)DNA bases

SOURCE: Off Ice of Technology Assessment.


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Metabolizes in the Ascites Fluid and in the Urineof a Human Patient Treated With Cyclophospha -mide: Induction of a Mitotic C,ene Conversion inSaccharomyces Cerevisiae, ” Mutat. Res.21:257-262, 1973.Siebert, D., and Simon, U., “Cyclophosphamide:Pilot Study of Genetically Active Metabolizes inthe Urine of a Treated Human Patient: Inductionof i’tlitotic Gene Conversions in Yeast, ” Mutat. Z?es.19:65-72, 1973.Speck, W. T., Stein, A. B., and Rosenkranz, H. S.,“hlutagenicity of Metronidazole: Presence of Se\-eral Active hletabolites in Human Urine, ” .T. Nat].Cancer Inst. 56:283-284, 1976,Sram, R. J., et a),, “The Genetic Risk of Epichloro-hydrin as Related to the Occupational Exposure)”Biol. Zbl. 95:451-462, 1 9 7 6 .Sram, R. J., et al., “Cuwogenetic Analysis of Periph-eral Lyrnphocwytes in Workers Occupationally Ex-posed to Epichlorohydrin,” AIutat. Res. 70:1 15-120, 1980.Strauss, G. H., and Albertini, R. J., “Enumerationof 6-Thioguanine-Resistant Peripheral Blood Lym-phocytes in Nlan as a Potential Test for SomaticCell Nlutations Arising In [’ivo, ” Afutat. Res.61:353-379, 1979.Szentesi, I., et al., “High Rate of Chromosomal

Aberration in PVC Workers, ” Mutat, Res, 37:313-316, 1976.

130. Thiess, A. M., et al., “Mutagenicity Study of Work-ers Exposed to Alkylene Oxides (Ethylene Oxide/Propylene Oxide) and Derivati\~es, ” J. Occup. Meal,23:343-347, 1981.

131. Tough, 1. M., et al., “Chromosome Studies on

132

133

134

Workers Exposed to Atmospheric Benzene: ThePossible Influence of Age, ” Europ. J. Cancer6:49-55, 1970.Tough, 1. M., and Court Brown, W. M., “Chromo-some Aberrations and Exposure to Ambient Ben-zene,” Lancet i:684, 1965.Van Doom, R., Bos, R. P., Leijdekkers, Ch.-M.,Waggenaas-Zegers, M. A. P., Theuws, J. L. G., andHenderson, P. Th., “Thioether Concentration andMutagenicity of Urine From Cigarette Smokers, ”Int. Arch. Occup. En\riron. Health 43 :159-166 ,1979.t’igliani, E. C., and Forni, A., “Benzene and Leu -kemia,” Entriron. Res. 11:122-127, 1 9 7 6 .

135. Wang, C. Y., Benson, R. C., Jr., and Bryan, G. T.,“Mutagenicity for Salmonella Typhimuriurn ofUrine Obtained From Humans Recei\ring Nitro-furantoin, ” J Nat]. Cancer Inst. 58:871-873, 1977.

136. Watanabe, T., et al., ‘( Cuytogenetics and Cytokinet -ics of Cultured Lymphocytes From Benzene-Exposed Workers, ” Int. Arch., Occup. EnIriron.Heahh 46:31-41, 1980.

137. Weinstein, I. B., and Perera, F. P., “klo]ecular Can-cer Epidemiolo&V, “ in: Banbury Report 13: Indi-cators of Genotoxic Exposure in Alan and Animals(New York: Cold Spring Harbor, 1982).

138. Wogan, G. N., “Aflatoxin-13NA Adducts and TheirDetection in Urine, ” in: Banlxqv Report 13: Indi-cators of Ctinotoxic Exposure in Alan and Anhlals(New York: Cold Spring Harbor, 1982).

139, Yamasaki, E., and Ames, B. N., “Concentration ofMutagens From Urine by Adsorption \\’ith theNonpo]ar Resin XAD-.2: Cigarette Smokers Ha\reItlutagenic Urine, ” Proc. Nat]. ,-tcad. Sci. [1. S.A.74:3555-3559, 1977.

140. Yu, L-C., et al., ‘(Human Chromosome IsolationFrom Short-Term Lymphocyte Culture for FlowCytometry)” Nature (London) 293: 154-155, 1981.

141. Yunis, J. J., et. al., “All Patients It’ith Acute Non-I}lmphocvtic Leukemia Itlav Ha\e a ChrmnosolmalDefect, ’’”Ne\ir Eng. 1 ,tfej. 305: 135-139, 1981.

Chapter 7

Genetic Screening forHeritable Traits

Contents

Red Blood Cell Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89Glucose-6-Phosphate Dehydrogenase Deficiency and Hemolytic Anemia . . . . . . . . . . . . 90Sickle-Cell Trait and Sickle-Cell Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91The Thalassemias and Erythroblastic Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91NADH Dehydrogenase Deficiency and Methemoglobinemia. . .. .. .. .. ... ... ......O 9 2

Traits Correlated With Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93Serum Alpha1 Antitrypsin Deficiency and Susceptibility to Emphysema . . . . . . . . . . . . 93Aryl Hydrocarbon Hydroxylase Inducibility and Susceptibility to Lung Cancer . . . . . . 94

Other Characterized Genetic Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Acetylation and Susceptibility to Arylamine-Induced Bladder Cancer . . . . . . . . . . . . . . . 95HLA and Disease Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96Carbon Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96Diseases of DNA Repair. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Less Well-Characterized Genetic Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Superoxide Dismutase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Immunoglobuhn A Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Paraoxanase Polymorphism . . . . . . . . . . . . . . . . . . . . . .. ., . .., ... ... ...,. . . . . . . . . 97Pseudocholinesterase Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98Erythrocyte Catalase Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98Dermatological Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98Priorities for Future Research .......,.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Red Blood Cell Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100Differential Metabolism of Industrial/Pharmacological Compounds . . . . . . . . . . . . . . . . . 100SAT Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Figure

Figure No. Page8.Distribution of Red Cell Phosphatase Activities in the English Population . . . . . . . . . . 99

-

Genetic ScreeningChapter 7

for Heritable Traits

Individuals differ widely in their susceptibilityto environmentally induced diseases. Differentialsusceptibility is known to be affected by devel-opmental and aging processes, genetic character-istics, nutritional status, and the presence ofpreexisting diseases (11,12). This chapter assessesthe way in which genetic factors contribute tothe occurrence of differential susceptibility to tox-ic substances.

Clearly, genetic factors do not act in isolationfrom physiological processes. Genetic influencesmay be exaggerated or diminished by one’s age,diet, or overall health status. For example, whilepeople with an erythrocyte glucose-6-phosphatedehydrogenase (G-6-PD) deficiency may be at in-creased risk to a variety of drugs, it is also likelythat their nutritional status may be able to miti-gate or enhance their susceptibility (23). Many dis-ease processes are affected by multiple factors,any one of which may not explain the variationin responses within a population.

It has long been suspected that biological fac-tors affect the occurrence of occupational dis-eases. In fact, during World War 1, it was specu-lated that TNT-induced adverse effects were in-tensified by inadequate diets (9,10). In 1938, J.B.S.Haldane (42) suggested a possible role for geneticconstitution in the occurrence of bronchitisamong potters and even raised the possibility ofeliminating the genetically predisposed personfrom potential unhealthy work environments.

This assessment of the evidence that selectedgenetic conditions affect the occurrence of occu-pational disease focuses on those few single genetraits where substantial data are available. For

each genetic trait, the following questions wereasked:

What is its prevalence in the population?Is it compatible with a normal lifestyle?With what diseases does the trait correlate?In what industrial settings might the traitscause a person to be at increased risk?Is there an increased risk for homozygousor heterozygous individuals, or both?What do epidemiological studies show, andare they well designed?What is the cost, ease, and predictive valueof the available tests for detection of the trait?(See app. F.)

This chapter also briefly discusses those traits forwhich there is limited evidence suggesting an as-sociation with occupational disease. The traitsdiscussed here represent only a fraction of a per-cent of all human traits. The discussion does notintend to imply that these traits are necessarilyresponsible for most of the occupational diseasesthat could result from genetic predisposition. Infact, the traits discussed here most likely comprisevery few of the potential predisposing traits whenincreased susceptibility to chemicals or ionizingradiation is the issue.

Many data on differential susceptibility to chem-icals come not from industrial settings but fromdocumented responses to prescription drugs.These studies are relevant in that the detoxifica-tion or activation pathways for drugs may operateon a wide variety of other chemicals. where rele-vant, drug studies have been included in the anal-ysis because it is possible that an extrapolationfrom a clinical to an industrial setting can bemade.

Red blood cell traits

Because human red blood cells (erythrocytes) all traits. Erythrocytes contain hemoglobin, theare so accessible, the genetic traits expressed in protein responsible for carrying oxygen to tissuesthese cells are among the best characterized of and carbon dioxide away from them. Any reduc-

89

✙✐ ● The Role of Genetic Testing in the prevention of Occupational Disease

tion in this ability, caused by either nonfunctionalhemoglobin or fewer erythrocytes, results in theclinical manifestation of anemia.

The prevalence of hereditary blood conditionsvaries greatly among different ethnic groups, withtheir highest occurrence being in tropical cli-mates. It appears that several of these traits havebeen evolutionarily selected over time becausethey provide a partial resistance to malaria. Sincemost of these traits in their heterozygous formare compatible with a normal lifestyle, they givea selective advantage to people in areas where ma-laria is common. However, such heterozygous in-dividuals may exhibit a greater sensitivity to tox-ic chemicals in an industrial setting.

G1ucose-6-phosphate dehydrogenasedeficiency and hemolytic anemia

G-6-PD deficiency is a sex-linked genetic condi-tion, the G-6-PD gene being located on the X chro-mosome. * The gene’s normal function is impor-tant for maintenance of erythrocyte membraneintegrity. Under hemolytic (destruction of redblood cell membrane) stress conditions (as in thepresence of oxidizing agents including some an-timalarial drugs), the erythocyte membranes ofG-6-PD deficient individuals break down and thosepersons develop anemia. Otherwise, these indi-viduals are healthy.

For industry, the first suggestions that G-6-PDdeficiency may be involved in worker susceptibili-ty to chemically induced anemia occurred dur-ing the early 1960’s (8)52,127). In addition, in 1963,Stokinger and Mountain (117) proposed a list of37 industrial chemicals known to cause hemolysisto which those with a G-6-PD deficiency may beat enhanced risk. They further suggested thatscreening tests to identify G-6-PD deficient in-dividuals be conducted as part of preemploymentmedical examinations in order to identify thoseindividuals before job placement. Later, Stokingerand Mountain (116) reported that more than 15industries, research centers, or health-orientedgroups either were using the G-6-PD test or had

*The deficiency is found mostly in men because of their singlecopy of the gene. Women can he heterozygous carriers and notf?xhibit the dt?ficit?ncbv. ttromen homozygous for the deficiency ar(?known, but rare.

inquired into its use. More specifically, they notedthat industries most interested in the test weremanufacturers of dyes and dye-stuff intermedi-ates, metals (especially lead), and drugs,

In addition to medical and industrial oxidizingagents as potential causes of hemolytic anemia inG-6-PD deficient individuals, interest recently hasfocused on the effects of copper and ozone onG-6-PD deficient erythrocytes. Because erythro-cytes of the Dorset sheep are G-6-PD deficient andalso are quite susceptible to copper-induced he-molysis, it was speculated that G-6-PD deficienthumans likewise may display an enhanced suscep-tibility to copper. Subsequent studies have sup-ported this hypothesis (9,13). An hypothesis thatG-6-PD deficient individuals may be at enhancedrisk to ozone toxicity has recently been supportedby in vitro experiments showing that G-6-PD defi-cient erythrocytes are more susceptible to oxidantdamage than normal erythrocytes (14).

Numerous surveys of G-6-PI] deficiency, em-ploying different methods of identification, havebeen conducted among various groups of peoplein different geographical locations (4). The fre-quency of this trait is very high among U.S. blackmales (13 to 16 percent). other population fre-quencies of this trait are: Caucasians: American,0.1 percent, British 0,1 percent, Greek, 2 to 32percent, Scandinavians, 1 to 8 percent, East In-dians, 0.3 percent, Mediterranean Jews, 11 per-cent, European Jews, 1 percent; Mongolian: Chi-nese, 2 to 5 percent, Filipinos, 12 to 13 percent.There are many genetic variants of the G-6-PDallele. of particular importance here is theMediterranean variant in which G-6-PD activityranges from 1 to 8 percent of normal, comparedto the A – variant of American blacks whichmaintains 15 to 25 percent of normal G-6-PD ac-tivity, The greater severity of the enzyme defi-ciency is of clinical concern because individualswith the Mediterranean variant are likely to beconsiderably more susceptible to oxidizing agentsand infectious agents (for example, hepatitis) andexperience more serious hemolytic crises (4).

Many substances commonly used in industryare known to cause hemolytic changes, and it hasbeen speculated that they present an increasedrisk to G-6-PD deficient individuals. A few of thesesubstances have been evaluated in vitro and

Ch. 7—Genetic Screening for Heritable Traits ● 9 1

found to display a greater stress on G-6-PD defi-cient cells. However, the only specific industrialsubstances for which proof exists that G-6-PD defi-cient individuals are at greater hemolytic risk thannormal individuals are certain aromatic aminoand nitro compounds (for example, naphthalene,TNT, and naladixic acid) (4,80). No quantitativerisk assessments of the hemolytic actions of thesesubstances on those individuals have been pub-lished. that is emerging is a growing body of invitro evidence strongly implicating the enhancedsusceptibility of G-6- PD deficient erythrocytes toa wide variety of industrial and environmentaloxidants. Such in vitro exposures have not beenrelated to actual exposures.

Sickle-ceIl trait and sickle cell anemia

These genetic conditions result from the pres-ence of an abnormal hemoglobin molecule, he-moglobin S (HbS) in the erythrocytes of affectedindividuals, HbS differs from the normal hemo-

globin A (HbA) only by the substitution of anamino acid at a single location in the hemoglobinprotein beta-chain. * The decreased solubility ofHbS under conditions of low oxygen may resultin the formation of a gel within red blood cells,distorting them and causing the cells to look likesickles under the light microscope. An individualwith sickle-cell anemia is homozygous for HbSwhile one with sickle-cell trait is heterozygous forHbS. The homozygous person has 100 percentHbS while the heterozygous person has from 20to 40 percent HbS; the latter will experience sick-ling only when blood oxygen is greatly reduced(22, 1 1.5).

While those with sickle-cell anemia are knownto have a reduced lifespan, the health hazards ofsickle-cell trait are considered minimal or nonex-istent under most circumstances (91 ). Some situ-ations have been thought to cause sickling prob-lems in those with sickle cell trait. For instance,four deaths were attributed to sickle cell trait inArmy recruits in basic training at a high altitude(55). The Air Force until recently had a policy thatexcluded blacks with sickle cell trait from the AirForce Academy and flight training (124). However,

● I hc hf’moglohin IIl(JlWLIlfI is c(JmposfI(i of tour protf’ill chciins,

two ident](al beta C}M ins and t~~o i(lcnt i(’al a lpha chains .

it has been determined that not enough data areavailable to support that policy. The overwhelm-ing majority of people with sickle cell trait in theUnited States apparently never have any prob-lems associated with this genetic condition.

The gene for HbS is found at high frequencyin equatorial Africa, parts of India, countries ofthe Middle East, and areas around the Mediter-ranean. Sickle cell trait is found in about 8 per-cent of U.S. blacks. The frequency of sickle-cellanemia is about 0.2 to 0.5 percent among Ameri-can blacks. However, because this disease mostlikely would have revealed itself in overt illnessprior to adulthood, preemployment physicaltesting would not be used to discover the condi-tion (22).

According to a survey of major industries (seech. 3), the majority of genetic screening done inthe workplace has been for sickle cell trait. Thepurpose of this testing is not known.

The thalassemias and erythroblasticanemia

Thalassemia is an erythroblastic anemia, a defi-ciency in the production of red blood cells, oc-curring early in life and varying in severitv from. .mild to fatal. The severe form, found in the homo-zygous state, is called thalassemia major; themilder condition, found in the heterozygous state,is called thalassemia minor. The classic Mediter-ranean form of thalessemia, the beta form, isthought to be caused by a deficiency in beta-chainproduction of hemoglobin A. A different form ofthalessemia, alpha thalessemia, involves a disrup-tion in alpha-chain synthesis. The homozygousstate for the alpha condition is fatal, leading tointrauterine death (76).

Of particular concern to this report is the healthstatus of both alpha and beta thalessemic heter-ozygous individuals because of the milder mani-festations of the disease and their considerablygreater prevalence in the population comparedto homozygous people. The frequency of alphathalassemia heterozygous individuals amongAmerican blacks is thought to range between 2and 7 percent (85,126). In more limited surveys,those of Greek ancestry were reported to havea 2 percent incidence of heterozygous alpha thal-


assemia (98). Beta thalassemia heterozygous in-dividuals comprise about 4 to 5 percent of Italian-Americans (93) and Greek-Americans (98). Thehealth status of heterozygous individuals is diffi-cult to generalize since there appears to be ex-tremely broad differential expression of the clin-ical features of the disease. However, what doesseem predictable is that symptoms of the disease,however mild, may be exacerbated when addi-tional stress is encountered, for example, in thepresence of bronchopneumonia or during preg-nancy. In a thalassemia heterozygous individual,auxiliary mechanisms of blood production alreadyhave been called into action and, under stress,may no longer be able to handle the expandedactivity needed to maintain normal hemoglobinlevels (76).

Since persons heterozygous for the thalassemictrait have a compromised adaptive capacity tomaintain blood production, it has been suggestedthat they may be at increased risk from hazard-ous chemicals. The research to date, mostly inEurope, has involved a limited clinical assessmentof occupational exposures to benzene and leadon persons heterozygous for beta thalassemia(33,37,40,99,106,107). In light of the limitednumber of individuals studied and the lack of en-vironmental monitoring, it is not possible to con-clude that susceptibility to benzene and lead tox-icity is enhanced in persons with thalassemia trait.However, the clinical studies suggest the need forepidemiologic investigations to test this hypoth-esis.

NADH dehydrogenase deficiency andmethemoglobinemia

The transportation of oxygen to tissues is con-tingent on the capability of hemoglobin to bindoxygen reversibly, a process that relies on the ironatom in the protein. The binding of oxygen byhemoglobin involves the oxidation of the ironatom. When the oxygen is released, the iron atomtypically returns to its reduced state. occasionallyit stays oxidized, thereby leaving the hemoglobinin an oxidized state called methemoglobin. Nor-mally, only about 1 percent of total hemoglobinis present in this state because the capacity of thered blood cell to reduce this state is several hun-dred times greater than the spontaneous rate of

oxidation. Methemoglobin levels accumulatewhen the rate of oxidation of the iron atom ex-ceeds the reducing capacity; a change in the pro-tein chain stabilizes methemoglobin, making itresistant to reduction; or there is a marked defi-ciency in the reducing ability of the red blood cell.The most important metabolic pathway for thereduction of methemoglobin involves an enzymecalled NADH dehydrogenase, which accounts forabout 60 percent of the normal reduction rate(110).

Methemoglobinemia in humans initially was re-ported in homozygous people who were exposedto certain drugs capable of increasing the rate ofoxidation of the iron atom of hemoglobin, but per-sistently high levels of methemoglobin have beenclinically diagnosed with no known exposure tochemicals that oxidize hemoglobin (62). Subse-quent research on such individuals has frequentlyrevealed an NADH dehydrogenase deficiency asthe cause of the high methemoglobin levels (110).

A very high occurrence of hereditary NADH de-hydrogenase deficiency has been reported amongAlaskan Eskimos and Indians (112), Navajo Indians(2), and Puerto Ricans (47,111). Heterozygous car-riers of this enzyme deficiency display about 50percent of the normal enzyme activity, with thefrequency of such carriers in the U.S. populationthought to be about 1 percent (94,125).

Methemoglobinemia acquired from industrialexposures to various chemicals, especiallyaromatic nitro and amino compounds, rangesfrom mild to severe. With 10 to 30 percent meth-emoglobin, only cyanosis (bluish skin) is observed.At 35 to 40 percent, headaches and shortness ofbreath on exertion are reported. At 60 percent,lethargy occurs, and above 70 percent, deathshave been reported. Biological monitoring for ex-posures to cyanogenic aromatic: chemicals at DuPent’s Chamber Works facility by measurementof methemoglobin levels and recording of cyano-sis was carried out beginning in the 1940’s (80).During the 10-year period following 1956, 187episodes of cyanosis were detected, occurring in143 employees. (These workers would be an ap-propriate group for clinical testings of NADHdehydrogenase activity.) The company regularlyused results of the biological monitoring of workcrews to pinpoint areas requiring tighter control


of exposures (80). In possibly analogous cases ofcyanosis in Vietnam where American militarypersonnel were given malaria prophylaxis, Cohen,et al. (19) did show that the affected men werepartially deficient heterozygotes for NADH dehy-drogenase.

It has been shown repeatedly that personshomozygous or heterozygous for NADH dehydro-

genase deficiency display an increased risk ofcyanosis following exposure to drugs that formmethemoglobin. However, there have been noreports of industrial exposures indicating thatthose with NADH dehydrogenase deficiency areat increased risk to methemoglobin-formingagents, probably because industrial screening forsuch a condition has not been conducted.

Traits correlated with lung disease 4

Serum alpha, antitrypsin deficiencyand susceptibility to emphysema

Homozygous serum alpha, antitrypsin (SAT) de-ficiency is an important biological factor predis-posing the occurrence of emphysema (26,66)71,78,103,105). In fact, it is recognized that nearly80 percent of those with this genetic conditiondevelop the disease. Since only 1 individual in4,000 to 8,000 displays the homozygous trait,there has been little concern about the screen-ing for such individuals. On the other hand, het-erozygous carriers who display an intermediateSAT deficiency (about 50 percent of normal val-ues) may be at increased risk of developing em-physema, especially if they smoke tobacco orwork in dusty environments. Heterozygous indi-viduals comprise about 3 percent of the U.S. pop-ulation, or about 7 million persons.

Initial studies of SAT deficiency and its role inthe occurrence of emphysema focused on the riskto the homozygous genotype. However, subse-quent reports began to mention that the hetero-zygous carrier also displayed a significantlyenhanced risk of developing emphysema, al-though at a much lower frequency than thehomozygous individual (67,79). In general, muchof the data supporting the notion that the heter-ozygote is at enhanced risk came from studies inthe United States, Germany, and Scandinavia.These studies covered about 1,400 patients withemphysema, 6.2 percent of whom were hetero-zygous for SAT deficiency (3,66)88,89)114)121).That percentage is highly significant when com-pared with the expected prevalence of about 3

percent for this group. Other research method-ologies also have supported these observations(27,70).

Despite a consistent trend in most research find-ings showing enhanced susceptibility of the het-erozygous individuals to obstructive lung damage,several reports have not supported that hypoth-esis (16,20,72,84,90). For the most part, thesedissenting reports have found no difference inpulmonary function between SAT heterozygouspersons and controls matched for age and sex,and little, if any, increased risk of emphysemawhen smoking was brought into the analysis, Be-cause about 90 percent of individuals with theheterozygous genotype will not develop sympto-matic disease, some researchers feel those studieshave not given the hypothesis of enhanced het-erozygote risk an adequate evaluation.

Environmental factors play a dominant role inthe etiology of emphysema. For example, studieshave indicated that cigarette smoke has beenfound to significantly lower SAT activity in ratsafter three puffs (51), while investigations withnormal individuals likewise have found thatchronic smokers displayed a nearly twofold de-crease in functional activity of SAT as comparedto nonsmokers (30). Other experimental studieshave suggested that cadmium (17,18) and ambientozone at levels approaching the current OSHAstandard of 0.1 ppm (time-weighted average overan 8-hour day) may be contributing factors in thedevelopment of emphysema because of their abili-ty to inhibit SAT activity (54).


Emphysema is a multicausal disease (58,87) andthe heterozygous state, by itself, is not a majorpredisposing factor in its development. It is possi-ble, however, that in combination with other pre-disposing factors, some of which have been iden-tified (1,31,69,77), the heterozygous individualcould be at an increased risk. It is necessary toevaluate the relative contribution of these vari-ables in the development of emphysema. If theassociations prove to be valid and are amenableto widespread screening, such screening mostlikely would involve an assessment of severalfactors.

Aryl hydrocarbon hydroxylaseinducibility and susceptibility tolung cancer

The differential ability to induce the enzymearyl hydrocarbon hydroxylase (AHH) has beencorrelated with lung cancer. This enzyme, foundin most mammalian tissues, is known to catalyzethe first step in the metabolism of polycyclicaromatic hydrocarbons (PAHs), many of whichare found in cigarette smoke and the industrialworkplace. Being an inducible enzyme (one whoseactivity can be increased in the presence of cer-tain compounds), AHH displays increased activi-ty following administration of a number of agentssuch as PAHs, various drugs, steroids, and insec-ticides (21). AHH is thought to play a key role inthe modification of PAHs into biologically activecompounds by metabolizing them to epoxideswhich can bind to DNA and other macromole-cules (39). Epoxide binding appears to be an in-itial cause of malignant transformation in cells.Consequently, PAH metabolism via AHH can re-sult in activation to more highly mutagenic andcarcinogenic intermediates.

There is considerable variation in the extent towhich AHH can be induced in cultured leukocytesfrom different individuals. The induction has beenreported to be under genetic control (59), withthe normal Caucasian population divided intothree distinct groups with low, intermediate, andhigh degrees of inducibility, all of which are com-patible with a normal lifestyle (60), This variationwas hypothesized to result from a single genewith the three groups representing the homozy-

gous low and high alleles and the intermediateheterozygote. The phenotypic frequencies werecalculated to be 53 percent for low inducers, 37percent for heterozygotes, and 10 percent forhigh inducers.

Since the inducibility of AHH was found to beunder genetic control and exhibited wide varia-tion in the population, Kellermann, et al. (60),sought to evaluate whether AHH inducibilitycould help to explain differential susceptibility tolung cancer presumably caused by PAHs whichmay have been activated to carcinogenic com-pounds. The lung cancer patients studied dis-played a marked shift from the normal pheno-typic frequencies in that only 4 percent were lowinducers, 66 percent were moderate, and 30 per-cent were high, The authors concluded that therisk of lung cancer for the groups with in-termediate and high inducibility was 16 and 36times greater, respectively, than that of the lowinducibility group.

A variety of research teams have sought to rep-licate and extend these findings because of theirpublic health implications. Four studies have sup-ported the initial findings (41,53,102,123). For themost part, these studies have shown that personswith lung and laryngeal cancer displayed signifi-cantly greater lymphocyte AHH inducibility thancontrols. With some exceptions these studies werebetter designed than the original Kellermann, etal. (60), report, but they did not investigate thegenetics, Not all reports, however, even supportthe association between AHH inducibility andsusceptibility to lung cancer (95,96).

A methodological issue that may lead to diffi-culties in reproducing the work of others is theseasonal variation in AHH levels; this variation im-plies that measurements of AHH activity cannotbe collected in a population over prolonged peri-ods of time. Also, the lymphocyte AHH inducibilityassay is difficult to standardize (65). A significantimprovement in the cell culture procedure or an-other way of measuring the genetic trait is essen-tial before large-scale population studies can beundertaken.

A genetic basis affecting susceptibility to envi-ronmentally induced lung cancer has been doc-umented overwhelmingly in animal studies (92)

. .

Ch. 7—Genetic Screening for Heritable Traits . 95

and supported by human epidemiologic investiga-tions (122). However, the identification of a pre-cise and reliable marker or predictor of risk tolung cancer—such as AHH inducibility—is cur-rently unresolved,

The theory of Kellerman and associates that sus-ceptibility to PAH-induced lung cancer is in parta function of the ability to induce AHH remains

to be unequivocally established, but is still ofpublic health interest. To date, the total numberof cancer patients studied in the testing of thishypothesis is less than 1,000. Given that in 1981the number of deaths from lung cancer in theUnited States alone was estimated to be more than105,000, there is a need to evaluate this hypothesisonce a valid and reliable test has been developed.

Other characterized genetic traits )

Acetylation and susceptibility toarylamine-induced bladder cancer

Acetylation in the liver is a common pathwayfor the metabolism of a variety of compounds.Humans display genetic variation with respect toacetylation, the population consisting of fast andslow acetylators. The responsible liver enzyme,N-acetyltransferase, is coded for by a single gene.The slow acetylator phenotype is a recessive traitwith an approximate 1:1 distribution of slow:fastphenotypes among North American Caucasiansand blacks, while among the Japanese there arenine fast acetylators to one slow one (44). Numer-ous reports in the literature indicate that the abili-ty to acetylate is associated with increased suscep-tibility to a number of acetylatable nitrogen com-pounds. For example, when acetylated metabo-lites have proved to be more toxic than the parentcompound, the fast acetylator is the individual atincreased risk (5,86). On the other hand, indivi-duals with the slow acetylator phenotype havebeen found to be at considerably increased riskto the development of neurological symptoms as-sociated with the antitubercular drug isoniazid(48), the antidepressant phenelzine (28), the anti-high-blood-pressure agent hydralazine (100), sulfadrugs, and the anti-leprosy drug, dapsone, pre-sumably because of lack of ability to detoxifythese substances by N-acetylation.

Humans are able to deactivate arylamines byacetylation, thus inactivating a class of potentbladder carcinogens. Persons who are fast ace-tylators have about 9 to 10 times more acetylaseactivity than the “slow” individuals (38).

Lower, et al, (81), hypothesized that humanswith the slow acetylator phenotype would be atincreased risk to develop arylamine-induced blad-der cancer. Their preliminary epidemiologic studysupports this hypothesis. The authors reportedthat a population of urban urinary bladder cancerpatients exhibited a small excess of individualswith the slow acetylation phenotype as comparedto a control group. Lower, et al. (81), did not in-vestigate the most ideal population to test thistheory, since the selection of patients did not in-volve persons occupationally exposed to aryla -mines. Furthermore, the study had importantmethodological limitations in that potential con-founding variables such as smoking and occupa-tion were not controlled.

Since 50 percent of the North American Cauca-sian and black populations are slow acetylators,the sheer number of those at potential increasedrisk is striking. Currently, the theory is wellfounded in cancer research with a variety ofanimal models (81). However, additional epidemi-ologic studies of populations with bladder cancerare needed to follow up the preliminary evidencethat the degree of risk for such cancer dependson one’s ability to acetylate arylamines. A Japan-ese study is being organized to test this hypothesis(82). The Japanese are particularly suited for thisstudy because of the low prevalence of the slowacetylator phenotype in that population and theavailability of a group of former workers exposedto high levels of arylamines in past decades(Omenn, personal communication).


HLA and disease associations

Just as each individual has his or her ownunique fingerprints, it is now known that eachindividual also has a biochemical fingerprintdetermined by the presence of specific proteinson the surface of cell membranes. This array ofcellular surface proteins has been best studiedwith leukocytes and is called the human leukocyteantigen (HLA) system (83). Several Striking associa-tions between many human diseases and variousHLAs have been revealed (6,24,109,118). For in-stance, the antigen B27 has been associated withankylosing spondylitis (a disease that causes spinalimmobility) and the antigen B8 with thyroid dis-ease.

These antigens are coded by a set of very closelypositioned genes. Since each person inherits atotal of 10 HLA genes, the number of possible an-tigen combinations is in the hundreds of millions(46).

Despite some striking statistical association ofcertain diseases with specific HLAs, any mecha-nistic relationship is yet to be uncovered, therebyprecluding at present the possibility of knowingwhether the relationship is causal or only associa-tional. Nevertheless, the recognition of the sta-tistical relationships of HLAs with a wide rangeof human diseases suggests that inherent geneticfactors are affecting the occurrence of the dis-eases within the population.

At present, there is not enough information tosuggest the use of HLA typing in an occupationalsetting, but this simple test may in the future beused to indicate classes of chemicals to which aperson is likely to be susceptible.

Carbon oxidation

Numerous drugs and environmental pollutantsare metabolized in part via oxidation. The meta-bolic significance of this process is profoundbecause oxidation may result in a metabolizeeither more or less toxic (or carcinogenic) thanthe parent compound. Interspecies differences inthe ability to oxidize various compounds haveresulted in differences in toxic and carcinogenicresponses. For example, the inability of guineapigs to oxidize aromatic amines is thought to ex-

plain their lack of susceptibility to developingcancer from these compounds.

Among humans, individual variations exist withrespect to the metabolism of certain drugs. Themagnitude of these differences may be consider-able. For instance, a 20,000-fold” variation in themetabolism of debrisoquine has been reported(49). Such differences help to explain the wide var-iation in the optimal dose requirement of debriso-quine (20 to 400 mg/day) to control blood pressurein hypertensive patients, a phenomenon of con-siderable clinical significance.

Experimental studies have revealed that theability to oxidize drugs such as debrisoquine iscontrolled by a single gene, with the low activitybeing recessive. Limited experimental evidencesuggests that the frequency of the low activitygene in the population varies markedly accordingto the ethnic group (Caucasian-British, 5 percent;Egyptian, 1.5 percent; Nigerian, 15 percent; andGhanaian, 12 percent). A report studyingNigerians has suggested that low activity oxidizersmay have a decreased frequency of bladder can-cer from aflatoxin, a compound known to requireactivation to become a carcinogen (50). Heterozy-gous individuals, who display an intermediate oxi-dation capability, are predicted to represent about50 percent of the population if homozygous reces-sive individuals make up 6 percent of the popula-tion (49).

The occupational and environmental health im-plications of these findings are notable. For ex-ample, many known mutagens and/or carcino-gens require an initial activation step via an ox-idative process. The extent to which humans dif-fer in their ability to activate potential toxic orcarcinogenic compounds may contribute signifi-cantly to explaining the variation in populationresponses to such agents. In addition, the numberof potentially affected people is enormous.

Diseases of DNA repair

There is a group of heritable traits* in whicha DNA repair defect has been proved or strong-ly implicated. Moreover, an increased frequen-

● Xeroderma pigrnentosum (XP), ataxia telangiectasia (AT), Fanconi’sanemia, and Bloom’s syndrome.


cy of chromosomal abnormalities is found in thelymphocytes of these individuals (with the excep-tion of xeroderma pigmentosum). Affected indi-viduals also are at increased risk for certaincancers, further linking chromosomal abnormal-ities with cancer (7)36)61)73, 108)113). The dis-eases, all results of homozygous recessive traits,cause overt illness and are not compatible witha normal lifestyle. On the other hand, it is possi-ble that the heterozygous conditions which showno clinical manifestations could lead to increasedsusceptibility to toxic chemicals or ionizing radia-tion in an occupational setting.

Individuals heterozygous for these traits havenormal frequencies for chromosomal aberrationsand SCEs (15,32,68). Evidence suggests that theseindividuals are deficient in particular aspects ofDNA repair and consequently may be at higherrisk than the general population to DNA-damagingchemicals or radiation. It has been estimated*

● IIsing the Har>cl~-\\’c~inl]erg equation

from the frequency of the homozygotes in thepopulation that the heterozygote frequency maybe at least 1 percent. Nonetheless, good tests foridentifying those individuals do not exist. The highestimated frequency suggests that many indivi-duals may be at increased risk from occupationalexposures.

The four major heritable recessive syndromesof DNA repair also are associated with an in-creased risk for cancer in homozygous and possi-bly heterozygous individuals (97,119), The resultsfor heterozygous individuals are not well docu-mented because so few of them have been stud-ied. The types of cancer for which one is at in-creased risk vary among syndromes and are notspecific for any one trait. This suggests that manytypes of cancer may be caused by, or related to,specific defects in DNA repair. Because many in-dustrial chemicals are known to damage DNA, itis possible that individuals heterozygous for thesetraits may be at increased risk for disease fromexposure to certain chemicals.

Less well-characterized genetic traits

Other human genetic variants also may put in-dividuals at potential risk to environmentaldisease. For the most part, these are highlyspeculative and are of research interest only.

Superoxide dismutase

This enzyme is known to play a critical role inthe cell’s defense against oxidizing stress. Recent-ly, it has been discovered that genetic variants ofsuperoxide dismutase exist within the human pop-ulation. The prevalence of the variant allele in theU.S. population is unknown, but, based on a Brit-ish study in which the heterozygote for the vari-ant was 6.2:1,000 (43), the projected prevalencein the United States may approach 1.2 million. Theextent to which this variant alters risk to any oxi-dizing agents remains to be determined.

Immunoglobulin A deficiency

This genetic condition is known to occur inabout 1 in every 400 to 800 persons and is thought

to increase the risk of respiratory tract infections(63,64). The extent to which persons with this con-dition are at increased risk to respiratory irritantgases such as ozone, nitrogen dioxide, and sulfurdioxide remains to be assessed.

Paraoxanase polymorphism

Human blood serum has been found to containan enzyme, paraoxanase, that hydrolyzes thecompound paraoxon, which is the oxidized me-tabolize of the insecticide parathion. Paraoxanase,coded for by a single gene, displays considerableinterindividual variability while its activity re-mains constant within a given subject (35,101).Approximately 50 percent of the population isthought to be homozygous for the low activityallele, exhibiting one-third to one-sixth the activityof those homozygous for the high activity form(34). An individual with low paraoxanase activitywould be expected to be at increased risk to par-athion toxicity, although there is no substantia-tion of this hypothesis.


Pseudocholinesterase variants

There are two types of cholinesterase: acetyl-cholinesterases (ACHase) and pseudocholinester-ase (pACHase), ACHase inactivates acetylcholine(ACH) produced at the neuromuscular junctionduring neurotransmission. pACHase is found inmany tissues as well as blood plasma. While itsfunction is unknown, it has been suggested thatit may hydrolyze certain cholinesters which in-hibit ACHase (74). While most people have iden-tical pACHase, a number of pACHase variants ex-ist. Most individuals with variant forms typicallyshow no symptoms, but some may exhibit an ex-treme sensitivity to the muscle relaxant, suxa-methonium, because they cannot hydrolyze suchsubstrates as efficiently as those with normalpACHase (25).

Research involving screening of large numbersof humans has revealed that the presence ofatypical or variant types of pACHase is undergenetic control (56,57). Gene frequencies havebeen determined for some of the variant geno-types. The most common “atypical” homozygousvariant (the dicubaine variant) occurs with a fre-quency of 1 in 2,800 Canadians of European an-cestry (56) and has been found to be extremelysensitive to the insecticide R02-0683 (74). This isof particular significance in light of the wide-spread use of this insecticide. Moreover, 3 to 4percent of the Canadian population tested werefound to be heterozygote carriers of intermediatesensitivity (56). Additionally, of the 10 recognizedgenotypes of pACHase, 4 are known to displaya marked sensitivity to suxamethonium, Theircombined frequency in individuals of Europeanancestry is 1 in 1)250 (120),

In terms of public health, the data indicate thatindividuals have differential sensitivity to the ac-tivity of various neuromuscular-acting drugs and

insecticidelike chemicals. Differences in sensitivityare directly related to the occurrence of pACHasevariants and their diminished ability to inactivatethe drug or insecticide analog. Individuals withsuch pACHase variants should be considered po-tentially at high risk to anticholinesterase insec-ticides (75). It should be emphasized that not alldrugs and insecticidelike compounds act withgreater sensitivity in atypical pACHase variants.

Erythrocyte catalase deficiency

Genetic variants of the red blood cell enzyme,catalase, exist in humans. This has resulted in thegrouping of humans into three classificationsbased on catalase activity levels: normal, hypo-catalasemic (50 percent of normal) , andacatalasemic (1 to 2 percent of normal). Since redcell catalase facilitates the detoxification of exog-enous and endogenous hydrogen peroxide (29),it has been hypothesized that those with a catalasedeficiency may beat risk for hydrogen-peroxide-producing agents such as ozone or radiation (12).Since there are an estimated 5 million hypocata-lasemics in the United States, it would be impor-tant to assess any differential susceptibility thisgroup may exhibit toward such stressor agents.

Dermatological susceptibility

Dermatitis is the single largest cause of occupa-tional disability (104). Susceptibility to irritants isknown to vary widely among individuals, andboth primary irritant and allergic contact derma-titis are probably dependent on genetic factors.Yet, with the possible exception of some HLA cor-relations, these genetic factors have yet to be iden-tified. Therefore, it is not now possible to geneti-cally screen individuals for their susceptibility toindustrial chemicals. On the other hand, a der-matological problem is easily noted and the of-fending chemical can be isolated.

Conclusions

The identification of genetic factors that may appears that genetic differences may in partcontribute to the occurrence of job-related disease explain a variability of responses to chemicals inis a science truly in its infancy. Nevertheless, it the workplace. What percentage of the total

——. .


variability may be explained by genetic factorsis uncertain. The biological foundations of theconcept of genetic screening to identify predis-positions to occupational disease are sound. In ad-dition, most of the well-studied traits are reliablyidentified by easy and inexpensive tests. It shouldbe recognized that other biological variables suchas age, nutritional status, preexisting diseases, andlifestyle also affect the body’s susceptibility to avariety of environmental insults. The study of fac-tors affecting susceptibility to occupationaldiseases, therefore, should not stop with a quan-tification of genetic influences, as important asthey may be, but also should incorporate theother biological variables.

Most variants discovered thus far are rare, withfrequencies of less than 1 per 1,000. The benefit/cost ratio of screening for those who possess rarealleles that predispose to disease could well benegative. Screening for variants that occur in atleast 1 percent of the population is more likelyto be cost beneficial. The following reservationsapply to screening for evidence of prevalent vari-ants as well as rare alleles:

● Screening tests might not be capable of dis-tinguishing with high specificity and sensitivi-ty one variant from another or from the pre-dominant allele (if one exists). When morethan one allele exists, the number of possi-ble different enzymes in the population, eachof which may have a mean activity differentfrom the others, exceeds the number of al-leles, The distribution of the activities of thesedifferent enzymes may overlap. For example,three alleles of the gene for red blood cell acidphosphatase have been found in the Englishpopulation. The distribution of phosphataseactivity in the population, which follows afairly smooth unimodal distribution (45) (seefig. 8), is accounted for by the overlappingdistribution of the activities of five of the sixdifferent enzymes that would be expectedfrom three alleles. In screening for acid phos-phatase activity, many classification errorswould be made regardless of the cutpoint.

Figure 8.—Distribution of Red Cell Phosphatase ActivitiesIn the English Population

r

100 140 180 220 280

Red cell acId phosphatase activity

SOURCE: H. Harris, The Pr/nc/p/es of Human B/octrerrrica/ Genet/cs (Amsterdam:

●

●

●

North-Holland Publishing Co., 1977).

Where continuous, unimodal variation in en-zyme activity in a population is observed, thechance of disease in response to an environ-mental agent also might vary continuously,correlating approximately with the amountof enzyme activity. Thus, even if it were pos-sible to distinguish those who possess one al-lele from those who possess another, it mightnot be appropriate to dichotomize the pop-ulation into two categories of those at highrisk of disease and those at low risk,The chance that a person with a specific allelewill develop disease on exposure may dependon the presence of other factors, some ge-netic and some environmental, For instance,the slow acetylator phenotype may explainonly a small percentage of the bladder cancervariance within the population.Despite the high degree of genetic diversity,and possibly even of differences in enzymeactivity conferred by different alleles at alocus, allelic differences may not be associ-ated with differences in susceptibility. Differ-ent alleles may coexist precisely because theydo not differ in the biological fitness they con-fer. Their respective frequency may dependon random genetic drift from one generationto the next.


Priorities for future research

Well-designed, prospective epidemiologic stud-ies are needed to assess the correlation betweenspecific genetic traits and predisposition to illness.A major weakness in several important existingstudies (59,60,81) is that both clinicians and lab-oratory research scientists have attempted to con-duct epidemiological research studies without theapparent assistance of persons specifically trainedin epidemiological research methodology. Unlessthe epidemiologist is involved in the initial designof the study as well as in subsequent analysis pro-cedures, there is a serious likelihood that expen-sive and time-consuming research will yield farless valuable and defensible data.

During epidemiological studies, researcherscould acquire HLA profiles when appropriate.This would begin to provide a greatly expandeddata base which would be useful in understand-ing the associations of HLA markers with envir-onmentally related diseases.

Red blood cell traits

Given that these traits are prevalent in thepopulation and that many potential hemolytic andoxidizing chemicals are employed in a wide vari-ety of industries, there is a clear need to assesswhether individuals with traits potentially predis-posing susceptibility to these chemicals are indeedat risk. Two approaches to this assessment couldbe undertaken,

Research could be initiated on the developmentof a predictive animal model that would simulatethe response of human red blood cell deficien-cies. This would allow for the rapid evaluationof large numbers of potential hemolytic com-pounds singly or in combination under preciseexposure conditions, It would also assist in provid-ing direction for epidemiologic research studies.An animal model recently has been developed inwhich guinea pigs are transfused with human redblood cells, thus overcoming interspecies differ-ences. Using this model, chemical exposures canbe done and the responses of the red blood cellsmonitored. Human red blood cells have beenshown to survive in the animals for 2 to 4 days,

allowing some good, preliminarily experiments tobe done.

The second approach involves epidemiologicalresearch studies in appropriate industries wherehemolytic and oxidizing agents (and benzene andlead) are used and where exposures approachFederal limits. Such research should attempt todifferentiate the susceptibility of the A – andMediterranean variants for G-6-PD deficiency.The studies also should assess any possible syner-gistic interaction between medications and hemo-lytic industrial chemicals.

Differential metabolism of industrial/pharmacological compounds

Further documentation of the extent to whichhumans differ both qualitatively and quantitative-ly in metabolizing foreign compounds is needed.More specifically, further work on genetic vari-ants of carbon oxidation and AHH could be con-ducted. The research should involve not only agenetic component but nutritional and aging con-siderations as well. Results from such studiesshould contribute markedly to the present under-standing of idiosyncratic drug reactions as wellas the occurrence of differential susceptibility toenvironmental toxins. These studies may involvea wide variety of chemical agents including drugsor industrial or commercial products.

In addition, methods for measuring AHH induc-ibility which are reproducible in differentlaboratories need to be developed.

Epidemiologic investigations are needed toassess the risk of individuals with the slowacetylator phenotype for developing arylamine-induced bladder cancer. Since the slow acetylatorrepresents about .50 percent of the population,the population at risk is extremely large. As inthe case of the other complex disease processes,arylamine-induced bladder cancer is affected bya variety of factors in addition to acetylatorphenotype. Some confounding metabolic variablesmay include the capacity to N-hydroxylate thearylamine and the capacity to deacetylate an ace-

— —

Ch. 7—Genetic Screening for Heritable Traits ● 101

tylated compound. Moreover, factors such as ageand sex need to be recognized.

It has been hypothesized that slow acetylatorsare at greater risk of developing arylamine-induced bladder cancer than fast acetylators.However, the extent to which people differ intheir ability to deacetylate previously acetylatedarylamines can markedly affect the outcome ofstudies designed to test the original hypothesis.Deactylation capability varies widely amongspecies and affects susceptibility to carcinogens.

The extent to which humans differ in this regardis not known,

SAT deficiency

Research could be conducted on the relativecontributions of SAT levels and other factorsthought to help cause development of emphy-sema. Data are needed to validate recent studiesthat suggest that ozone exposure at ambient sum-mertime levels and cigarette smoking may resultin a marked reduction in SAT levels.

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Ch. 7—Genetic Screening for Heritable Traits ● 103

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Part IV

Legal, Ethical, andEconomic Issues

Chapter 8—Legal Issues Raised by Genetic Testing in the Workplace . . . . . . . . . . . . . . . . . . . . 111

Chapter 9—Application of Ethical Principles to Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . 141Chapter 10—Prospects and Problems for the Economic Evaluation of Genetic Testing . . . . . . 151

Chapter 8

Legal Issues Raised byGenetic Testing in the

workplace

Contents

PageBasic Rights and Duties Governing Employment and Medical Practices ... , ,., . . . . . . . 112

Employer Rights and Duties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112New Rights and Duties Created by Workers’ Compensation Laws . . . . . . . . . . . . . . . . . 112Exceptions to the “Exclusive Remedy’’ Rule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Dual Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113Willful and Intentional Torts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Products Liability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114Rights and Duties in Company Medical Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

The Doctor-Employee Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115The Doctor-Employer Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115Duty to Conduct Medical or Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116Employees Right to Refuse an Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116Testing Solely for Research Purposes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116Disclosure of Health Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117Employee Access to Medical Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117Confidentiality of Medical Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Statutory Regulation of Company Medical and Employment Practices . . . . . . . . . . . . . . . 118Occupational Safety and Health Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

Genetic Testing and the General Duty Clause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120Employee Variability in Standards Setting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120Genetic Monitoring and OSHA Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121OSHA Regulation of Employer Medical Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121Medical Removal Protection and Rate Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122Access to Exposure and Medical Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Title VII of the Civil Rights Act of 1964 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123Disparate Impact of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124Business Necessity and Job Relatedness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124Employee Refusal To Submit to Medical Tests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

The Rehabilitation Act and State Fair Employment Laws . . . . . . . . . . . . . . . . . . . . . . . . . 126Medical Examinations and Screening Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127Is Genetic Susceptibility or Chromosomal Abnormality a Handicap? . . . . . . . . . . . . . . 127Job Relatedness of Screening and Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128Reasonable Accommodation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

Collective Bargaining Agreements and Employment Practices . . . . . . . . . . . . . . . . . . . . . . . 131Protected Activities of Employees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131Employee Access to Safety and Health Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131Provisions in Collective Bargaining Agreements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132Union’s Duty of Fair Representation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132Contract Enforcement and Arbitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ...... 133Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Chapter 8

Legal Issues Raised byGenetic Testing in the workplace

Genetic testing raises many legal issues forwhich there are few clear answers. The most fun-damental question is whether the technology iscompatible with existing laws and the establish-ed legal rights of employees. This question em-bodies a number of issues within the broad spec-trum of employee-employer relations, rangingfrom the nature of the doctor-employee relation-ship through the proper use of the test resultsto the employer's responsibility to prevent occu-pational illness. These questions may be specifiedas follows:

Who has the legal responsibility for achiev-ing and maintaining a safe workplace?—What does “safe” mean?—How is safety to be achieved?To what extent does the law protect the in-terests of individuals or groups who may beat increased risk of occupational illness?When, if ever, does an employer have a du-ty to use certain medical procedures, includ-ing genetic testing?What are the legal constraints on occupa-tional medical testing procedures, whetherused routinely or for research?—What information must be given to the

employee?—What use can be made of the results?What are the employer’s rights to use em-ployee selection methods that it deems ap-propriate?Under what circumstances could the Occupa-tional Safety and Health Administration(OSHA) require medical tests in general andgenetic testing in particular?To what extent can employers and employeesor their unions negotiate their own answersto these questions?

No Federal statute specifically covers or evenrefers to genetic testing in the workplace. NoFederal court cases have dealt with the subject.Consequently, there are no direct legal precedentsto guide decisionmaking. However, there aremany established legal principles governing therights and duties of employers, employees, com-pany medical personnel, and unions. These canbe applied to the issues raised by this new tech-nology,

There are three major ways that legal rights andduties governing emlployer-employee relations arecreated. The first is by judicial decision, whichproduces a body of legal principles known as thecommon law. The second is by legislative decree.Federal and State statutes can expand, modify,or overturn common law rights and duties or cre-ate new ones. The first major example of this inemployer-employee relations was the enactmentof workers’ compensation laws by all of the Statesin the first part of this century. other applicablestatutes include the National Labor Relations Act(NLRA), the Occupational Safety and Health Actof 1970 (OSH Act), the Civil Rights Act of 1964,and the Rehabilitation Act of 1973. The third wayis by contractual arrangements between employ-.ers and unions. These are known as collectivebargaining agreements and are authorized by theNLRA. Rights and duties with respect to companyemployment and medical practices may be cre-.ated, modified, or enhanced by collective bargain-ing agreements so long as they are not incompati-ble with existing law.

These sources of law provide a useful frame-work for addressing the legal issues raised by ge-netic testing in the workplace.

111


Basic rights and duties governing employmentand medical practices _ —————. .

The common law provided the initial source oflegal principles governing relationships amongemployers, employees, and company physicians.Workers’ compensation laws substantially mod-ified the relationship between employer and em-ployee, but the common law continues to be rele-vant, especially in the doctor-employee relation-ship and in litigation concerning occupational ill-ness, such as the asbestos cases.

Employer rights and duties

Under common law, an employer had virtual-ly unfettered control in selecting its employees.The employer could hire or refuse to hire for anyreason or no reason at all. This right included theright to refuse to hire an individual because ofthe employer’s opinion that the prospective em-ployee was physically incapable of performing thejob. Once hired, the employee could be fired “atwill” by the employer for any reason or no rea-son at all, including the employer’s belief that theemployee could no longer perform the job be-cause of his physical condition. This has beenmodified by State and Federal antidiscriminationstatutes.

Under common law, employers had five mainduties for the protection of employees. Thesewere to: 1) provide a safe place to work, 2) pro-vide safe tools and equipment for the work,3) warn of dangers about which the employeemight reasonably be expected not to know, 4) pro-vide a sufficient number of suitable coworkersto ensure the safety of each worker, and 5) pro-mulgate and enforce rules that would make thework safe. These duties are still recognized bythe law in the 50 States and the District of Co-lumbia.

An employee who suffered from an injury orillness related to his employment had a right tosue the employer for damages. Because these suits

were based on common law negligence, * employ-ers usually were able to escape liability by invok-ing the common law defenses of contributory neg-ligence, assumption of risk, and the fellow serv-ant rule (53). That is, if the injury or illness wascaused in any part by the negligence of the in-jured worker or any coworker, or if the employeeexpressly or impliedly assumed the risk of work-ing in a hazardous job, there was no recovery.The concept of assumption of the risk may berelevant in some cases involving genetic testing.

New rights and duties created byworkers’ compensation laws

Beginning in 1910 with New York, the Statestook steps to relieve the hardship of industrial ac-cidents on individual workers and their familiesby passing workers’ compensation laws. Todayeach State has such a statute. The major objec-tives of these laws are to: 1) provide sure, prompt,and reasonable income and medical benefits towork-accident victims, or income benefits to theirdependents, regardless of fault; 2) provide a singleremedy and reduce court delays, costs, and work-loads arising out of personal injury litigation;3) eliminate payment of fees to lawyers and wit-nesses, as well as the expense of time-consumingtrials and appeals; 4) encourage maximum em-ployer interest in safety and rehabilitationthrough an appropriate experience-rating mech-anism; and 5) promote study of the causes of acci-dents in order to prevent future accidents (66).

Workers’ compensation is a form of ‘(strictliability” whereby the employer is charged withthe injuries arising out of its business without

“Negligence is conduct (an act or omission) that involves an un-reasonable risk of harm to another person. For the injured partyto be compensated, he must prove in court that: 1) the defendant’sconduct was negligent, 2) the defendant’s actions in fact caused theinjury, and 3) the injury was not one for which compensation shouldbe denied or limited for reasons of overriding public policy,

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace 113

regard to fault. Common law damage actions* areprecluded, but so too are common law defenses.The employee is assured of medical expenses andincome maintenance; employers are protectedagainst potentially large personal injury judg-ments, including those for “pain and suffering. ”In addition, employers are assured of relativelyfixed production costs that can be passed alongto the consumers, since the employer carries in-surance to pay workers’ compensation claims.Resort to this system is, with some exceptions,the “exclusive remedy” available to injuredworkers.

Virtually all private sector employees arecovered by State workers’ compensation laws andgovernment employees are protected by similarlaws. Where the statute does not apply, injuredemployees retain their common law rights andremedies.

Each State law sets its own eligibility require-ments, benefit levels, and administrative mecha-nisms for claims processing. The resulting widerange in eligibility and benefit levels is one of themost frequent criticisms of workers’ compensa-tion.

One of the most troubling aspects of worker’scompensation law is in dealing with occupationaldisease. Claimants must prove that the diseasefrom which they suffer is work related and notone of the “ordinary diseases of life” (41)62). Thisis extremely difficult to do for many occupationaldiseases, which have long latent periods andwhose causes are poorly understood. Consequent-ly, occupational disease cases are six times morelikely to be contested than accident or other cases(32), and relatively few claimants prevail (7).

Exceptions to the “exclusiveremedy” rule

There are a number of exceptions to the generalstatement that workers’ compensation is the onlyremedy available to an employee suffering fromwork-related injury or illness. Two of the excep-tions are most relevant here.

● The term “action” is synon~mous with suit or lausuit.

DUAL CAPACITY

In a minority of jurisdictions, an employer maybecome liable to its own employee if the employ-ee’s injury or illness resulted from the breach ofa duty arising outside the scope of an employer-employee relationship. In these situations theemployer is said to be acting in a “dual capacity. ”The most important of these for genetic testingis when an employer provides medical services,whereby it incurs the risk of medical malprac-tice claims.

One category of these claims involves the failureof the company physician to detect or to informan employee of illness. For example, in Bednar-ski v. General Motors Corp., * a wrongful deathaction * * was permitted to be brought based onthe company’s failure to diagnose or to informthe plaintiff’s decedent that he had lung cancer,even after performing a series of physical ex-aminations and X-rays. Many of these failure todiagnose or inform cases are based on non-work-related illnesses that were allegedly detectableduring preemployment examinations (8,9,73).

An employer might also be found liable fornegligently failing to discover an employee’s pro-pensity to contract a work-related illness, therebypermitting the employee to be exposed to condi-tions that bring about the disease (14,56). If sucha case were brought, however, the plaintiff wouldbe required to prove that a reasonably prudentcompany doctor exercising ordinary skill andjudgment would have detected the employee’slikelihood of contracting an occupational disease.It is unlikely, at least at the present time, that anemployer would be liable where the employee’smedical condition could only be detected throughsophisticated biochemical or cytogenetic pro-cedures and the employer did not use these pro-cedures. On the other hand, the negligent mis-use of these procedures by the employer mightprovide the basis for liability.

Two other points related to dual capacity med-ical malpractice are relevant. First, even wherethe examining physician is not negligent, the

*88 Nlich. App. 482, 276 N.\\’ .2d 624 ( 1979). Arrord, Hooter 1,It’illiams, 203 AX] 861 (hid. 1 964) (silicosis).

* *A t$’rongful death action is a suit claiming that the defendantconduct \\rongfull}’ caused someone’s death and that the plaintiff,usua[!v the survi~ring spouse or children, was harmed as a r[~su]t.


employer may be liable if established companymedical practices are inadequate (36). Second, insome jurisdictions the company physician may besued individually for negligence and is not pro-tected by the employer’s immunity under work-ers’ compensation laws (30,31).

WILLFUL AND INTENTIONAL TORTS*

In almost all jurisdictions, an exception to theexclusive remedy rule is recognized if theemployee can prove that the employer specificallyintended to harm him (4)35,59). This is a fairlyhigh hurdle for a plaintiff employee to clear, InMandolidas v. Elkins Industries, Inc.,** however,the West Virginia Supreme Court of Appealsgreatly expanded the rule and held that an em-ployer is liable for employee injuries resultingfrom the employer’s willful, wanton, or recklessmisconduct: “[W]hen death or injury results fromwillful, wanton or reckless misconduct, suchdeath or injury is no longer accidental in anymeaningful sense of the word, and must be takenas having been inflicted with deliberate intentionfor the purposes of the workmen’s compensationact. ” A recent Ohio case also adopted this view-point (11).

The Mandolidas case could arguably support anaction against an employer by an employee if thefollowing conditions were met: 1) the employerwas using genetic screening tests, 2) the tests werehighly predictive, 3) the tests identified the em-ployee as susceptible, 4) the employer placed anemployee into a high risk instead of a low riskenvironment, and 5) the employer contracted thedisease for which he was identified as being atrisk.

A more substantial body of law exists to allowrecovery for injury or illness caused by the fraudor deceit of the employer. The cases usually in-volve concealment of an existing illness. For ex-ample, where employers have fraudulently con-cealed from employees the fact that they weresuffering from lung cancer (37) or silicosis (21),the employees were permitted to bring damageactions for injuries caused by the aggravation oftheir initial condition. There is also some limited

“~ tort is a ci~fil wrong, other than breach of contract, for whicha court will award damages or other relief.

● *246 S. E,2Ci 907 (M’. \’a. 1978).

case law to the effect that fraudulent concealmentof information about hazardous working condi-tions would permit an injured employee to recov-er damages (34). These cases on fraudulent con-cealment might support an action where the con-cealment involved the results of genetic monitor-ing, if the results validly predicted that employeeswere at an increased risk of developing cancerand the plaintiff developed cancer.

Products liability

The “exclusive remedy” provisions of workers’compensation laws apply only to actions broughtby injured employees against their employer.Some jurisdictions permit suits against other com-panies, for example, the manufacturer of a prod-uct used by the employee on the job. This prod-ucts liability litigation —where the employeealleges that an injury or illness was caused by aproduct manufactured by the defendant and sup-plied to the employee’s employer—is rapidly ex-panding. Perhaps the best known type of case,and certainly the most prevalent number of thesecases, involves asbestos.

Asbestos and other products liability suits oftenare based on the allegation that the manufac-turers failed to warn all those who might handlethe product of its hazardous nature. In the leadingcase of Borel v. Fibreboard Paper ProductsCorp., * the Fifth Circuit Court of Appeals ac-cepted such a claim by ruling that the defendantmanufacturer of insulation material that con-tained asbestos had a duty to warn all users ofits asbestos products, including insulation work-ers who did not make the product but simply in-stalled it, of the foreseeable dangers associatedwith handling asbestos.

Products liability conceivably could become anissue for genetic testing. For example, if a com-pany manufactured a chemical that was a sus-pected carcinogen, it might feel compelled to usecytogenetic monitoring to help it determine thepotential hazards associated with the chemical,not only to protect its employees but also to beable to warn its customers’ employees. Failure totake such steps might provide grounds for law-suits similar to those for asbestos.

*493 F.2d 1076 (5th Cir. 1973), cert. denied 419 U.S. 869 (1974),

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace ● 115

Rights and duties in companymedical practices

THE DOCTOR-EMPLOYEE RELATIONSHIP

The nature of the doctor-employee relationshipis clouded by the dilemma of the conflicting dutiesof the occupational physician. On one hand, thedoctor is an employee of the company and thushas the duty to further the company’s interests.on the other, when the doctor examines or treatsemployees, this interaction looks very much likethe standard doctor-patient relationship.

The tension between the doctor’s conflictingduties may be seen in the following example. Sup-pose a person’s annual checkup by his personalphysician reveals a condition that would makehim susceptible to disease in a certain work en-vironment. The doctor has the duty to inform thepatient of the risk, and the patient can choose toact on that information as he sees fit. If, however,the examination was a preemployment one con-ducted by the company physician, the doctor’sprimary duty would be to inform the employer,with the likely result that the person would notbe hired or would be placed in a job differentfrom the one for which he was originallyconsidered.

It is important to determine whether a physi-cian-patient relationship exists between anemployee and an employer-provided doctor. Ifthere is no such relationship, the doctor owes noduty to the employee except to use ordinary carenot to injure the employee during the course ofthe examination. If there is a physician-patientrelationship, the physician must render medicalcare with the skill and learning commonly pos-sessed by members of the profession. The physi-cian also would have the following legal duties:1) to discover the presence of disease, 2) to in-form the patient of the results of the examina-tion and of any tests performed, 3) to advise theemployee of risks associated with continued ex-posures, and 4) to preserve the confidentiality ofcommunications and records.

The traditional view is that there is no phy-sician-patient relationship between an actual orprospective employee and an employer-provideddoctor (2, 39, 58). Courts that adhere to the.

dichotomy between employer-provided and tra-ditional patient-obtained medical care look towhether the physician is treating or merely ex-amining the individual or for whose benefit thephysician is performing the service. If the phy-sician is merely examining the individual or per-forming services for the benefit of the employer,no physician-patient relationship will be found.

There are indications that this is changing, andthe current state of the law is less certain (49).The distinction between treating and examiningseems simplistic and artificial. {occupational physi-cians examine and treat; the benefit of their serv-ices goes to both employer and employee. There-fore, to determine if there is a physician-patientrelationship, other factors also need to be con-sidered, including whether there is an ongoingmedical relationship between the parties or mere-ly a single examination, what the reasonable ex-pectations of the physician and patient are as tothe nature of the examination, whether any diag-nosis or treatment is contemplated by the exam-ination, and the nature of the employee’s consentto the examination. In fact, the employee’s expec-tations as to the nature of the exam may createa duty on the part of the employer’s physicianto inform potential employees of any serioushealth problems that the doctor discovers orshould have discovered with the exercise of rea-sonable care. This duty would arise not out of aphysician-patient relationship per se, but out ofthe natural reliance by the potential employee onthe physician to inform him of any uncoveredhealth problems. Acting on this reliance, the ap-plicant may forego additional examinations to hisdetriment.

THE DOCTOR-EMPLOYER RELATIONSHIP

Unlike the doctor-employee relationship, therelationship between the employer and the doc-tor is more clear-cut. Generally, the doctor isviewed as representing the employer, and, under.the legal doctrine known as respondeat superior,actions of the doctor are attributed to the em-ployer. Thus, if the doctor is found to be liablefor malpractice or other improper actions withrespect to an employee, the employer generally.will be held liable too.


DUTY TO CONDUCT MEDICAL OR GENETIC TESTING

Employers are under no general legal duty toconduct preemployment or periodic medical ex-aminations, except where required by OSHAstandards covering specific health hazards or pur-suant to a provision in a collective bargainingagreement. Nevertheless, approximately 48 per-cent of all employees in urban workplaces are re-quired to take a preplacement physical examina-tion and nearly 34 percent of all such employeesare provided with periodic medical examinations(45).

Under these circumstances, is there a duty toconduct genetic testing during the course of theseexaminations? The physician has a duty to usereasonable care and customary medical proce-dures. Since this technology does not meetestablished scientific criteria for routine use, thephysician does not have a duty to use the tests,However, if sufficiently high correlations betweengenetic endpoints and disease are eventually dem-onstrated and the tests become a commonly usedmedical procedure, the occupational physicianmay have a duty to use them when conductingmedical examinations.

EMPLOYEE’S RIGHT TO REFUSE AN EXAM

With the increasing use of occupational medicalscreening, examinations, and procedures comesthe growing likelihood that an applicant oremployee would refuse to take such an exam onreligious, ethical, medical, privacy, or othergrounds. Thus, the question arises whether anapplicant or employee has a right to refuse med-ical tests and still retain his job. Unless the testprocedure violates a specific statute, regulation,or collective bargaining agreement, there is noconstitutional or common law right to refuse (28).

TESTING SOLELY FOR RESEARCH PURPOSES

An employer may want to conduct genetic testssolely for research purposes, where no job actionsare taken with respect to employees. In this situa-tion, absent a specific provision in a collectivebargaining agreement, it would appear that theemployee has no right to refuse to take part inthe testing and still retain his job. Research onmethods to determine the health effects of work-

place exposures can be a valid condition of em-ployment.

There are constraints on how the research maybe conducted. If an employer had received Fed-eral funds for the research or were conductingthe research with a university that had receivedFederal funds for the project, the researchers arerequired by the National Research Act* to estab-lish an Institutional Review Board (IRB) in orderto protect the rights of the human subjects. TheDepartment of Health and Human Services (DHHS)has promulgated regulations which, among otherthings, specify the criteria for IRB membershipand approval of the research. * * One of the mostimportant of the criteria for approval is that in-formed consent to the research must be given byeach subject. While the regulations specify at leasteight elements of informed consent, these ele-ments basically condense to the following require-ments: 1) all of the important information, suchas the procedures, the risks, and the possiblebenefits, must be disclosed to the employee interms he or she can understand; 2) the employeemust understand that information; 3) the em-ployee must be mentally competent to consent;4) the consent must be voluntary; and 5) a state-ment must be provided describing the extent towhich confidentiality of records identifying thesubject will be maintained. A further discussionof these regulations is not warranted becausemost occupational medical research is not likelyto be federally funded.

Research to establish the validity of genetictesting most likely will be governed by State law.A few States have enacted statutes coveringhuman experimentation. * * * However, State tortlaw (common law) probably will be the source ofapplicable law. Tort law generally provides fewlimitations on such experimentation other than therequirements of informed consent and avoidanceof negligence (27). Unlike the elements of in-formed consent in the DHHS regulations, how-ever, the State-law-developed doctrine of in-formed consent does not deal with the issue of

*42 [’.s,[:. $2891-3(2) ( 1976).* ● 45 C.F. R. $46 [1981).● * *See, fbr eximple, N.Y, Pub. Iiealth La\v 6 $244(J-2446 (NlcKin-

nt?y 1977); Wis. Stat. Ann. ~.5 1.61 (W’est Supp. 1981).

.


confidentiality of medical records. Furthermore,in the workplace, the requirements for informedconsent are likely to be minimal. Since participa-tion in research can be a valid condition of em-ployment, employees probably would not haveto be told much, if anything, about the research,unless it involved a significant risk. Since genetictesting involves low-risk procedures, employeesprobably would not have to be informed of thetests. Of course, the employee would have to con-sent to the medical examination in which bloodwas drawn.

Despite the generally limited legal restrictionson medical research under State law, an employerstill might hesitate before embarking on a re-search program involving genetic testing. Anemployer may fear that a plaintiff in a lawsuitclaiming work-related illness could get access tothe results via discovery * procedures and usethem to build a better case against the employer,even if the employer believed the results did notestablish the validity of the tests.

DISCLOSURE OF HEALTH RISKS

Although a rule** under the OSH Act requiresthat employees (but not applicants) be given ac-cess to their medical records, employers and oc-cupational physicians do not have an affirmativeduty under this rule or the common law to dis-close the results of medical exams to employeesor applicants. However, as noted previously, with-holding medical information can give rise to civilliability, where an illness, whether or not occupa-tional, was detected or should have been detected.

This principle possibly could be extended tosituations where individuals were merely at risk.Since employers have a common law duty to ap-prise employees of latent dangers, a company maybe liable for failure to disclose that employees areworking with a hazardous product. In addition,a physician may be liable for failure to disclosethe health risks of the job, if the company givesmedical examinations,

“L)isrmcrj IS the right of parties in a lawsuit to ha~c acress toInfornlatlon in the possession of their ad~ ersary rclm’ant to the suit.“1’his right of :i[xPss is quite hrmd The theory underl}’ing discmw~’is t }xi t thr pr rtIes should not k “ii rJIl)LJsh Pd” at t ria] h\ I in f[)rrna -

tlon that was prmiously unknow n to them and ciet rirnental to their(’iise

● ● 29 (’ F K. $191020 ( 1981)

Disclosure of information about hazardoussubstances provides the employer with the op-portunity to use the defense of assumption of therisk in lawsuits based on common law theoriesof negligence. That is, if an employee who wasat increased risk of disease knowingly placedhimself in the risky environment, he could notlater sue the employer or physician for negligenceif he developed the disease (13,72).

EMPLOYEE ACCESS TO MEDICAL RECORDS

In view of their concern about possible misuseof information from genetic screening and a likelydesire to know of risks to their health, employeesand applicants might want to have access to theirmedical records. As of 1980, employees have aright to see their medical records pursuant toOSHA's Access to Employee Exposure and MedicalRecords Standard. * Besides OSHA’s access stand-ard, which applies only to toxic substances andwhich is still being challenged in the courts, thereare few legal requirements that employers giveemployees a right of access to medical records.Five States—Connecticut, Massachusetts, Maine,Ohio, and Wisconsin—provide for such a right,usually as part of a broader right to review theemployee’s entire personnel record. * * Applicantshave no rights to company medical records. Theonly other source of an access right is througha collective bargaining agreement.

CONFIDENTIALITY OF MEDICAL RECORDS

One concern of employees or applicants whohave been genetically screened would be to pre-vent the spread of embarrassing, damaging, orfalse information about themselves, particularlyto other potential employers. Thus, they wouldwish to know to what degree such informationwould be kept confidential.

The Code of Ethics for Physicians Providing oc-cupational Medical Services provides that “em-ployers are entitled to counsel about the medicalfitness of an individual in relation to work butare not entitled to diagnoses or details of a specific

*45 E’ed, Reg. 35,212-3,5,303 (X!aj 2:3, 1 980), (’(Miif/(’(/ ‘1 t 2!1 ( ‘ F K‘$I91O 20 (1981).

“‘[’[)nn [len Stat Ann title 31, $ 128c (\$r[Jst Supp 1981); NlassAnn 1,a\\s rh 149 , $ 19A ( 1976), XI(>. R(J\ Stiit Ann t ilk 26, $631(J1’est Supp. 1981); O h i o Re\ (;()(l(> $411323 (Pagf> 198(1}: tl IS S t a t

,Ann. title 1 :}, $ I 03.13 (It’est Sul)p 1981 I


nature. ” In practice, however, management ac-cess to employee medical records is often muchmore extensive (49)55,70).

There are few legal restrictions on such dis-closures within the company. Often as a condi-tion of employment, employees sign blanketwaivers authorizing the company to use medicaland personnel records as it deems necessary.Even if a waiver is not signed, it has been assertedthat “workers have little genuine expectation oftrue confidentiality as to employment medicalrecords” (49). In one case, the court stated thatthe employment exam “was wholly for the benefitof the Company, and the doctor owed to it alonethe duty to perform efficiently the work the Com-pany had employed him to do. Appellant must becharged with knowledge of this” (39). Thus, therewas an implied waiver of confidentiality by theemployee’s consenting to the examination. Final-ly, liability for wrongful disclosure would haveto be based on a breach of the physician’s dutyof confidentiality and, as discussed earlier, manycourts have found that there is no physician-patient relationship where the physician is pro-vided by the company.

With respect to disclosure of medical informa-tion to parties outside the company, there are also

few restrictions under common law. In any law-suit alleging damage from such disclosure, theplaintiff would have to overcome the defense thatthere was no duty of confidentiality because therewas no doctor-patient relationship between thecompany physician and the employee or job ap-plicant (54).

Some State and Federal statutes provide a vari-ety of protections from disclosure. OSHA’s accessstandard gives OSHA the right to employee med-ical records in personally identifiable form, butlimits the disclosure of such information and pro-vides safeguards to ensure confidentiality. TheDHHS regulations on human experimentation re-quire, “where appropriate,” adequate provisionsto protect the privacy of subjects and to main-tain the confidentiality of data. *

The most extensive regulation of medical infor-mation is California’s Confidentiality of MedicalInformation Act. * * It requires employers who re-ceive medical information to establish proceduresto ensure its confidentiality. Further, employerscannot disclose this information to others withoutthe employee’s written consent.

*45 (:. F’.R. $46.11 1(a)(7).* “(;al, (;i\’, (;ode Ann. $56 [[leering Sup]). 198.2)

Statutory regulation of company medicaland employment practices — ——. .-. —— —..

Three Federal statutes—the Occupational Safety or could be required, prohibited, or otherwiseand Health Act of 1970, the Civil Rights Act of regulated pursuant to the act.1964, and the Rehabilitation Act of 1973—aredirectly applicable to medical and employee selec-tion practices used by employers. The OSH Act*was enacted “to assure so far as possible everyworking man and woman in the Nation safe andhealthful working conditions . . . .“* * The act pro-vides the Government with broad regulatory au-thority over physical conditions in the work en-vironment. Since genetic testing may play a rolein the prevention of occupational illness, questionsnaturally arise about whether genetic testing is

Title VII of the Civil Rights Act of 1964, asamended, * and sections 503 and 504 of of theRehabilitation Act of 1973** govern employmentrights. Title VII prohibits employment discrimina-tion on the basis of race, color, religion, sex, ornational origin. The Rehabilitation Act prohibitsemployment discrimination against otherwisequalified handicapped individuals by employerswho are Government contractors or recipientsof Federal assistance. These statutes embody the

*29 (1 s (’ $$6.51-678 (1976 &? Sllpp. 111 1979)● * $2! 2!1 [1.s (:, $651 ( lg~~),

.~~ [ I ,s (; (j~()()()(> ( 1976 Is?, supp. 11 1 !)7s1.

“ ● 2:1 (“.s (: $$701-796 ( 1976 &L. Supp. 111 1 979)

.


policy that individuals are not to be discriminatedagainst on the basis of immutable characteristicsand that their abilities are to be judged on an in-dividual basis. Since one major type of genetictesting—genetic screening—could result in em-ployment discrimination against classes of individ-uals with particular inherited traits, the questionarises as to whether such discrimination is prohib-ited by these two acts.

This question is not answered simply by assert-ing that the OSH Act requires every employee,even those who may be genetically susceptible toillness, to have a safe working environment andtherefore federally mandated exposure levels ofhazardous substances must be low enough to pro-tect these people. The broad policy of worker pro-tection embodied in the act is limited by require-ments that Government exposure standards betechnologically and economically feasible and thatthey be imposed only after a finding of a signifi-cant risk of material health impairment. Thus,there is a tension between the social goals of max-imizing equal employment opportunity and safetyin the workplace.

This section examines how these three statutesand State fair employment practices laws dealwith the sometimes conflicting policy goals andvarious legal questions created by genetic testing.

Occupational Safety and Health Act

The OSH Act is the only comprehensive statuteaddressing hazards in the workplace and there-fore is the primary vehicle for hazard eliminationin that setting. Section 5(a) of the act requiresemployers to furnish a place of employment freefrom recognized hazards and to comply with allstandards promulgated under the act. “Recog-nized hazards” has been interpreted by the courtsto mean recognized by the employer or the in-dustry and that there is a recognized way of deal-ing with it; that is, it is preventable (46). SectionS(b) requires each employee to comply with “allrules, regulations, and orders issued pursuant tothis Act which are applicable to his own actionsand conduct .“ * Despite the seeming similarity ofthese provisions, it is clear that “[f]inal respon-

sibility for compliance with the requirements ofthis Act remains with the employer” (60). Em-ployees cannot assume the risk with respect tohealth and safety hazards as they could undercommon law. Only the employer may be issuedcitations, assessed penalties, and ordered to abateviolative conditions. Employees may only petitionthe Secretary of Labor to enforce the require-ments of the act; the employer is required by lawto obtain the compliance of employees, even ifthis entails disciplining disobedient employees.Violations of the act or rules promulgated there-under can result in civil or criminal penaltiesagainst the employer. The act does not supersedeor affect rights and duties created by commonlaw or workers’ compensation statutes.

Employer duties under the OSH Act are specificand nondelegable. An employer may not rely on. .a union to provide safety training, and it may notshift the burden of compliance to employees or.supervisors. Under the act, employees may notassume the risk nor consent to work in conditionsthat violate the act’s requirements.

An important right of employees under the OSHAct is the right to refuse to work under extremelyhazardous conditions where there is insufficienttime to eliminate the hazard by resort to regularenforcement channels. This right, based on thebroad antidiscrimination provision in section11(c), was established in an OSHA regulation, *which was unanimously upheld by the SupremeCourt in Whirlpool Corp. v. Marshall.**

If cytogenetic tests showed an increasednumber of chromosomal abnormalities in one ormore employees, could they walk off the job? Theanswer is probably not. First, because of thedebatable predictive ability of these procedures,it is unlikely that the employee or employees. . .could demonstrate the regulation requirementthat there be a “real danger of death or seriousphysical injury. ” Second, and more important,most occupational illnesses are developed over aperiod of time. Therefore, it is likely that theemployee would fail to meet the “imminence” or“urgency” requirement of the regulation. To date,all of the work refusal cases have involved safe-ty hazards.

*29 (’ F K $1977 12(?))(2) ( 1:J81 )

* “445 [’ S. 1 ( 1 \J80)

120 ● The Role of Genetic Testing in the Prevention of Occupation/ Disease

Given the employer’s duty under the OSH Actto maintain a safe workplace, is genetic testingcompatible with or contrary to that duty? Toanswer this question, it is necessary to considerseveral more specific questions that are focusedon the particular types and applications of genet-ic testing and the various requirements that canbe imposed on employers pursuant to the act.These are addressed in the remainder of thissection.

GENETIC TESTING ANDTHE GENERAL DUTY CLAUSE

The first clause of section 5(a) of the OSH Act,which requires employers to maintain a work-place free from recognized hazards, is known asthe general duty clause, Does it require employersto use genetic monitoring to identify hazards?Does it require or permit the use of geneticscreening to identify potentially susceptibleworkers?

The general duty clause simply imposes a re-quirement on employers without stating themeans by which that requirement can be met.Thus, it would not support an argument that ge-netic testing is required by the OSH Act. Neitherwould it support an argument that genetic testingis prohibited by the act. Although genetic testingcould be adverse to the interests of particularemployees, it certainly would not be a “hazard. ”These conclusions, however, leave open the ques-tion of whether OSHA can require, prohibit, orregulate genetic testing under its power to setsafety and health standards.

EMPLOYEE VARIABILITY IN STANDARDS SETTING

Section 5(a)(2) of the OSH Act gives the Sec-retary of Labor broad power to require a safeworkplace by setting standards that can governvirtually all aspects of the work environment inany way related to safety or health. The standardsmay be promulgated in one of three ways. First,under section 6(a), the Secretary of Labor was ini-tially authorized to adopt without rulemaking pro-ceedings “established Federal standards” devel-oped under other Federal acts and “national con-sensus standards” produced by nationally recog-nized, private standards-producing organizations.This special authority, which expired in 1973, was

included in the act to ensure that workers wouldbe protected as soon as possible after the act’seffective date. Second, under section 6(b), newstandards may be promulgated by following cer-tain rulemaking procedures. Third, emergencytemporary standards may be promulgated undersection 6(c) without rulemaking procedures if cer-tain conditions are met.

In 1971, pursuant to section 6(a), OSHA adoptedas established Federal standards 450 thresholdlimit values (TLVs) developed by the AmericanConference of Governmental Industrial Hygienists(ACGIH). By definition, TLVs do not consideremployee variability, but set levels to which“healthy” workers may be exposed withoutadverse health effects. * These TLVs still form thebackbone of OSHA health standards, with only21 additional health standards having been pro-mulgated under section 6(b) during OSHA’s first10 years,

Section 6(b)(5) provides that in promulgatingstandards regulating toxic substances or harm-ful physical agents the Secretary must set stand-ards to ensure, to the extent feasible, that ‘(noemployee” will suffer material impairment ofhealth or functional capacity, even if exposed forhis or her entire working life.** Based on thisseemingly absolute language and because of thewide variability in human susceptibility to occupa-tional disease, it might be assumed that OSHA hasthe authority and in fact is required to promulgatehealth standards that protect even the most sus-ceptible worker. However, does this mean thatOSHA must adopt standards that will ensure thata blind person can drive a truck without suffer-ing an impairment? Does farm work in the SunBelt have to be made safe for a person with xero-derma pigmentosom, a genetic defect that createsan increased risk for skin cancer?

There are two limitations on the broad languageof Section 6(b)(5), one in the section itself and theother imposed by a recent Supreme Court deci-sion. The first limitation is that employees can be

● iL TI,\’ represents the maximum time-weighted average concen-tration to which a healthy worker may be exposed for a normal4@hour week up to 8 hours a day o~’er a working lifetime (4o to50 years) without becoming i]] (l).

* *29 LJ.S.C. $65503)(5) (1976) (emphasis added).

——


protected only to the ‘(extent feasible.” Thislanguage was interpreted in a recent SupremeCourt case, American Textile Manufacturers In-stitute v. Donovan (“the Cotton Dust case ”).* Atissue was an OSHA standard governing employeeexposure to cotton dust. The standard containedmany different provisions, some of which theCourt struck down and some that it upheld. Inupholding the provisions setting exposure limitsto the dust, the Court ruled that the phrase “ex-tent feasible” does not require or permit OSHAto perform a cost-benefit analysis of the impactof its standards but does require that the stand-ards be technologically and economically feasible.By “technologically feasible, ” the Court meantcapable of being done, and by “economically feasi-ble” it meant feasible for the industry but notnecessarily for individual companies. The ex-posure limit provisions met these requirements.In setting the limits, OSHA acknowledged that12.7 percent of exposed employees would still suf-fer from the ill effects of exposure to cotton dust.

The second limitation on the language of sec-tion 6(b)[5) was imposed by the Supreme Courtin Industrial Union Department, AFL-CIO v.American Petroleum Institute (“the Benzenecase”). * * The industry had challenged an OSHAstandard that had lowered the permissible ex-posure limit (PEL) for benzene from 10 parts permillion (ppm) to 1 ppm, a level that OSHA had de-termined to be feasible. The plurality opinion,concurred in by four of the nine Justices, heldthat the Secretary of Labor must determine onthe basis of substantial evidence that a standard“is reasonably necessary or appropriate to remedya significant risk of material health impairment .“The opinion stated further that the OSH Act “wasnot designed to require employers to provideabsolutely risk-free workplaces)” but was only in-tended to require “the elimination, as far as possi-ble, of significant risks of harm. ”

From the above discussion, it is clear that OSHAcan and must set exposure limits to toxic sub-stances or harmful physical agents that protectsusceptible individuals, but only to the extent thatit finds that exposures above the limit present asignificant risk of material health impairment and

● 1(11 s (’t. 2478 ( 1 981).* ● 448 [ 1.s 607 ( 1 980),

that the limit is technologically and economical-ly feasible. * A question unresolved in the Benzenecase is whether significant risk is to be measuredwith respect to each individual or on some groupbasis. In other words, it is unclear whether OSHAcould promulgate a PEL designed to protect a verysmall number of susceptible individuals or if itfirst must find a significant number of workersto be at risk.

GENETIC MONITORING AND OSHA STANDARDS

Some OSHA health standards regulate employeeexposure to substances identified as mutagens orclastogens, such as vinyl chloride and arsenic.Since genetic monitoring potentially could iden-tify such substances, could this technique berelied on or required by OSHA in the regulatoryprocess?

OSHA might use the technique to provide dataabout the harmfulness of a particular substance.If the technique could be used to indicate that asubstance was a mutagen or clastogen, data fromstudies using genetic monitoring could be con-sidered with other evidence when OSHA was set-ting a standard for a particular substance.

If the technique were sufficiently predictive asa biological dosimeter or as a way to identify agroup of workers at increased risk, OSHA mightrequire its use as part of a standard governinga hazardous substance. In that situation, OSHAmight rely on the D.C. Circuit Court decision inthe lead standard case, which upheld OSHA’s au-thority to attempt to prevent the subclinical ef-fects of lead disease (38)67).

OSHA REGULATION OFEMPLOYER MEDICAL PROCEDURES

Section 6(b)(7) of the OSH Act gives the Secre-tary of Labor authority to prescribe the type andfrequency of medical examinations or other teststo determine the adverse health effects from ex-posure to toxic substances, OSHA’s 21 healthstandards regulating toxic substances require a

* Arcording to Assistant Secretar\f of Labor Thorne G. ,Au(>hter,mer~ new. standard must mu meet four requirements: 1 ) it musthr addrmseti to a hazard prmenting a significant risk to workers;2 J it most be denloost ratrd that the standard will reduce the risk;31 the standard must tw t(’(llrlologi(’:ill~” and [~([)rl(~r~li(:tll)’ fe~isiblc(In an industr~’w idr basis; and 4) the standiird must be the mosteffic’irnt, or cost -efffW ii e, l~a~ to protf’ct u orhers ( 1S,61 )


variety of medical procedures. In general, em-ployers must conduct preplacement examina-tions. The physician must furnish employers witha copy of a statement of suitability for employ-ment in the regulated area, must conduct peri-odic (usually annual) examinations, and in someinstances must conduct examinations at termina-tion of employment.

OSHA standards for 13 carcinogens requirecompany doctors to take a complete medicalhistory of exposed employees and consider ge-netic factors. * According to an OSHA directive,however, this does not require genetic testing ofany employee and does not require the exclusionof otherwise qualified employees from jobs on thebasis of genetic testing (50).

In general, OSHA has not become involved inregulating the procedures and criteria by whichphysicians make their determinations of the med-ical fitness of employees. One notable exceptionconcerns the “multiple physician review” pro-cedure, in which employees can select their ownphysician if they disagree with the findings of thecompany physicians. The Fifth Circuit Court ofAppeals struck down this provision in the com-mercial diving standard, which required medicalexamination of employees who were to be ex-posed to hyperbaric conditions (65). On the otherhand, the Court of Appeals for the District of Col-umbia Circuit upheld such a provision in the leadstandard (38)67). The distinction between the twocases appears to be that the provision in the leadstandard was shown to be related to a safe orhealthy workplace while that in the diving stand-ard was seen primarily as a job security provi-sion and therefore outside the scope of the act,Thus, OSHA probably could regulate genetictesting to the extent the regulations were relatedto enhancing workplace health.

MEDICAL REMOVAL PROTECTIONAND RATE RETENTION

In general, OSHA standards do not indicatewhat measures an employer may or must takewhen an employee or applicant is medically un-fit for assignment or continued work in an areawhere there is exposure to toxic substances. In

● 29 (:.F.R. $1910,1003- 1910,1016.

fact, the OSH Act has little applicability to job ap-plicants. Its provisions continually refer toemployees but do not refer to applicants foremployment, and the term “employee” is notdefined in the definitions section of the act to in-clude applicants, Thus, unless prohibited by a col-lective bargaining agreement or some antidiscrim-ination law, the employer would be free to refuseto hire an applicant or to discharge an employeebased on the employer’s determination of medicalfitness.

OSHA’s only attempt to regulate the effects ofmedical examinations on employment involvesmedical removal protection (MRP) and rate reten-tion (RR) of employees previously exposed to cer-tain toxic substances. when a periodic medicalexamination indicates that the employee is show-ing symptoms of the adverse effects of exposure,the employee is removed from further exposure—to a “safe” job if there is an opening—until itis medically advisable for the employee to return.If the new position is at a lower rate of pay orif a safe job is not available, RR would require themaintenance of wage and benefit levels duringthe period of medical removal. Thus, MRP andRR attempt to protect employee health withoutreducing employee benefits, thereby shifting theeconomic burden to the employer and ultimate-ly to the consumer.

MRP and RR provisions in OSHA health stand-ards have become increasingly stringent. For ex-ample, the vinyl chloride standard provides forMRP, but not RR;* the asbestos standard providesfor MRP of employees for whom respirators areineffective, but RR is required only if there is anavailable position. * * The most sweeping MRP andRR provision is in the lead standard.*** Employ-ees with blood-lead levels above the specified limitmust be removed until the level has returned toan acceptable limit. Removed employees retaintheir earnings rate, seniority, and benefits for upto 18 months.

OSHA’s authority to require MRP and RR wascalled into question by the Supreme Court’s deci-sion in the Cotton Dust case. Although the Court

*29 ~.F.R. $1910,1017(k)(5) (1981),* ● 29 C.F.R. $1910, l(lol(d)(z)(iv)k) (1981),* ● *29 C.F,R, j 1910.1025(k) [1981).

Ch. 8–Legal Issues Raised by Genetic Testing in the Workplace ● 123

did not decide the issue of whether OSHA has thestatutory authority to promulgate any regulationcontaining MRP and RR, the Court held that “theAct in no way authorizes OSHA to repair generalunfairness to employees that is unrelated toachievement of health and safety goals . . . .“*Because OSHA had not made a finding when pro-mulgating the cotton dust standard that MRP andRR were related to achieving health, the Courtstruck down that provision of the standard andremanded it to the Secretary of Labor for fur-ther consideration.

ACCESS TO EXPOSUREAND MEDICAL RECORDS

Section 8(c)(3) of the OSH Act directs theSecretary of Labor to issue regulations requiringemployers “to maintain accurate records ofemployee exposures to potentially toxic materialsor harmful physical agents which are requiredto be monitored or measured under section 6.”On May 23, 1980, OSHA promulgated the rulegranting employees a right of access to exposureand medical records. * *

Under the rule, any current or former employ-ee or an employee being assigned or transferredto work where there will be exposure to toxicsubstances or harmful physical agents has a rightof access to four kinds of exposure records: en-vironmental monitoring results, biological moni-toring results, material safety data sheets, and anyother record disclosing the identity of a toxic sub-stance or harmful physical agent. The employeemay designate a representative to exercise his orher rights, and labor unions have a right of ac-cess to employee exposure records without indi-vidual employee consent. OSHA also has a rightof access to exposure records. On July 13, 1982,OSHA proposed revisions to the rule, whichwould narrow its scope significantly. * * *

Access to employee medical records is morerestricted. Employees have a right of access totheir entire medical files regardless of how theinformation was generated or is maintained. Thedefinition of employee does not include job ap-

plicants. * A limited discretion is also given physi-cians to deny access where there is a specificdiagnosis of a terminal illness or a psychiatric con-dition. Unions must obtain specific written con-sent before gaining access to employee medicalrecords. OSHA has a right of access to employeemedical records, but those records in a personallyidentifiable form are subject to detailed pro-cedures and protections.

Title VII of the Civil Rights Act of 1964

Title VII of the Civil Rights Act of 1964, asamended, * * prohibits discrimination in the hir-ing, discharge, compensation, or other terms, con-ditions, or privileges of employment because ofan individual’s race, color, religion, sex, or na-tional origin.

Aggrieved individuals must file a charge withthe Equal Employment Opportunity Commission(EEOC) within 180 days of the alleged discrimi-natory act. After a period of up to 180 days forinvestigation and conciliation by EEOC, the charg-ing party may file an action in Federal districtcourt.

The term “discrimination” is not defined in ti-tle VII, but one court defined it as “a failure totreat all persons equally where no reasonabledistinction can be found between those favoredand those not favored” (6). The Supreme Courthas recognized two main forms of employmentdiscrimination, “disparate treatment” and “dis-parate impact.” Disparate treatment occurs whenan employer simply treats some people less fa-vorably than others because of their race, color,religion, sex, or national origin. Proof of dis-criminatory motive is required. Disparate impactinvolves employment practices that appear to beneutral in their treatment of different groups butin fact affect one group more severely and can-not be justified by the requirements of the jobor business. Proof of discriminatory motive is notrequired.

The disparate impact concept was establishedby the Supreme Court in Griggs v. Duke Power

Co.*** A unanimous Court struck down the ern-“ 101 S.Ct at 2506“ *45 Fed Reg 35,212 (1980), codified at 29 C.F.R, $1910.20 (1981).● * *47 E’ed Reg. 30,420” ( 1982)

● 45 Fed. Reg at 35,261,● *4z CI.S,C; , $2000e (1976 & Supp. 11 1978)● ● “401 LI,S, 424 (19711,


ployer’s use of certain standardized tests becausethey disqualified black applicants at a substantiallyhigher rate than white applicants and were notshown to measure job capability.

In Albemarle Paper Co. v. Moody, * the Courtclarified Griggs and held that a plaintiff mayestablish a prima facie case of disparate impactby showing that “the tests in question select ap-plicants for hire or promotion in a racial patternsignificantly different from that of the pool of ap-plicants .“ The burden is then on the employer toshow that “any given requirement [has] . . . amanifest relationship to the employment in ques-tion. ” The plaintiff may still rebut this evidence,however, by demonstrating that “other tests orselection devices, without a similarly undesirableracial effect, would also serve the employer’slegitimate interest in efficient and trustworthyworkmanship .“

A crucial but still unresolved issue is how dif-ferent the comparative test results must be inorder to support a finding that there was a dis-parate impact. Most Supreme Court and lowercourt decisions have considered disparate impacton an ad hoc basis. According to EEOC guidelineson employee selection procedures, “[a] selectionrate for any racial, ethnic or sex group which isless than four-fifths (4/5) (or eighty percent) of therate for the group with the highest rate will gen-erally be regarded . . . as evidence of adverseimpact .“* * This formula is not binding on thecourts.

DISPARATE IMPACT OF GENETIC TESTING

The frequencies of genetic traits in the popula-tion often vary along racial or ethnic lines. Someexamples of these are sickle cell trait, G-6-PD defi-ciency, and thalassemia trait. According to onestudy of G-6-PD-deficient individuals (10), thepopulation frequencies for the trait are as follows:

Americans (whites). . . . . . . . . . . . . . . . . 0.1 percentAmericans (black males). . . . . . . . . . . . . . 16 percentBritish. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0.1 percentChinese. . . . . . . . . . . . . . . . . . . . . . . . . . . 2-5 percentEuropean Jews. . . . . . . . . . . . . . . . . . . . . . . 1 percentFilipinos . . . . . . . . . . . . . . . . . . . . . . . . . . 12-13 percent

Greek. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-2 percentIndians (Asian). . . . . . . . . . . . . . . . . . . . . 0.3 percentMediterranean Jews. , . . . . . . . . . . . . . . . 11 percentScandinavians. . . . . . . . . . . . . . . . . . . . . . 1-8 percent

Comparing these percentages to each other ratherthan to the population categories indicates thatthe use of G-6-PD screening would have a dis-parate impact on various groups based on race,sex, and national origin. For example, if 1,000British and 1)000 Filipinos were screened, only1 British person but 120 to 130 Filipinos wouldbe expected to show a G-6-PD deficiency. Similar-ly, it has been estimated that ‘1 out of 12 blackshas sickle cell trait, but only 1 out of 1)000 whiteshas it, a ratio of 83 to 1.

For title VII purposes, the use of G-6-PD or sicklecell trait screening (or other procedures with adisparate impact) would establish a prima faciecase of discrimination. This does not necessarilymean there is a violation, but only that the burdennow is placed on the employer to justify the useof the tests.

If future study should reveal that geneticmonitoring has a disparate impact by race, asimilar legal analysis would apply.

BUSINESS NECESSITY AND JOB RELATEDNESS

In discussing employer defenses in Griggs, theSupreme Court indicated that “[tlhe touchstoneis business necessity. If an employment practicewhich operates to exclude Negroes cannot beshown to be related to job performance, the prac-tice is prohibited.”* Based on Griggs, two inter-twined defenses have emerged, “business necessi-ty” and “job relatedness.” Although the Griggsopinion used the terms in the same sentence anddid not differentiate between them, subsequentdecisions have attempted to do so. Business ne-cessity applies when a general employment prac-tice is used, the purpose of which is not to deter-mine whether an applicant or employee is capableof performing the job requirements. For exam-ple, an employer would attempt to use a businessnecessity defense to justify not hiring someonewho had been convicted of a crime.

Job relatedness is somewhat narrower and goesto whether the criteria used in determining

*422 U.S. 405 (1975).* *29 C.F.R. $1607.4 (1981), “401 U.S. at 431.

— . . .

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace . 125

whether an applicant or employee is qualified foremployment bears a reasonable relationship tothe demands of the job. For example, height andweight requirements and passing scores on stand-ardized tests would be evaluated under jobrelatedness.

The standards used for determining the meritsof the business necessity and job relatednessdefenses are similar. The key to business necessityis:

. . . whether there exists an overriding legitimatebusiness purpose such that the practice is nec-essary to the safe and efficient operation of thebusiness. Thus the business purpose must be suf-ficiently compelling to override any racial im-pact, the challenged practice must effectivelycarry out the business purpose it is alleged toserve, and there must be available no acceptablealternative policies or practices which would bet-ter accomplish the business purpose advanced,or accomplish it equally well with a lesser dif-ferential racial impact (57).

Once the employer presents evidence to showthat its employment practice is grounded on busi-ness necessity, the courts balance all the relevantfactors to determine whether the need for thepractice sufficiently outweighs any disparate im-pact. In the case of genetic testing, whetheravoiding tort liability or costly engineering con-trols would be a business necessity is an openquestion.

Job relatedness essentially involves an analysisof an applicant’s qualifications and a comparisonof legitimate job requirements with the employ-er’s method for determining fitness. In AlbemarlePaper Co. v. Moody,* the Supreme Court citedwith approval EEOC’s Uniform Guidelines on Em-ployee Selection Procedures and held that “dis-criminatory tests are impermissible unless shown,by professionally acceptable methods, to be‘predictive of or significantly correlated with im-portant elements of work behavior which com-prise or are relevant to the job or jobs for whichcandidates are being evaluated. ’ “ However, theEEOC guidelines have been criticized and theSupreme Court has refused to follow portions ofthem, particularly when the agency has changed

*422 Li.s, 405 (1975)

its position on an issue (40). Whether a risk of ill-ness is a job-related characteristic is an openquestion.

Any distinction between the defenses of busi-ness necessity and job relatedness becomes virtu-ally obscured in the context of genetic screeningof workers and applicants. An employer’s justifi-cation for using screening procedures would nec-essarily involve elements of both defenses. If asuit were to be filed, arguably a court could re-quire an employer’s defense to include proof that:1) there is a valid reason for excluding workerswho are presently capable of performing the re-quired work but who may become physicallyunable or impaired at some point in the future;2) it is important to the business that employeesnot be suffering from an occupational illness;3) the specific screening procedure used accurate-ly and reliably identifies the presence of the ge-netic trait; 4) there is a high correlation betweenthe trait and the individual’s susceptibility to dis-ease at the permissible exposure level; 5) the com-pany cannot feasibly reduce exposure throughengineering controls, personal protection devices,or job placement; and 6) the company cannot in-sure itself at a reasonable cost against potentialtort liability.

EMPLOYEE REFUSAL TO SUBMITTO MEDICAL TESTS

Does an applicant or employee have the rightto refuse to submit to a medical test where theemployer’s use of the results would violate titleVII? From an employee standpoint, section 704(a)of title VII offers the best chance of success. Thissection provides that an employer may not retali-ate against an employee or applicant who opposedany employment practice made unlawful by titleVII or who participated in any proceeding underthe title. Most of the cases brought under this sec-tion involve alleged employer retaliation after theemployee files a charge with EEOC, Nevertheless,there are some cases holding that other forms ofemployee activity are protected when they op-pose discriminatory employment actions (3,48).

No court has ever resolved the question ofwhether section 704(a) protects an employee whorefuses to submit to a test that he or she believesis discriminatory (and that cannot be justified by


the employer). In the one case where the issuewas raised, the case was decided on othergrounds (43). It is clear, however, that anemployee need not be correct; only a good faithbelief is required (42,51).

Based on these considerations, it is possible thatan applicant or employee validly could refuse tosubmit to genetic testing and any retaliation bythe employer would violate title VII.

The Rehabilitation Act and Statefair employment laws

The Rehabilitation Act of 1973* was the firstcomprehensive Federal effort to bring handi-capped individuals within the mainstream ofAmerican life. Of the several provisions of the act,sections 503 and 504 have a direct bearing on theemployment rights of the handicapped.

Largely as a result of the Federal initiative, 41States and the District of Columbia also haveenacted laws prohibiting discrimination in em-ployment on the basis of handicap. Unlike theFederal law, which applies only to Federal con-tractors and recipients of Federal funds, Statelaws prohibiting employment discriminationagainst the handicapped have a wider coverageand usually exempt only small employers, There-fore, State law is much more important in casesinvolving the handicapped than in other kinds ofdiscrimination cases.

Section 503 provides that any contract in ex-cess of $2)500 entered into with any Federaldepartment or agency shall contain a provisionrequiring that the contracting party take affirm-ative action to employ and promote qualifiedhandicapped individuals. The term “handicappedindividual” is defined as “any person who (A) hasa physical or mental impairment which substan-tially limits one or more of such person’s majorlife activities, (B) has a record of such an impair-ment, or (C) is regarded as having such an impair-merit. ” Based on this broad statutory definition,and on the definition contained in the implement-ing regulations, it has been estimated that as manyas 40 million to 68 million persons are covered

by the statute (47), Responsibility for enforcingsection 503 is vested in the Office of Federal Con-tract Compliance Programs (OFCCP) in the De-partment of Labor. Individuals who believe theyhave been discriminated against must pursuetheir remedies through OFCCP; the courts havenot permitted these individuals to sue directly,

Section 504 provides that no otherwise qualifiedhandicapped individual shall, solely by reason ofhandicap, be excluded from the participation in,be denied the benefits of, or be subjected to dis-crimination under any program or activity receiv-ing Federal financial assistance. Unlike section503, no minimum amount of financial assistanceis required for coverage under section 504, andthe courts have held that aggrieved individualscan sue employers under this section. Section 504also incorporates the same broad statutory defini-tion of handicap as section 503.

Two key terms in the definition of handicappedindividual—’’physical or mental impairment” and“substantially limits’’—are not defined in thestatute. However, regulations promulgated pur-suant to sections 503 and 504 offer guidance. Theregulations under 503 state that a handicappedperson is ‘(substantially limited” if “he or she islikely to experience difficulty in securing, retain-ing or advancing in employment because of ahandicap.”* The regulations under section 504define ‘(physical or mental impairment” as:

. . . (A) any physiological disorder or condition,cosmetic disfigurement, or anatomical loss af-fecting one or more of the following body sys-tems: neurological; musculoskeletal; specialsense organs; respiratory, including speechorgans; cardiovascular; reproductive, digestive,genito-urinary; heroic and lymphatic; skin; andendocrine; or (B) any mental or psychologicaldisorder, such as mental retardation, organicbrain syndrome, emotional or mental illness, andspecific learning disabilities. * *

It has been estimated that 3 million firms—abouthalf the businesses in the country–are coveredby the act, either as Government contractors orrecipients of Federal funds (63),

*29 U.S. C. ‘$$701-796 ( 1976 & Supp, 111 1979)*41 C.F.R. $60-741.2 (1981).* ● 45 C,F.R, $84,3 (j)(2)(i) (1981).


MEDICAL EXAMINATIONS ANDSCREENING TESTS

Under the guidelines and model regulations pro-mulgated to implement section 504) an employerreceiving Federal financial assistance may notmake preemployment inquiry about whether theapplicant is handicapped or about the nature andseverity of an existing handicap unless a pre-employment medical examination is required ofall applicants and the information obtained fromthe examination is relevant to the applicant’s abil-ity to perform job-related functions.

Under the section 503 regulations, a Federalcontractor may require a preemployment medicalexamination of a handicapped applicant, even ifan examination is not required of the nonhandi-capped. Nevertheless, if the employer’s jobqualification requirements “tend to screen outqualified handicapped individuals, the re-quirements shall be related to the specific job orjobs for which the individual is being consideredand shall be consistent with business necessityand the safe performance of the job.”*

Despite the slight difference in language and ap-proach between the section 503 and 504 regula-tions, both serve to limit the use of discriminatorypreemployment examinations and tests. Never-theless, it still must be determined whether ge-netic differentiation is a handicap and whetherthe screening procedures are job related.

IS GENETIC SUSCEPTIBILITY ORCHROMOSOMAL ABNORMALITY A HANDICAP?

The definition of “handicapped individual”basically includes persons who are, were, or arebelieved to be suffering from an impairment. Thegoal of genetic testing is to identify individualsor groups who are not at present impaired, butwho may be or are likely to become impaired inthe future under special circumstances. An im-portant threshold question is whether these in-dividuals are handicapped and thereby protectedby the Rehabilitation Act.

In OFCCP v. E. E. Black Ltd. (17), a carpenter’sapprentice was required to submit to a pre-employment medical examination which revealed

*41 C.F.R. $60-741.6 (c)(2) ( 1980).

a lower back anomaly known as sacralization ofthe transitional vertebra. This is a congenital con-dition found in 8 to 9 percent of the population.Although the disabling long-term effects of thecondition are in dispute in the medical profession,the employer conceded that the condition did notaffect the applicant’s current capability to per-form the duties of a carpenter’s apprentice.Nevertheless, relying on its medical officer’s con-clusions, the company determined that the appli-cant’s spinal formation made him a poor risk forlater development of back problems and deniedhim employment. The apprentice filed a com-plaint with OFCCP, charging the employer withviolating section 503.

The Labor Department found in favor of thecarpenter’s apprentice and ruled that the com-pany’s use of preemployment medical examina-tions tended to disqualify handicapped applicantsdespite their current capability to perform thejob. The Labor Department refused to limit thedefinition of “impairment” to permanent disabil-ities such as blindness or deafness. Instead, im-pairment was held to be “any condition whichweakens, restricts or otherwise damages an indi-vidual’s health or physical or mental activity, ” re-sulting in “a current bar to employment of one’schoice with a Federal contractor which the indi-vidual is currently capable of performing. ”

On judicial review, the U.S. District Court forthe District of Hawaii agreed with the LaborDepartment that the Rehabilitation Act’s cover-age was intended to be broad, but it held that theinterpretation in the Assistant Secretary ofLabor’s opinion in Black was overly broad (23). *The court pointed out that under the AssistantSecretary’s definition of “handicap”:

. . . a worker who was offered a particular jobby a company at all of its plants but one, but wasdenied employment at that plant because of the

*The court granted partial summar~r judgment to the l,ahor De.partment on two points: 1) the definition of “handicapped indi~’idual ”contained in the act and regulations is constitutional; and 2] the ap-prentice ttas a “qualified handicapped indi~idua]” under the act andregulations. On all other issues, summar~’ ~udgment was denied,In a subsequent decision, the case u as rertmndd to the Departm-ent of Lahor for a decision on whether the emplo~’er met itshurden for showing a husiness necessity defense and for formukl-tion of a standard for the determination of husim?ss necrssit~ inthis kind of case (22).


presence of plant matter to which the employeewas allergic, would be covered by the Act. Anindividual with acrophobia who was offered 10deputy assistant accountant jobs with a particu-lar company, but was disqualified from one jobbecause it was on the 37th floor, would becovered by the Act. An individual with some typeof hearing sensitivity who was denied employ-ment at a location with very loud noise, but wasoffered positions at other locations, would becovered by the Act (p. 1099).

According to the court, the Assistant Secretary’sdefinition ignored critical language in the act thatrestricts its coverage to handicapped individualswho are “substantially limited” in pursuit of a ma-jor life activity. Thus, the court held that not everyphysical condition that limited employment wascovered by the act; to be protected, an individualmust have been rejected for a position for whichhe or she was qualified because of an impairmentor perceived impairment that constitutes, for theindividual, a substantial handicap to employment.The court discussed several factors to be consid-ered in determining whether an impairment sub-stantially limits employability, including the num-ber and types of jobs from which the individualis disqualified, the location or accessibility of simi-lar opportunities, and the individual’s own job ex-pectations and training. With respect to the num-ber and type of jobs from which the individualmight be disqualified, the court stated that it mustbe assumed that all similar employers would usethe same preemployment examination.

Based on this definition, the court still con-cluded that the applicant was subject to the pro-tections of the act. First, the applicant’s back con-dition was found to be an impairment or, at least,was regarded as such by the employer. Second,the impairment was found to constitute a substan-tial handicap to employment because the appli-cant would have been disqualified from all or sub-stantially all apprenticeship programs in carpen-try. Third, the court rejected the employer’s con-tention that Congress did not intend to protectjob applicants who have been denied employmentbased on risk of future injury,

In the context of genetic screening, it may notbe that important whether a slight genetic dif-ferentiation is in fact a handicap so long as it isperceived to be a handicap by the employer. Both

section 503 and section 504 include within thedefinition of handicap an individual who is “re-garded” as having an impairment. Further, on thebasis of the Black case, a person with a particulargenetic trait that is viewed as making him or hersusceptible to disease might be found to be hand-icapped by a court, One factor that the court didnot consider in Black and that is especially rele-vant for genetic screening is the consequences oflabeling a person with a congenital or geneticanomaly as handicapped, especially since thosefactors could be handicaps only in certain envi-ronments. The adverse psychological impacts ofsuch labeling could outweigh the benefits con-ferred by the protection of the act.

Most of the cases concerning the definition ofa handicapped individual have been tried in Statecourts under analogous handicapped discrimina-tion laws. The results have varied widely, and itwould be difficult to assess whether a given Statewould be likely to consider genetic differentialin itself as a handicap. Nearly all of the reportedcases have been decided under the laws of Wis-consin, New York, Washington, and Oregon (40).The Wisconsin and Washington cases have de-fined the term handicap very broadly, Other Statecourts, however, have refused to read the statuteso broadly, often on the grounds that the legisla-tures had not intended them to be universal anti-discrimination laws (40).

In New Jersey, a 1981 amendment to the Stateemployment discrimination law * specifically pro-hibits employment discrimination based on an in-dividual’s “atypical hereditary cellular or bloodtrait. ” This is defined to include sickle cell trait,hemoglobin C trait, thalessemia trait, Tay-Sachstrait, or cystic fibrosis trait. Thus, New Jersey hasbecome the first jurisdiction expressly to pro-scribe discriminatory use of some types of genet-ic screening in the workplace. Florida, NorthCarolina, and Louisiana prohibit discriminationin employment based on sickle cell trait.

JOB RELATEDNESS OF SCREENINGAND MONITORING

Determining that an individual is covered by theact is only the beginning step in analyzing thelegality of genetic testing, The Rehabilitation Act

● 1981 N.J. Sess. Law Serv. 535, 538 (West).

.


protects otherwise qualified handicapped individ-uals. It still must be decided whether the personis otherwise qualified; if not, the employer wouldnot violate the act by refusing him or heremployment.

Pursuant to the regulations under the act, aqualified handicapped person is one who can per-form the essential functions of the job withreasonable accommodation to his or her handi-cap. * The regulations under section 503 permitmental or physical screens to the extent they arejob related and are consistent with businessnecessity and the safe performance of the job. * *The regulations under section 504 permit suchscreens only to the extent they are job related.** *Thus, the questions become whether geneticscreening is job related or consistent with busi-ness necessity and safety and, if so, whether ge-netic susceptibility can be reasonably accommo-dated. This section addresses the first questionand the next addresses the second.

The Labor Department’s decision in Black con-ceded that employers could exclude handicappedindividuals from jobs on the basis of legitimatejob requirements, but it held that only an in-dividual’s current capability to perform could bethe subject of inquiry in preemployment medicalexaminations. The district court termed this in-terpretation “clearly contrary to law. ” The courtposed the situation where, if a particular personwere given a job, he or she would have a 90 per-cent chance of suffering a heart attack within 1month:

A job requirement that screened out such anindividual would be consistent both with busi-ness necessity and the safe performance of thejob. Yet, it could be argued that the individualhad a current capacity to perform the job, andthus was a qualified handicapped individual. * * * *

However, the court did not formulate its ownlegal standard for the circumstances under whichpossible future injury can be the basis of deny-ing employment.

*41 C.F.R. $60-741.2 (19811; 45 C. F’.R. $84.4 (k)● *41 C.F.R. j60-741.6[c) (1981).● ” *45 C.F.R. $84.13(a) (1981).“•” ● F Supp. at 1104

In Black, the court based its determination onits reading of the OFCCP regulation that permittedscreens that were consistent with business neces-sity and safe performance of the job. The com-parable regulation under section 504, however,refers only to job relatedness. Thus, a discrimi-nation case based on genetic screening broughtunder 504 could have a different outcome, de-pending on how job relatedness is defined. If acourt were to define it literally, risk of future ill-ness would not appear to be related to job per-formance. However, if the court were to defineit only in a general sense –for example, the Griggscase used it as being synonymous with businessnecessity—then risk of future illness might prop-erly bar someone from employment. Whether thecourt would look only to the person’s current ca-pability to perform the job or would accept a busi-ness necessity defense based on the need for jobsafety is an unresolved question.

The basic principle that a job requirement thatscreens out qualified handicapped individuals onthe basis of possible future injury may be lawfulis in agreement with cases decided under Statehandicapped discrimination laws. However, it isalso clear that the burden is on the employer tojustify the denial of employment, regardless ofwhether the problem is viewed as whether theemployee is otherwise qualified or whether theemployer has made out a business necessitydefense.

An employer seeking to justify using a screen-ing procedure that adversely affects handicappedindividuals has a difficult burden of proof. Asdiscussed earlier, in Albemarle Paper Co. v.Moody, * the Supreme Court cited with approvalEEOC’s Uniform Guidelines on Employee Selec-tion Procedures * * and held that “discriminatorytests are impermissible unless shown, by profes-sionally acceptable methods, to be ‘predictive ofor significantly correlated with important ele-ments of work behavior which comprise or arerelevant to the job or jobs for which candidatesare being evaluated. ’ “* * * For example, in Blackit was necessary for the employer to prove that:an important part of the job required the lifting

1981)*4z2 L1.s, 405 (1975).

* *29 C.F.R. Part 1607 (1980).* * *42z [1,S, at 432, [luoting 29 C, F’,R. $ 160i’.4(~]


of heavy objects, individuals with back problemswould not be able to perform the job, and the X-rays of the apprentice’s back had a high predic-tive value in determining the likelihood that theindividual would suffer from back problems. Asimilar analysis would apply to genetic screening.

The relationship between job requirements andfuture risk of injury has been addressed in Statehandicapped discrimination cases. In a Wiscon-sin case (18), the employer excluded an epilepticwelder based on evidence that 10 to 30 percentof epileptics under medication still will haveseizures. The Wisconsin Supreme Court termedthis degree of future risk “a mere possibility” andheld that the employer’s action was illegal. Thecourt stated that in order to justify an exclusion-ary practice the employer must show that thereis a “reasonable probability” that the character-istics of the employee will result in future hazardsto the employee or coworkers. No statistical cri-teria have ever been established for defining “rea-sonable probability, ” but the employer’s burdenwould appear to be quite difficult to satisfy.

Similarly, in an Oregon case (33), an applicantfor the job of heavy appliance salesperson wasrejected on the advice of the company physicianbecause he had suffered a subendocardial infarc-tion 6 years earlier and had subsequently com-plained of sporadic angina. The Supreme Courtof Oregon upheld the Bureau of Labor’s rulingthat the disqualification was unjustified becausethe employer failed to show a “high probability”of future risk of heart attack.

In a California case (64), the employer had dis-charged a truck driver with a congenital, but notdisabling, back condition. The court held that amere possibility that the employee might en-danger his health sometime in the future was in-adequate justification for the employer’s action.

When there is a strong likelihood that a pre-existing condition will be aggravated by exposurein the workplace, an employer’s exclusionary

practice is likely to be upheld, Thus, in a NewYork case (71), the court upheld an employer’srefusal to hire an applicant who was sufferingfrom dermatitis, where the company physicianconcluded that exposure to the chemical elementsin the plant would so exacerbate the dermatitisas to render the applicant unable to perform hisduties.

Moreover, employee exclusionary practices aremuch more likely to be upheld where the em-ployee’s health risk could endanger the health orsafety of others (40). This has been especially truein cases involving common carriers, such as buses(68).

REASONABLE ACCOMMODATION

Even if an employer can prove that the screen-ing procedure used is job related and highlypredictive, the employer still may not be per-mitted to discharge or refuse to hire the individualif “reasonable accommodation” is possible. Al-though neither section 503 nor section 504 men-tions a duty to accommodate, the regulationsunder both sections require reasonable accommo-dations unless it would impose an undue hard-ship. According to the section 503 regulations,“reasonable accommodation” may include mak-ing facilities accessible, job restructuring, part-time or modified work schedules, acquisition ormodification of equipment or devices, and similaractions. It is likely, however, that reasonable ac-commodation to individuals with proven suscepti-bility to occupational health hazards would be fo-cused on practices such as shift rotation, dividingmaximum exposure time, more frequent monitor-ing and medical surveillance, and the added useof personal protection equipment. It is doubtfulthat an employer will be required to reduce ex-posure levels beneath OSHA PELs to accommo-date a susceptible handicapped employee. MostState fair employment practice laws do not re-quire reasonable accommodation (40).


Collective bargainingemployment practices

Protected activities of employees

The National Labor Relations Act (NLRA)*grants employees the right to organize into unionsand to negotiate with their employer over wages,hours, and conditions of employment. The agree-ments that result from these negotiations, knownas collective bargaining agreements, can createrights and duties between the parties that gobeyond those otherwise required by law. Safetyand health matters are considered to be condi-tions of employment and subject to collectivebargaining (44).

Although numerous exceptions abound, safe-ty and health concerns traditionally have not beenlooked on with a sense of urgency by either em-ployers (19) or rank-and-file employees (26).**Moreover, in times of high unemployment andeconomic recession it may be assumed that em-ployees would give the highest priority to wages,hours, and job security.

A union is under no duty to bargain for specificsafety and health provisions. In fact, as long asit acts in good faith, it is not prohibited from mak-ing contracts that might have an unfavorable ef-fect on some employees (24). The decision ofwhether or how best to protect susceptible em-ployees is a policy decision based on various fac-tors, such as the number of employees involved,the nature of the risk, the predictiveness ofscreening procedures, and the relative strengthof the union’s bargaining position. A union mightbe willing to use economic weapons or forego eco-

agreements and

● 29 [1. S.(; . $ j 151-168 (1976).“ ‘The study found that “a little more safety and health” was well

behind other job improvements, such as increased retirementbenefits, more medical insurance, more paid vacations, shorterworkweek, greater chance for promotion, and greater job securi-ty, as emplo~rment conditions for which workers woLIld be willingto forego a 10 percent pay raise (26).

nomic gains to obtain a provision prohibiting theemployer from using genetic screening on theassumption that some qualified applicants ormembers otherwise will be excluded. On theother hand, a union might bargain to require theemployer to use cytogenetic monitoring on theassumption that these techniques may show dan-gerously high levels of exposure to certain chemi-cals. The union could then bargain for lower ex-posure levels or other methods of worker pro-tection.

Employee access to safetyand health information

Union efforts at negotiating on safety and healthmatters are often complicated by an inability toobtain detailed information about conditions inthe workplace. Unions frequently have requested,but have been denied access to, employee medicalrecords and the identities, properties, and healthhazards of various chemicals used in the work-place (49). Employers often object to the releaseof this information, asserting a proprietary in-terest, undue burden, physician-patient privilege,employee confidentiality, or trade secrecy.

In Minnesota Mining and Manufacturing Co. *and two companion cases (12,20), the National La-bor Relations Board (NLRB) held that unions havea right to obtain individual employee medicalrecords, the generic names of all substances usedin the workplace, and other safety and healthdata. In the Minnesota case, NLRB said, “Few mat-ters can be of greater legitimate concern to indi-viduals in the workplace, and thus to the bargain-ing agent representing them, than exposure toconditions potentially threatening their health,

*261 N. L.R,B. NO. 2 [1982)


well-being, or their very lives.” NLRB rejected theemployer’s claim of proprietary interest as irrele-vant and claim of undue burden as unsubstanti-ated. With respect to physician-patient privilegeand confidentiality, NLRB noted that the uniondid not request the names of individual employeesand that confidentiality would be safeguarded byhaving physicians interpret and analyze the docu-ments. Moreover, NLRB held that even wheresupplying the union with statistical or aggregatemedical data may result in identification of someindividual employees, the important need for thedata outweighs any minimal intrusion on employ-ee privacy. Finally, as to trade secrets, * NLRBordered the parties to bargain about conditionsof disclosure, but, if necessary, the board wouldstrike the balance between the competing claimsof the parties,

Provisions in collectivebargaining agreements

Safety and health provisions have been includedin collective bargaining agreements for manyyears, but the passage of the OSH Act in 1970served to promote greater awareness of work-place hazards and increase the importance at-tached to safety and health in union contracts (25).Some commentators believe that the collectivebargaining process offers great hope in fosteringthe improvement of workplace safety and health(5). However, it should be noted that only about20 percent of all workers belong to unions.

Numerous safety and health matters can benegotiated, ranging from medical removal protec-tion and rate retention to the formation of jointlabor-management safety and health committees.According to one study (16), 82 percent of the con-tracts in the sample** contained occupationalsafety and health clauses. The subjects most oftencovered were safety equipment, first aid, medicalexaminations, accident investigation, employeeobligations, hazardous work, and safety com-mittees.

● A trade secret is a formula, pattern, device, or compilation ofinformation that is used in one’s business and that provides an op-portunity to obtain an advantage over competitors who do not knowor use it.

● *The sample contained 400 collective bargaining agreementsfrom a cross-section of industries,

Medical examinations are required in 30 per-cent of all manufacturing and 28 percent of allnonmanufacturing contracts. Petroleum (86 per-cent), mining (75 percent), transportation (72 per-cent), rubber (67 percent), and stone+ lay-glass (54percent) are the industries where these provisionsare most often found. Of the collective bargain-ing agreements in all industries containing pro-visions for medical examinations, 29 percent re-quire physical exams for newly hired workers,34 percent require physical exams when employ-ees are rehired or return to work from layoff orleave, and 74 percent require physical exams peri-odically or at management’s request. In 40 per-cent of these provisions, employees may appealan unfavorable medical opinion (16).

As a matter of widespread practice, applicantsand new employees have limited rights undermost collective bargaining agreements. For exam-ple, the great majority of contracts allow theemployer to place new employees on probationfor periods ranging from 1 to 4 months. Duringthis period, the new employees cannot join theunion and they can be fired without union in-volvement. This practice would hamper negotia-tions for restrictions on preemployment geneticscreening. However, unions could legally negoti-ate on this point because applicants are con-sidered employees under NLRA and thus subjectto its benefits (52). Under the act, therefore,unions would have broad authority to negotiatewith employers on whether genetic screeningcould be used and, if so, under what conditions.

Union’s duty of fair representation

Although unions have authority to negotiate ongenetic testing, are they legally required to do so?It is well settled that a union has a duty, both inits bargaining and its contract enforcement, toserve the interests of all of its members withoutdiscrimination toward any, This is known as theduty of fair representation. A breach of this du-ty will not be established by simple negligence,but requires a showing that the union acted ar-bitrarily, perfunctorily, or in bad faith (69).

With respect to genetic screening, two ques-tions arise. First, does the duty of fair repre-sentation extend to employees who are found to

—


be susceptible to occupational illness on the basisof their genetic constitution? It is clear that, asemployees, they are entitled to fair representa-tion. Second, does a union’s duty of fair represen-tation extend to job applicants who are refusedemployment on the basis of genetic screening?The answer to this question is less clear. Ap-plicants are considered “employees” under NLRA(52), and the union would probably have a dutyto enforce an existing agreement containing a pro-vision dealing with preemployment geneticscreening. However, it is unlikely that the unionwould have a duty to negotiate a contract withsuch a provision (29).

Contract enforcement and arbitration

Most collective bargaining agreements containan express provision for resolving contract dis-putes through an internal grievance procedure.

If a dispute remains unresolved, however, almostall contracts provide that it will be submitted toan arbitrator voluntarily selected by the partiesto the contract.

Since each arbitration decision is based on thespecific contract involved, the way arbitratorsconstrue medical examination provisions cannotbe generalized. Nevertheless, in cases involvingdischarge or denial of reinstatement to employ-ees with physical disabilities, dismissal will usuallybe held to be inappropriate unless the evidenceindicates that the employee’s disability preventshim or her from performing a job or exposes theemployee or other employees to a serious risk ofphysical harm or injury (74). Even in cases wherecontinued exposure may be injurious to the work-er, arbitrators have been willing to allow em-ployees to decide whether to continue work toas long as they are able to and create no risks toothers.

Conclusion .—. —..

Genetic testing raises legal questions related toworkplace safety and employee rights. The com-mon law, State workers’ compensation statutes,and the OSH Act outline the rights and duties ofemployers and employees with respect to safe-ty. Title VII of the Civil Rights Act of 1964, theRehabilitation Act of 1973, and State fair employ-ment practice laws govern rights and duties withrespect to hiring, firing, and conditions of employ-ment. Although these statutes and the court casesinterpreting them by and large have not dealtwith genetic testing, they provide legal principlesthat are directly applicable to the issues raisedby this technology. The principles can provideguidance and some answers to the questions athand; however, many important questions remainunresolved. In such a situation, the collectivebargaining agreements authorized by NLRA couldprovide a means for employers and unions tonegotiate mutually agreeable solutions to theproblems raised by genetic testing.

With respect to safety in general, it is clear thatthe common law and the OSH Act place the re-sponsibility for workplace safety on the employer.

Failure to meet the responsibility can result inworkers’ compensation payments, damages as-sessed against the employer for tort liability, orcivil or criminal penalties against the employer.

This responsibility would not require the em-ployer to use genetic testing, even if it were highlypredictive of future illness. If the employer choseto use a highly predictive test, it would likely benegligent if it ignored the results of screening andplaced the employee in a high-risk rather thana low-risk environment. However, recovery ofdamages by such an employee who developed thepredicted illness would probably be barred by the“exclusive remedy” provision of workers compen-sation laws and possibly by the doctrine of as-sumption of the risk, if the employee had beeninformed of the risk. If the risk had been con-cealed from the employee, recovery would prob-ably not be barred under workers’ compensationlaws, and the employer would face the possibil-ity of punitive damages.

Under the OSH Act, the Secretary of Labor isempowered to promulgate standards that protect


all employees from toxic substances to the extentthat the standards are directed toward a signifi-cant risk of material health impairment and tothe extent that they are technologically and eco-nomically feasible. These standards can, amongother things, set maximum exposure levels, re-quire personal protection gear, and mandate vari-ous medical procedures. The feasibility require-ment may leave some percentage of exposedworkers at risk, depending on the circumstancesof the particular hazardous substance and indus-try. Of those workers at risk, some maybe genet-ically susceptible and others may be at increasedrisk because of genetic damage. An open ques-tion is whether the courts would allow a standarddesigned to protect a very small number of sus-ceptible individuals or would invalidate it on thegrounds that it failed to address a significant riskbecause of the small number of workers involved.

The OSH Act and regulations thereunder nei-ther prohibit nor require genetic testing. How-ever, the Secretary of Labor has broad author-ity to regulate employer medical procedures aslong as the regulation is related to worker healthand meets the feasibility and significant risk re-quirements. Therefore, the Secretary could re-quire genetic testing in its various forms, if thetechniques were shown to be reliable and reason-ably predictive of future illness. The Secretaryalso could regulate the use of genetic testing, butonly to the extent that the regulation was relatedto employee health. The act grants no authorityover rights or conditions of employment per seand no authority to protect applicants for employ-ment from discrimination.

State and Federal law places few restrictionson either the way medical exams or testing pro-cedures must be conducted in the workplace orwhat the employer does with the resulting infor-mation other than the requirements that the pro-cedure not be negligently performed and that theemployee be informed of potentially serioushealth risks. Participation in medical exams ormedical research can be a valid condition of em-ployment. As a result, employees or applicantswould have no right to refuse to participate with-out jeopardizing their job. How much the em-ployee needs to be told about the research is un-clear, except in two cases. If the research were

federally funded, subjects must understand therisks and other aspects of the study and consentto them. A few States have statutes that requireInstitutional Review Boards in order to protectresearch subjects, and these boards may requireinformed consent.

With respect to the data generated by genetictesting, there are few requirements regardingconfidentiality except in the State of California.But employees have a right of access to medicalrecords under OSHA regulations and unions havea similar right under a recent decision by NLRB.This access could help prevent abuse of genetictesting. However, those who face the greatest riskof being denied employment because of their ge-netic makeup—job applicants-would not have ac-cess to the test results.

For those applicants or employees who weresubject to some adverse job action because oftheir genetic makeup, Federal and State an-tidiscrimination statutes may offer some relief,depending on the circumstances of the case. Afew States prohibit employment discriminationbased on certain genetic traits, usually sickle celltrait, To the extent that genetic screening has adisparate effect on the employment opportunitiesof one of the protected classes under title VII, anadversely affected genetically susceptible employ-ee in one of those classes would have a prima faciecase of discrimination against the employer. Theemployer would then have to carry the heavyburden of justifying the screening program onthe basis of job relatedness or business necessity.It is presently unclear whether avoiding tort liabil-ity or the cost of engineering controls is a businessnecessity or whether the employee’s capacity toperform the job without a risk of future illnessis a job-related characteristic. However, it is clearthat any job selection method must be predictiveof the characteristic for which it allegedly selects.Since genetic screening has not been shown tobe predictive of future occupational illness, a pro-gram that had a disparate impact on the employ-ment opportunities of the classes protected bytitle VII probably would violate that act.

The Rehabilitation Act and similar State lawsoffer greater potential than title VII for aiding theemployment opportunities of genetically suscep-

— .


tible individuals; however, for those laws to beapplicable, two currently unresolved legal ques-tions must be settled in favor of the employees.The first is whether or not genetic makeup is ahandicap. If not, these employees would have norights under these laws. If it is a handicap, thenext question is whether a reasonable probabil-ity of future illness would be a valid job-relatedrequirement or something going to the necessi-ty of the business. Some State courts have ruledthat employment may be denied to handicappedindividuals on the basis of a reasonable probabil-ity of future illness. If the courts were to rule thatfuture risk of illness was not a legitimate area ofinquiry for employers, the Rehabilitation Act andsimilar statutes would prohibit adverse job actionson the basis of genetic makeup. If risk of illnesswere recognized as a legitimate concern, the em-ployer would have the burden of showing thatthe genetic screening techniques were reasonablypredictive of illness. Even if the employer dem-


1.

2.3.

4.

5.

6.

7.

8.

9.

10.

11,

American Conference of Governmental IndustrialHygienists, Threshold Limit Values, 1980.Annot., A. L. R.3d, vol. 10 (1966), p. 1071.Armstrong v. Index Journal Co., 647 F.2d 441 (4thCir. 1981).Austin v. Johns-Manville Sales Corp., 508 F. Supp.313 (D. Maine 1981).Bacow, L,, Bargaining for Job SafettiV and Health(Cambridge, Nlass.: MIT Press, 1980).Baker v. California Land Title CO., 349 F. Supp. 235,238 (D. C., Cal. 1972).Baron F., Handling Occupational Disease Cases, p.3, 1981.Beadlingv. Sirotta, 41 N.J. 555, 197 A.2d 857 (1964)(alleging negligent diagnosis prevented employ-ment ).Betesh v. United States, 400 F. Supp. 238 (D.D.C.1974) (Hodgkins disease).Beuder, E., Hemolytic Anemia in Disorders of RedCell Metabolism, 1978,Blankenship i. Cincinnati hlilacron Chemicals, Inc.,69 ohio St. 2d 608, 433 N.E. 2d 575 (1982).

12. Borden Chemical, 261 N. L.R.B. No. 6 (1982).13. Borel v. Fibreboard Paper Prods. Corp., 493 F.2d

onstrated this, however, it might have to accom-modate the “genetically handicapped” employeeanyway. Such accommodation probably wouldnot require the installation of expensive engineer-ing controls. In addition to these unresolved ques-tions, a limitation on the Rehabilitation Act fromthe plaintiff’s perspective is that plaintiffs mustpursue their remedies under section 503 throughOFCCP rather than suing employers directly.

Virtually all of these questions could be subjectsof bargaining between employers and unions.Thus, individual employers and unions could de-cide for themselves whether the employer coulduse genetic testing, the circumstances underwhich it could, and the use that could be madeof the results. Unions, however, would have nolegal duty to bargain over such issues or to takespecial steps to protect workers who were genet-ically predisposed to occupational disease.

14

15

16

17

18.

19.

20.21

22

23

1076, 1096-1100 (5th Cir. 1973), cert. denied, 419U.S. 869 (1974) (defense available in products ]ia -bility action based on exposure to asbestos).Brown v. scullin Steel Co., 364 Mo. 225, 260 S.W.2d513 (1953).Bureau of National Affairs, 11 Occup. Safety &Health Rep., No. 7, July 16, 1981, p. 131.Bureau of National Affairs, Basic Patterns in UnionContracts, 9th cd., 1979, pp. 107-I11.Bureau of National Affairs, 19 Fair Empl. Prac. Cas.1624, 25 Empl. Prac. Dec. (CCH) f 30,260, U.S. De-partment of Labor, 1979.Chicago, M., St. P. & Pac. R.R. v. ILHR Dept., 62Wis. 2d 392, 215 N.W.2d 443 (1974).Cohen, “The Occupational Safety and Health Act:A Labor Lawyer’s Overview, ” Ohio St. L. J., vol.33, 1972, pp. 788, 789.Colgate-Palmolive Co., 261 N. L.R.B. No. 7 (1982).Delamotte v. Unitcast Div. of Midland Ross Corp.,64 C)hio App. Zd 159, 411 N.E.2d 814 (1978).E. E. Black, Ltd. v. Donovan, 27 Empl. Prac. Dec.(CCH) fl 32,199, Aug. 5, 1981.E, E. Black, Ltd. v. Marshall, 497 F. Supp. 1088,1099 (I). Hawaii 1980).


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Under Sections 503 and 504 of the RehabilitationAct of 1973,” St. Louis U. L. J., vol. 22, 1978, pp.25, 30.

48. Novotny v. Great Am. Fed. S. &L. Assln., 584 F.2d1235 (3d Cir. 1978).

49. OSHA Access to Employee Exposure and MedicalRecords Standard, 45 Fed. Reg. at 35,242-413,1980.

50. OSHA Instruction STD 1-23.4, Aug. 22, 1980.51. Payne v. McLemorek Wholesale & Retail Stores,

654 F.2d 1130 (5th Cir. 1981), cert. denied, 102 S.Ct. 1630, 1982.

52. Phelps Dodge Corp. v. NLRB, 313 U.S. 177 (1941).53. Prosser, W., Law of Torts, 4th cd., 1971, pp.

526-530.54. Quaries v. Sutherland, 389 S.W.2d 249 (Ten, 1965).55. Reinhart, “Federal Protection of Employment Rec-

56

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69.70.

71.

ord Privacy,” Harv. J. Legis., vol. 18, 1981, p. 207.Rister v. General Elec. Co., 47 Wash. 2d 680, 289P,2d 338 (1955).Robinson v. Lorillard Corp., 444 F.2d 791, 798 (4thCir.), cert. denied, 404 U.S. 1006 (1971).Rogers v. Horvath, 65 Mich. App. 644, 237 N.W.2d595 (1975).Sanford v. Presto Manufacturing Co., 92 NM. 746,594 P.2d 1202 (1979).Senate Report No. 91-1282, 91st Cong., 2d sess.,1970, pp. 10-11.Shabecoff, P., “Safety Agency to Forgo ‘Cost-BenefitAnalysis, ’ “ N. Y. Times, July 13, 1981.Small, “Gaffing at a Thing Called Cause,” Tex. L.Rev., vol. 31, 1953, p. 630.St. Louis Post-Dispatch, “Hire the Handicapped”:Now More Than Just A Slogan,” May 15, 1977, p.6B, cited in Wolff, supra note 47, p. 26 n.9.Sterling Transit Co. v. Fair Employment PracticeCommission, 28 Fair Empl. Prac. Dec. (CCH) f 32,543(Cal. App. 1981).Taylor Diving and Salvage Co. v. U.S. Departmentof Labor, 599 F.2d 622 (5th Cir. 1979).US. Chamber of Commerce, Analysis of WorkersCompensation Laws, vol. vii, 1980 ed.United Steelworkers of America v. Marshall, 647F.2d 1189, 1252-59 (D.C. Cir. 1980), cert. deniedsub nom., Lead Indus. Ass h., Inc. v. Donovan, 101S. Ct. 3148 (1981).Usery v. Tamiani Trial Tours, Inc., 531 F.2d 224(5th Cir. 1976).Vaca v. Sipes, 386 U.S. 171 (1967).Westin, A. (cd.), “The Privacy Commission Recom-mendations on Employee Access,” Individual fi”ghtsin the Corporation, 1980.Westinghouse Elec. Corp. v. State Div. of HumanRts., 63 App. Div. 2d 170, 406 N. Y.S.2d 912 (1978).

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace . 137

72, Williams v. E. 1, du Pent de Nernours & Co,, 112 74. Wolkinson, “Arbitration and the EmploymentS.E,2d 485 (S.C. 1960) (defense available where em- Rights of the Physically Disadvantaged,” Arb. J.,ployee, despite physician’s advice, continued work vol. 36, No. 1, March 1981, pp. 23, 24.and aggravated his ulcer).

73. Wojcik v. Aluminum Co. of Amer., 18 Misc. 2d 790,183 N. Y.S.2d 351 (1959) (tuberculosis).

S.E.zd (S.c. ployee,

Wojcik Y.S.2d

l. dll .Nemours Co" \·Volkinson,

Zd

Chapter 9

Application of Ethical Principlesto Genetic Testing

—

Ethical Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. ”.. Autonomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Nonmaleficence and Beneficence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........Justice . . . . . . . . . . . . . . . .. ... .. ..... . . . . . . . . . . . . . . . .. ... ..

Applications to Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Routine Use of Tests of Doubtful Clinical Value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Genetic Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ... .. .. Genetic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Medical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .High Correlation Between Genetic Endpoints and Risk of Disease . . . . . . . . . . . . . . . . .

Genetic Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 . . . . . . . . . . .Genetic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Special Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ... ... ..... . . . .Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 9

Application of Ethical Principlesto Genetic Testing

The use of genetic testing in the workplacetouches on areas of basic concern to most peo-ple: opportunity for employment, job security,health, self-esteem, and privacy. Genetic screen-ing may enable workers to have greater controlover their health by providing medical informa-tion on which to base job site selection and useof personal protection devices. It could be usedby management to better match employees totheir jobs or to reduce levels of exposure to haz-ardous substances. It also could be used to ex-clude or transfer people from jobs and conceiv-ably could result in classes of people being stig-matized. While genetic monitoring might permitemployees or management to take preventivehealth measures, it may simply create unjustifiedfears of nonexistent hazards. Moreover, bothtechniques result in the collection of informationof an extremely personal nature. Thus, the tech-nology has both risks and benefits, depending onhow it is used.

Because genetic testing procedures are relative-ly new and have not been widely used, there islittle direct experience on which to make judg-ments regarding their use. Nor are there directlegal precedents. Under those circumstances, itis appropriate for policy makers and others in-volved in decisions concerning genetic testing tolook to ethical principles for guidance. These prin-ciples can assist decisionmakers in ensuring thatthe technology is used justly and with the greatestregard for human values.

Ethics is the study of moral principles govern-ing human action. These principles, or generalprescriptive judgments, create moral duties thatguide action in particular circumstances. Some-times, however, the principles conflict in their ap-plication and provide no clear guidance. Then dif-

ficult choices must be made. Such is the case withgenetic testing in the workplace.

This technology raises a number of questionsthat can be put in a framework suitable for ethicalanalysis:

1.

2.

3.

Do employers, occupational health specialists,or society in general have any particularobligations toward workers who may be atincreased risk for disease because of theirgenetic constitution or because of exposureto hazardous substances? If so, what arethey?Are genetic screening and monitoring forgenetic damage compatible with ethicalprinciples?Does the answer to the second question de-pend on the particular circumstances in-volved? If so, the following must be exam-ined:a.

b

c.

d.

e.

What moral rights and duties exist be-tween the worker and company medicalpersonnel?Must participation in genetic testing pro-grams be voluntary, and if so, how is thatto be guaranteed?What rights and obligations exist regard-ing the use of medical information?What ethically permissible actions maybe taken on the basis of information gainedthrough genetic testing programs?Do the answers to these questions dependon whether the testing is being done forresearch purposes or as part of a medicalprogram?

To address these questions, it is first necessaryto consider some basic ethical principles. Theirapplication to the various ethical questions raisedby genetic testing then will be discussed.

141


Ethical principles

Four ethical principles are most relevant to anassessment of this technology: autonomy, nonmal-eficence, beneficence, and justice.

Autonomy

The principle of autonomy has two aspects. Thefirst relates to the ability of a person to make con-sidered judgments and decisions that lead to actsthat foster self-reliance or independence, In thissense, autonomy depends on being able to planand act deliberately, based on one’s own judgmentabout the consequences of certain behaviors andtheir value or utility to oneself or others. Thisleads to the notion that individuals should be freeto act as they wish, regardless of how foolish theiractions may appear to be and without interfer-ence by others, so long as their actions do notharm others or interfere with their liberty (2). Thesecond aspect of autonomy derives from the beliefthat people should be treated as ends rather thanmeans, a principle known as respect for persons.In other words, in evaluating the actions of others,one should respect them as persons with the sameright to their judgments as one has to his or herown (2). Thus, the principle of autonomy imposesthe dual moral obligation not to interfere withthe autonomous actions of others and to respecttheir personhood and beliefs,

A corollary of the principle of autonomy is therequirement to secure informed consent frompersons before taking actions that may put themat risk, The rule of informed consent requires fulldisclosure of all important information, compre-hension of the information, the ability to choosefreely, and the mental competence to make deci-sions (7). Thus, the rule serves to protect individ-ual autonomy.

Not everyone is capable of full self-determina-tion. This capacity develops during a person’s life,and some individuals lose it in whole or part be-cause of illness, mental disability, or circum-stances that severely restrict their liberty. For ex-ample, children, prisoners, or those who are ininstitutional settings may be less capable ofautonomous actions (7).

Autonomy may be compromised in other ways.These include situations where behavioral optionsare limited, where direct or implied coercion isused toward actions favored by others, or wherecircumstances limit the ability to act knowledge-ably in one’s own interest.

Workers as a group may be situated in waysthat limit their full expression of autonomy. Pre-ordained rules of behavior, job requirements, lim-ited resources or information, and concern overjob security can limit autonomy. Whether or notparticular limitations are justified will depend ona determination of the validity of reasons for over-riding the principles of autonomy.

Respect for persons gives rise to the obligationto protect those with diminished autonomy (7).The extent of protection generally would dependon the degree to which their autonomy is dimin-ished. Some persons require little protectionbeyond ensuring that they undertake activitiesvoluntarily and with an awareness of possible ad-verse consequences; others may have to be ex-cluded from activities that harm them.

The principle of autonomy is not absolute.Where the prospect of severe harm is evident,some commentators have argued that interven-ing in order to protect the individual is justified(3,6). Thus, it maybe justified to intervene wherepersons are otherwise competent to exercise au-tonomous thought and action (as is the case forthe great majority of workers), but who may beunable to so act because of their ignorance of therisks or their inability to understand those risksdue to their complex technological nature.

Genetic testing has the potential to be used ina way that restricts the autonomy of prospectiveemployees or workers already on the job. For in-stance, preemployment tests that presumablyidentify genetically susceptible individuals may beused to restrict the type of job an employee is per-mitted to undertake or to ban the worker fromemployment in the industry altogether. Similar-ly, testing done during employment, which de-tects early warning indicators of possible futuredisease, might be used preemptively to remove

Ch. 9—Application of Ethical Principles to Genetic Testing ● 143

employees from a given station or set of jobduties. Each of these steps, if taken unilaterallyby an employer, could be seen as a restriction ofthe autonomy or liberty of the individual workerto elect a suitable job and/or to accept the attend-ant risks.

Nonmaleficence and beneficence

Nonmaleficence is the obligation not to harmothers (2). Beneficence is the obligation to helpothers further their important and legitimate in-terests when we can do so at minimal risk toourselves (2). In practice, it is difficult to separatethe two principles, because avoiding harms andproducing benefits exist along a continuum. How-ever, one philosopher, William Frankena, sepa-rated this continuum into the following duties:

1. One ought not to inflict harm.2. One ought to prevent harm.3. One ought to remove harm.4. One ought to do good.

Frankena stated that each of these duties shouldtake precedence over the next, so that nonmale-ficence is the strongest duty, and doing good isthe weakest (5). Beneficence is usually consideredto encompass the second, third, and fourth ele-ments; it is distinguished from nonmaleficence inthat it requires positive steps to help others andnot merely restraint from harming them (2).

In a workplace setting, this priority listing couldcorrespond to an employer’s duty to: 1) not know-ingly subject workers to conditions that are like-ly to cause injury or ill health, 2) take steps to pre-vent the likelihood of workers becoming injuredor diseased, 3) remove harmful substances, and4) take affirmative actions to improve workerhealth.

our society generally accepts the proposition,as reflected in our legal system, that we cannotlegitimately impose an affirmative duty to dogood, but may impose negative injunctions toavoid harm. However, in certain cases, usuallyinvolving special relationships such as that ofemployer- employee or doctor-patient, society im-poses a duty to prevent or to remove harm. Forexample, the policy embodied in the OccupationalSafety and Health Act of 1970 that all workplaces

be safe and healthy can be interpreted as the legalimposition on employers of at least a duty to pre-vent harm and remove potentially harmfulconditions.

Arguments in favor of genetic testing rely onthe principles of beneficence. If the tests are ableto identify individuals or populations at increasedrisk, the employer has the duty to prevent harmby preventing exposure to harmful substances orto remove the harm by reducing the level ofexposure.

Such action may conflict with the principle ofautonomy, however, where it overrides a person’sown informed choice. An example would bewhere a job was denied to a susceptible personwho was willing to accept the risk. Whether ornot such paternalistic actions are justified dependson whether one places beneficence above auton-omy. Generally, ethicists favor autonomy overbeneficence (2), a choice also widely reflected injudicial decisions and legislation.

The concept of beneficence embodies the no-tion of maximizing possible benefits and minimiz-ing possible harms (2). This leads to the require-ment for a risk/benefit assessment whenever atechnology is claimed to provide benefits, suchas prevention of illness. As applied to genetictesting, this would require at a minimum that theclaimed benefits in fact exist, In other words, theassociation between one’s genetic makeup anddisease or between damage to one’s chromosomesor DNA and disease must be scientifically demon-strated.

Justice

Justice is a broad and elusive concept. Differentmoral philosophers have explained it in terms offreedom, fairness, equality, or entitlement. Mostwould agree, however, that an injustice occurswhen a benefit to which a person is entitled isdenied without good reason or when a burdenis improperly imposed. A more positive and oftenquoted statement of the principle of justice is thatequals should be treated equally, and unequalsshould be treated unequally (2), But what doesthis tautology really mean? Who is equal and whois unequal?


A somewhat more useful formulation of theprinciple of justice says that individuals who areequal in relevant respects should be treated equal-ly, and individuals who are unequal in relevantrespects should be treated differently in propor-tion to the differences (2). The problem thenbecomes to determine relevant differences. Mostcommentators would allow distinctions based onability, experience, need, and merit to justify dif-ferential treatment, depending on the circum-stances. In addition, the other moral principlesalready discussed provide some guidance in deter-mining whether particular differences are rele-vant (2).

A slightly more restricted notion of justice isthe concept of distributive justice, which refersto the proper distribution of social benefits and

burdens among different classes of people, Thereare several widely accepted formulations of justways to distribute benefits and burdens on thebasis of relevant differences. These are: to eachperson an equal share; to each person accordingto individual need; to each person according toindividual effort; to each person according tosocietal contribution; and to each person accord-ing to merit. These principles may give conflict-ing results in particular cases (2).

Thus, it is clear that a precise statement of therequirements of the principle of justice is best leftto a case-by-case analysis. Its application to genetictesting will be discussed in the context of the par-ticular ethical issues raised in the followingsection.

Applications to genetic testing

Ethical principles can provide some guidanceto policymakers and others who must decidewhether or not genetic testing should be done inthe workplace and, if so, under what circum-stances. This section first considers the routineuse of genetic tests for clinical purposes at theircurrent level of development, where there is lowcorrelation between the endpoints and risk ofdisease. It then considers the use of genetic testingat its current level of development for purposesof medical research. Next, because the technol-ogy is developing, it considers the issues raisedby the clinical use of these tests, where there isan assumed high correlation between genetic end-points and risk of disease. Finally, two particularproblems that arise in all three of these situationsare considered: What should an employee be toldabout test results? What are the obligations of theemployer and company medical personnel tomaintain confidentiality of medical data?

Routine use of tests of doubtfulclinical value

GENETIC SCREENING

The use of genetic screening to identify indi-viduals who might be at an increased risk of

disease in a workplace environment could not bejustified by the principle of beneficence wherethere was a low correlation between the geneticendpoints and disease. There would be greatuncertainty over whether or not that individualwould be at increased risk of harm. Thus, itwould be uncertain whether the employer couldprevent harm. At the same time, there would besome risks to the workers. First, there would besome physical risks associated with the medicalprocedures. Second, there would be risks to theworker from the use of the information, Theseinclude adverse job actions, loss of self-esteem,and possible stigmatization from being labeled“genetically inferior.” Such a label conceivablycould result in the person being barred from cer-tain jobs in an entire industry. In addition, itwould be particularly troublesome if placed onhistorically disadvantaged groups because it couldhelp continue that status. In view of the substan-tial risks and uncertain benefits, one could notargue that poorly predictive tests could be usedto prevent harm.

If the person labeled as susceptible were firedor excluded from a desirable job, such actionwould not comport with the principle of justice,It would be difficult to argue that genetic makeup

Ch. 9—Application of Ethical Principles to Genetic Testing ● 145

was a relevant characteristic for treating onegroup of workers differently from another, whenthe scientific data at best show only a weakassociation between genetic makeup and suscep-tibility to disease.

GENETIC MONITORING

Under circumstances where there is only aweak association between cytogenetic or noncyto-genetic endpoints and disease, the use of geneticmonitoring in the course of clinical practice wouldalso raise ethical concerns; however, monitoringmay be somewhat less at variance with acceptedethical principles than genetic screening. Argu-ably, there could be a small benefit to an entiregroup of people if the tests indicated they mightbe at an increased risk of disease. Moreover, therisks would be minimal; they include the physicalrisks of drawing blood and the possibility thatsome anxiety about future illness would be cre-ated unnecessarily. Presumably, there would beless of a risk of adverse job actions than forscreening because monitoring cannot identifyindividuals who might be at increased risk. As-suming the workers were not subject to job dis-crimination or other adverse action, there wouldnot be problems with respect to the principle ofjustice.

The strongest ethical argument against suchtesting, whether screening or monitoring, wouldbe based on autonomy. The concept of respectfor persons requires people to be treated as ends,not means. Using medical procedures of ques-tionable value on people could only be justifiedby the voluntary and informed consent of thosesubject to the procedure.

Medical research

The use of techniques of low or uncertain clin-ical value for purposes of research can be ethical-ly justified when certain conditions are met (7).The underlying purpose would be beneficent; ifthe research showed the techniques to be usefulor led to their further development, society wouldbenefit. Those workers participating in the re-search also might benefit at some future time. Therisks to them would be similar to those discussedpreviously, except that there would presumablybe less of a risk of adverse job actions being taken.

However, there would still be the psychologicalrisk of a person gaining information about himselfthat he might prefer not to know.

Under these circumstances, where participantsin medical research are not likely to benefit direct-ly from the medical interventions, the principleof autonomy becomes paramount. This principleusually requires that the subjects enter into theresearch voluntarily and with adequate informa-tion (7). In practice, this means that the subjectsmust give informed consent to the procedures.

The elements of informed consent are dis-closure of information, comprehension of infor-mation, and voluntariness (7). Competence to con-sent is sometimes viewed as an element of in-formed consent and sometimes as a precondition.In any event, it would not be relevant here be-cause it refers to the mental capacity to make deci-sions on a rational basis. Workers actually on thejob are presumably competent.

The type of information disclosed usually in-cludes the research procedure, its purpose, therisks and possible benefits, the fact that the sub-jects may ask questions, and the fact that theymay withdraw at any time. Generally, the sub-jects should be told what a “reasonable person”or perhaps a “reasonable volunteer” would wantto know about the experiment (7).

Information must be presented in a way thatis understandable to potential subjects. Moreover,the investigators are generally considered to havean obligation to determine that the informationwas understood. (7).

Voluntariness requires conditions free of coer-cion or undue influence (7). This maybe especiallyproblematical in an occupational setting whereworkers may perceive their job security or poten-tial for promotion to be affected by their willing-ness to participate in the research.

High correlation between geneticendpoints and risk of disease

GENETIC SCREENING

In the hypothetical case where particular ge-netic traits correlated with an increased risk ofdisease, genetic screening could be supported by


the principle of beneficence, depending on howthe results were used. Clearly, the data generatedby the tests would identify a potential harm, andgiven this information, steps could be taken toprevent the harm or to remove it. How the in-formation is used then becomes the paramountquestion.

One action that the employer could take wouldbe to bar genetically predisposed workers fromcertain jobs, by not hiring them, by placing themin other jobs when hired, or by transferring them.This action might be considered beneficent be-cause harm to the employee would be averted.However, another action, also consistent withbeneficence, would be to lower exposures to thepoint where these people would not be at in-creased risk, Still another action might be todevise personal protective equipment for them.The principle of beneficence provides littleguidance in choosing among these alternatives.

The principle of justice provides some guidance.One way of considering the problem would beto ask if genetic makeup is a relevant character-istic on which to treat a small part of the workforce differently. One could argue that geneticmakeup is relevant because, in our hypotheticalcase, these people are more prone to illness. Thisillness would result in additional costs tothemselves, the employer, and society. It maybeunfair for society or the employer to bear thesecosts for the benefit of these few individuals. Onthe other hand, these people are not responsiblefor their genetic makeup. Therefore, it is arguablyunfair to single them out for special treatment.In addition, their genetic makeup may be irrele-vant because it is not related to their ability todo the job efficiently and without risk to others.

Another way to address the problem is to askwho, if anyone, has the obligation to compensategenetically disadvantaged workers? Three schoolsof thought on distributive justice are relevant: thelibertarian school; the utilitarian school; and theneeds-based school,

The libertarian school emphasizes merit andcontribution. Under this theory, a worker orgroup is entitled to get back exactly that propor-tion of the national wealth that he or they created(4). If genetically disadvantaged workers were not

contributing to the national wealth, even if thereason was because they had been denied jobs,they would not be entitled to compensation, ac-cording to this school.

The utilitarian school emphasizes considerationof all of the various principles of distributivejustice with the goal of maximizing public andprivate benefits (2). Under this theory, one couldargue that compensation could materially helpthese individuals at little cost to society, whichwould bear the costs directly through govern-ment compensation plans or indirectly, when theemployer passed on the costs in the price of theproduct. On the other hand, if the costs of com-pensation were large and the number of workerswere small or if employers were forced out ofbusiness by having to install extremely expensiveengineering controls, one could argue againstcompensation.

The needs-based school emphasizes fundamen-tal needs; that is, something without which a per-son will be harmed or at least detrimentally af-fected. If genetically disadvantaged workers facedat least moderate difficulty in finding any job ora job at an adequate wage level, this theory wouldrequire compensation.

The principle of autonomy is also important inthis hypothetical situation. Respect for personswould probably require that genetically suscep-tible workers be informed of their condition. Atthe same time, autonomy would appear to requirethat such workers be given the right voluntarilyto assume the risk, if given adequate informationin a comprehensible way. In situations of conflictbetween autonomy and beneficence, most ethi-cists generally favor choosing autonomy. Thus,paternalistic behavior on the part of the employerto exclude the employee for the latter’s benefitbut without his consent generally would beviewed as unethical, However, society sometimesaccepts paternalistic actions when they benefitaffected groups, such as compulsory vaccinationor fluoridation of the water. If genetically suscep-tible workers were given alternative jobs at equiv-alent pay and benefits, the paternalistic behaviorof excluding them from certain jobs probablywould be ethical.

Ch 9—Application of Ethical Principles to Genetic Testing . 147

GENETIC MONITORING

If there were a high correlation between cyto-genetic or noncytogenetic endpoints and risk ofdisease, genetic monitoring could be justified bythe principle of beneficence. The reasons wouldbe essentially the same as those discussed forscreening.

The actions that an employer may take on theresults of monitoring are somewhat different,however. Unless the monitoring tests were so pre-dictive that high-risk individuals could be iden-tified, a situation that would be the same asscreening, monitoring would only identify a high-risk group already on the job. The most likelycourses of action open to the employer would beto do nothing, to lower exposure levels, or per-haps to take some intermediate action such as pro-viding personal protection devices,

Doing nothing to alleviate a known risk wouldbe unethical. Since the employer actually createdthe risk, inaction would amount to inflicting harm.Moreover, autonomy would appear to require in-forming the workers of their increased risk, aris-ing from being members of the group.

Lowering exposure levels or providing protec-tion devices would be consistent with the princi-ple of justice. No discrimination would be in-volved, and employees would not unfairly bearthe burden of the actions.

Special problems

Two problems deserve special attention becausethey arise regardless of the predictiveness of thevarious tests: What information should be givento workers about testing procedures and the re-sults? Who besides the employees should have ac-

cess to medical data and under what circum-stances?

The principle of autonomy implies a duty toprovide employees with information about theirhealth, even where the significance of the infor-mation might be uncertain. This duty would beeven stronger when the information was highlypredictive of a risk of disease.

Autonomy would also appear to require thatworkers be fully informed of the nature of med-ical procedures to which they are subjected.While the concept of informed consent would bemost crucial in a medical research situation, it isalso applicable to clinical interventions. In the lat-ter case, even though the procedures are clearlybeneficent, their application to the workerwithout his informed consent is a paternalisticaction,

Once medical data have been collected, the issueof who has access to the data arises. As a generalrule, medical data are considered confidential onthe grounds that respect for a person’s autonomyrequires respect for his or her privacy. Thestringency of this rule, however, is a matter ofmuch debate, particularly in the work environ-ment where the employer is viewed as havingsome rights to that information. The Code ofEthical Conduct for Physicians Providing Occupa-tional Medical Services states that employers areentitled to be informed of the medical fitness ofindividuals for work but are not entitled todiagnoses or details of a specific nature (I). Onepotential consequence, however, might be thatworkers determined to be genetically unfit couldbe stigmatized and have difficulty finding otheremployment for similar jobs.

Conclusions .

Genetic screening and monitoring are not in- omy, nonmaleficence, beneficence, and justice.herently unethical. The tests are morally justified Whether or not they are consistent with theseto the extent they enhance worker health in a principles will depend on how the tests are donemanner consistent with the principles of auton- and how the information is used.


Ethicists generally agree that autonomy re-quires that no medical procedure, especially thoseof unestablished clinical validity, be done on a per-son without his informed consent. This principlewould also require that the person be told theresults and what they mean and that medical databe held confidential.

Ethical principles constrain how the results ofgenetic testing may be used. With a low correla-tion between genetic endpoints and disease, itwould be unethical for the employer to act ad-versely to the employee’s interests, such as bydenying him or her a job. In the hypothetical caseof a high correlation between genetic endpoints


1. American Occupational Medical Association, ‘(Codeof Ethical Conduct for Physicians Providing Occupa-tional Medical Services,” 1 of Occupational Medi-cine, vol. 18, August 1976.

2. Beauchamp, T., and Childress, J., Principles of Bio-znedica] Etk”cs (New York: Oxford University Press,1979).

3. Dworkin, Charles., “Paternalism,” The Monist, Jan-uary 1972.

4. Feinberg, J., social Philosophy (Englewood Cliffs,N. J.: Prentice-Hall, Inc., 1973), p. 114.

and disease, the morally correct course of actionis significantly less clear. An employer may bejustified in allowing a susceptible person to as-sume the risks on the basis of informed consent.On the other hand, the most ethically feasiblecourse of action for an employer once geneticmonitoring identifies a group at increased riskwould be to inform the workers and to reduceworkplace exposure. Failure to do so would beinflicting harm, and it is unlikely that the groupwould consent to assuming this risk. Finally,whether or not genetically susceptible people areentitled to compensation depends on which the-ory of distributive justice is chosen.

5. Frankena, William, Ethics, 2d ed. (Englewood Cliffs,N.J.: Prentice-Hall, Inc., 1973), p. 47.

6. Gert, B., and Culver, C., “Paternalistic Behavior,”Philosophy and Public Affairs 6, fall 1976, pp. 45-57.

7. National Commission for the Protection of HumanSubjects of Biomedical and Behavioral Research, TheBefmont Report: Ethical Principks and Guidelinesfor the Protection of Human Subjects of Research,DHEW publication No. (OS) 78-0012 (Washington,D. C.: U.S. Government Printing Office, 1978).

Chapter 10

Prospects and Problems forthe Economic Evaluation of

Genetic Testing

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Economic Evaluation in Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Identifying and Measuring Consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Problem of Value Judgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Framework for Economic Evaluation ..., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Alternatives Compared . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Population Studied . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .The Consequences Considered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Methods for Aggregating Consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Study Design.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Using the Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Economic Evaluation of Genetic Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Economic Evaluation of Cytogenetic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Chapter IO References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table

Table No.17. Hypothetical Break-Even Number of Cases Averted by SAT Testing per

1,000 Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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157

Chapter 1 0

Prospects and Problems forthe Economic Evaluation of

Genetic Testing

Introduction

Genetic testing in the workplace has potentialbenefits and costs to workers, employers, andsociety as a whole. The magnitude of those ben-efits and costs and their distribution among thesectors of society will help determine the desira-bility of this approach to improving occupationalhealth. The techniques of economic evaluation—cost-benefit and cost-effectiveness analyses—aremethods for collecting, organizing, and present-ing evidence about the benefits and costs of alter-native courses of action. They are systematic ap-proaches to examining the tradeoffs among thedifferent kinds of consequences—for example,dollar outlays today versus improved levels ofhealth 5 years hence—stemming from a decision.

The usefulness of economic evaluation rests onits ability to improve decisions. Even when eco-nomic analysis is severely limited by uncertain-ties about the magnitude, direction, or value of

certain consequences—as is the case with genetictesting—it can still be a useful exercise. The veryidentification of key areas of uncertainty, for ex-ample, can be used to set priorities for furtherresearch, It can also show how sensitive the re-sults of an analysis are to changes in assumptionsconcerning these uncertain elements of the de-cision.

This chapter considers the fundamental prin-ciples and limitations of economic evaluation andproposes a general framework for economic eval-uation. Then, the specific issues and problemsthat arise in applying the framework to genetictesting are discussed. The goal is to illustrate thekinds of information that are currently availableto support such analysis and the present level ofknowledge about the costs and benefits of theseapproaches to occupational health.

Economic evaluation in health

The analytic pillars of economic evaluation arecost-benefit and cost-effectiveness analyses. Theyshare a common purpose—to help decisionmakersunderstand the consequences of the choices be-fore them. This objective is approached from dif-ferent perspectives under the two techniques.Consequently, each technique has strengths andlimitations that make it more or less acceptableto analysis of particular problems.

General principles

In theory, a cost-benefit analysis identifies,quantifies, and places a value on all consequences,both positive (benefits) and negative [costs) aris-

ing from each possible alternative course of ac-tion. If all such consequences are valued in thesame unit of measure (for example, dollars), thedecisionmaker would merely have to tally thesevalues and compare them across all possible alter-natives. The alternative with the highest level ofnet benefit (or lowest net cost) would be preferredto all others.

In practice, no cost-benefit analysis is ever com-pletely comprehensive or accurate in measuringconsequences, and the valuation of such conse-quences, even when they can be measured, isreplete with conceptual and methodological dif-ficulties. Consequently, in practice a cost-benefit

151


analysis is not a definitive decisionmaking tool butrather a useful framework for arraying informa-tion (11).

Indeed, the Achilles’ heel of cost-benefit analysisis its need to assign a monetary value to all meas-ured consequences of each alternative. This valueis generally accepted as the sum of the values ofthe consequence to each affected member ofsociety. But how does one assess the value thata person places on a reduction in the probabilityof early death, pain, or discomfort associated withillness, especially when the changes may occurat different times in the future? The question ofhow to value consequences has been addressedat length in the cost-benefit literature (11). Meth-ods do exist (some of which are discussed below)that are generally accepted by economists as rea-sonable for assigning monetary values to someimportant consequences. None, however, is com-pletely satisfactory, and the technique of cost-effectiveness analysis was developed to sidestepthe valuation problem.

In cost-effectiveness analysis, the monetarycosts of an alternative are compared with one ormore measures or indexes of effectiveness, suchas “number of lives saved,””number of life-yearssaved, ” or “quality-adjusted life-years saved”(11,16). The effectiveness measure must act as asurrogate for all of the nonmonetary conse-quences that are otherwise unmeasured. Onlythose alternatives whose consequences are wellrepresented by the selected effectiveness measureshould be compared with one another. Conse-quently, cost-effectiveness analysis can be usedto compare only a narrow range of alternatives.Whereas cost-benefit analysis is theoreticallypowerful enough to compare widely different al-ternatives, such as occupational health programsversus housing programs, cost-effectiveness anal-ysis can be used only to compare alternatives withthe same or a very similar range of nonmonetaryconsequences, such as different approaches toreducing workers’ exposure to a particular in-dustrial carcinogen.

Economic evaluation does not require the ag-gregation of all benefits and costs into a singleindex. Recently, some scholars have advocated asocial accounting approach in which all of the im -

portant dimensions of benefit and cost are ar-rayed and, to the extent possible, their magnitudeestimated (11,17). Some dimensions would bemeasured in dollars, some in physical units, andsome in constructed scales. The decisionmakerwould have a balance sheet showing the perform-ance of each alternative on each dimension. Theadvantage of this disaggregated approach is thatimportant but hard-to-measure consequences ofan alternative will not be ignored. However, ifmany dimensions of outcome are important butcannot be measured precisely, the enumerationof effects can obscure rather than clarify the dif-ferences among alternatives.

Identifying and measuringconsequences

What are the consequences of alternative strat-egies for achieving occupational health? Suchstrategies typically reduce exposure to illness- orinjury-causing hazards. This exposure reductionpresumably lowers the incidence or severity ofoccupational illness. These positive health effectsare bought at the price of the occupational healthprogram expenditures. But the positive health ef-fects of the program also mean reductions in thecost of illness. The cost of illness has three com-ponents, each of which maybe altered by the pro-gram’s health effects. First, the reduction in theincidence and severity of illness over workers’lifetimes will mean fewer expected expendituresfor health and medical care at various points inthe future. The discounted value* of these imme-diate and future monetary outlays is called thedirect cost of illness.

The consequences of a strategy do not end withthese direct costs. When a worker dies or fallsill, his or her productivity is lost or diminished.This productive activity has a value in the marketplace, and its loss is referred to as the indirectcost of illness. Thus, a program that improvesworker health will reduce the indirect cost of ill-

*An outlay in the future cannot be compared directly with onemade today because the postponement of the expenditure allowsfor the investment of those funds in alternatives and because peo-ple prefer a benefit today to one in the future. The value of thefuture expenditure must therefore be discounted by a rate equalto the return from those alternative investments.

Ch. 10—Prospects and Problems for the Economic Evacuation of Genetic Testing 153

ness as we]]. But the consequences of illness gostill further. Quite apart from its effect on pro-ductivity, illness brings about pain, suffering, anx-iety, emotional distress, and grief in patients, theirfamilies, friends, and others. The value of theselosses are the psychosocial costs of illness (l).

The “benefit” of an occupational health strategyis the value of changes in these costs of illnessdue to the program, The goal of cost-benefit anal-ysis is to measure the impact of a program orstrategy on the cost of illness and to compare thisbenefit with the cost of the program. If the dif-ference between benefit and cost is positive, socie-ty would be better off if it were to implement thestrategy. If the net benefit is negative, however,the program is not worth its cost. The assump-tion underlying these conclusions is that all of thecosts and benefits can be quantified.

The challenges to measurement and valuationof the cost of illness are great, even when thehealth effects of a program are known with preci-sion. There are two different conceptual ap-proaches to measuring the cost of illness: humancapital and willingness to pay, Illness is somethingthat people are clearly willing to pay to avoid, andin theory, this willingness to pay is the value ofthe health benefits resulting from a program. Butfor a variety of reasons it is not easy to determinehow much people would be willing to pay to re-duce, say, the probability of contracting a givendisease at some point in the future. * Consequent-ly, most cost-benefit analyses employ the humancapital approach to valuing benefits.

The human capital approach measures onlythose benefits that have a value in the marketplace: the direct and indirect costs of illness.Psychosocial costs are left to be considered insome other way. Under this method, the valueof lost production due to illness or death is meas-ured by the market price for workers’ labor. Oc-cupational health strategies directed toward thosemembers of society with lower wages or lowerrates of participation in the work force, such aswomen, minorities, and the elderly, thereforewould be valued at less than those aimed atothers.

Cost-effectiveness analysis typically does not in-volve the valuation of either the indirect orpsychosocial costs of illness. The effectivenessmeasure (such as life-years saved) presumablyacts as a proxy for both of these. The net costsof a program are defined as the sum of the directprogram cost and the change in the direct costof illness-that is, present and future medical carecosts. If this net cost is negative, the program iscost-saving without even considering effective-ness. But if program expenditures outweigh thediscounted value of savings in direct medical carecosts, ratios of net cost to effectiveness then areconstructed for each alternative under study.

The cost-effectiveness approach also containsbuilt-in value judgments, For example, the “life-years saved” measure would treat 10 extra yearsof life to a 45-year-old patient the same as 10 ex-tra years of life to a 70 year old, There is substan-tial evidence from survey research that the valueof these outcomes is not the same in most peo-ple’s minds (4), but a cost-effectiveness analysisusing the life-years measure would not be ableto account for such differences.

problem of value judgments

Biases and value judgments are inherent in alleconomic evaluations, no matter how comprehen-sive. Value judgments creep in through the fram-ing of the question, the choice of measures ofbenefit, effectiveness, and cost, the choice of datasources, and the design of measurement instru-ments, A value judgment also is present in thegeneral neutrality of economic evaluation towardthe winners and losers of a decision, Each alter-native will affect the distribution of benefits andcosts among segments of the population. Thesedifferences generally are netted out in economicevaluations under the assumption that if the win-ners could more than compensate the losers, so-ciety as a whole would be ahead, whether or notthe compensation actually takes place. * In reali-ty, of course, such compensation rarely occurs;consequently, economists increasingly have cometo view the analysis of distributional conse-quences of alternatives as a fundamental element

*For a discussion of the willingness-to-pay concept, and the dif-ficulties of measuring it, see ref. 6. *For a discussion of the compensation test, see ref. 7.


of economic evaluation, especially when they aremajor (17).

Perhaps the most important value judgment inany economic evaluation is the definition of alter-natives, Relevant alternatives can be easily ex-cluded from consideration simply because theyare not recognized at the time the study is de-signed. In genetic testing, the definition of astrategy must include not only the testing proto-col and procedures, but also the followup and en-forcement activities that follow testing. Minor

Framework for economic

There are five critical elements of any economicevaluation, be it cost effectiveness, cost benefit,or some hybrid of the two. This section identifiesand discusses the five components.

Alternatives compared

The most important characteristic of an evalua-tion is the set of alternatives chosen for study,since the usefulness of an analysis for any deci-sion depends on the choice of relevant alterna-tives. There are two entirely different kinds ofrelevant alternatives for genetic testing in theworkplace. The first involves strategies for re-search on genetic testing, including developmentand refinement of the testing technology and epi-demiological and clinical research on the relation-ship between occupational exposure and diseasein various human populations.

The second set of alternatives involves the useof these tests to screen or monitor specific workerpopulations with the purpose of following up onthe test results with strategies to reduce exposure.These are strategies of intervention, as opposedto research.

It is possible to structure the research questionas one for economic evaluation on the rationalethat limited research resources should be allo-cated to projects that can promise the highestratios of benefit to research cost. But the meas-urable benefits of research rest largely on thebenefits of the interventions subsequently made

modifications in the definition of a genetic testingstrategy, such as the inclusion or exclusion ofcounseling services for employees, can have majoreffects on program costs, anticipated health ef-fects, and psychosocial consequences. Yet, avail-able funds may limit the number of alternativestrategies that can be compared, so choices mustbe made as an analysis is designed. Often, one can-not be certain that the best strategy has been in-cluded as an alternative in the study.

evaluation

possible by it. Thus, even economic evaluationsof alternative research strategies must considerinterventions. To date, the use of economic anal-ysis as a guide for biomedical research has beenlimited. This is primarily the result of the inherentdifficulty of predicting the outcomes of researchprojects, their timing, and even their probabilityof occurring. Consequently, the discussion insubsequent sections will concentrate on alterna-tive strategies for implementation of genetictesting.

Population studied

The definition of the population to which thealternatives apply is also an important attributeof any analysis. A comparison of two alternativescan have widely different results depending onthe characteristics of the population. For exam-ple, the potential importance of age as a factorin susceptibility to exposure argues for separa-tion of populations into age groupings. Narrow-ly defined populations have an advantage in thatthe interpersonal variation in measured costs andbenefits is low. On the other hand, if the workerpopulation is defined so narrowly that few fallinto each category, the analysis may lack the sta-tistical power to identify differences among alter-natives even when they actually exist.

The population also may be defined so narrowlythat the benefits and costs associated with a strat-egy cannot be achieved in actual practice, Con-

—

Ch. 10—Prospects and Problems for the Economic Evacuation of Genetic Testing ● 155

sider, for example, the costs and benefits of ge-netic screening for thalassemia trait in workers.If the study were to compare alternatives onlyfor workers in specific high-incidence ethnic orracial groups, the results might be irrelevant forthe actual operation of an occupational health pro-gram, where it may not be ethical or lawful torequire the test on the basis of race or nationali-ty. In other words, an economic analysis mightshow the desirability of screening for thalassemiatrait if the procedure were limited to blacks andMediterraneans, whereas in reality no screeningprogram could be limited to that population.

The consequences considered

As discussed earlier, an economic evaluationmay be characterized by the range of conse-quences (costs and benefits) included in its pur-view. It is possible to consider only the direct costsof a program. If, for example, a screening pro-gram can be shown to reduce net direct costs(consisting of the sum of the cost of administer-ing the program and the net reduction in the dis-counted costs of present and future health care),consideration of other consequences, such as theindirect and psychosocial benefits, may be unnec-essary. However, a usual precondition to the ac-curate estimation of the net direct costs of astrategy is the ability to estimate the impact ofthe program on the health of workers and there-fore on their need for medical care. Thus, evenignoring the indirect and psychosocial costs, eco-nomic evaluation generally cannot evade the needfor some estimate of a strategy’s health effects.

Inclusion of indirect cost impacts into an eco-nomic assessment adds an additional degree ofcomplexity to the evaluation problem. Even whenit is possible to assess the impact of a programon the incidence of disease, it may be difficult toassess its impact on the person’s ability to workat his or her level of productivity.

Methods for aggregating consequences

The consequences of any action will be distri-buted over time and among the members of socie-ty. These effects must be aggregated into coher-ent summary measures if the analysis is to be use-ful to decisionmakers.

The usual approach for dealing with effects oc-curring through time is to discount future costsor benefits by an appropriate rate. The furtheraway in the future that a consequence will oc-cur, the less importance or value it will have whendiscounted, There is no generally accepted ‘(cor-rect” rate at which future consequences shouldbe discounted to their present value. Discountrates of 3, 5, and 10 percent per year are com-mon, Even nonmonetary effectiveness measuressuch as ‘(lives saved” are often discounted ineconomic evaluations, though it is difficult todetermine the appropriate discount rate for thesekinds of effects. Estimates of lifetime direct andindirect costs vary widely with the choice of dis-count rate (3,6).

Aggregating consequences across individualsalso is necessary. Two issues are pertinent to theaggregation methods employed. The first is thestatistical issue of the best measure to representa potential distribution of impacts. Commonly ac-cepted measures such as the mean or median mayobscure important effects occurring in a subsetof the population. The direct and indirect costsof large changes in health status may be quite dif-ferent from those of smaller changes, and meas-ures such as the mean may not reflect these im-portant differences.

The second issue is one of equity. Consequencesare likely to be differentially distributed amongsectors of the society, Exposed workers compriseone affected group, the industrial employer an-other. Workers in other industries and the gen-eral public are other affected sectors. Analysescan be, but rarely have been, structured to showhow the costs and benefits of a program are dis-tributed among these groups.

Study design

All analyses ultimately rest on estimates of theexpected effect of each alternative on the conse-quences of interest. How these estimates are de-rived will determine their validity and, hence, thevalidity of the economic evaluation itself. Thus,the issues inherent in study design in general—internal and external validity-are important ineconomic evaluation as well (2).


Most economic evaluations contain one or moreestimates that are based on assumptions or rulesof thumb. Estimates are often necessary becauseof a lack of data. When such estimates are in-cluded in the analysis, however, validity necessari-ly suffers. An accepted procedure for dealing withuncertainty is to conduct a sensitivity analysis, astudy of the impact of changes in assumptions on

an evaluation, it is necessary precisely and fullyto define the alternative strategies, specify thepopulation to which the alternative strategies willapply, determine the consequences to be includedand the methods of measurement, select methodsof aggregating consequences over time and acrossindividuals, and identify those estimates whosevalidity is sufficiently suspect to warrant sensitivi-

the findings of the evaluation. If the results of the ty analysis. These steps will be applied in the nextanalysis are insensitive across the entire reason- sections asable range of correct values (that is, the most pre- analysis offerred alternative remains so regardless of as- monitoringgumptions), then its findings can be consideredvalid.

the use of economic evaluation forgenetic screening and cytogeneticis explored,

Using the framework

The five components of economic evaluation de-scribed above define the analysis. In structuring

Economic evaluation of genetic screening

To carry out an economic evaluation of geneticscreening in the workplace, the following kindsof information must be available:

. a detailed description of the proposed testingstrategy, including followup procedures,

● estimates of the prevalence of the genetictrait in the worker population under study,and

. estimates of the differential effect of worksiteexposure on the incidence and severity of dis-ease in the target population.

Genetic screening programs consist of a fami-ly of strategies for identifying and reducing ex-posure of workers with particular genetic traits.A strategy may or may not include counseling ofworkers with positive test results. The costs andbenefits of any such program will depend not onlyon the type of screening test but also on the fol-lowup actions associated with positive and nega-tive test results. For example, a preemploymentscreening test might result in job denial, whereasa program for employed workers could result intransfer or termination. Alternatively, the choicemight be left to the employee, who could remainin the position, request a transfer, or resign. Each

of these strategies has different implications forcosts and benefits and for the distribution of theseconsequences among the sectors of society.

The definition of the strategy also depends onthe configuration of the screening program itself.Since the tests for detecting genetic conditions arerarely perfectly sensitive or specific but involvesome false positive and false negative results, thetesting strategy may well include retesting of allthose with initial positive results, Or, when twoor more different tests, one more costly thananother, are available to detect a condition, thetesting strategy might consist of a broad screen-ing with the less costly procedure and using themore expensive test to retest positives. Programcosts will depend on the configuration selected,

The prevalence of genetic traits in worker pop-ulations also may vary. Some susceptible workersmay self-select themselves out of high-risk envi-ronments. Therefore, reliable data on the preva-lence of a trait in given populations is not alwaysavailable.

The benefits of a genetic screening strategy pre-sumably are manifested in the reduced incidenceof the disease associated with the genetic trait.

—. —.

Ch. 10—Prospects and Problems for the Economic Evaluation of Genetic Testing . 157

A necessary condition for such an impact is thatthe person with the condition be truly at en-hanced risk because of exposure to hazardoussubstances found in the work environment, andthe followup action must reduce the probabilityof the disease. Thus, the complicated chain of rela-tionships between the existence of a genetic trait,occupational exposure to a hazardous agent, anddisease onset must be known if the effects of astrategy on worker health are to be estimated.At present, the evidence is generally inadequateto assess the relationship between genetic traitsand increased susceptibility to industrial ex-posure. Yet, even lacking data on these basic rela-tionships, economic evaluation can provide someinsights that may assist in decisionmaking regard-ing the use of genetic screening.

As an example of how economic evaluationmight proceed, consider screening for heterozy -gous serum alpha1-antitrypsin (SAT) deficiency inwork environments containing respiratory irri-tants. This condition has been selected as an ex-ample because estimates of its prevalence in thegeneral population are available and some workhas been done to estimate the economic costs ofthe illness it may provoke-emphysema. Evidencehas accumulated that people who display an in-termediate deficiency of SAT are at increased riskof developing emphysema. Assume for the pur-poses of this example that a correlation has beenshown between intermediate SAT deficiency andan increased risk for respiratory disease in workenvironments containing respiratory irritants.About 3 to 4 percent of the population in theUnited States is thought to have this genetic con-dition. Tests for SAT deficiency are relatively in-expensive. Suppose a large-scale screening pro-gram could be implemented for $20 per person.The cost of screening 1,000 workers, then, wouldbe $20,000. Assume also that a worker with a pos-itive test result is removed from an environmentcontaining respiratory irritants. The followingquestion can be asked: How many cases of em-physema would have to be prevented or delayedby such an action to make the test program payfor itself in direct and indirect benefits? The directand indirect costs of emphysema in 1979 were

estimated at $1,300 per person* (10). If this esti-mate is accepted as accurate, the screening pro-gram would have to prevent 15.3 cases of emphy-sema (in the 1,000 workers screened) in order topay for itself in direct and indirect cost savings.This implies that emphysema would have to beprevented in 37 to 50 percent of the SAT-deficientworkers detected in the screening program.

Since estimates of the average cost of a SATscreening test and the direct and indirect costsof emphysema are uncertain, an analysis of thesensitivity of the break-even point to differentvalues of these parameters is shown in table 17.The practical lower limit of the average cost ofa genetic screening test is about $5. * * At this unitcost, the break-even number of cases declines to8 to 16 percent of the SAT-deficient population.Although there are no epidemiological studies re-lating different levels of exposure to respiratoryirritants in work environments with increasedrisks of emphysema in SAT-deficient individuals,

*This estimate is only a rough approximation of the discountedlifetime costs associated with a new case of emph~sema, It is anestimate of the costs incurred in 1979 by all then-extant cases ofemphysema, These “prevalence costs” o~’erestimate the lifetime costsof a new case because they are not discounted. Conversely, to theextent that the incidence of emphysema has been growing, the totalcosts in 1979 disproportionately represent the early and presumablyless costly stages of the illness. The extent to which these sourcesof overestimation and underestimation compensate for one anotheris unknown. Good data on the incidence of emph~wema in the L~nitedStates do not exist; hospitalization rates have been ciecreasing since1970, but the pre~’alence of the condition has been on the increase(9),

* *The a~erage unit cost of a worksite hypertension screening pro-gram \\’as recently estimated at $6 (13), Since hypertension screen-ing in~’oli~es minimal equipment and technician time, it is likely thatit represents a lower bound on other types of wrorksite screeningtests as we]],

Table 17.—Hypothetical Break-Even Number of CasesAverted by SAT Testing per 1,000 Workers(break-even percent of SAT-deficient workers)

Direct and indirect cost Cost per testof emphysema $20 $5$1,040 . . . . . . . . . . . . . . . . . . . . . 19.2

( 4 9 - 6 4 % ) (12-41 %)$1,300 . . . . . . . . . . . . . . . . . . . . . 15.3

(37-50%) (10-31%)$1,560 . . . . . . . . . . . . . . . . . . . . . 12.8 3.2

(32-430/o) (8-10°/0)SOURCE: Office of Technology Assessment.


it is known that only 10 percent of all SAT heter-ozygotes will develop the disease (8) and that em-physema may be brought on by multiple causes(5,8). Thus, the likelihood is low that a SAT defi-ciency screening program can be justified interms of its impact on direct and indirect benefits.Moreover, additional research into the relation-ship between exposure and disease is unlikely tochange this conclusion, given what is alreadyknown about the potential impact of screeningon the incidence of emphysema,

This conclusion does not suggest, however, thatthe SAT screening issue should be put to rest. Psy-chosocial consequences have not been includedin the analysis; these can be extremely importantin a debilitating disease like emphysema. Suppose,for example, that a program of screening and sub-sequent removal of susceptible individuals fromexposure is able to prevent emphysema in only5 percent of SAT-deficient workers who wouldotherwise be exposed. This implies that societywould incur a net direct and indirect cost of$1,460 to $11,800 for each case of emphysemaprevented, depending on assumptions aboutscreening costs, direct and indirect illness costs,and the frequency of SAT-deficient heterozygotesin the population tested. Is it worth up to $10,000to prevent the psychosocial consequences of acase of emphysema? And how do these psycho-social costs compare to the psychosocial costs ofa positive finding on a genetic screening test? Pos-itive test results, whether correct or incorrect,may cause anxiety and disruption to people’s lives(that is, psychosocial costs). This is especially trueif workers are denied jobs or lose self-esteem be-cause they are labeled as “susceptible. ” Thus, the$1,460 to $11,800 net direct and indirect cost percase averted cannot be measured against only onetype of psychosocial cost.

Note also that the different categories of costwould be borne by different actors. The costs ofscreening might be incurred by the employer (andultimately in part by the public in higher prices)or by the government. The direct and indirectbenefits would be shared by the individual work-er and the public (through impacts on health in-surance and disability programs), The psychoso-cial costs and benefits primarily accrue to work-ers themselves. Thus, the immediate monetary

costs of a screening program are borne by theemployer and the public, while the worker andthe general public stand to gain monetary benefitsin the future and workers may gain psychosocialbenefits in the future at the expense of monetaryand psychosocial costs in the near term,

It is interesting to compare the principles ofeconomic evaluation with a set of criteria sug-gested by Stokinger and Scheel for applying ge-netic screening to the workplace (14). These in-vestigators listed the following conditions thatshould be met for a genetic screening to be ap-propriate:

●

●

●

●

the condition detected by the test should havea relatively high prevalence in the workerpopulation;people with the condition should be suscep-tible to agents commonly occurring in indus-try;the genetic condition should be compatiblewith an apparently normal life until exposureoccurs; andthe test should be simple, inexpensive, andamenable to large-scale use.

These conditions are consistent with but morerigid than economic analysis. For example, itmight be highly cost effective to screen for a rarecondition if the testing cost is low and the healtheffects of exposure reduction are very large. Theconditions of Stokinger and Scheel do not makesuch tradeoffs explicit, whereas an economic eval-uation does.

The prevalence of a trait can be so high thatgenetic screening becomes impractical. A pro-gram consisting of genetic screening with subse-quent removal of the worker from the high ex-posure environment must then be compared withother strategies for reducing exposure levels ofall workers. If, for example, 70 percent of allworkers are susceptible, it may be more cost ef-fective to take general action to reduce exposureof all workers. How high the prevalence must be-come before screening is eclipsed by more generalexposure reduction strategies depends on the par-ticular situation. For example, slow acetylationrates have been linked to aromatic amine-inducedcancer. Approximately 12)000 workers were ex-posed to these chemicals in the workplace in 1974

Ch. 10—Prospects and Problems for the Economic Evaluation of Genetic Testing ● 159

(15). Yet, about 50 percent of the U.S. populationhave slow rates of acetylation. Thus, it may bemore effective to reduce exposure levels to allworkers than to remove about half of the workersfrom the potential labor pool. The feasibility ofeither alternative would depend on the pervasive-ness of exposure to the offending chemicals andthe technical barriers to reducing ambient expo-sure levels. Of course, much more informationwould be needed before such an hypothesis couldbe accepted or rejected, but the question couldbe addressed through economic evaluation of therelelvant alternatives.

Whether one sees the SAT example given aboveas informative or misleading depends on expec-tations about the use to which the informationwill he put in decisionmaking. Critics of cost-benefit and cost-effectiveness analyses claim that

incomplete analyses such as that provided aboveare given too much attention merely because theresults are in a quantified form. Moreover, theunquantified effects, despite their importance,tend to be ignored because they are bothersome.Supporters of the approach Would claim that theanalysis clarifies the central tradeoff between netdirect and indirect costs to society and psycho-social benefits and costs to workers. Both sideswould agree, however, that economic evaluationis severely, perhaps fatally, flawed when substan-tial uncertainty is present in the central estimatesof effectiveness or benefit. Sensitivity analysis canremove some of the limitations, but when the re-sults of the analysis are highly sensitive to esti-mates of cost or effectiveness, as they are in thecase of SAT testing, economic analysis is of limitedusefulness.

Economic evaluation of cytogenetic monitoring

The case for using cytogenetic studies to mon-itor workplace exposure to hazardous materialrests on the hypothesis that exposure to muta-genic or carcinogenic agents is related to somaticchromosomal damage, which is in turn correlatedwith an increased risk of disease. If this hypoth-esis is accepted, and particularly if the relation-ship between exposure level, degree of chromo-somal damage, and risk of disease is known andquantified, then cytogenetic tests might be usedas biological monitoring devices for workplacehazards.

The potential uses of cytogenetic monitoring areto identify carcinogenic agents and to identifypopulations at risk due to overexposure to theseagents. Ultimately it might be possible to use thetests to develop standards for safe levels of oc-cupational exposure to chemicals and radiation.

It is difficult to lay out a specific strategy forevaluation of a cytogenetic monitoring programbecause of the profound lack of knowledge aboutthe relationships between occupational exposure,chromosomal damage, and disease in human pop-ulations. For the sake of discussion, however, letus suppose that the research evidence were suf-

ficient at this time to justify the use of cytogeneticmonitoring to identify carcinogenic agents. Sup-pose that it has been established that there is ahigh correlation between chromosomal damagein a group and subsequent cancer rates. Then,employers might establish programs for periodicmonitoring of workers who are routinely exposedto industrial chemicals. The cost of such a pro-gram would be highly sensitive to features suchas the frequency of testing (that is, monthly, quar-terly, yearly), the sample size in each testingperiod, the methods of recordkeeping and quali-ty control, and the actual cytogenetic proceduresemployed. Cytogenetic studies are relatively ex-pensive laboratory procedures. The estimatedcost is between $100 and $300 per test, depend-ing on a laboratory’s volume and organization,although testing costs may be reduced in the fu-ture with the development of automated methods.At an average cost per test of $100, however, thefeatures of the monitoring program make anenormous difference in program costs. For ex-ample, testing 500 workers once each year wouldcost $50,000, whereas a quarterly testing programof the same number of workers would cost$200,000 annually.


Both the costs and benefits of a monitoring pro-gram depend on the actions taken on the basisof its results. If significant chromosomal damagewere followed by removal of the chemical fromthe workplace or some other method of exposurereduction, the major hypothesized benefit wouldbe a reduction in the rate of exposure-inducedcancer. The costs of exposure reduction woulddepend on the technical and economic relation-ships in the production process. If no action weretaken, neither benefits nor additional costs wouldensue. It is reasonable to assume that an expen-sive monitoring program would be undertakenonly if some benefits could be expected; therefore,a program for exposure reduction must be as-sumed to be a natural sequel to cytogenetic mon-itoring.

To estimate the economic benefits of cytogenet-ic monitoring programs, it is necessary to know,or at least to estimate, the probability that theagents found in the monitored workplaces willbe found to produce chromosomal damage, Fur-ther, precise analysis would demand that the im-pact of exposure on cancer rates be estimatedwith reasonable certainty. But if the latter wereknown, the need for a monitoring program of thetype outlined above is questionable. Thus, theprospects are poor for reasonably accurate apriori estimates of the health effects, and hencebenefits, of cytogenetic monitoring.

Though it is not possible now, and may neverbe, to estimate the benefits of cytogenetic moni-

Conclusion

toring with any precision, it is useful to considerthe order of magnitude of the economic benefitsthat would result from each case of cancer thatmight be prevented by such a program. The di-rect and indirect costs per case of cancer wereestimated in 1978 at about $22)000, consisting of$5,000 in direct and $17,000 in indirect costs*(12). These costs vary with the age of onset andthe type of cancer, but they can be taken as ageneral guide to the order of magnitude of themonetary benefits associated with each case ofcancer prevented. In a pioneering but highly spec-ulative study, Abt attempted to estimate the com-bined indirect and psychosocial costs of cancer(1). These costs were estimated at $137,000 percase. Thus, even though this estimate is basedlargely on assumptions and rules of thumb, it il-lustrates the overwhelming importance of psy-chosocial costs in the consequences of cancer.

The stakes are clearly high on both sides of theissue. The costs of cytogenetic monitoring arepotentially high, but the costs of cancer are alsohigh. At present there is insufficient evidence toassess the value of cytogenetic monitoring be-cause the relationships between chromosomaldamage and clinically relevant effects have notbeen demonstrated. Yet, the magnitude of thecosts involved argues for increased research intothese relationships.

*These are prevalence costs. Possible sources of inaccuracy inthese estimates are discussed in an earlier footnote,

Cost-benefit and cost-effectiveness analyses are risk of disease, preclude the rigorous applicationeconomic methodologies that can be useful in of these tools to this technology. However, thesestructuring the analysis involved in decisionmak- tools can help identify the uncertainties involveding and in assessing the desirability of alternative and provide a rough sense of the benefits, bur-outcomes. The significant uncertainties associated dens, and tradeoffs associated with genetic test-with genetic testing, particularly the limited evi- ing programs.dence of an association between endpoints and

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Ch. 10—Prospects and Problems for the Economic Evacuation of Genetic Testing ● 161


1. Abt, C., “The Social Costs of Cancer, ” Social Indi-cators Research 2:1 75-190, 1975.

2. Campbell, D., and Stanley, J., Experimental andQuasi-Experimental Designs for Research (NewYork: Rand ILlcNally, 1963).

3. Hodgson, T., “The State of the Art of Cost of IllnessEstimates, ” draft paper (Hyattsville, Md.: NationalCenter for Health Statistics, 1982).

4. Kalish, R., and Reynolds, D., Death and Ethnicittiy:A Ps}’cho-Cultural Stuc@ (Los Angeles: Universityof Southern California Press, 1976).

5. Kazazian, H., “A Geneticist’s L’iew of Lung Disease)”American Retie}v of Respiratory Disease 113:261-266, 1976.

6. Landefeld, J. S., and Seskin, E. “The Economic Val-ue of Life: Linking Theory to Practice, ” AmericanJournal of Public Health 72(6):555-565, 1982.

7. Mishan, E. J., Cost-Benefit Ana[Vsk: An Introduc-tion (New York: F. A. Praeger Publishing Co., 1971).

8. Mittman, C., et al., “The PiMZ Phenotype, ” Amer-ican Re~7iew of Respiratory Disease 113:261-266,1978.

9. National Center for Health Statistics, Health Inter-view Survey, 1980.

10. National Heart, Lung, and Blood Institute, personalcommunication with Dr. Hannah Peavy, 1982.

11, Office of Technology Assessment, U.S. Congress,The Implications of Cost-E ffecti\~eness Ana@sk of

Medical Technology (Washington, D. C.: U.S. Gov-ernment Printing Office, August 1980), OTA-H-126.

12. Rice, D., and Hodgson, T., “Social and EconomicImplications of Cancer in the United States, ” apaper presented to the Expert Committee on Can-cer Statistics of the World Health Organization,June 20-26, 1978.

13. Ruchlin, H., and Alderman, M., “Cost of WorksiteHypertension Treatment, ” U.S. Department ofHealth and Human Services, Public Health Serv-ice, NIH-81-21 15, November 1980.

14. Stokinger, H., and Scheel, L., “Hypersusceptibilityand Genetic Problems in Occupational Medicine—A Consensus Report, ” Journal of OccupationalMedicine 15:7, 1973, pp. 564-573.

15. U.S. Department of Health and Human Services,8

16

17.

National Institute of Occupational Safety andHealth, Quarter@ Hazard Summary Report, Aug.6, 1980.Weinstein, M., and Stason, W. “Foundations ofCost-Effectiveness Analysis and Medical Practices, ”iVew England Journal of Medicine 296(13):716-21,1977.Weisbrod, B. A., “Benefit-Cost Analysis of a Con-trolled Experiment: Treating the Mentally Ill,” Jour-nal of Human Resources 16:523-48, fall 1981.

Part V

Congressional Issuesand Options

Chapter 11—Issues and Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

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Chapter 11

Issues and Options

Contents

PageIssue: What Actions Could Congress Take With Respect to Genetic Testing

in the Workplace? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167Issue: How Could Congress Regulate Genetic Testing in the Workplace? . . . . . . . . . . . . . 169Issue: How Could Congress Foster the Development and Use of This Technology? . . . . 171

c h a p t e r 1 1

Issues and Options

Genetic testing is an emerging technology. It hasthe long range potential to play a role in theprevention of occupational disease, but it also hasthe potential for misuse. Although only a hand-ful of companies are using genetic testing now,many more are interested. Current law providessome incentive for its use and some safeguardsagainst its misuse. Established ethical principlesalso provide some guidance for its use. However,many questions remain unanswered. Under thesecircumstances, it may be appropriate for Con-gress to balance the competing interests and tomake the value judgments necessary in order tomaximize the technology’s potential benefits andminimize its risks.

This chapter provides an array of issues andoptions for congressional consideration. Theymay be grouped loosely around the following fun-damental policy questions:

●

●

●

Should the technology be stimulated and, ifSO, how?Should there by any constraints on the useof the tests and, if so, what?To what degree should society protectworkers who are at increased risk fordeveloping disease, at what cost, and whoshould bear that cost?

The first issue is an overview of the optionsrelated to all of these questions. The issues andopt ions that follow focus on particular aspects.

ISSUE: What actions could Congress takewith respect to genetic testing inthe workplace?

OPTIONS:

A. Maintain the status quo.

Congress could choose not to take an-y actionto stimulate, constrain, or regulate genetic testing.This would allow private parties to continue re-search into the merits of the technology. Con-straints on its use would develop through courtrulings in lawsuits between these parties or bynegotiations between companies and unions. In-

terested congressional committees could continuetheir practice of holding oversight hearings toraise the issues for public discussion.

The primary argument supporting this optionwould be the view that congressional actionwould be premature. The technology is not be-ing widely used, and it is primarily in the researchphase of its development. In addition, there areexisting constraints on its potential misuse. Theseinclude the possibility of lawsuits and adversepublicity. Finally, much of the important infor-mation necessary for legislation is unavailablebecause it is unknown. For genetic screeningtechniques, this information includes the numberof workers who might be genetically predisposedto disease, the extent to which they might faceadverse employment actions, the availability ofother employment opportunities, and the cost ofsafeguarding these workers. For genetic monitor-ing techniques, this information includes theirpredictive value, the extent to which they mightbe used, and the costs associated with either usingor not using them.

The arguments against this option relate to howsociety controls an emerging technology. Manypolicy decisions will need to be made with respectto genetic testing, and arguably Congress is a bet-ter forum for doing so than the courts or privateparties. Congress can gather all information andviewpoints and then balance the conflicting in-terests. In addition, while the courts often playa major regulatory role for any technology, theyare limited in their ability to encourage the de-velopment of a technology in a positive manner.However, Congress can do so by providing fundsfor research or other incentives.

B. Stimulate the technology’s development anduse.

Congress could stimulate the technology by pro-viding additional money for research on the tech-niques, for epidemiological studies to determineassociations between genetic indicators and dis-ease, and for basic research on the cause of oc-cupational disease in general. If genetic testing

167


could be developed to the point where the testsare predictive of an individual’s or group’s in-creased risk for occupational illness, its use couldresult in a number of direct and indirect benefits.The principal direct benefit would be a lower in-cidence of occupational disease among workers.They and their families would be spared someof the pain, cost, and emotional trauma that ac-company illness. In addition, employers wouldsave some of their direct and indirect costs of oc-cupational disease-employee time lost fromwork, insurance premiums, legal fees, and mone-tary damages assessed in lawsuits. Society wouldbenefit through the greater health and produc-tivity of its work force, A major indirect benefitof developing this technology might be a greaterunderstanding of the causes of occupationaldisease and disease in general.

The principal argument against this option isthe concern about the potential misuse of thetechnology and about potential adverse impacts.Some of these concerns relate to unfair employ-ment discrimination and attention being directedaway from other ways to address occupationaldiseases. These concerns might be dispelled byregulation to direct the technology’s developmentin socially desirable ways, In fact, if the tests werehighly predictive of future illness, the Occupa-tional Safety and Health Administration (OSHA)could require their use and constrain how theywere used, so long as those constraints wereshown to enhance worker health and were notdirected toward prohibiting fair employmentpractices.

Another drawback to this option is the fact thatthere is no information on the amount of occupa-tional disease that could be prevented by genetictesting, even if the tests were reliable predictorsof disease. Similarly, there is no information onwhat it would cost to get the tests to the pointof clinical usefulness.

C. Prohibit the use of genetic testing in the work-place.

The principal reason for prohibiting genetictesting in the workplace would be concern overits potential misuse, particularly at its currentstage of development where its ability to predictfuture disease has not been demonstrated. This

potential for misuse probably would be greaterfor genetic screening than for genetic monitor-ing because the former is targeted toward iden-tifying individuals at increased risk while the lat-ter focuses on groups at increased risk. However,concern exists that employers might use eitherscreening or monitoring to exclude individualsfrom jobs. Existing law may offer protection insome circumstances, but there are many ques-tions to be resolved. The collective bargainingprocess could be used by unions to negotiate pro-tection for workers, but the primary focus of bar-gaining has been economic matters. While healthmatters have also been important, genetic engi-neering apparently has not been a bargainingissue. In addition, most of the work force is notunionized. Moreover, these remedies are nothelpful if a susceptible person does not know whyhe or she was denied a job. Finally, while ethicalprinciples provide guidance for the proper useof this technology, it is difficult to know if theyare being followed.

The principal drawback to this option is thatit is a drastic solution to the problem of potentialmisuse, Genetic testing does not appear to bewidely used. Law, ethics, and public opinion pro-vide incentives against its misuse. Moreover, ban-ning its use would prevent research that mightdetermine its usefulness in preventing occupa-tional disease or provide basic knowledge aboutoccupational disease.

Another argument in favor of this option wouldbe the claim that an employee’s risk of future ill-ness is not an appropriate factor for job selection,even if screening or monitoring were highly pre-dictive. Employees have no control over their ge-netic makeup and generally have no control overprevious exposures to harmful agents. In addi-tion, their increased risk would not affect theircurrent ability to do the job.

There are at least two counterarguments to theassertion that risk of illness should not be a jobselection factor. First, society accepts the proposi-tion that immutable characteristics can be prop-er criteria for employment selection. Intelligenceis at least an implicit selection criterion for manyprofessional jobs and physical attributes are ex-ceedingly important for jobs ranging from pro-

.

Ch. 11—issues and Options ● 169

fessional basketball to neurosurgery. Second, thisviewpoint places the autonomy interests of theindividual above the interests of society in lower-ing the costs of occupational illness even whenit may not be feasible to take other steps, suchas lowering exposure.

D. Regulate the technology.

This option represents a judgment that anyrisks presented by the technology can be con-trolled and that the claimed benefits will be ofvalue to society. The option would permit re-search to continue, yet constrain the manner inwhich genetic testing is used. One type of con-straint would be limitations on what job actionsemployers could take on the basis of test results.Another type of constraint would be a require-ment that the tests meet minimum standards ofscientific validity before employment decisionswere made on the basis of the results. Such a stat-ute need not specify detailed standards; it couldadopt a standard such as ‘(reasonably predictiveof future illness” and allow the appropriate agen-cy to provide details.

This option has the advantage of addressing thepotential risks of genetic testing immediately andin a comprehensive manner rather than waitingfor the law to develop on a case-by-case basisthrough the courts. Congress may be uniquelyable to study the problem fully, balance compet-ing interests, and provide comprehensive yet tar-geted solutions.

A possible drawback of this option is that theproblem may not yet be “ripe” for congressionalaction. On the basis of available evidence, genetictesting in the workplace does not appear to bewidespread. Moreover, there is no available evi-dence about: 1) the number of workers who po-tentially could be screened or monitored if thetests were sufficiently predictive, 2) the numberwho might be excluded from jobs, 3) the ease withwhich excluded workers could find comparablejobs, and 4) the costs of various regulatory alter-natives. on the other hand, congressional actionnow could prevent potential misuse before thetechnology becomes widespread, and legislationcould create a mechanism for gathering some ofthe presently unavailable data.

E. Encourage the development of voluntary guide-lines on the acceptable use of genetic testing.

Congress could ask the National Academy of Sci-ences or a similar body to establish a special com-mission of representatives from industry, labor,academia, and other sectors of society to draftguidelines for the use of the tests. This wouldallow the parties most involved to make the dif-ficult value judgments in balancing competing in-terests and would avoid direct governmental reg-ulation.

ISSUE: How could Congress regulate ge-netic testing in the workplace?

OPTIONS:

A. constrain employment actions that may betaken on the basis of genetic testing.

Congress could address many of the concernsraised by genetic testing by regulating how em-loyers may use the results of the tests, even if theywere highly predictive. The following representssome possible elements of such an approach:1) prohibit job exclusion on the basis of geneticmakeup or genetic damage, 2) prohibit job trans-fers because of genetic makeup or genetic damageunless the transfer were to a comparable job atcomparable pay and benefits, 3) require strict con-fidentiality of medical information, and 4) requirethat employees be told the results of testing andbe given counseling.

This option would clearly protect the interestsof workers, preventing potentially serious con-sequences to individuals who have no controlover the reason for discrimination against them,In addition, no difficult judgment would have tobe made as to how predictive the tests should bebefore they are permitted.

There are at least two major disadvantages tothis option. First, it may be too broad. If notcarefully drafted, a statute could reach geneticdiseases (not traits) that do affect an employee’scurrent ability to perform the job safely and effec-tively. It is generally accepted that inability to per-form a job, even for medical reasons, is a validcriterion for job selection. Second, if workers with

170 The Role of Genetic Testing in the Prevention of occupational Disease

certain traits were in fact predisposed to occupa-tional illnesses and chose to ignore that informa-tion, the additional direct and indirect costs oftheir illnesses eventually would be borne by soci-ety. This would be the case even if employerswere required to install additional engineeringcontrols, since the costs of those controls wouldbe passed on to society. On the other hand, if ex-cluded workers were unable to find comparablejobs, society would bear the costs of lost produc-tivity and possibly additional unemployment pay-ments. The answer to the question of who shouldbear the costs associated with genetically predis-posed or damaged individuals will depend notonly on economic analyses but on prevailing po-litical views of distributive justice.

B. Prohibit employment decisions on the basis ofgenetic testing unless the employer can dem-onstrate that the results are reasonably (or sub-stantially) predictive of future illnesses.

This option places the burden on an employerto justify the claimed correlation between testresults and risk of illness. The specific criteria formeeting a necessarily general statutory standardcould be provided by agency regulation and caselaw.

There are several advantages to this option, es-pecially when compared to option A. First, it fo-cuses on the immediate concern of job denial onthe basis of poorly predictive tests, thus protect-ing employees’ interests. Second, it protects em-ployers’ interests in lowering their costs from oc-cupational diseases, by excluding workers whenthere is a rational, scientific basis for doing so.Third, it would allow research on the techniquesto continue.

The principal drawback of this option is thatit could be a de facto determination without a fullpublic debate that future risk of illness is a prop-er job selection criterion. On the other hand, thereis a substantial lack of the type of informationdesirable for deciding this fundamental issue atthis time.

C. Amend the Rehabilitation Act of 1973 to statethat genetic makeup is a handicap and clarifywhether individuals who are genetically pre-disposed to illness are considered to be “other-wise qualified” within the meaning of that act.

A major advantage of this option would beworking with an existing statute rather thandevising an entirely new one, Sections 503 and504 of the Rehabilitation Act deal with problemsthat conceptually are very similar to those posedby genetic screening. If applied to genetic screen-ing, the act would require at a minimum that thetests be reasonably predictive of future illness.

On the other hand, this option would force leg-islative activity into an existing statutory frame-work that may not be completely suited to geneticscreening. The Rehabilitation Act was designedto bring millions of handicapped people into themainstream of American life. Genetic screeninghas not created a problem anywhere close to themagnitude of that addressed by the Rehabilita-tion Act. Moreover, section 503 requires employ-ers to take affirmative action to employ the hand-icapped. Congress may not wish to require affirm-ative action to employ people who are genetical-ly predisposed to occupational illness, if thatpredisposition can, in fact, be demonstrated.

D. Require that research on employees be doneaccording to existing Federal regulations de-signed to protect human subjects of research.

The Department of Health and Human Serviceshas promulgated regulations governing federal-ly funded biomedical and behavioral research onhumans. The regulations contain provisions de-signed to protect the interests of the research sub-jects. Requiring private companies to follow theseregulations in research involving genetic testingor any other kind of research done in the work-place would mitigate the potential for abuse.

E. Require full disclosure to employees and theirrepresentatives of the nature and purpose ofall medical procedures performed on employ-ees.

Under current law, employees and unions haveaccess to employee medical records, but employ-ers are not required to disclose the nature andpurpose of medical procedures and how the re-sults are used. Required disclosure of this infor-mation to the employee at the time the procedurewas being performed would be a strong incen-tive to employers for self- regulation. If workersand their medical advisors had full knowledge ofa company’s medical procedures, they could take

Ch. 11—Issues and Options . 171

steps to prevent abuses, through negotiation orlegal action. Publicity alone could prevent theworst abuses. This would also protect the auton-omy interests of workers by allowing them to bepart of a decisionmaking process that affects theirhealth and economic interests. Some of the argu-ments against this option would be that it mightbe burdensome and costly for employers and thatit would intrude too much on the professionaljudgment of the occupational medical specialist.

ISSUE: How could Congress foster the de-velopment and use of this technol-ogy?

OPTIONS:

A. Fund research for the development of testswith high reliability and validity..

Genetic variability and differential susceptibility’to toxic chemicals are well-established conceptsin the scientific literature. Currently, there aremany genetic screening tests that could be donein a workplace setting to detect potentially suscep-tible individuals. For the most part, these tests arereliable and valid for identifying the genetic traits.in question; a notable exception is the test for arylhydrocarbon hydroxylase (AHH) inducibility, Re-search on developing tests for those traits thatare more prevalent in the population should re-ceive higher priority because they are more like-ly to hate a high predictive value. The only testcovered in this report that falls into this categoryis AHH inducibility.

With respect to genetic monitoring, it is less wellestablished scientifically that exposure to toxicchemicals and ionizing radiation can cause geneticdamage in humans, although there is an over -whelming amount of evidence that this is true inexperimental mammals. Not known at all is theimpact of genetic damage on one’s risk for disease,especially cancer, or on future generations, yetthe current thinking of the scientific communityis that increased amounts of genetic damage isgenerally deleterious,

Alternatives are needed to the time-consumingcytogenetic tests currently in use. If geneticmonitoring is to be done on a large scale, the avail-ability of automated tests becomes important. The

development of various noncytogenetic methodscould be useful in this respect. Those that showpromise currently include tests for detection of:mutagens in urine, alkylated hemoglobin, HGPRTmutation in lymphocytes, hemoglobin mutations,chemically damaged deoxyribonucleic acid bases,and LDH-X variants in sperm. For both cytoge-netic and noncytogenetic tests, a better under-standing of the factors that contribute to geneticdamage in the absence of occupational exposureis needed (that is, a “normal” or baseline response)in order for the tests on exposed populations tobe meaningful.

The government agencies which could be in-volved in these studies include the Environmen-tal Protection Agency (EPA), the National Institutefor Occupational Safety and Health (NIOSH), andthe National Institute for Environmental Healthand Safety (NIEHS).

B. Fund epidemiologic studies in occupational set-tings directed by NIOSH or NIEHS.

Data are most lacking concerning the correla-tion of genetic traits or genetic damage to an in-creased risk for disease. Epidemiologic studies inan occupational setting can address this problem.If these studies were to be undertaken, they mustuse good epidemiological practices and documentexposures. Studies should only be undertaken ifthey are likely to yield statistically reliable data.For instance, genetic monitoring studies wouldrequire exposure levels high enough to yield aclear-cut statistical response between exposed andnonexposed groups without having to use exces-sively large numbers of people. Especially impor-tant would be to establish a dose-response rela-tionship. Genetic screening studies would haveto focus on genetic traits that have a significantprevalence in the population (greater than 1percent).

Epidemiologic studies are very costly and dif-ficult to control, especially if they run over longtime periods. Some genetic screening studiescould be done in a short time ( I to 3 years) once.a population with the trait was selected because,presumably, the symptoms of disease resultingfrom exposure would manifest themselves soonafter exposure. These traits include the red bloodcell traits. Most of the other traits reviewed here


are potentially correlated with diseases whichhave a long latent period, such as emphysema andcancer. To assess correctly the exposure infor-mation with the disease endpoint, much longerepidemiologic studies (10 to 30 years) are nec-essary.

For genetic screening, higher priority shouldbe given to studies on traits with a high preva-lence in the population. These include SAT defi-ciency, AHH inducibility, carbon oxidation abili-ty, and the association of particular human leuk-ocyte antigens with risk for disease.

Epidemiologic studies using genetic monitoringtechniques would have to be long term in orderto determine the association between geneticdamage and cancer. The chemicals chosen forstudy would have to be selected carefully. Manyof the agents discussed in this report are knownalready to cause cancer in humans (for example,ionizing radiation, benzene, vinyl chloride), andoccupational exposure to these is very low andpossibly not detectable by the genetic techniquesnow in use.

C. Establish a federally funded data bank, directedby NIOHS, EPA, or NIEHS, to be used in thestudy of the causes of differential susceptibili-ty to occupational disease.

Because the study of the effects of harmfulagents includes many scientific disciplines, itwould be useful to have the relevant data col-lected in an accessible location. This computerizeddata bank could include not only genetic factorsaffecting toxicity, but developmental, aging, nutri-tional, and lifestyle factors as well. The data bankwould include epidemiologic studies that havebeen or are being done in occupational settings,either governmentally or privately funded (some-what in the same manner as EPA’s Gene- Tox Pro-gram). Those working in the field of genetictoxicology could draw on the information in thebank in order to design studies and to preventduplication of effort. The toxicology data wouldbe of considerable value to various regulatoryagencies in their standard setting.

Appendixes

Appendix A: Survey Design and Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Appendix B: Report From the National Opinion Research Center . . . . . . . . . . . . 179

Appendix C: Survey Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

Appendix D: Background Frequencies for Chromosomal Aberrations . . . . . . . . . 227

Appendix E: Background Frequencies for Sister Chromatic Exchanges ,...,.. 231

Appendix F: Screening Tests (Available at Hospitals or Medical Centers) forHeritable Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

Appendix G: Other Contractors and Contributors . . . . . . . . . . . . . . . . . . . . . . . . . 235

A p p e n d i x A

Survey Design and Methodology

Study design

SOURCE OF DATA

The survey was conducted for OTA from February25 to June 8, 1982, by the National Opinion ResearchCenter (NORC), a nonprofit survey research corpora-tion affiliated with the University of Chicago. NORCsent confidential questionnaires to the chief executiveofficers of the 500 largest U.S. industrial companies, *the chief executive officers of the 50 largest privateutility companies, * * and the presidents of the 11 ma-jor unions that represent the largest numbers of em-ployees in those companies. ● * *

These recipients were selected based on discussionswith industry scientists who indicated that a com-pany’s size rather than its major product line wouldmore likely be the determining factor for testing.Moreover, hazardous substances are found through-out the industrial sector, including utilities, not justin the chemical industry. A company’s decision to im-plement genetic testing most likely would he based onthe extent and sophistication of its medical program,and sophisticated programs most probably would befound in large companies. Further, because unionsalso are interested in the health of their members, theywere thought to be a potential source for undertak-ing such programs. All 561 recipients were surveyed,rather than just a sample, in order to eliminate sam-pling error that might result from a small number ofcompanies testing and to avoid other potential prob-lems associated with sample selection.

QUESTIONNAIRE

Development. -A questionnaire addressing the pur-poses of the study was developed by the OTA staffand NORC over a period of approximately 2 months,during which it was extensively reviewed and revised.Reviewers for technical accuracy included individualsin science, medicine, and law, and persons affiliatedwith the American Industrial Health Council, theChemical Manufacturers Association, the AmericanOccupational Medical Association, the American Acad-emy of Occupational Medicine, and the Genetic Toxi-cology Association. * * * * Their comments were evalu-

“Identified by Fortune 500 listing of [1 S compames engaged in manu.farturing mining, Fortune, vol 103 S0 9, %Iay 4, 1981

* “Identlfled hy Fortune Magazine [,Ist (’, Fm’fune klagazine, i’ol 103,NO 9, May 4, 1981

● ● “Identified m the flrectory of National (Iruons and F.mployws ,4s50.oatlon [ 19791 bj the U S Department of I~bor

w “ “ “In view of time ronstramts, these people gale thmr oplmons as in-dl~ duals rather th~o ~> rq)rewotatlt es of their orgamzatmn

ated for objectivity and relevance to the purpose ofthe survey. The questionnaire then was revised toreflect the results of the review and prepared forpretest.

The bottom 25 companies in the Fortune 500 wereselected for the pretesting phase, which was adminis-tered from February 25 to March 12, 1982. Eleven (44percent) of the 25 companies responded. Analysis ofthe results indicated that the questionnaire was rea-sonably clear and consistent and that it should pro-vide the data sought. A draft of the final instrumentwas reviewed by the OTA project panel, which in-cluded representatives from industry, academia, andlabor. Minor format changes were made, and twoquestions were deleted. The rest of the survey popula-tion was questioned from March 23 to June 8, 1982.Because the questionnaire’s changes were relativelyminor, the pretest responses were included in the finalanalysis.

Instrument. —The questionnaire is a four-pageprinted instrument. Two slightly different versionswere used, depending on whether the document wassent to a company or a union; however, the differ-ences are semantic in nature. (See app. C.) The ques-tionnaire was composed of:

●

●

●

●

●

●

introductory paragraphs, which give instructionsand define terminology;eight questions on genetic screening and eight oncytogenetic monitoring;*a question on actions taken as a result of eithertype of testing;a question relating to the use or development ofgenetic tests in animal studies;a question to determine the major industrial sec-tor in which the companies did business; anda space for explaining the answer to any questionor providing additional information.

The questionnaire reflected two assumptions. Onewas that the individual who would respond to thequestionnaire would be familiar with genetic testing.This assumption was believed to be appropriate be-cause genetic testing has been widely discussed byvarious professional groups concerned with occupa-tional health, including committees within major in-dustrial trade associations. The second was that thedefinitions of genetic screening and cytogenetic

“I’he questionnaire used slightly different twmmolo~y for the tests thanused in this report It used the term “biochemical genetic testing” to referto genetic screening and the term ‘{cytogenet]c testing” to refer to rjto-genetic momtormg

175


monitoring would be carefully and consistently fol-lowed in answering the questionnaire. Because differ-ent experts use the terminology in slightly differentways, these terms were defined in the first paragraphof the questionnaire. No reason or evidence was foundto invalidate these assumptions.

Confidentiality. —Providing confidentiality to the in-dividuals answering the survey was viewed as crucialfor securing both a high rate of participation and ac-curate information, particularly in view of the sensi-tive nature of the subject (l). No identifying markswere placed on the questionnaire, and respondentswere urged not to do so on their own. Results couldbe compiled only in aggregate form. Followup proce-dures were possible because respondents were askedto return, separate from the questionnaire, post cardsthat named their organization and stated that the ques-tionnaire had been completed and returned.

SURVEY

The questionnaires were sent to 561 chief executiveofficers and presidents, with the suggestion that theyroute it to the person responsible for health and safe-ty matters. This approach sought to demonstrate theimportance of the survey and to ensure that the ques-tionnaire quickly got to the appropriate person in theorganization, thereby increasing the chances of a time-ly response.

Questionnaires were accompanied by two one-pageletters-one from OTA’s Director, John H. Gibbons,and one from NORC’s project director, CynthiaThomas—and by a post card and a return envelope.A list of the names of the members of the project’sadvisory panel also was enclosed. (See app. C for copiesof the questionnaire, letters, and advisory panel mem-bership list.)

NORC began followup procedures on April 19 bysending 98 letters to nonrespondents. A second effortinvolved telephone calls to 200 of the nonrespondents.The effort concentrated on the top 100 companies ofthe Fortune listing and on those in key industrial

groups, such as chemicals, rubber and plastic prod-ucts, metal manufacturing, and pharmaceuticals.

By the June 8, 1982, cutoff date, 366 organizationshad answered the questionnaire, a 65.2-percent re-sponse rate, and 26 organizations had specifically de-clined to do so, a 4.6-percent refusal rate. Those whodeclined generally gave either no reason for refusalor the reason of corporate policy not to respond tosurveys. Questionnaires from seven more organiza-tions were received after the cutoff date. None of theseorganizations reported any testing activity and werenot substantially different from the earlier respond-ents. Since these reponses were received after theclose of the survey period, they are included as non-respondents for analysis purposes.

Response patternCan the results of this survey be generalized to the

population of Fortune 500 companies, large utilitycompanies, and major unions? An answer to this in-volves two additional questions: Are the responsesequally distributed among the groups represented inthe survey? Are characteristics of the respondents dif-ferent from the nonrespondents? These two questionsare discussed in turn.

Two weeks into the survey, April 13, 1982, approxi-mately one-third (30.5 percent) of the contacted orga-nizations returned the post card indicating they hadparticipated in the survey. At that time, little varia-tion was seen in the response rate by size or type oforganization. The largest discrepancy was betweenthe unions, with a 27.3-percent response rate, and theutility companies, with a 38-percent response rate. Bythe close of the survey (June 8, 1982), however, thediscrepancy in response rate became quite noticeable.The large corporations had the highest response rates:68 percent for utilities and 61.5 percent for the top200 companies in the Fortune 500 listing; the unionsand small corporations had the lowest response rates:36.4 percent for unions and 44 percent among the bot-tom 300 companies in the Fortune 500 listing. (Seetable A-l.) The variation in response pattern between

Table A-1 .—Distribution of Returned Post Cards by Organization Size and Type

Cumulative number of post cards received by:

Apr. 13, 1982 June 8, 1982

Organization size/type Yes No Percent received Yes No Percent received

Fortune 500 companiesTop 200 . . . . . . . . . . . . . . . . . . . . . 65 135 32.50/o 123 77 61 .50/0Bottom 300 . . . . . . . . . . . . . . . . . . 64 216 28.0 132 168 44.0Utilities: top 50. . . . . . . . . . . . . . . 19 31 38.0 34 16 68.0Unions: 11 . . . . . . . . . . . . . . . . . . . 3 8 27.3 4 7 36.4

Total: 561 . . . . . . . . . . . . . . . . . . . 171 30.5 ”/0 293 52.20/oSOURCE: National Opinion Research Center, survey conducted for OTA, 19S2

App. A—Survey Design and Methodology ● 177

April 13 and June 8 is undoubtedly due to a numberof factors, most probably the followup efforts whichbegan in the third week of the survey and focused onthe top 100 companies of the Fortune 500 listing andorganizations in selected industrial classifications suchas utilities. Thus, the results of this survey may bemore applicable to the larger manufacturing/miningand utility companies than to smaller manufacturing/mining companies and unions.

Analysis of selected characteristics of respondentscompared with nonrespondents is limited to the For-tune 500 companies. Nonrespondents were identifiedby the process of elimination using the post cardresponses. The 193 nonrespondents included the 38companies that sent in anonymous questionnaires butno post card. Respondents and nonrespondents werecompared on the following characteristics: geographiclocation, size of organization, and type of industry.Rates of response and nonresponse did not differgreatly geographically. (See table A-2.) The largest var-iation occurred among the Central States where a5-percentage-point variation occurred between thenonrespondents and the respondents. For size of com-

pany, however, the rate of nonresponses did differwidely from the rate of responses. (See table A-3. ) Forexample, 53 percent of the nonrespondents were inthe smallest companies, compared with 32 percent ofthe respondents. This discrepancy was not unex-pected, because the followup concentrated on largercompanies and the response rates may reflect theseefforts. Rate of nonresponse did not vary greatly fromrate of response with respect to industry classifica-tion. (See table A-4. ) Eleven industries had a slightlyhigher rate of response than predicted, as evidencedby a comparison with the expected response rate (totalcompany rate). Of these industries, five (chemicals,petroleum refining, rubber and plastic products, metalmanufacturing, and pharmaceuticals) were the key in-dustries selected for followup activities and the ratesfor the remaining six (glass/concrete, electronics, meas-uring equipment, motor vehicles, aerospace, and of-fice equipment) may be explained by such factors asthe effect of followup based on size of company orchance.

Thus, whereas the results of the survey may bemore representative of the larger manufacturing/

Table A-2.—Distribution of Nonrespondents, Respondents, and Total Companies by Geographic Location(based on Fortune 500 companies)

Non respondents Respondents Total companies

Percent of total Percent of total Percent of totalGeographic Iocationa Number nonrespondents Number respondents Number companies

Northeast . . . . . . . . . . . . . . . . . . . . . . . . . . 82 420/o 133 43% 215 430/0Southeast. . . . . . . . . . . . . . . . . . . . . . . . . . 8 4 22 7 30 6Central . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 41 111 36 191 38Mountain . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1 7 2 9 2West . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 11 34 11 55 11

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 307 500aThe following are included i n the respective geographic locations

Northeast” Maine, Vermont, New Hampshire, Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Pennsylvania, Maryland, Delaware,Southeast’ Virginia, North Carolina, South Carolina, Georgia, Florida, Alabama, Tennessee, Mississippi, Louisiana,.Central” North Dakota, South Dakota, Nebraska, Kansas, Oklahoma, Texas, Montana, Iowa, Missouri, Arkansas, Michigan, Wisconsin, Illinois, Indiana, Ohio, Kentucky,

West V(rginla.Mounfa/n. Montana, Wyoming, Utah, Colorado, New Mexico, Arizona.West” Alaska, Hawaii, Washington, Idaho, Oregon, California, Nevada.

SOURCE National Opinion Research Center, survey conducted for OTA, 1982.

Table A-3.—Distribution of Nonrespondents, Respondents, and Total Companies by Size(based on Fortune 500 companies)


Percent of total Percent of total Percent of totalSize of companv Number nonrespondents Number respondents Number companies, .Fortune 100 . . . . . . . . . . . . . . . . . . . . . . . . 29 15% 71 230/o 100 20 ”/0Fortune 200 and 300 . . . . . . . . . . . . . . . . 62 32 138 45 200 40Fortune 400 and 500 . . . . . . . . . . . . . . . . 102 53 98 32 200 40

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 307 500SOURCE” National Opinion Research Center, suwey conducted for OTA, 1982.


Table A“4.—Distribution of Nonrespondents, Respondents, and Total Companies by Industry Classification(based on Fortune 500 companies)


Percent of total Percent of total Percent of totalIndustry classification Number nonrespondents Number respondents Number companies

Mining, crude oil . . . . . . . . . . . . . . . . . . .Food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Tobacco . . . . . . . . . . . . . . . . . . . . . . . . . . .Textile. . . . . . . . . . . . . . . . . . . . . . . . . . . . .Apparel . . . . . . . . . . . . . . . . . . . . . . . . . . . .Furniture . . . . . . . . . . . . . . . . . . . . . . . . . .Paper, fiber, wood . . . . . . . . . . . . . . . . . .Publishing, printing . . . . . . . . . . . . . . . . .Chemicals . . . . . . . . . . . . . . . . . . . . . . . . .Petroleum refining . . . . . . . . . . . . . . . . . .Rubber, plastic . . . . . . . . . . . . . . . . . . . . .Leather . . . . . . . . . . . . . . . . . . . . . . . . . . . .Glass, concrete. . . . . . . . . . . . . . . . . . . . .Metal manufacturing . . . . . . . . . . . . . . . .Metal products . . . . . . . . . . . . . . . . . . . . .Electronics, appliances . . . . . . . . . . . . . .Shipbuilding, railroad, and

transportation equipment . . . . . . . . . .Measuring equipment . . . . . . . . . . . . . . .Motor vehicles . . . . . . . . . . . . . . . . . . . . .Aerospace . . . . . . . . . . . . . . . . . . . . . . . . .Pharmaceuticals . . . . . . . . . . . . . . . . . . . .Soaps, cosmetics . . . . . . . . . . . . . . . . . . .Office equipment . . . . . . . . . . . . . . . . . . .Industrial and farm equipment . . . . . . . .Musical instruments, toys. . . . . . . . . . . .Broadcasting, motion pictures . . . . . . . .Beverages . . . . . . . . . . . . . . . . . . . . . . . . .

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

723

1551

168

1211

213

141112

4463633

23333

193

3.67011.90.52.62.60.58.34.16.25.71.00.51.67.25.76.2

2.12.13.11.63.11.61.6

11.91.61.61.6

631

3840

145

2830

41

13241225

511131111

51020

238

307

2.0%10.1

1.02.61.3—4.61.69.19.81.30.34.27.83.98.1

1.63.64.23.63.61.63.26.50.61.02.6

1354

413

91

30134041

62

16382337

915191417

81343

56

11

500

2,6%10.80.82.61.80.26.02.68.08.21.20.43,27.64.67.4

1.83.03.82.83.41.62.68.61.01.22.2

alndu~trial ~la~~ification is based on Fortune 500 listing for each company; that listing was the Standard Industrial Classification Code

SOURCENational Opinion Research Centefi survey conducted forOTA, 19S2.

mining corporations and private utility companies as Appendix A referenceidentified in Fortune magazine listings, the respond- l.Jones, WesleyH., “Generalizing Most Survey Inducementents do not appear to differ greatly from the non- Methods: Population Interactions With Anonymity andrespondents in geographic location or type of com- Sponsorship)” Public Opinion Quarter@, spring 1979,pany. p. 108.

— ..——.

A p p e n d i x B

Report From the National OpinionResearch Center

WORKPLACE SURVEY :

BIOCHEMICAL GENETIC OR CYTOGENETICTESTING IN THE WORKPLACE --

PAST, PRESENT AND FUTURE

DRAFT REPORT

Prepared byCynthia T h o m a s

National Opinion Research Center

S u b m i t t e d t oThe Office of T e c h n o l o g y A s s e s s m e n t

Contract Number 233-2450

F i r s t D r a f t : June 10, 1982Revised ; August 20, 1982

179

180 The Role of Genetic Testing in the Prevention of Occupationl Disease

SUMMARY

The National Opinion Research Center has conducted a mail survey ofthe 500 la rges t U .S . Corpora t ions , 11 unions , and 50 u t i l i t i e s to de terminehow many organiza t ions have ever engaged in or might be considering the use ofbiochemical genet ic or cytogenet ic tes t ing of employees or potentialemployees . U l t i m a t e l y , r e s p o n d e n t s f r o m 3 7 3 o r g a n i z a t i o n s r e p l i e d t o t h eq u e s t i o n n a i r e , e i t h e r b y m a i l o r t e l e p h o n e , y i e l d i n g a r e s p o n s e r a t e o f64.5%. T w e n t y - s i x o r g a n i z a t i o n s d e c l i n e d t o c o m p l e t e t h e q u e s t i o n n a i r e ,g e n e r a l l y c i t i n g r e a s o n s o f t i m e o r s u r v e y r e l e v a n c e . S i x o r g a n i z a t i o n sr e p o r t t h a t t h e y a r e p r e s e n t l y t e s t i n g . Two of them are chemical companies ,t w o a r e u t i l i t i e s a n d t w o a r e i n t h e e l e c t r o n i c s i n d u s t r y . Seventeeno r g a n i z a t i o n s h a v e t e s t e d i n t h e p a s t . O n l y o n e o r g a n i z a t i o n r e p o r t s c u r r e n tt e s t i n g b u t n o p a s t t e s t i n g . F i f t y - n i n e o r g a n i z a t i o n s (16 .1% ) m i g h t p o s s i b l yt e s t i n t h e f u t u r e .

———. —

App. B—Report From the National Opinion Research Center ● 181

1 .

the

how

WORKPLACE SURVEY :

BIOCHEMICAL GENETIC OR CYTOGENETICTESTING IN THE WORKPLACE --

PAST, PRESENT AND FUTURE

INTRODUCTION

The National Opinion Research Center has conducted a mail survey of

500 largest U.S. corporations, 11 unions, and 50 utilities to determine

many organizations have ever engaged in or might be considering the use of

biochemical genetic or cytogenetic testing of employees or potential

employees. This survey contributes to a larger research effort conducted by

the Office of Technology Assessment for the Committee on Science and

Technology of the U.S. House of Representatives. The research questions the

survey was designed to address include:

(1) the frequency of past,present and anticipated biochemicaland/or cytogenetic testing in the workplace and whether it hasbeen conducted on a routine,special or research basis;

(2) the names of the tests used, for whom, and for what purpose;

(3) the actions,if any, taken by the company on the basis of theresults of the tests; and

(4) the criteria against which tests have been measured todetermine acceptability for use.

I I . METHODOLOGY

D u r i n g F e b r u a r y a p r e t e s t d r a f t o f t h e q u e s t i o n n a i r e w a s s e n t b y

F e d e r a l E x p r e s s t o t w e n t y - f i v e o r g a n i z a t i o n s i n t h e F o r t u n e 5 0 0 . T h e

objective was to determine whether the questionnaire could be answered

properly and whether a reasonable rate of response could be expected. Without

any follow-up, approximately 50% of these organizations returned a completed


q u e s t i o n n a i r e Since only relatively minor changes in the formatting of the

instrument were required, and two items were deleted, we were able to include

these responses in the f ina l ana lys i s .

On March 25, 1982, questionnaires were sent to 475 chief executive

of f i cers o f the la rges t corporat ions , presidents of 11 unions and chief

executives of 50 uti l i ty companies. Questionnaires were accompanied by two

one-page l e t t e r s , one from the Office of Technology Assessment, signed by John

Gibbons, the Direc tor , and one from NORC, signed by Cynthia Thomas, NORC's

p r o j e c t d i r e c t o r , and by a post card and a return envelope. A l i s t o f the

names of members of an advisory panel to OTA of experts in genetics,

occupational medicine, and law, also was enclosed.

The letter from OTA introduced the study by stating that the

Committee on Science and Technology of the U.S. House of Representatives had

asked for the assistance of leading organizations in completing the

ques t ionna i re . The CEOs were asked to direct the questionnaires to their

ch ie f execut ives for hea l th a f fa i r s .

NORC's letter mentioned the importance of the study, the confiden-

tial nature of the information, and the use of a pre-paid post card to be

returned by the respondent indicating that a questionnaire was completed, in

order to keep the identity of responding organizations separate from the

questionnaires.

Half of the questionnaires were sent by Federal Express and half by

first class mail, since the budget for postage was limited. Two hundred cases

were targeted for follow-up telephone calls, with priority given to companies

in the Fortune 100 and in key industry groups, including those involved in


c h e m i c a l s , rubber and plastic products , metal manufacturing, and”

pharmaceuticals .

F r o m t h e p r e t e s t , w e l e a r n e d t h a t t h e o f f i c e o f t h e c h i e f e x e c u t i v e ,

a s s u g g e s t e d i n t h e c o v e r l e t t e r , o f t e n r e f e r r e d t h e q u e s t i o n n a i r e t o s o m e o n e

e l s e i n t h e o r g a n i z a t i o n , such as a chief medical officer.S o m e t i m e s s e v e r a l

subsidiaries had to be consulted before the questionnaire could be completed.

Consequently, it was realistic to expect the questionnaire to take several

weeks or more to be completed after its receipt. To allow enough time for

organizations to respond, the first telephone follow-ups during the main field

period were scheduled for the week of April 19. Up to and including the 20th

of April, 219 post cards and 239 questionnaires had been received.

Telephone follow-up calls were initiated with 200 of the

organizations which had not sent in post cards by April 21. The office of

the chief executive officer was contacted, the purpose of the study and the

urgency of a response was stated, and the respondent, generally an executive

secretary or administrative assistant, was asked to determine whether the

questionnaire had been received and, if so, who now had it. The procedure

usually either resulted in the request for an additional questionnaire, or the

identification of one or a series of executives to whom the questionnaire had

b e e n r e f e r r e d .

R e p e a t e d f o l l o w - u p c a l l s w e r e m a d e t o t h e o f f i c e s o f t h o s e r e p o r t e d

t o b e i n p o s s e s s i o n o f t h e q u e s t i o n n a i r e , e a c h t i m e a l l o w i n g a r e a s o n a b l e t i m e

p e r i o d f o r t h e r e s p o n d e n t t o e x p e d i t e t h e r e t u r n o f t h e p o s t c a r d b e f o r e a n

a d d i t i o n a l c a l l w a s m a d e . U l t i m a t e l y , 373 q u e s t i o n n a i r e s w e r e r e t u r n e d o r t h e

i n f o r m a t i o n r e q u i r e d t o c o m p l e t e t h e m w a s o b t a i n e d b y t e l e p h o n e o r i n a


le t ter , yie ld ing a response ra te o f 64 . 5%, inc luding the pre tes t cases . The

number of post cards received was 307, including post cards from the pretest .

Twenty-six organizations declined to complete the questionnaire ( 4 . 6 % ) ,

genera l ly c i t ing reasons o f t ime or survey re levance .l R e s u l t s p r e s e n t e d i n

the following tables are based on responses received by June 1 (the f irst 366

c a s e s ) . No questionnaires received after that date contained any instances of

t e s t i n g . An analysis of non-respondents is presented in Appendix A.

1 S p e c i f i c a l l y , ten organizations stated that their policy is not to replyto surveys.Three claimed they were not interested or had no time, oneobjected to the methodology, and twelve refused by telephone giving no reason.


I I I . REVIEW OF Till? LITERATURE : SURVEY DESIGN METHODOLOGY

The survey was designed to obtain accurate responses from a

reasonably high proportion of potential respondents as cost efficiently as

possible, within a l imited budget. Severa l i s sues re la ted to the se lec t ion o f

p r o c e d u r e s f o r c o m p l e t i n g t h i s s u r v e y h a v e b e e n a d d r e s s e d i n t h e l i t e r a t u r e .

We were not able to find any studies dealing with the topic of biochemical

genetic and cytogenetic testing, however. Some of the advice in the

l i t e r a t u r e , and related approaches chosen for this study, are reviewed below.

Method of Administration

Typically,serious studies of elite populations (people high in

status, income,or education) employ a personal interview, with open ended

questions,for data collection.Generally, however, such studies are

concerned with opinions and unusual experiences or perceptions. The

literature on elite interviewing, consequently, focuses on the conduct of

personal interviews and is of little help in providing guidance for this

survey,2 which was completed by mail with telephone followups.

Most information to be obtained for this study was factual --

whether or not testing had taken place, and if so, what types of testing.

Consequently, the function of the elite respondent, the chief executive

o f f i c e r ,was to provide impetus for the questionnaire to be completed --

principally by routing it to the appropriate official within his organizatio

Therefore,a personal interview was not necessarily appropriate.Indeed, the

2S e e , for e x a m p l e , Lewis Anthony Dexter,Elite a n d S p e c i a l i z e dInterviewin~ ( E v a n s t o n :Northwestern University Press, 1970).


cost o f data collection was the principal criterion for selecting a method of

administering the instrument. Consequently, a survey by mail was selected as

the approach to data collection.

Obtaining a High Rate of Response

Most of the literature on obtaining high response rates for mail

surveys deals with surveys of the general population, and not with surveys of

organizations. 3 Nevertheless, some of the principles can be applied to

contacts with organizations.

Confidentiality/Anonymity

It is generally believed important to convey to respondents that the

information they provide will remain anonymous (as well as to ensure that it

does), especia l ly when the topic may be a sensi t ive one . T h e r e w e r e i n d i c a -

tions that corporations would find this topic of cytogenetic and biochemical

t e s t i n g s e n s i t i v e . 4 One study suggests that high income respondents are more

l i k e l y to r e a c t f a v o r a b l y t o a s s u r a n c e s o f a n o n y m i t y t h a n t h o s e w i t h l o w

incomes and, c o n s e q u e n t l y , t o c o m p l e t e q u e s t i o n n a i r e s . 5 It was decided to

protect anonymity by omitting any identifying information on the questionnaire

a n d b y a s k i n g r e s p o n d e n t s to s e n d a post card naming the i r o r g a n i z a t i o n a n d

i n d i c a t i n g t h a t a q u e s t i o n n a i r e h a d b e e n c o m p l e t e d .

3See, for enmple, Don A. Dillman, Mail and Telephone Surveys: The TotalDesign Method (New York: John Wiley & Sons, 1978).

4A r t i c l e s in the New Y o r k T i m e s h a d contributeci to t h e c o n t r o v e r s y .

5Wesley H. Jones, “Generalizing Mail Survey Inducement Methods:Population Interactions with Anonymity and Sponsorship,” Public OpinionQuarterly (POQ), Spring, 1979, p. 108.

App. B— Report From the National Opinion Research Center ● 187

T h e r e a r e s e v e r a l p i t f a l l s t o t h i s a p p r o a c h t h a t s h o u l d b e n o t e d .

First, organizations may return post cards but not questionnaires, and vice

versa. (We received 307 post cards and 373 questionnaires; even some of these

may not have been matched pairs.) Second, organizations which did not return

post cards were contacted by telephone and, in some cases, were re-sent

questionnaires if they could not find them. Some of them may have sent in a

questionnaire without a post card and later completed and returned a second

questionnaire. We have no way to know whether this happened, but believe it

occured in only a couple of cases. It is also possible, of course, for

questionnaires or post cards to be lost in the mail or lost between the desk

of the chief executive officer and the company’s mail room.

Questionnaire Design

Instrument design, it has been found, can be important in dealing

with sensitive questions in an interview. Although methodological work on

this topic generally has dealt with face-to-face interviews of members of the

general population, some findings can be applied to this mail survey. 6 T h e r e

are indications, for example, that whether to report any threatening behavior

is not influenced by such factors as question length. Reports on the amount

of a behavior, however,

response categories and

.

seem to be affected

the opportunity for

.

by availability of open–ended

the respondent to explain an

answer. Several questions in the survey were constructed to allow respondents

to explain or qualify their answers.

6 Norman M. Bradburn, et al., Improving Interview Method and Questionnaire——Design (San Francisco, Jossey–Bass Publishers, 1980) , pp. 18-25.


Importance Factor

The literature suggests that the more important the survey is

perceived to be by the respondent,the more likely (s)he is to complete a

questionnaire.7 Several methods were used in this survey to convey a sense of

importance to respondents.Sponsorship of the study by the U.S. Congress was

emphasized,along with the possibility that hearings would be held.The

letter from OTA was individually addressed and signed by the Director. The

questionnaire was printed on a folded sheet of paper rather than xeroxed on

separate pages.As noted, some questionnaires were sent by Federal Express

and others by first class mail;both mailing methods indicate that the

communication is important.As shown below, however, the Federal Express

mailing may have conveyed a greater sense of importance than we ultimately

needed. Finally, during telephone followups, the caller once again conveyed

the urgent need for responses to the questionnaire.

‘See, for example Kent L. Tedin and C. Richard Hofstetter, “The Effect Of

Cost and Importance Factors on the Return Rate for Single and MultipleMailings,”Public Opinion Quarterly, Spring, 1982, pp. 122-127.


I v . RESULTS

Response Patterns

It i s not easy to ga in the a t tent ion o f the ch ie f execut ive o f f i cers

of major corporations with a questionnaire, especially when many of them

report receiving hundreds a year and have established corporate policies of

not responding. Table 1 shows the cumulative totals of post cards received by

the end of each weekly time period during the main survey. Separate rates are

shown for organizations which received Federal Express versus f irst class

mai l ings . In Table 2, organizations also are l isted according to whether they

are among the two hundred largest or three hundred smallest of the

corporat ions , or whether they are uti l i t ies or unions.

It can be seen from Table 1 that organizations that received the

questionnaire by Federal Express held a lead in the post card returns

throughout the survey period, but the size of the lead diminished

s ign i f i cant ly a f te r the f i r s t week . By the end of week 10, 52.9% of the 293

postcards received had been returned by organizations which had received a

Federal Express mailing; 47% of those returning post cards had received a

f i r s t c l a s s m a i l i n g . The small difference in rates of return suggests to NORC

that Federal Express was not a particularly cost effective method of mail lng,

given that i t cost $1,450 for the Federal Express mail ings and only $50 for

those sent f irst class. The seventeen additional cases contributed by the more

expensive approach each cost $82 more than the others.

Whether better rates of response were obtained from larger or

smaller companies is of interest . It should be remembered that all of the 200

largest companies received telephone followups, whereas companies in the

190 ● The Role of Genetic Testingin the prevention Of Occupational Disease

bottom 300 were recontacted only if they belonged to a key industry group.

Table 2 shows that, prior to week 3, when telephone follow-ups began,

approximately 33% of the largest organizations had returned post cards,

whereas 28% of the smallest organizations had done so. Over time, the lead of

the la rges t corpora t ions increased , suggesting that the impact of follow-up

activit ies was greatest for this group, as i t should have been. Of course,

other factors as well may have contributed to the higher response rate of

larger companies. The response ra te for u t i l i t i e s was re la t ive ly h igh , a t

68%, and for unions low, at 36%.

Response Quality

Coverage

Generally, those responding to the questionnaire with whom we talked

on the telephone attempted to locate someone within the company with the

expertise to answer the questions. Some organizations in the Fortune 500 are

holding companies,’ owning subsidiary organizations that operate

autonomously. Some organizations refused to respond because they

to devote resources to contacting their subsidiaries to ask about

were unable

t e s t i n g .

Others either answered to the best of their knowledge or made efforts to

contact their subsidiaries. We have no knowledge about the level of effort

employed in completing each questionnaire.

7Fortune includes holding companies in their listings if more than 50% ofrevenues are from manufacturing or mining.


Missing Data

A limitation of an anonymous questionnaire is that it is not

possible to contact the respondent about missing information or unclear

responses. Generally, the proportions of cases missing information on any

particular item was low. On questions 1-6, approximately 3% of respondents

failed to answer each item, generally by leaving it blank. Eight

questionnaires (2%) did not include enough information so that the company

could be classified as a corporation or utility.

Table 1

POST CARDS RECEIVED BY WEEK, BY TYPE OF MAILING,(MAIN SURVEY O N L Y )

Time Period

Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10

3/31 - 4 /6 4/7 - 4 /13 4/14 - 4 /20 4/21 - 4 /27 4/28 - 5/4 5/5 - 5 /11 5/12 - 5 /18 5/19 - 5 /25 5/26 - 6/1 6/2 - 6/8Cumu1. Cumul. Cumul. Cumul. Cumul. Cumul. Cumul. Cumul. Curall.

Number % Number % Number % Number % Number % Number % Number % Number % Number % Number %

P o s t C a r d s :

Type ofM a i l i n g :

F e d e r a l

Express

FirstClass

102 - 171 - 219 - 234 - 245 - 256 - 266 - 275 - 279 - 293 -

68 66.7 96 56.0 118 53.8 124 53.0 128 52.0 134 52.3 138 52.0 146 53.0 148 53.0 155 52.9

34 32.4 75 43.4 101 46.1 110 47.0 117 48.0 122 48.0 128 48.0 129 47.0 131 47.0 138 47.0

App.

B—

Report

From

the

National

Opinion

Research

Center

● 1

93

TABLE 2

POST CARDS RECEIVED BY ORGANIZATION SIZE AND rYPE

Time Per: oa

weeK .) weeK '+ WeeK) HeeK b WeeK I weeK tI .... !K '1 WeeK lU 3/31 - 4/6 4/7 - 4/13 4/14 - 4/20 4/21 - 4/27 4/28 - 5/4 5/5 - 5/11 5/12 - 5/18 5/19 - 5/25 5/26 - 6/ 6/2 - 6/8

CUClUl. Cumu1. Cumu1. Cumu1. Cumu1. Cumu1. Cumul. Cumu1. Cu::rul. Number % Number % Nu",'h. ...... 'P

,. tJ.l""hn .. ,. ~,.",h.l!lo"

., l.! •• _l...a .. ., 1..t •• _'h..do. ., ~ .. -"" ........ ., ""1_\"'_" .,

~ •• _l...ft. .,

~C5t Cu::d II: 102 171 219 234 245 256 266 275 279 293

Organiza-tion Size/ .!lEe:

Corporationa

Top 200 34 17 .C 65 3Z.~ 84 42.C 91 46.L 97 49.0 103 )l.l 109 :>:> .l 114 57.0 111 58.5 123 61.5

Bottoll 300 53 17.6 84 28.0 100 33.0 107 36.0 112 37.0 117 39.0 121 40.0 124 ~1.0 124 '1.0 132 44.0

Utllitlea 14 28.0 19 38.0 31 62.0 32 64.0 32 64.0 32 64.0 32 64.0 33 66.0 34 6 C.O 34 68.0

UniODe 1 9.0 3 27.0 4 36.0 4 36.0 ~ 36.0 ~6.0 4 36.0 4 36.0 ~ 36.0 4 36.0

Total. 102 19.0% lil 31.97% 219 40.9% 234 43.7% 245 45.7% 256 57.8% 266 49.7% 275 51.4% 279 52.1% 293 54.8%


Test ing : Overall Rates

The following tables summarize the answers to the various questions

on tes t ing . Percentages are based on the total number of responses included

in the ana lys i s : 366 . The questionnaire contains the precise phrasing of

each question.

Few organizations report current biochemical genetic or cytogenetic

testing; sl ightly more have conducted any such tests in the past twelve years;

s t i l l more ant i c ipate a t l eas t a poss ib i l i ty o f conduct ing such tes t s in the

fu ture . Organizations were instructed on the questionnaire to include in

their answers any instances of testing, so that positive responses can include

isolated instances of testing as well as long term testing programs. Table 3

summarizes these results by type of organization, main industrial

c l a s s i f i c a t i o n , and according to industrial group. 8 Among the six

organiza t ions current ly t es t ing (1 .6%) , two of them are engaged in the

chemica l indust ry as the i r pr inc ipa l ac t iv i ty . Two others are uti l i t ies, and

the other two are in the electronics industry.

Seventeen organizations (4.6%) have tested in the past . Half of

these are in the chemical industry. Of those organizations that have tested

in the past twelve years, f ive are s t i l l t e s t ing today . Only one organiza t ion

reports current testing hut no testing in the past twelve years.

8Each organization was rated according to the f irst industrial group intowhich i t c lass i f i ed i t se l f and then according to o ther indust r ia l ca tegor iesl i s ted , up to three . The table shows testing by main (f irst) industrialcategory and, in parentheses, any representation in that industry.


Table 3

TESTING : CURRENT, PAST AND FUTURE TESTERSBY ORGANIZATION TYPE AND MAIN INDUSTRY

Current Testing

N = 6Organization type:

Corporations

Unions

Utilities

Other

Main Industry:

Chemicals

Utilities

Petroleum

Pharmaceuticals

Rubbers, Plastics

Metals

All others (any others)

Total

4

0

2

2

2

0

0

0

0

2

6 (1.8%)

Past Testing Future Testing No Testing

N = 17 N = 59

16 49

0 0

1 9

1

8

1

0

0

0

0

8

17 (5.2%)

11

10

4

3

3

2

26

59 (18.1%)

N = 244

234

5

5

0

14

5

26

8

1

22

244

244 (74.8%)


Fifty-nine organizations (16.1%) may test in the future, they report .

according

conducted

More animal testing is conducted than testing in the workplace,

to answers to question 18 on whether the organization ever has

test on animals. Twenty-four organizations report testing on

animals for chromosomal aberrations; ten have tested for genetic

predisposit ion to harmful effects from chemicals. Of those testing on

animals, five have ever tested on humans. (See Table 4.)

Table 4

ANIMAL TESTING, BY EVER TESTED IN WORKPLACE

Animal Test for:Current or

Past Workplace Chromosomal GeneticTesting aberrations Predisposition

N = 24 N = 10

No 20 9

Yes 4 1

App. B—Report From the National Opinion Research Center . 197

Types of Testing: Biochemical Genetic and Cytogenetic

Organizations that reported some biochemical genetic testing were

asked whether they had ever tested employees for any red blood cell and serum

disorders (A), l iver de tox i f i ca t ion sys tems (B) , immune system markers (C), or

heterogygous chromosomal instabil i t ies (D). Within each of these four broad

categories A through D, several examples were included. Of those testing,

there were fourteen organizations that have tested for red blood cell and

serum disorders (category A), three in category B, five in category C and no

organizations reporting a test in category D. Those organizations testing in

category A frequently have conducted more than one test within this category,

such as sickle cel l trait , G-6-PD, or SAT. The most frequently used test is

t h a t f o r s i c k l e c e l l t r a i t , for which ten organizations have tested. G–6-PD

and SAT were both the second most frequently used individual tests. (See

Table 5 for summary of the frequency of individual biochemical genetic tests .)

For each individual test , companies were asked about the purpose of

the testing and the type of employee tested. Testing was usually routine,

less often for research purposes, or conducted for other reasons. These other

reasons are not specified.

The type of employee chosen for testing was most often based on

ethnicity and race for sickle cell testing, and job category for other types

of tests. No organization reported basing a test on employees’ sex.

Organizations that report having conducted cytogenetic testing w e r e

asked whether they had looked for chromosomal aberrations (CA), sister

chromatic exchanges (SCE), mutations by assaying the DNA (DNA), mutations by

assaying the enzymes (ENZ), or something else. Four organizations have tested

for chromosomal aberrations and two for SCE. No one claimed to have tested

198 .

The

Role

of G

enetic T

esting in

the P

revention of

Occupational

Disease

Table 5

TYPE OF T8STING BY REASONS TESTED

Sickle Methemo-Cell G-6-PD SA1' O'lohin An", Aa An" na A ...... f"a ,.."

Number Number Number Number Nnmhf'>l" Ntlmhpr Nllmh&>r N'"m'h",,1'" !\Tn"",'ho?'

Reasons/Types tested:

(a) Testing routine? 5 3 1 0 1 1 4 1 0 (b) Testing for

research? 1 0 2 1 2 1 0 1 2 (c) Other reasons? 6 2 2 1 2 1 3 3 0

Table

TYPE OF TESTING BY EMPLOYEED CATEGORY TESTED

N .. 18)

2. Testing by: (a) Job category? 1 2 2 0 2 1 1 2 1 (b) Ethnlcity/race? 7 0 0 0 0 0 0 0 0 (c) Sex? 0 0 0 0 0 0 0 0 0

Total testing 10(2.7%) 4(1.1%) 4(1.1%) 1(.3%) 3(.8%) 2(.5%) 41.1%) 4(1.1%) 2(.5%)

aTest not specified by company.

bSince categories above are not mutually exclusive, total can be less than/more than sum of categories.


for mutations, by assaying either the DNA or the enzymes. CA testing was done

for unspecified reasons by three companies; SCE testing was done for research

purposes. Job category was the only one of the three employee-related

characteristics taken into account in deciding whom to test except for sickle

cell. (See Table 6 . )

Several questions were asked for each type of testing (biochemical

genetic and cytogenetic) about factors considered in decisions to implement

testing programs and criteria employed in selecting specific tests. All

categories provided received at least one response. Ten responses indicated

that data was reviewed either from animal studies or from epidemiologic

studies in decisions on whether to perform biochemical genetic testing. In

four instances, such reviews were conducted in deciding whether to implement

cytogenetic testing. The various criteria for selecting a particular test

were fairly evenly employed, although cost appears to have been less important

than the various scientific criteria. (See Table 7 for the distribution of

responses.)

R e s u l t s o f T e s t i n g

O r g a n i z a t i o n s h a v e t a k e n a c o n s i d e r a b l e r a n g e o f a c t i o n s a s a r e s u l t

of the biochemical genetic or cytogenetic testing programs they have

conducted. The most common action reported is informing an employee of a

p o t e n t i a l p r o b l e m . E i g h t o r g a n i z a t i o n s h a v e t a k e n s u c h a n a c t i o n . F i v e o f

the categories are related to actions taken to inform the employee or to

protect him, ranging from the most minimum such activity - merely informing

the employee - to the most extreme, that of discontinuing a product.


Employees were informed in eight Instances (out of the 18) and a product was

discontinued only once. In seven cases, an employee was either transferred or

another job was suggested. The actions taken, by frequency, are l isted in

Table 8 .


Table 7

TYPE OF TESTING BYFACTORS/CRITERIA FOR SELECTING TESTS

Factors in implementing testing

Cost benefit analysis

Data from animal studies

D a t a - e p i d e m i o l o g i c s t u d i e s

Legal consequences of nottesting

Unions/employee initiative

Other

No response

Biochemicalgenetic Cytogenetic

N-17 N-18

Number Number

2

4

6

3

0

2

2

0

3 0

4 a 3 a

2 0

Criteria for selecting tests

Predictive value of test 5 1

S e n s i t i v i t y o f t e s t 3 0

Specificity of test 5 1

Scientific consensus 4 2

Cost of test 2 0

Other 4 3 b

No response 2 1

alncludeS r e a s o n s related to p r o t e c t i n g e m p l o y e e s , research ‘indin~s*

blnC~ude~ research f i n d i n g s t13enera~J*


Table 8

RESULTS OF TESTING

N = 18

Action Type Number

Informed employee

Transferred employee

Personal protection devices

Other action

Suggested other job

Engineering controls

Implemented research program

Discontinued/changed product

8

5

3

3

2

2

1

1

Comments on the Questionnaire/Postcards

Respondents were encouraged to qualify their responses or to comment

on the questionnaire either on the questionnaire itself or on the postcard.

Three companies currently testing provided comments on their questionnaires.

One of them stated that their . . . “Answers should not be taken to imply any

large scale program or problem.” Once mentioned testing for pre-placement and

as a part of annual physicals. The third uses testing in “continuing health

evaluations” of certain employees.

Two former testers offered comments. One claimed that testing had

been used at the request of the State health department for a brief period.


Another reported sickle cell testing as part of a “preventive medical program”

on certain people of child bearing age.

Seven possible testers made comments. One noted that “what may be

done will depend upon demonstrations that indicated procedures have practical

u t i l i t y . ” Others expressed observations about the potential for testing in

the i r organiza t ion .

Comments received on post cards and from organizations which have

never tested, and have no plans to test (approximately 37 were received)

ranged from statements that the questions were inappropriate to their

organizations to beliefs that testing had no proven value. Many questioned

the usefulness of the survey. Several organizations felt that the

questionnaire could be misleading becuase information was not requested on how

much tes t ing was done.

v. CONCLUSIONS

There was great uncertainty at the onset of this study as to whether

to expect any cytogenetic or biochemical genetic testing among the major U.S.

corporations, unions and utilities. Six organizations, however, did report

testing. Of the organizations that tested in the past, only one continues to

t e s t , suggesting a tendency for testing to decline. On the other hand, fifty-

nine organizations answered “possibly” to the question of whether they

anticipated conducting testing in the next five years.

It is interesting to speculate as to why so many organizations may

h a v e s t a t e d t h a t t h e y “ p o s s i b l y ” a n t i c i p a t e c o n d u c t i n g t e s t i n g i n t h e n e x t

f ive years , especially since many organizations have dropped their testing


programs . Some may have chosen to hedge their bets - - as a result of the

c u r r e n t c o n t r o v e r s y s u r r o u n d i n g t h e i s s u e , p e r h a p s g o o d r e a s o n s f o r t e s t i n g ,

not now apparent to them, may surface . P e r h a p s , a l s o , some are not aware of

t h e i s s u e s s u r r o u n d i n g t e s t i n g a n d s i m p l y d o n o t k n o w w h e t h e r t h i s t o p i c m a y

some day apply to them.

App. B—Report From the National Opinion Research Center 205

APPENDIX A1

ANALYSIS OF NONRESPONDENTS

The analys is of nonrespondents among the Fortune 500 companies i s based

upon 193 cases , inc luding 38 companies who sent in anonymous quest ionnaires

but did not send in postcards ident i fy ing themselves as respondents .

G e o g r a p h i c a l l y , n o n r e s p o n d e n t s , l i k e r e s p o n d e n t s , w e r e s p r e a d f a i r l y

evenly across the country , as shown in Table A-1 .

TABLE A-1

LOCATION OF ALL COMPANIES AND NONRESPONDENTS

Region Nonrespondents CompaniesNumber P r o p o r t i o n Number P r o p o r t i o n

Northeast 82 42% 215 43%

S o u t h e a s t 8 4% 30 6%

C e n t r a l 80 41% 191 38%

Mountain 2 1% 9 2%

West 21 11% 55 11X

The nonrespondents were concentrated in the smaller two hundred

companies. This most probably reflects the fact that our follow-up activities

focused on the larger three hundred companies, in addition to industries in

k e y i n d u s t r i a l g r o u p s . The breakdown of nonrespondents by company size is

shown in Table A-2.

1 This appendix was prepared by Ken Cohen.


TABLE A-2

SIZE OF NONRESPONDING COMPANIES

NonrespondentsSize of Company Number P r o p o r t i o n

Fortune 100 29 15%

Fortune 200-300 62 32%

Fortune 400-500 102 52%

Companies in the combined key code industr ies (chemicals , petroleum

r e f i n i n g , r u b b e r a n d p l a s t i c p r o d u c t s , m e t a l m a n u f a c t u r i n g a n d

pharmaceut icals ) had a nonresponce rate of 31%, which is somewhat lower than

the overal l nonrepsonse rate of 38 .6% for the Fortune 500 companies . (Again ,

these companies were t h e f o c u s o f o u r f o l l o w - u p e f f o r t s ) . Otherwise ,

p a r t i c u l a r i n d u s t r i e s d i d n o t d e v i a t e s i g n i f i c a n t l y f r o m t h e o v e r a l l r a t e s .

The breakdown by industr ia l type i s g iven in Table A-3 .

Conclusion

T h e s e t a b l e s t o n o t s u g g e s t t h a t a n y p a r t i c u l a r t y p e o f o r g a n i z a t i o n w a s

m o r e l i k e l y t h a n a n y o t h e r t o r e f u s e t o r e s p o n d t o t h e q u e s t i o n n a i r e .

—


TABLE A-3

NONRESPONDENTS BY INDUSTRY TYPE

Nonrespondents Total CompaniesIndustry Type Number Proportion Number Proportion

10 - Mining, Crude Oil

20 - Food

21 - Tobacco

22 - Textile

23 - Apparel

25 - Furniture

26 - Paper, Fiber, Wood

27 - Publishing, Printing

28 - Chemicals

29 - Petroleum Refining

30 - Rubber, P l a s t i c

31 - Leather

32 - Glass, Concrete

33 - Metal Manufacturing

34 - Metal Products

36 - Electronics, Appliances

37 - Shipbuilding, Railroad &Transport Equipment

7

23

1

5

5

1

16

8

11

11

2

1

3

14

11

10

4

3.6%

11.9%

- - -

2.5%

2.5%

- - -

4%

5.7%

5*7%

- - -

- - -

- - -

7.2%

5.7%

5.2%

2%

13

54

4

13

9

1

30

13

40

41

6

2

16

38

23

37

9

2.6%

10.8%

---

2.6%

1.8%

---

6%

2.6%

8%

8%

1.2%

---

3.2%

7.6%

4.6%

7.4%

1.8%

208 Ž The Role of Genetic Testing in the Prevention of Occupational Disease

Total CompaniesIndustry Type Number P r o p o r t i o n Number P r o p o r t i o n

38 - Measuring Equipment 4 2% 15 2.6%

40 - M o t o r v e h i c l e s 5 2.5% 19 3.8%

41 - Aerospace 3 - - - 14 2.8%

43 - Soaps, Cosmetics 3 - - - 8 1.6%

44 - Office Equipment 3 - - - 13 2.6%

45 - Industr ia l & FarmEquipment 23 11.9% 43 8.6%

46 - J e w e l r y , S i l v e r w a r e o - - - 0 - - -

47 - M u s i c a l I n s t r u m e n t s ,Toys 3 - - - 5 1%

48 - B r o a d c a s t i n g ,M o t i o n P i c t u r e s 3 - - - 6 1.2%

49 - Beverages 3 - - - 11 2.2%

A p p e n d i x C

Survey Materials

Trcnwmmr AS S E S S M E W fWARO Uungrtd$ of tfie 31ttiteb f%!af~s -HN U. Glf3mw

ITD STP4ENS, A14SKA, CHAIRMANO FFICE OF T E C H N O L O G Y A S S E S S M E N T

-~MORRIS K. UDAl& ARI?L, VICE CHAIRMAN

ORRIW 0. NATCM. UTAH GEORGE E. f3ROWN, Jm.. WF.CHAR- McC. MA7?+IA8. J“- MO. JONN O. D(NGEU MICH. WASHINGTON, D.C. 20510~wARO M. KEN PWDY. MAsS. tiRRy wlNN, Jn.. tiNg.C R NIZ7 F. HOUING9, S.C. GREN= E. MIwR, OHIOHOW&30 W. -NQ4. NW. CQOPER EVAMS, lOWA

JoHu IL OlclooNsMarch 22, 1982

Dear Mr.

The Committee on Science and Technology of the U.S. House of Representativeshas requested this off ice to carry out a comprehensive study of the policy is suesarising from potentia1 occupationa1 genetic testing. The Committee expects thestudy to provide the Congress with full and fair in formation on a complex andsensitive topic. A crucial component of our study will be information and advicefrom leading U.S. corporations. Since your company is a world leader in many areasrelevant to the study, we believe it is extremely important for us to benefit fromany experience you may have with such testing programs.

The Office of Technology Assessment (OTA) is a nonpartisan congressionalagency that assists the Congress in dealing with complex technical issues. OTA isgoverned by a bipartisan Congressional board composed of six Representatives andsix Senators. A council of ten members eminent ‘in science, technology, andeducation serves in an advisory capacity. This study is also being assisted by anadvisory panel of experts in genetics, occupational. medicine, law, and policy fromindustry, labor, and academia. A list of advisory panel members and theiraffiliations is enclosed.

We have asked the National Opinion Research Center of the University ofChicago (NORC) to assist OTA by collecting and processing data via a questionnaire.The data will be presented to OTA in aggregate form only, and the raw data will bedestroyed.

NORC’S brief questionnaire is attached. We believe it will be most helpful

if you direct it to your chief executive for health affairs. We respectfully

request a response to the questionnaire as soon as possible and are prepared toshare the results of the analysis with you when it is completed.

If you have any questions about the study or about OTA, please “feel free tocontact me at (202) 224-3695, or Geoffrey M. Karny, OTA project director, at (202)

226-2090. Cynthia Thomas, NORC project director, can be contacted about the surveyat (212) 971-8200.

Sincerely,

&

,

John H. Gibbons

209


NORCNat ional Opin ion Research Center University of Chicago

461 Eighth Avenue New York, N. Y 10001 212/971-8200

March 23, 1982

As one of the leading corporations in this country, your organization hasbeen selected to participate in an important survey we are conducting for theOffice of Technology Assessment (OTA) of the United States Congress on thestate–of-the-art of genetic and cytogenetic testing programs. The enclosedletter from the OTA describes this study in more detail.

The National Opinion Research Center (NORC) is a not–for-profit academicresearch corporation affiliated with the University of Chicago. The oldestsurvey research facility established to do social research in the publicinterest, NORC has conducted over a thousand studies since its founding in1941, and has developed careful and systematic methods for ensuringconfidentiality. Names are never associated with responses to questions, anddata collected are used only for statistical purposes.

It is very important that you complete the enclosed brief questionnaireas soon as possible. Your answers to the questions should include anyinstance of testing in your corporation, or in any of your subsidiarycompanies.

To ensure confidentiality, the questionnaire carries no identifyinginformation. Please mail the completed questionnaire in, the prepaid NORCenvelope. Then, complete and mail the enclosed prepaid post-card. This willinform us that you have participated in the survey by completing aquestionnaire.

If you have any questions about the questionnaire, please feel free totelephone me at (212) 971-8200.

Thank you very much.

Sincerely yours,

Cynthia ThomasProject Director

. .

App. C—Survey Materials . 211

NORC/4354 3/82

WORKPLACE SURVEY

INSTRUCTIONS FOR COMPLETING THE QUESTIONNAIRE

The questions concern biochemical genetic and/or cytogenetic testing that may havebeen conducted by your company on one or more employees or potential employees.By conduct we mean do, contract for, or arrange for. By biochemical genetic testswe mean tests which screen healthy, asymptomatic individuals for the particulargenetic traits listed in question 7, and not standard blood chemistry tests ortests used solely for diagnosis. Cytogenetic tests are intended to detectchromosomal aberrations or sister chromatid exchanges.

Do not sign the questionnaire or record any identifying information on it.Answers should include any instances of testing in your corporation.

Please return the questionnaire to NORC before April 12.

1. Is your company currently conducting biochemicalY e s N O

genetic testing of employees or potentia1employees ?

2. Has your company conducted any biochemicalgenetic testing of employees or potentialemployees in the past twelve years?

3 . Does your company anticipate conductingbiochemical genetic testing in the next five Yes No years?

Possibly

4. Is your company currently conducting cytogenetictesting of employees or potential employees ? Y e s N o

5 . Has your company conducted any cytogeneticYes

testing of employees or potential employees inN o

the past twelve years?

6. Does your company anticipate conductingcytogenetic testing during the next five years? Yes No

possibly

IF YOUR COMPANY NEVER HAS DONE EITHER BIOCHEMICAL GENETIC OR CYTOGENETIC TESTING,SKIP TO QUESTION 18.

—


IF BIOCHEMICAL GENETIC TESTING HAS EVER BEEN DONE, PLEASE ANSWER QUESTIONS 7-11. If NOT, PLEASE

7. Has your company tested workers for . . .

SKIP TO Q. 12.

Yes No

• 1c1

• 1

A.

B.

c.

D.

any red blood cell and serum disorders, Including sickle cell trait, glucose-6-phosphatedehydrogenase deficiency (G-6-PD), methemoglobin reductase deficiency, serum alpha-l-antitrypsin deficiency (SAT),alpha and beta thalassemias?

any liver detoxification systems,including aryl hydrocarbon hydroxylase inducibility

(AHH), slow VS fast acetylation?

any immune system markers,including allergic respiratory disease, contact dermatitis,histocompatibility markers (HLA)?

any heterozygous chromosomal instabilities,including Bloom syndrome, Fanconi syndrome,ataxia-telangiectasia, xeroderma pigmentosum?

ENTER BELOW NAME OF EACH SPECIFIC CONDITION TESTED FOR (e.g., G-6-PD).Answer Questions 8 & 9 FOR EACH. IF more than4CONDITIONS, RECORD ON ADDITIONAL SHEET OF PAPER.

ENTER SPECIFIC CONDITION NAME HERE--->

Yes No— — Yes No— Yes No Yea No— —

8 . Was testing done . . .

a) routinely (e.g., yearly) or duringregular specified circumstances?

b) for research purpo.sea (e.g.,hypothesis testing)?

❑ 0

❑ 0c) for any other reasons?

9 . Was testing.to detect increased risk ofdisease ● ver based on m ● mplope’e . . .

a) job category? ❑ o

b) sex?

c) ethnic or racial background?

❑ !J

n10. What factors have been considered in A. Cost benefit analysis

decisions to implement any biochemi-B. Data suggesting a possible association

cdl genetic testing programs?between chemical exposure and illnessin animal studies

c. Data suggesting a possible associationbetween chemical exposure and illness

in ● pidemiologic studies

D. Legal consequences of failure to test uE . Union/employee initiative

F. Something ● lse. What?

Predictive value of the teat D. Scientific consensus

Cost of the teat

11. What criteria were ● mployedchoice of a specific test?

in t h e A.

B.

c.

Sensitivity of the test E.

Specificity of the test F. Something else. What?

—.

App. C—Survey Materials ● 213

IF CYTOGENETIC TESTING HAS EVER BEEN DONE,PLEASE ANSWER QUESTIONS 12-16.IF NOT, PLEASE SKIP TO Q. 18.

your company tested workers for exposure to chemicals by12. Has looking for . . .

A.

B.

c.

D.

E.

chromosomal aberrations

sister chromatid exchanges (SCE)

mutations by assaying the D N A

mutations by assaying the enzymes

something else? What?

ENTER BELOW NAME OF EACH SPECIFIC CONDITION TESTED FOR (e.g., SCE). ANSWER QUESTIONS 13 & 14 FOR EACH. IF MORE THANCONDITIONS, RECORD ON ADDITIONAL SHEET OF PAPER.

ENTER SPECIFIC CONDITION NAME HERE--)

1 3 . Was testing done . . .

a) routinely (e.g., yearly) or duringregular specified circumstances?

b) for research purposes (e.g.,hypothesis testing)?

c) for any other reasons?

14. Was testing to detect increased risk ofdisease ever based on an employees. . .

a) job category?

b) sex?


Yes No— —

❑ lcl

❑ 0

❑ i l

❑ ! 3

Yes No—

❑ 0

❑ 0

❑ n❑ n

Yes No. Yes No—

❑ 0

❑ o❑ 0

❑ 0❑ 0

15. What factors have been considered in A.decisions to implement any cytogene-tic t e s t i n g p r o g r a m s ?

B.

c.

D.

E .

F .

Cost benefit analysis

Data suggesting a possible associationbetween chemical exposure and illnessin animal studies

Data suggesting a possible associationbetween chemical ● xposure and illnessin epidemiologic studies

Legal consequences of failure to teat

Union/employee initiative

Something else. What?

16. What criteria were employed in thechoice of a specific test?

A. Predictive value of the test D. Scientific consensus ❑B. Sensitivity of the test E. Coat of the test

C. Specificity of the test F. Something ● lee. What? ❑


17. Which actions has your company ever taken as a result of biochemical genetic or cytogenetictesting ?

A. Informed employee of a potential E. Recommended personal protectionproblem devices

B. Suggested employee seek job elsewhere F. Implemented a research program

c . Placed an employee or transferred an G. Discontinued a product or changed —employee to a different job in the

• 1materials in a product

company

H. Some other action. What? uD. Implemented engineering controls

18. Has your company ever conducted any testing on wholeanimals or their cultured cells for . . . Yes No—

A. chromosomal aberrations or sister chromatid exchangesas a result of exposure to workplace chemicals? ❑ o

B. genetic predisposition to harmful effects from exposureto workplace chemicals?

19. What is the major industrial classification of your company (such as chemicals, foodor textiles)?

20. Please use this space for your comments, if any, about these questions.

Thank you for completing this questionnaire. The information you have provided will be held instrict confidence. Data will be made available to Congress in statistical form only.


T EC H NO L O G Y ASSESSMRW E30AR0 a Q l l g u w 5 0 [ tbe ?!Mttl !iMIk$ JOHN H. GIBBONS

TED STEVCN!3. AUSKA. CHAlf? MANMORRIS K. UDALI- ARIZ.. VICE CHAli?MAN O FFICE OF T ECHNOLOGY A SSESSMENT

OI?F?IN O. HATcH. U T A H CCORGE E. DROWN. JR. ~.CHARLES A-C. AA ATH1-% Jm. UO. JoHN D. DING ELI- MlCM. WASHINGTON , D.C. 20510U)WARD M . KCNNllDY. MA$25. URfl Y WINN. in. KANS.CRNE5T F. HOLUNOS. S-C CLARCNCIZ E. MIU-ER. OHIONOWARO w. CANNON. NW. CCIOPFX EVAJW, IOWA

JONN N. alllams March 22, 1982

Dear Mr.

The Committee on Science and Technology of the U. S . House of Representativeshas requested this o f f i c e to carry out a comprehensive study of the policy is suesarising from potential occupational genetic testing. The Committee expects thestudy to provide the Congress with full and f a i r information on a complex andsensitive topic . A crucial component of our study will be information and advicefrom leading U.S. labor organizations. Since your union is a world leader in manyareas relevant to the study, we believe it is extremely important for us to benefitfrom any experience you may have with such testing programs.

The Office of Technology Assessment (OTA) is a nonpartisan congressionalagency that assists the Congress in dealing with complex technical issues. OTA isgoverned by a bipartisan Congressional board composed of six Representatives andsix Senators. A council of ten members eminent in science, technology, andeducation serves in an advisory capacity. This study is also being assisted by anadvisory panel of experts in genetics, occupational medicine, law, and policy fromindustry, labor, and academia. A list of advisory panel members and theiraffiliations is enclosed.

We have asked the National Opinion Research Center of the University ofChicago (NORC) to assist OTA by collecting and processing data via a questionnaire.The data will be presented to OTA in “aggregate form only, and the raw data will bedestroyed.

NORC’S brief questionnaire is attached. We believe it will be most helpful

if you direct it to your director for health and safety. We respectfully request aresponse to the questionnaire as soon as possible and are prepared to share theresults of the analysis with YOU when it is completed.

If you have any questions about the study or about OTA, please feel freeto contact me at (202) 224-3695, or Geoffrey M. Karny OTA Project director} at(202) 226-2090. Cynthia Thomas, NORC project director, can be contacted about

the survey at (212) 971-8200.

Sincerely,


NORCN a t i o n a l O p i n i o n R e s e a r c h C e n t e r “University of Chicago

461 Eighth Avenue New York, N. Y. 10001 212 /971 -8200

March 23, 1982

Dear

As one of the leading unions in this country, you have been selected toparticipate in an Important survey we are conducting for the Office ofTechnology Assessment (OTA) of the United States Congress on the state-of-the-art of genetic and cytogenetic testing programs. The enclosed letter from theOTA describes this study in more detail.

The National Opinion Research Center (NORC) is a not-for–profit academicresearch corporation affiliated with the University of Chicago. The oldestsurvey research facility established to do social research in the publicinterest, NORC has conducted over a thousand studies since its founding in1941, and has developed. careful and systematic methods for ensuringconfidentiality. Names are never associated with responses to questions, anddata collected are used only for statistical purposes.

It is very important that you complete the enclosed brief questionnaireas soon as possible. Your answers to the questions should include anyinstance of testing in your union.

To ensure confidentiality, the questionnaire carries no identifyinginformation. Please mail the completed questionnaire in the prepaid NORCenvelope. Then, complete and mail the enclosed prepaid post–card. This willinform us that you have participated in the survey by completing aquestionnaire.

If you have any questions about the questionnaire, please feel free totelephone me at (212) 971-8200.

Thank you very much.

Sincerely yours,

Cynthia ThomasProject Director

App. C—Survey Materials Ž 217

NORC/4354 3/82

WORKPLACE SURVEY

INSTRUCTIONS FOR COMPLETING THE QUESTIONNAIRE

The questions concern biochemical genetic and/or cytogenetic testing that may havebeen conducted by your union on one or more union members or potential members.By conduct we mean do, contract for, or arrange for. By biochemical genetic testswe mean tests which screen healthy, asymptomatic individuals for the particulargenetic traits listed in question 7, “ “and not standard blood chemistry tests ortests used solely for diagnosis. Cytogenetic tests detect chromosomal aberrationsor sister chromatid exchanges.

Do not sign the questionnaire or record any identifying information on it.Answers should include any instances of testing in your union.

Please return the questionnaire to NORC before April 12.

1. Is your union currently conducting biochemicalgenetic testing of members or potential members? Y e s N o

2 . Has your union conducted any biochemical genetict e s t i n g o f m e m b e r s o r p o t e n t i a l m e m b e r s i n t h e Y e s N opast twelve years?

3 . Does your union anticipate conducting biochemicalgenetic testing in the next five years? Y e s N o

Possibly

4 . Is your union currently conducting cytogenetictesting of members or potential members? Y e s N o

5. Has your union conducted any cytogenetic testingof members or potential members in the past Y e s N otwelve years?

6 . Does your union anticipate conducting cytogenetictesting during the next five years? Yes No

Possibly

IF YOUR UNION NEVER HAS DONE EITHER BIOCHEMICAL GENETIC OR CYTOGENETIC TESTING,SKIP TO QUESTION 18.

—


IF BIOCHEMICAL GENETIC TESTING HAS EVER BEEN DONE, PLEASE ANSWER QUESTIONS 7-11. IF NOT, PLEASE SKIP TO Q. 12.

7.Yes No

Has your union tested members for . . .

A.

B.

c.

D.

any red blood cell and serum disorders, including sickle cell trait, glucose-6-phosphatedehydrogenase deficiency (G-6-PD), methemoglobin reductase deficiency, serum alpha-l-antitrypsin deficiency (SAT), a l p h a a n d b e t a thalassemias? ❑ 0

any Liver detoxification systems,including aryl hydrocarbon hydroxylase inducibility

(AHH), slow vs fast acetylation? ❑ 0

any immune system markers including allergic respiratory disease, contact dermatitis,histocompatibility markers (KM)? ❑ ID

any heterozygous chromasomal instabilities including Bloom syndrome, Fanconi syndrome,ataxia-telangiectasia,xeroderma pigmentosum?

ENTER BELOW NAME OF EACH SPECIFIC (CONDITION TESTED FOR (e.g., G-6-PD).ANSWER QUESTIONS 8 & 9 FOR EACH.IF MORE THAN 4(CONDITIONS, RECORD ON ADDITIONAL SKEET OF PAPER.

SPECIFIC CONDITION NAME HERE-)

8. Was testing done . . .

a) routinely (e.g., yearly) or during

regular specified circumstances?

b) for research purposes (e.g.,hypothesis testing)?

c) for any other reasons?

9 . Was testing to detect increased risk of

disease ever based on a member’s . . .

a) job category?

b) s e x ?


Yea No— —

❑ n

❑ 0

❑ O

❑ 0

❑ n❑ ID

10. What factors have been considered in A.decisions to implement any biochemi- B.cal genetic testing programs?

c.

D.

E.

F.

❑ 0

❑ o

❑ 0

❑ 0

Yea No Yes No— —

❑ 0

❑ n

❑ 0

❑ 0 ❑ 0

❑ 0Cost benefit analysis uData suggesting a possible association

between chemical exposure and illness

in animal studies

Data suggesting a possible associationbetween chemical exposure and illness

in epidemiologic studies 1--1

Legal consequences of failure to test

Union member initiative

S o m e t h i n g e l s e , W h a t ?

11. What criteria were employed in the A. Predictive value of the test D. Scientific consensus ❑choice of a specific test?

B. Sensitivity of the test E. Coat of the test ❑C. Specificity of the test P. Something else. What? ❑


IF’ CYTOGENETIC TESTING HAS EVER BEEN DONE , PLEASE ANSWER QUESTIONS 12-16. IF NOT, PLEASE SKIP TO Q. 18.

1 2 . Has your union tested members for exposure to chemicals by looking for . . .

Yes No

A. chromosomal aberrations

B. sister chromatid exchanges (SCE)

. mutations by assaying the DNA

D. ❑ utatfons by assaying the enzymes ❑ 0

E. something else? What?

ENTER BELOW NAME OF EACH SPECIFIC CONDITION TESTED FOR (e.g., SCE). ANSWKR QUESTIONS 13 & 14 FOR FACE. IF MORE THAN 4CONDITIONS, RECORD ON ADDITIONAL SHEET Ok’ PAPER.

ENTER SPECIFIC CONDITION NAME HERE-:

13. Was testing done . . .

a) routinely (e.g., yearly) or during

regular specified circumstances?

b) for research purposes (e.g.,hypotheses testing)?

c ) for any other reasons?

14. Was testing to detect increased risk of

disease ever based on a member’s . . .

a) job category?

b) s e x ?

c ) ethnic or racial background?

I IYes No Yes— —

❑ o• 1

No Yes No. —

❑ lcl

❑ n ❑ 0

❑ n ❑ lcl

❑ 0 ❑ n❑ o

❑ 0 ❑ o ❑ o15. What factors have been considered in A. Coat benefit analysis

decisions to implement any cytogene-tic testing programs?

B. Data suggesting a possible associationbetween chemical exposure and illnessin animal studies

c. Data suggesting a possible associationbetween chemical exposure and illness

in epidemologic studies

D). Legal consequences of failure to test

E. Union member initiative

Q. Something else. What?

Yes No—

❑ icl

❑ 0

❑ (3

❑ 0

❑

❑

16. What criteria were employed

choice of a specific test?

in the A. Predictive value of the test• 1 D.

B. Sensitivity of the test E .

C. Specificity of the test F.

Scientific consensus

Cost of the test ❑S o m e t h i n g e l s e . W h a t ? ❑


.7.. Which actions has your union ever taken as a result of biochemical genetic or cytogenetic

Ž

●

✎ ✎ ✎

.. .

Informed member of a potentialproblem

Suggested member seek jobelsewhere

Suggested member seek transfer toa different job in the corporation uRecommended corporation implementengineering controls u

Recommended corporation providepersonal protection devices

F. Recommended corporation implementa research program

G. Recommended corporation discontinuea product or change materials in ap r o d u c t

H. Implemented our own researchprogram

I . Negotiated items C,D, E or F ina health/safety contract

J. Some other action. What?

❑

8. Has your union ever conducted any testing on wholeanimals or their cultured cells for . . . Yes’

A. chromosomal aberrations or sister chromatid exchangesas a result of exposure to workplace chemicals?

B. genetic predisposition to harmful effects from exposureto workplace chemicals?

Q9. What are the major industrial classifications (such as chemical, food, or textiles) ofthose companies in the Fortune 500 in which your members work?

0. Please use this space for your comments, if any, about these questions.

Thank you for completing this questionnaire. The information you have provided will be held instrict confidence. Data will be made available to Congress in statistical form only.

●

App. C—Survey Materials . 221

OCCUPATIONAL GENETIC TESTING ADVISORY PANEL

Arthur D. Bloom, M. D., ChairProfessor of PediatricsDirector of Clinical Geneticsand DevelopmentColumbia University

J. Grant Brewen, Ph.D.DirectorMolecular and Applied GeneticsLaboratoryAllied Chemical Corporation

Eula B ingham, P h . D .Professor, Environmental HealthUniversity of CincinnatiFormer Director, OSHA

Patricia Buffler, Ph.D.Associate Dean for Researchand Associate Professor ofEpidemiologyUniversity of TexasSchool of Public Health

Ira Cisin, Ph.D.Director, Social Research GroupGeorge Washington University

Burford W. Culpepper, M.D.Assistant Director, MedicalDivisionE. I. DuPont de Nemours & Company

James D. EnglishAssociate General CounselUnited Steel Workers of America

Neil Holtzman, M.D.Associate Professor of PediatricsJohns Hopkins University

Thomas O. McGarityProfessor of LawUniversity of Texas at Austin

Rafael Moure, Ph.D.Industrial HygienistOil Chemical & Atomic Workers Union

Robert F. Murray, Jr., M.D.Professor of Pediatrics and MedicineChief, Division of Medical GeneticsHoward UniversityCollege of Medicine

Elena N ight inga le , M.D., Ph.D.Senior Program OfficerInstitute of MedicineNational Academy of Sciences

Gilbert Omenn, M.D., Ph.D.Science and Public Policy FellowThe Brookings Institution

William N. Rem, M.D., M.P.H.Associate Professor of MedicineDirector, Rocky Mountain Centerfor Occupational and Environmental HealthUniversity of Utah

Stuart Schweitzer, Ph.D.Professor and DirectorProgram in Health Planningand Policy AnalysisUCLA School of Public Health

Robert Veatch, Ph.D.Professor, Medical EthicsThe Kennedy Institute of EthicsGeorgetown University

Paul Kotin, M.D.ConsultantFormer Medical DirectorJohns-Manville Corporation


Respondent Comments About Survey

Respondents were asked to comment about any aspect of the survey or

questionnaire in a space provided on the questionnaire and one the postcard.

The following list comprises the totality of comments received from the

respondents. They have been grouped by status of tester: Current Tester,

past Tester, Future Testers with prior testing experience, and No Testing

(Past, Present, Future), Information contained at the end of a quote Is

descriptive information about the respondent provided by the contractor. In

cases where a number of appears, it is the Standard Industrial Classification

(SIC) Code as given by the respondent. The quotes are printed as written by

respondent. No edit ing has been done.

Comments by present testers

“Answers should not. be taken to imply any large scale program or problem.Medical/Ind Hygiene depts have done ‘common sense’ preventive sampling andt e s t i n g t o r e a s s u r e employees in specif ic small areas of c o m p a n y w h e r e e v e nl o w l e v e l r i s k m i g h t o c c u r "

- p r e s e n t l y b i o c h e m i c a l g e n e t i c t e s t i n g a n d p a s t b i o c h e m i c a lg e n e t i c t e s t i n g

“We do a chemical profile (blood test) that tests 20 different factors (sic)in the blood and CBC as a matter of course for pre-placement and annualphysical.”

-presently biochemical genetic testing and past biochemicalgenetic testing

"Cytogenetic testing is one aspect of continuing health evaluations on

personnel engaged in “hands on” maintenance work in 500 KV electrictransmission lines.”

-presently cytogenetic testing and past cytogenetic testing

Comments by past testers

“Sickle cell trait testing was offered as a service to employees for a brief

period at the request of the state health department. It was never used as ascreening procedure in relation to the job.”

-past biochemical genetic testing

—.


“Only testing has been for sickle trait or mediterranean anemia trait in a few

people of child bearing age as part of preventive medical program notconsistently”.

-past biochemical genetic testing

Comments by companies that anticipate future testing, but have not conducted

any testing to date:

“Company supports research activities relevant to No. 18 through trade

associations and C1lT.”

“Such tests as described in 18A are run on materials and products routinely aspart of an overall safety assessment.”

“Some essential questions have been omitted--namely,1. are materials being used with chromosomal and/or genetic harmful

effects?

2. is there clinical evidence or even suspicion to justifyperforming such tests? (in a given workplace)

3. a r e t e s t s r e s u l t s i n d i c a t o r s ( v a l i d a n d r e l i a b l e ) o f a c t u a l o rp o t e n t i a l h e a l t h r i s k s t o e m p l o y e e s ? ”

“18A, “Chromosomal aberrations” may be included in a mutagenic screen onchemicals or as a followup to mutagenic testing.”

“It is conceivable we may wish to initiate a limited project of cytogenetic orbiochemical genetic testing in employees “exposed” to nuclear radiation innext 5-10 years. Our stringent monitoring controls on radiation exposure maynot result in this requirement. However, it is just a possibility.”

“What may be done (#3 and #6) will depend upon demonstration that indicated

procedures have practical utility.”

FROM A UNION QUESTIONNAIRE: “(NAME DELECTED BY NORC) Plant may have beencytogenetic testing by company for which they worked benzene (sic)”

Comments from companies not now, previously, or in the future planning totest.

It --- Inc. is a multifacility manufacturing co. that is not involved in

genetic testing.” (540, aircraft)

“We do not perform health testing for the specific purpose of detecting

genetic or cytogenetic health effects of occupational exposure to chemicals.We have not conducted this type of health testing since we have not identifiedchemicals to which our employees are exposed that could potentially causethese genetic health problems.” (563, electric utility)

“I really wonder if the value of this project will compare favorably with the

cost of it - our federal budget deficit is large and we have operated in thered for decades - this looks like the sort of expenditure the USA could getalong without!” (547, cement and construction materials)


“Not needed. Virtually no chemical exposure. Operations are light assemblyof prefinished parts of materials”. (612, recreational vehicles)

“ T o t a l l y o u t o f c o n t e x t w i t h t h e n a t u r e o f o u r b u s i n e s s . ” (613, electronicequipment)

“Does not seem relative to our business”. (616, gas and oil production)

“The need or cause for such testing has never been revealed”. (617, cement)

“Our company presently has done noise level testing at all facilities and“Blood-Lead Chemistry” and “Chest X-ray” testing of all employees working inpainting rooms on an annual basis”. (618, Hand tools)

“Privacy of individual employees should not be imposed upon unless there is aclear indication from Public Health authorities that program is warranted andpublic is informed in a manner that would educate employees on the need forit.” (619, books and journals)

“We h a v e n o i n f o r m a t i o n t h a t a n y p r o d u c t s w e p r o d u c e r e q u i r e a n y s u c ht e s t i n g ” . (620, refractories and building materials)

“Company maintains minimal risk environments [through] selective andcontrolled use of chemical and physical agents in conjunction with continuingindustrial hygiene appraisals. (622, cross linked plastics)

“Ref. Question #18: The American Petroleum Institute acting on behalf of theindustry, is engaged in a major, on-going program of animal testing. Genericpetroleum products are employed in this toxicology testing program whichincludes genetic considerations.” (286, chemicals)

“We are computer and word processing system manufacturers and are not involvedin chemical or genetic work.” (292)

“Thank you for sending questionnaire. However, it does not seem relevant to

our business or to our future plans.” (219; flat glass, fluid systemcomponents, plastic products)

FROM A UNION QUESTIONNAIRE: “Union never conducted tests. Company screeningoften by union demand has been limited to clinical tests and biologicalmonitoring, no cytogenetic or biochemical genetic tests”. (103, union)

“We have conducted and continue to conduct chemical exposure testing on wholeanimals and their cultured cells for chromosomal aberrations and sisterchromatid exchanges. This is sometimes done as one part of our toxicologicalevaluations conducted to enable the proper planning and management whichassures safe handling and usage of intermediate and product materials.” (453,petroleum products and petrochemicals)

“We have used these tests as screening procedures in animals. We do not findthem sufficiently validated for use on our employees, or prospectiveemployees.” (478, petrochemicals)

App. C—Survey Materials Ž 225

“In our opinion none of our Industrial operations are associated withenvironmental hazards which indicate any employee health benefit from eitherbiochemical genetic or cytogenetic testing.” (479, mining, smelting)

“We believe cytogenic (sic) testing methodology to screen human populationsrequires further standardization and validation before we would consider usingit in our employee population. As a general principle, we are reluctant toutilize a test on employees unless we can explain the result and course ofaction required. Question 7C was confusing. It was not clear to us whatmeasurements are envisioned in the category of allergic respiratory disease orcontact dermatitis.” (366, petroleum)

“Due to the great diversity of operations of this corporation, thisquestionnaire is not applicable.” (371, no industrial code given)

“We do not engage in any form of biochemical genetic testing or cytogenetictesting. We are primarily a metal forming industry.” (375)

“I have no questions about the above. As a physician who has been in full timeoccupational practice for 33 years I was amazed to read in the lay press thatsome union officials were alleging widespread use or plans for use of genetictesting by industry.” (385, chemicals)

“To date we have not had t-he exposure, and therefore have not seen the need todo these tests.” (305, Food)

“Attention John Gibbons: How can your organization afford Federal Expressservice from zip code 10001 to 10591 - 20 miles to the North of Manhattan.Signed, A Hard Working Taxpayer” (201, Food processing)

“Our employees are incidentally exposed to degreasers, solvents and non-leadbased paints. We look to NIOSH to define areas where biochemical and othertesting is prudent. We would discontinue use of any product which wouldexhibit qualities that would make such testing prudent however we wouldperform the testing of any of our employees so exposed.” (207, fabricatedmetal products)

“This questionnaire is another example of wasting Federal tax monies. I would

hope that Congress has more important business to conduct than the abovequestionnaire. Also there must be a more economic way to mail it than FederalExpress overnight letter at $9.50.” (231, Lumber and Paper mfg.)

“Biochemical genetic testing: If any thing should be done, it would beaccomplished post-natally since appropriate family history would beavailable. Cytogenetic testing: would be appropriate in areas of exposure topotential chromosomal damaging agents (radation, chemicals, etc.)” (403,manufacturing and resale electricity)

“Is any industry doing this testing?” (118, Food)

“We have reviewed the current data on cytogenetic testing both in animals andin man and feel that. these techniques are not yet applicable to standardmedical surveillance of workers. It is recognized that the techniques mayhave potential value in risk assessment, and we hope that continued research


work will better define that applicability. We feel strongly that currentcapabilities in the field do not allow the widespread use of these techniquesat the present time.” (121, manufacture of medical products for the healthcare industry, including both devices and drugs)

n - _ Inc. was selected to participate in a survey conducted by NORC for theOffice of Technology Assessment (OTA) of the U.S. Congress on the state of theart of genetic and cytogenetic testing programs. By error, we received a copyof the questionnaire to be completed by a Union as well as a copy to becompleted by a corporation.I was concerned to note that the questionnaires were different in thatquestions no. 19 and 20 appearing on the union version of the form were absentfrom the corporation version. I am hopeful that any information you receivedfrom the union on these two questions will be deleted from the report toCongress since the data is obviously biased.Many corporations have decided not to implement genetic and cytogeneticprograms since the correlation of results of such testing with frank clinicaldiseases has not been demonstrated. This lack of predictability can lead toincorrect conclusions on the part of environmentalists and governmentalagencies in assessing the risk of certain chemicals and substances. doesconcur with the scientific literature which indicates that the proportion ofoccupational diseases attributable to genetic predisposition ranges from 10 to20 per cent with diseases attributable to chromosomal aberrations ranging 1 to5 per cent.If you have any additional questions, please let me know.” ( )

A p p e n d i x D

Background Frequencies forChromosomal Aberrations

The data presented in table D-1 are not intended fordirect comparisons of values obtained between labora-tories; rather, they are meant to convey a sense of therange of normal background values for chromosomalaberrations reported in the literature.The following abbreviations are used for culture

media: D—Difco; E—Eagle’s basal; [G—Gibco; H—Ham’sF1O; M–McCoy’s 5A; T-TC 199; and 1640–RPMI1640.

The following abbreviations are used for aberrations:(CTD-chromatid breaks; C—chromosome breaks;

R—rings; D-dicentrics; E-exchanges; Cu—"unstable”aberrations, according to Buckton, et al.; Cs—"stable”aberrations, according to Buckton, et al,; AC —abnor-mal cells. All values are percentages. Gaps are not in-cluded, except where noted otherwise. In some casesit has been necessary to recalculate the original data.A continuous line covering more than one complex

aberration indicates that the aberrations were com-bined in the resulting frequency.

Table D-1 .—Background Frequencies for Chromosomal Aberrations

N u m b e r o f N u m b e r o f C u l t u r e C u l t u r eReference

- -

L e g a t o r a n d H o l l a e n d e r , 1 9 7 5 . . , . . .Lubs and Samuelson, 1967 . . . . . . . . . . .

subjects cells medium time(hr) CTD C R D E Cu CS AC

— —— —

6.078.3

7510

311,084

1,299524

52134

79

1020

20

68

1531611

44135

38565

343444

735342175

18

65

311243

2.291 ?

T

T?

7?

T?

?M

H

MEH

TT?

7

?7

varied

T?7

varied7

1640H

HH?

?68-72

7272

7272

5056

6.72 1.48 0 0.17 0.175.9 1.0 0,223,720

29,70915,75425,9807,6535,200

-13,40079 7,900

1,00020 2,000

1,950

7,406

1,43023,20012,700

?1,312

50038 1,140

500600500

34 3,40034 3,400

8,000

2795,0543,4002,100

15,000

3,600

3001,800

3,1002,400

356297

6.0~7.0

Littlefield and Goh, 1973 . . .Mattei, et al., 1979. . . . . . . . . . . . . . . . .

– 3.0 0 0.12 0.324.6 1.7 0.71

— —— —

1,84.7

1.3-1.81,08

0.93

~ 0.6a

- 0 . 9

- 0 7

Aula and von Koskull, 1976 .., . .Ayme, et al., 1976 . . . . . . . . . . . . .

Husgafvel-Pursiainen, et al , 1980. . . . . . . . . . .A Review, 1975 . . . . . . . . . . . . . . . . .

— — — — — — —— .2.4 1.4 0.81

— — — — — — —— —— – 0 . 1 8 0.80

— — 0.23 0,59Awa, et al,, 1971 ., . . . . . . . . . . . — —Honda, et al., 1969 . . . . . . . . .Brandom, et al., 1978a . . . . . . . . .

46-50~48

2.7 0.4 0.1 0 0.1— - 0 . 7 - 0 . 2— —~0.2

0.4 0.2— —

Brandom, et al., 1978b ., ., . . 50 or 72 — —— – 0 . 6 5

0.9 0.2 0 0 0. — – 0.078 –— – 0 0 2 —

~1,11,1—

— —Brandom, et al., 1972 . . . . . . . . . .Lloyd, et al., 1972 . . . ... . . .Bauchinger, et al., 1980 . . . . . . . . . . . .

Burgdorf, et al., 1977 ., ., . . . . . . . .Nordenson, et al., 1978 ., . . . . . . . .Tough and Brown, 1965 ......., . . . . .

50 & 724848

— —.— —— — —

7272

40-50

— — . — — . 0-3— — — — 1,6— — 0.6 0.4 –— — 0.6 0.8— — 0.6 0.4 —— — 1.67 0.5 —— — 0.4 0.4 –— — 0,49 0.04 –— — 0,61 0.09 –

— — 1,4— — — — 2.5— 0.18 — — 1.37— — — — 2.06— — — — 1.33

— — 2.38

0,4 0.1 ————————

——————.

—40-50Tough, et al,, 1979. ...., . . .

—

68-7068-70

72

7256-5856-68

Forni, et al., 1971a ., . . . . . . . . . . .Forni, et al., 1971b . . . . . . . . . . . . . . . . . . . .Picciano, 1979b ... . ., . . .

—

0.35 0.061.1———

Watanabe, et al., 1980 . . . . . . ., . . . . .Kucerova, et al., 1977 ... . . . . . . . . .Sram, et al., 1980. . . . . . . . . . . . . . . .

—0.280.97

——

2.15—

0.0872 0.51Picciano, 1979a ., . . . . . . . . .

Mitelman, et al., 1980 ... ... . . . . . . . 72 1,6b — —— — —

— — 2.9— — — ~0.67

?— — — ‘?— — — 0.67— — — 6.0— — — 4.7

72 —45 l/~ 0.11

Shiraishi and Yosida, 1972. .., . . . . .Deknudt, et al , 1973 . . . . . . . 0.33 0

0,42 — –45-48 4.4648 —

48 & 72 —

O ’ R i o r d a n a n d E v a n s , 1 9 7 4D e k n u d t a n d L e o n a r d , 1 9 7 5 ,Bui, et al,, 1975 . . . . . . . .

— — —— — —

— — — —

227


Table D-1 .—Background Frequencies for Chromosomal Aberrations—Continued

Number of Number of Culture CultureReference subjects cells medium time(hr) CTD C R D E Cu Cs AC

Bauchinger, et al., 1976 ., . . . . . . . . . . . . . . .

Forni, et al., 1976 . . . . . . . . . . . .Deknudt, et al., 1977 ...., . . . . . . . . . .O’Riordan, et al., 1978 . . . . . . . . . . . . . . . . . . .Forni, et al,, 1980 . . . . . . . . . . . . . . . . . . . . .Maki-Paakkanen, et al., 1981 . . . . . . . . .Funes-Cravioto, et al, . . . . . . . . . . . . . . . . . . .Maki-Paakkanen, et al., 1980 ....., . . . . . . . . .Hogstedt, et al., 1981 . . . . . . . . . . . . . . . . . .Thiess, et al., 1981 . . . . . . . . . . . . . . . . . . .Ducatman, et al., 1975 . . ... . . . . . . . . . . . .Purchase, et al,, 1976 ......, . . . . . . . . . . . . .

Szentesi, et al,, 1976 . . . . . . . . . . . . . . . . . . . . . .

Hansteen, et al., 1975 ...., . . . ...

Fleig and Thiess, 1978, . . . . . . . . . . . . . . . .

Kucerova, et al,, 1979 ...., . . . . . . . . . . . . .

Anderson, et al,, 1980, . . . . . . . . . . . . . . . . . . .

15

11201312124216152110195

4944163220

86

1,6501,0753,0001,2431,1301,2004,2003,2001,5002,100500

1,900500

2,5232,9881,6003,2002,000800600

H

THHT?T?TTGD

48 0.2 – 0.26 — — 0.47

4.88C2.53 C

—

2-04,762.41.61.4—————1.792,332.11.81.331 171.00.383.472.471.82.5——8.52.01.380.81.4

68-70 – – – – – – –48 — – — — — — —

45-48 0.08 – — — – 0.8 0.02487727250

70-7265-68

48 or 72

———————————————

———————————————

— — —— — —

0.08 –— —

— — —— — —— — —— — —— — —— — —— — —— — —— — —— — —

— —— —— —— —0.3 2.90.53 0.100.50 00.35 –0.56 –

48

? 48 — —— — —— — —

— —?‘?

D

??

48 & 72

— —— — —

Firs t sampl ing:Second sampling:

First sampling:Second sampling:— — —

— —0.5 00.5 00.75 00.13 0

8 800565

1,7001,900500

1,40011,0001,000651

1,8001,594398288

Kirkland, et al., 1978 ......, . . . . . . . . . . . 171957

22

107

1810114

T 48 — — ———

———

— — —— — —

— —Meretoja, et al., 1981 . . . . . . . . . . . . . . . .Hogstedt, et al., 1980 . . . . . . . . . . . . . . . .Bauchinger, 1981 ....., . . . . . . . . . . . . . . . .

Waksvik, et al., 1981 . . . . . . . . . . . . . . . . . . . . .Verschaeve, et al., 1976 . . . . . . . . . . . . . . . .Thiess and Fleig, 1978 .., . . . . . . . . . .Cervenka and Thorn, 1974 .., . . . . . . . . . . . . .Hook, et al., 1974 . . . . . . . . . . . . . . . . .

TMH

HT?

T?

64-667248

— ——

0.16— — — — —

0.05 0.09 — —— — —48

7270-72

7272

0.3—————

— ——————

— — — — —— — — — —— — — — —— — — — —

— — — — — —— —aExclud1ng CTD and c’blncludes only breaks and exchangescGaps Included.

SOURCE Office of Technology Assessment

Appendix D references 38(kV-Systems, ” Radiat. Environ. Bio. 19:23.5-238, 1981.

Bauchinger, M., et al., “Chromosome Analyses ofNuclear-Power Plant Workers, ” Int. J. Radiat. Biol.38:577-581, 1980.

Bauchinger, M., et al., “Chromosome Aberrations inLymphocytes After occupational Exposure to Leadand Cadmium, ” Mutat. Res. 40:57-62, 1976.

Brandom, W. F., et al., “Chromosome Aberrations asa Biological Dose-Response Indicator of Radiation Ex-posure in Uranium Miners,” Radiat. Res. 76:159-171,1978.

Brandom, W. l?., et al., “Somatic Cell Genetics of Urani-um Miners and Plutonium Workers, ” in Late Effectsof Ionizing Radition, 1:507-518 (Vienna: interna-tional Atomic Energy Agency, 1978).

Brandom, W. F., et al., “Chromosome Aberrations inUraniurn Miners Occupationally Exposed to 222Radon, ”Radiat. Res. 52:204-215, 1972.

Buckton, K. E., et al., "(A Study of the ChromosomeDamage Persisting After X-Ray Therapy for Ankyl -

“A Review of Thirty Years Study of Hiroshima andNagasaki Atomic Bomb Survivors, ” J. Radiat. Res.,Suppl., 1975.

Anderson, D., et al., “Chromosomal Analysis in VinylChloride Exposed Workers: Results From Analyses18 and 42 Months After an Initial Sampling, ” Mutat.Res. 79:151-162, 1980.

Aula, P., and von Koskull, H., “Distribution of Sponta-neous Chromosome Breaks in Human Chromosomes ,“Hum. Genet. 32:143-148, 1976,

Awa, A. A., et al., “Chromosome Aberration Frequencyin Cultured Blood Cells in Relation to Radiation Doseof A-Bomb Survivors,” Lancet ii:903-905, 1971.

Ayme, S., et al., "Nonrandom Distribution of Chromo-some Breaks in Cultured Lymphocytes of NormalSubjects, ” Hum. Genet. 31: 161-175, 1976.

Bauchinger, M., et al., “Analysis of Structural Chromo-some Changes and SCE After occupational Long-Term Exposure to Electric and Magnetic Fields From

App. D—Background Frequencies for Chromosomal Aberrations ● 229

osing Spondylitis, ” Lancet ii:676, 1962.Bui, T-H., et al., “Chromosome Analysis of Lympho-

cytes From Cadmium Workers and Itai-itai Patients, ”Environ. Res. 9:187-195, 1975.

Burgorf, W., et al., “Elevated Sister Chromatid Ex-change Rate in I,ymphocytes of Subjects TreatedWith Arsenic, ” Hum. Genet. 36:69-72, 1977,

Cervenka, J., and Thorn, H. L,., “Chromosomes andSpray Adhesives, ” N. Eng. J. Med. 290:543-545, 1974.

Deknudt, Gh., et al., “Chromosome Aberrations ob-served in Male Workers Occupationally Exposed toLead, ” Environ. Physiol. Biochem. 3: 132-128, 1973,

Deknudt, Gh., et al., “Chromosomal Aberrations inWorkers Professionally Exposed to Lead, ” J. Tox-icol. Environ. Health 3:885-8:)1, 1977,

Deknudt, Gh., and Leonard, A., “Cytogenetic Investiga-tions on I.eukocytes of Workers From a CadmiumPlant, ” Environ. Physiol. Biochem. 5:319-327, 1975.

Ducatman, A., et al., "Vinyl Chloride Exposure andHuman Chromosome Aberrations, ” Mutat. Res.31 : 163-168, 1975.

Fleig, 1., and Thiess, A. M., “Mutagenicity of Vinyl Chlo-ride: External Chromosome Studies on Persons Withand Without VC Illness, and on VC Exposed Ani -mals, ” J. Occup. Med. 20:557-561, 1978.

Forni, A., et al., “Chromosome and Biochemical Studiesin Women Occupationally Exposed to Lead, ” Arch.Environ. Health 3.5: 139-145, 1980.

Forni, A., et al., ‘(Initial Occupational Exposure to Lead:Chromosome and Biochemical Findings, ” Arch.Environ. Health 31:73-78, 1976.

Forni, A., et al., “Chromosome Changes and Their Evo-lution in Subjects With Past Exposure to Benzene, ”Arch. Environ, Health 23:385-391, 1971,

Forni, A., et al., “Chromosome Studies in Workers Ex-posed to Benzene or Toluene or Bet}], ” Arch. En-viron, Health 22:373-378, 1971.

Funes-Cravioto, F., et al., ‘{(chromosome Aberrationsand Sister Chromatid Exchange in Laboratory andFactory Workers and Their Children ,“ in: H. J. Evansand L). (D. C ,Lloyd, eds., “Mutagen-induced Chromo-s o m e ntw@: [ ‘nit’ (:rsit} Press,1 978),

Iiansteen, 1-1,., et al., “Effects of l’iny] Ch]oride in hlan:A (;ytogenetic FolloIv-up StuciJ~, ” Afutat. Res. 31:163-168, 197.5.

Ho#tedt, B., et al,, “hlicronuclei and Chromosome,lberrations in Bone kiarroi~’ (;ells and [,ymphocjrtesof Iiu ma ns F.xposed hlainl~’ to Petroleum \’apors, ”Hereditas W: 179-187, 1981.

Hogstedt, B., et al., “Cytogenetic Study of Pesticidesin Agricultural it’ork, ” Hereditas 92:1 77-178, 1980.

flonda, ‘I’., et al., ‘((:hromosorne Atwrrations and (:ul -ture ‘t’irl]e, ” [J’tqq’enf?t, 8:1 17-1 ZLI, 196S.

Hook, E. B., et al., “Negati\7e Outcome of a Blind Assess-ment of the Association Bet\\reen Spra]r Adheshw Ex-posure and Human Chromosome Breakage, ” I’ature(London) 249:165-166, 1974.

Husgaft~el-Pursiainen, K., et al,, “Smoking and SisterChromatid Exchange,” }fereditas 92:247-2.50, 1980.

Kirkland, D. J., et al., “Chromosomal []aHla~P and HairDyes, ” Lancet i:124-128, 1978.

Kucerova, hf., W al., “Comparatiife Evaluation of theFrequency of Chromosomal Aberrations and theSCF, Numbers in Peripheral I,Jmpho[}tes of \t’ork -ers occupationally F.xpo5ed to l’ir~Jl (;hloridc illono -mer, ” ~t~utc? t. ~~S. 67:97-1 ()(), 1979,

Kucero~7a, hf., et al., “Alutagenic Effect of Epichloro-hydrin: 11. Analysis of Chromosomal Aberrations inLymphocytes of Persons C)ccupationall) Exposed toKpichlorohydrin, ” ,Ifutat. Res. 48:35.5-360, 1977.

Legator, M. S., and Ho]]aender, A. (eds. ), “()(>(>l]l);iti()r~:i]Nlonitoring for (knetic Hazards, ” ,LInn. IA’. 1’. ,Al(a(/.

Sci. 269: 1975.I,ittlefield, L. G., and Goh, K-O., “CJrtogenetic Studies

in Control Nlen and L1’omen: I, \ ‘ariations in AhPrI’a-tion Frequencies in 29,709 hleta}~hasri From 305

Cultures ohtained ()~wr a Three-J’rar Period ,“ (jl’ttJ-genet. L’ell (knet. 12:1 7-34, 1973.

Lloyd, D. C., et a]., ‘(The In(-idence of [~nstah]e Chro-mosome Aberrations in Peripheral Blood I.J7mpho-cytes From [Tnirradiatccl and ()(ucll]l:iti()rl[ill~ I~x-posed People, ” Afural. Re.s. 72:.523-532, 1980.

I.uhs, H. A., and Sarnuelson, J., ‘((;hl’or~losor~l[~ ,lbnor-malities in [Jymphocjrtes From Normal Fiunlan Sul)-jects ,“ CJtogenet. 6:402-411, 1967.

kIaki-Paakkanen, J., et a]., “Chromosonlr Aberrationsand Sister Chrornatid Exchanges in I, Pad-k’, ~posed1$’orkers, ” Hereditas 94:269-27.5, 1 $)81.

hlaki-Paakkanen, J., et al., “’I’(~l~]erl(>-F,x~)os(+(l J1’orkersand Chromosome Aberration s,” J. ‘f’(~.k ice]. lh]~’iron,Health 6:775-781, 1980.

Nlattei, N1. G., et al., “Distribution of Spontaneous (’chr-

omosome Breaks in Nlan ,“ q’tog(=mt. [.’(’11 (L’llet.23:9.5-102, 1979.

Nleretoja, ‘I’., et al., “occupational St~rrne Exposureand Chromosornal Aberrations ,“ ,kfutat Res, .56: 193-197, 1977.

Nlitelman, F., et al., “occupational Exposure to EpoxyResins Has NO CJ40genetic Effect ,“ ,!lutat. fles. 77’:345-348, 1980.

lNorclenson, E., et al,, “(1(’c~l[)iitiollal and I;r31i1’orlrllent:i IRisks In and Around a Snleltrr in Norttwrn SJiTmlen:11, Chrornosomal Aberrations in J\’ork(~rs Esposedto Arsenic, ” Herditas 88:47-.50, 1978,

()’Riordan, Al. 1,,, et a]., ‘([;]lr’or~losor~le” Studies on BloodI,~~mp]~~~~tes o f hlen ()(’(’~l~liitiolliill~r h;xposd to(Yadmiunl,” ,Iluta t Re.s, .58 : 30.5 -:1 1 1, 1978.


O’Riordan, M. L., and Evans, H. J., “Absence of Signifi-cant Chromosome Damage in Males OccupationallyExposed to Lead, ” Nature (London) 247:50-53, 1974.

Picciano, D., “Cuytogenetic Investigation of Occupation-al Exposure to Epichlorohydrin, ” A4uta~. I/es. 66:169-173, 1979.

Picciano, D., “Cytogenetic Study of Workers Exposedto Benzene, ” Enkriron. Res. 19:33-38, 1979.

Purchase, I. F. H., et al., “Chromosomal Effects inPeripheral Lymphocytes, ” Proc. lby. Soc. Med.69:290-291, 1976.

Shiraishi, Y., and Yosida, T. H., “Chromosomal Abnor-malities in Cultured Leukocyte Cells From Itai-itaiPatients, ” Proc. Japan Acad. 48:248-251, 1972.

Sram, R. J., et al., “Cytogenetic Analysis of PeripheralLymphocytes in Workers Occupationally Exposedto Epichlorohydrin, ” Mutat. Res. 70: 115-120, 1980.

Szentesi, I., et al., ‘(High Rate of Chromosome] Aberra-tion in PVC Workers, ” ltfutat. Res. 37:313-316, 1976.

Thiess, A. M., et al., “hlutagenicity Study of WorkersExposed to Alkylene Oxides (ethylene oxide/propyl-

ene oxide) and Derivatives, ” J. OCCUp. Med. 23:343-347, 1981.

Thiess, A. M., and Fleig, I., “Analysis of Chromosomesof Workers Exposed to Acrylonitrile, ” Arch. Toxicof.41:149-152, 1978.

Tough, I. M., and Court Brown, W. M., “ChromosomeAberrations and Exposure to Ambient Benzene, ”Lancet i:684, 1965.

Tough, I. M., et al., “Chromosome Studies on WorkersExposed to Atmospheric Benzene: The Possible In-fluence of Age,” Europ. J. Cancer 6:49-55, 1970.

Verschaeve, L., et al., ‘(Chromosome Aberrations In-duced by Occupationally Low Mercury Exposure, ”Environ. Res. 12:306-316, 1976.

Waksvik, H., et al., “Chromosome Analyses of NursesHandling Cytostatic Agents, ” Cancer Treat Rep. 65:607-610, 1981.

Watanabe, T., et al., “Cytogenetics and Cytokineticsof Cultured Lymphocytes From Benzene-ExposedWorkers, ” Int. Arch . Occup. En\~iron. H e a l t h46:31-41, 1980.

A p p e n d i x E

Background Frequencies forSister Chromatid Exchanges

These data are not intended for direct comparisons, but rather to convey a sense of the variabilityin the literature.

The following abbreviations are used for culture media: EB—Eagle’ basal; G--Gibco 1A; ii—Ham’s F10;MEM —Delbecco's minimal essential medium; T-TC 199; and 1640.

Table E-1 .—Background Frequencies for Sister Chromatid Exchanges

Number of CultureReference Number of subjects cells/subject medium Bud R ( g/ml ) SCE/ce l l

Carrano, et al., 1980 . . . . . . . . . . . . . . . . . . . 8 40-80 MEM variable 7.59Morgan and Crossen, 1977 . . . . . . . . . . . . . . 50 20 H 10 7.9Crossen, et al., 1977 . . . . . . . . . . . . . . . . . . . . 20 20 G 10 6.37Lambert, et al., 1978 . . . . . . . . . . . . . . . . . . . . 14 smokers >= 20 ? 100 16,2

2 9 n o n s m o k e r s — 13.1Husgafvel-Pursiainen, et al., 1980 . . . . . . . . . 43 smokers 30 T 5 9.6

40 nonsmokers 8.1Goh, 1981 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 old 30 ? 3 9.07

23 young 8.05Butler and Sanger, 1981 . . . . . . . . . . . . . . . . . 19 > 1 5 EB 6 8.4Butler, 1981 . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 > 2 0 6 8.1-8.7Burgdorf, et al., 1977 . . . . . . . . . . . . . . . . . . . 44 ~ 1 5 T 30 5,8Watanabe, et al., 1980 . . . . . . . . . . . . . . . . . . . 7 - 4 0 T 10 11.4Mitelman, et al., 1980 . . . . . . . . . . . . . . . . . . . 18 20 7 ‘? 8.7Maki-Paakkanen, et al., 1981 . . . . . . . . . . . . 12 30 ? 5 9.8Funes-Cravioto, et al. . . . . . . . . . . . . . . . . . . . 15 20 T 7 13.5

6 12.2Hogstedt, et al., 1981 . . . . . . . . . . . . . . . . . . . 15 30 T 5 8.0Garry, et al., 1979 . . . . . . . . . . . . . . . . . . . . . . 12 20 MEM 4.5 5.98Hansteen, et al., 1975 . . . . . . . . . . . . . . . . . . . 16 30 ‘? 2 7.5Kucerova, et al., 1979 . . . . . . . . . . . . . . . . . . . 8 50 ? ? 9.41Anderson, et al., 1981 . . . . . . . . . . . . . . . . . . . 6 30 1640 25 6.68Kirkland, et al., 1981 . . . . . . . . . . . . . . . . . . . . 14 varied 1640 1 50? 10.77Bauchinger, et al., 1981 . . . . . . . . . . . . . . . . . 22 40 ? 10 7.09Waksvik, et al., 1981 . . . . . . . . . . . . . . . . . . . . 10 30 7 5 6.5Sorsa, et al., 1981 . . . . . . . . . . . . . . . . . . . . . . 10 ‘? ? 7 ~8.OSOURCE Office of Technology Assessment

Appendix E references

Anderson, D., et al., “Chromosomal Analysis in VinylChloride Exposed Workers: Comparison of theStandard Technique With the Sister -Chromatic Ex-change Technique, “ Mutat. Res. 83:137-144, 1981.

Bauchinger, M., et al., “Analysis of Structural Chromo-some Changes and SCE After Occupational Long-Term Exposure to Electric and Magnetic Fields From380 kV Systems, ” Radiat. Environ. Biophys. 19:235-238, 1981.

Burgdorf, W., et al., “Elevated Sister Chromatid Ex-change Rate in Lymphocytes of Subjects TreatedWith Arsenic, ” Hum. Genet. 36:69-72, 1977.

Butler, M. G., and Sanger, W, G., “Increased Frequen-

cy of Sister-Chromatid Exchange in Alcoholics ,“Mutat. Res. 85:71-76, 1981.

Butler, M. G., ‘( Sister-Chromatid Exchange in Four Hu-man Races, ” Mutat. Res. 91:377-379, 1981.

Carrano, A. V., et al., Variation in the Baseline SisterChromatid Exchange Frequency in Human Lympho-cytes, ” Environ. mutagen. 2:325-337, 1980.

Crossen, P. E., et al., “Analysis of the Frequency andDistribution of Sister Chromatid Exchanges in Cul-tured Human Lymphocytes, ” Hum. Genet. 35:345-352, 1977.

Funes-Cravioto, F., et al., “Chromosome Aberrationsand Sister Chromatid Exchange in Laboratory andFactory Workers and Their Children, ” in: H. J. Evansand D.C. Lloyd, eds., "Mutagen-Induced Chromo-

231

232 . The Ro/e of Genetic Testing in the Prevention of Occupation/ Disease

some Damage in Nlan, ” (Edinburgh: University press,1978).

Garry, V. F., et al., “Ethylene Oxide: Evidence of Hu-man Chromosomal Effects, ” Environ. Mutagen. 1:375-382, 1979.

(hh, K-C)., “Sister-Chromatid-Exchange in the AgingPopulation, ” J. Med. 12:195-198, 1981.

Hansteen, I-L., et al., “Effects of l~inyl Chloride in Man:A Cytogenetic Follow-up Study, ” Mutat. lies. 31:163-168, 1975.

Hogstedt, B., et al., “Nlicronuclei and ChromosomeAberrations in Bone Nlarrow Cells and Lymphocytesof Humans Exposed Mainly to Petroleum Vapors, ”Hereditm 94: 179-187, 1981.

Husgafvel-Pursiainen, K., et al., “Smoking and SisterChromatid Exchange, ” Hereditas 92:247-250, 1980.

Kirkland, D. J., et al., “Sister-Chromatid ExchangesBefore and After Hair Dyeing, ” ,Wutat. Res. 90:279-286, 1981.

Kucerova, NI., et al., ‘(Comparative Evaluation of theFrequency of Chrornosomal Aberrations and theSCE Numbers in Peripheral Lymphocytes of Work-ers occupationally Exposed to Vinyl Chloride Mono-mer, ” Afutat. Res. 67:97-100, 1979.

Lambert, B., et al., “Increased Frequency of SisterChromatid Exchanges in Cigarette Smokers,” kier-editas 88:147-149, 1978.

Maki-Paakkanen, J., et al., “Chromosome Aberrationsand Sister Chromatid Exchanges in Lead-ExposedWorkers, ” Hereditas 94:269-275, 1981.

Mitelman, F., et al., “Occupational Exposure to EpoxyResins Has No Cytogenetic Effect, ” kfutat. I?es.77:345-348, 1980.

Morgan, W. F., and Crossen, P. E., “The Incidence ofSister Chromatid Exchanges in Cultured HumanLymphocytes, ” Mutat. Res. 42:305-312, 1977.

Sorsa, M., et al., “Monitoring Genotoxicity in the Occu-pational Environment, ” Scand. J. G4[ork EnLJiron.Health 7 (suppl 4):61-65, 1981.

Waksvik, H., et al,, “Chromosome Analyses of NursesHandling Cytostatic Agents, ” Cancer Treat, Rep.65:607-610, 1981.

Watanabe, T., et al., “Cytogenetics and Cytokineticsof Cultured Lymphocevtes From Benzene-ExposedWorkers, ” Int. Arch, Occup. En\~iron. Health 46:31-41, 1980.

A p p e n d i x F

Screening Tests (Available at Hospitalsor Medical Centers) for Heritable Traits

G-6-PD deficiency

Numerous screening tests have been designed toidentify the glucose-6 -phosphate-dehydrogenase (G-6-PD)deficient erythrocytes. The most simple, reliable, andspecific screening procedure is the fluorescent spottest (2), This procedure has been widely employed(4,9,13, 15) and has been shown to be highly reliablein detecting the deficiency. It has also been automatedand made available for widespread screening (3,14).Detection of G-6-PD levels lower than about 50 per-cent normal is achieved.

Sickle-cell trait

Several screening methodologies for sickle-cell ab-normalities have been developed. The procedure con-sisting of cellulose-acetate electrophoresis (CAE) fol-lowed by solubility testing has been favorably re-garded because of speed, cost, simplicity, accuracy,and ability to differentiate the various types of hemo-globin (1). Quantification of hemoglobin types is eas-ily performed. In order to verify the electrophoresisprocedure for HbS, any blood found to have HbS issubsequently evaluated via the solubility test as HbSdisplays abnormal solubility. CAE followed by a solu-bility test to confirm the presence of HbS has beenthe procedure recommended by the National SickleCell Disease Program and the National Hemoglobino-path) Standardization Laboratory at the Centers forDisease Control (1 1,1 2).

Thalassemias

Pearson, et al, ( 10) have developect an electronicmeasurement of mean corpuscular volume (MCV)which meets the requirements for a screening test foralpha and beta thalassemic heterozygotes. The proce-dure is rapid, automated, and inexpensive. It yieldedno false negatives out of a study population of 300.However, it is possible that false positives may occurfor persons with an iron-deficiency condition. Further,persons who are so-called "silent carriers” (exhibitingno clinical symptoms) of alpha or beta thalassemia can-not be detected by this screening test. The frequencyof the silent carrier is thought to be uncommon forbeta thalassemia.

NADH dehydrogenase deficiency

The definitive diagnosis of hereditary methemoglobi-nemia requires the demonstration of deficient NADHdehydrogenase activity in red cells. The Hegesh, et al,(6) assay is considered preferable because of its speci-ficity, accuracy at low enzyme activity levels, and easeof operation.

Serum alpha1-antitrypsin(SAT) deficiency

Several reliable, easily administered, and inexpen -sive tests have been developed for the screening oflarge populations for SAT deficiency. All of these testsare sensitive for the recessive homozygous condition,but only one of them (8) can reliably detect the inter-mediate heterozygous Ievels. The authors claim thatthis test is a practical screening procedure which couldbe applied in large scale.

Slow v. fast acetylation

Urine tests for detecting slow and fast acetylatorshave been developed in order to deal with the poten-tial medical problem of slow acetylators being at en-hanced risk of developing adverse reactions to isoni -azid, an antitubercular treatment. The procedure isstraightforward and simple, displaying an excellentcapability to distinguish fast from slow acetylators (7).

HLA typing

The methodology for determining human leukocyteantigen types is considered simple and is frequentlyconducted in numerous medical centers in the UnitedStates. The typical cost is now less than $100 for a com-plete analysis (5).

Appendix F references

1. Barnes, M. G., Komarmy, 1.., and ,Novak, A. H., “AComprehensive Screening Program for Hemoglo-binopathies,” JAMA 219:701-705, 1972,

2. Beutler, E., “A series of Net\ Screening Proceduresfor Pyruvate Kinase Deficiencyr, G-6-PD Deficiency

233

234 “ The Ro/e of Genetic Testing in the Prevention of Occupational Disease

and Gluthathione Reductase Deficiency, ” Bfood28:553-562, 1966.

3. Dickson, L. G., Johnson, L. B., and Johnson, D. R.,“Automated Fluorometric Method for Screeningfor Erythrocyte G-6-PD Deficiency, ” Cljn. Chem.19:301-303, 1973.

4. Dow, P. A., Petteway, M. B., and Alperin, J. B.,“Simplified Method for G-6-PD Screening UsingBlood Collected on Filter Paper, ” Amer. J. PathoL61:333-336, 1974.

5. Harsanyi, Z., and Hutton, H., Genetic Prophec@v:Beyond the Double Helix (New York: Rawson,Wade, Publishers, Inc., 1981).

6. Hegesh, E., Calmonovici, N., and Avron, M., ‘(NewMethod for Determining Ferrihemoglobin Reduc-tase (NADH-Methemoglobin Reductase) in Erythro-cytes,” J. Lab. Clin. Med. 72:339, 1968.

7. Jessamine, A. G., Hodkin, M. M., and Eidus, L.,“Urine Tests for Phenotyping Slow and Fast Acety -lators)” Canacl. J. Pub. Hhh. 65:1 19-123, 1975.

8. Lieberman, J., and Mittman, C., “A New ‘Double-Ring’ Screening Test for Carriers of Alpha l-Anti-trypsin Variance, ” presented at American ThoracicSociety Meeting, Kansas City, MO.) Nlay 22, 1972.

9. .

10.

11.

12.

13.

14

15

McIntire, M. S., and Angle, C. R., “Air Lead-Relationto Lead in Blood of Black School Children Deficientin G-6-PD, ” Science 17:520-522, 1972.Pearson, H. A., O’Brien, R. T., and McIntosh, S.,“Screening for Thalassemia Trait by ElectronicMeasurement of Mean Corpuscular Volume,” NewEng. J. Med. 288(7):351-353, 1973.Schmidt, R. M., ‘{Standardization in Detection ofAbnormal Hemoglobins: Volubility Tests for Hemo-globin S,” JAMA 225:1255, 1973.Schmidt, R. M., “Laboratory Diagnosis of Hemoglo-binopathies,” JAMA 224:1276-1280, 1973.Szeinberg A., and Peled, N., “Detection of G-6-PDDeficiency in the Newborn Using Blood SpecimensDried on Filter Paper,” Isr. J. Med. Sci. 9:1353-1354,1973.

Tan, I. K., and Whitehead, T. P., ‘{Automated Fluor-ometric Determination of G-6-PD and 6-Phospho-gluconate Dehydrogenase Acti~rities in Red BloodCells, ” Clin. Chem. 18:440-446, 1969.Yeung, C. Y., Lia, H. C., and Leung, N. K., ‘(Fluores-cent Spot Test for Screening Erythrocyte G-6-PDDeficiency in Newborn Babies,” J. Peal. 76:931-934,1970.

A p p e n d i x G

Other Contractors and Contributors

Other contractors

Four contractors played an important role in thisassessment by contributing to or reviewing the work.of the principal contractors. They are:

Philip G. Archer, Sc.D,University of Colorado Medical CenterDenver, Colo.

Epidemiology Resources, Inc.Chestnut Hill, Mass.

D. R. Jagannath, Ph.D.Litton Bionetics, Inc.Kensington, Md.

Marvin S. Legator, Ph.D.University of Texas Medical BranchGalveston, Tex.

Other contributors

Many people provided valuable advice and assist-ance to OTA during this assessment. In particular, wewould like to thank the following:

American Industrial Health CouncilWashington, D.C.

Angela AulettaEnvironmental Protection AgencyHealth and Safety Review DivisionWashington, D.C.

Robert C. BarnardCleary, Gottlieb, Steen &, HamiltonWashington, D.C.

Clyde J. BehneyProgram Manager, Health ProgramOffice of Technology Assessment

Fred BergmannProgram Director, Genetics ProgramNational Institutes of Health, NIGMSBethesda, hid.

Alexander CapronExecutive DirectorPresident’s Commission for the Study of Ethical

Problems in Medicine and Biomedical andBehavioral Research

Washington, D.C.

Anthony V. CarranoBiomedical Sciences DivisionLawrence Livermore National LaboratoryLivermore, Calif.

Jerry L. R. ChandlerOffice of the DirectorNational Institute of Occupational Safety and HealthRockville, Md.

Zsolt HarsanyiE. F. Hutton Group, Inc.New York, N.Y.

Peter InfanteHealth Standards ProgramOccupational Safety and Health AdministrationWashington, D.C.

Joseph IrrHaskell LaboratoryE. I. du Pont de Nemours & Co.Wilmington, Del.

James JensenProfessional Staff MemberSubcommittee on Investigations and OversightHouse Committee on Science and TechnologyU.S. House of RepresentativesWashington, D.C

Bruce W. KarrhCorporate Medical DirectorE. 1. du Pont de Nemours & Co.Wilmington, Del.

Karl KronebuschHealth Programoffice of Technology Assessment

Max LyonGenetic Systems CorporationSeattle, Wash.

Ken MillerWorker's Institute for Safety and HealthWashington, D.C.

Thomas MurrayThe Hastings CenterHastings-on-Hudson, N. J’.

Daniel NebertNational Institute of Child Health and Human

DevelopmentNational Institutes of HealthBethesda, Md.

235


R. Julian Prestonoak Ridge National Laboratoryoak Ridge, Term.

Anthony RobbinsProfessional Staff MemberCommittee on Energy and CommerceU.S. House of RepresentativesWashington, D.C.

Sheldon SamuelsAFL-CIOWashington, D.C.

Gail StettenDirector, Cytogenetics LaboratoryThe Johns Hopkins UniversityBaltimore, Md.

Charles TrahanGeneral Accounting OfficeWashington, D.C.

Theodora TsongasHealth Standards ProgramOccupational Safety and Health AdministrationWashington, D.C.

Michael Shodell peter VoytekDirector, Banbury Center Reproductive Effects Assessment GroupsCold Spring Harbor, N.Y. Environmental Protection Agency

Jane E. Sisk Washington, D.C.

Health ProgramOffice of Technology Assessment

Index

Index

deficiency, 7, 90sickle cell, 51, 91in thalassemia, 91-92

Arsenic (see Chemicals)Arylamines (see Chemicals )Aryl hydrocarbon hydroxylase (AH

predictive value of, 18prvalence of, 19, 172research on, 1(10and susceptibilily to lung cancer,

Asbestos (see Chemicals)

H) inducib i l i ty , 11 , 19

9 4 - 9 5

Assessment of occupational studies, 60-6 1A t o m i c B o m b C a s u a l t y ( c o m m i s s i o n ( w e R a d i a t i o n E f f e c t s

Research Foundation

Benzene (see Chemicals)Body fluids

in detection of genetic traits or abnormalities, 53-54mutagens in, 18, 75-77

Cadmium (see Chemicals)Cancer ( S e e a l s o C a r c i n o g e n e s i s 6 , 1 9 , 2 5

acf:t~’ I;it ion and suscept ihi] it }’ to a rkrla mine -induced, 9.7,1 ()()-101

a r-j’] hjd roc;t rbon h}’d r-ox }’l:isc (,4 HH ) i nd ucih ilitj’ a n d5Ll S(’(>pt ii)i]itj’ to, 94-9.5, 100

in atomic homh sufn’ilors, 70-71and car-bon (),x id a t ion abi] i tj’, 96, 100in Chcmi(’al, smelt ing, and gold mining t~orkers, 72and defect il f’ 1) h’ ,,1 rcpa i r, 97

(’arhon oxi(!;ition ahilitj , 1 1h i g h pre~alence of, ]9, 1 7 2implirati(ms for ()(’(’~l~);iti()rl:ll and [’r]\il-ollrllerlt:il health, 96research orl, 100”and sus(’eptil)ilit~’ to ranc[~rl 96

(;:il-(>irl[~gf;rlf’sis “1)~ arsenir, 71l)j ar>jlilmincs) 9,5correlation ;t’ith (’llr.{)rllos{)rllal abf’rrat ions and sistf?rrhromatid cxrhangr (S(:ljl, 69

t)~ f:~)i(:}llor’f)ll~(jr’irl, 72mutations in, 10, 52-53, 68-691)~, pol}(~(.11( aromatir lljr(ir-()(’~irl)()rls, 94

hj linjl chloride m o n o m e r , 73(:hf’rn i(iils

arsenic, 71-72arj’lamincsl 1 1, :15, 100”

ashfxtos, 5, 23I)enzenf’, 19, 72,, 121

radmium, 72-7:3carcinO,g’f:nic, .52-.53clastogensf 121

differential] susceptihilitj to, 11(?l>i(;lllorOll\[lr’irl, 72

eth~’lene oxide, 72genetic damage from, 10, 18, 46, 52.,53hazardous, 24lead, 72-73occupat ional ekposure to, 6, 24parathion, 97pol~c~’clic aromatic 11~[11’o(:;~r’t~orls, 94uranium 71~in}’1 chloride 19, 73-74zinr, 73

(:}l[)li]lf’ster;isf?s, 97(:hromosornal :il)errations Owc al,so Cjtogenctic studies), lo,

1 8 , 28, 3,5, 37f r o m a r s e n i c exposllrf’l 71in atomic bomb surl’iiors, 70-71t)ii(’k~rOLl[ld frr(lurnries, 227-229 ~tal]lf>)f r o m hf’nzf~ne e~posure, 72f r o m c a d m i u m exposurfl, 73a n d ca rcinogenicity, 69disease and, 68-69f r o m t’~]i(:lllor’ohj[ir’in” exposure, 72f r o m ethllcnf; oxide e x p o s u r e , 72ext r-a }’ c h r o m o s o m e , 79in unexposed populations, 70f r o m lifljl chloridf’ monomf~r c~posurel 73-74

(~tlr’orllosorllf~s (Lsflf’ (;hromosoma] ah[~rr:itions)(;omrnittee on the BiolO~i(’ill ~;fff’cts of ionizing Ril(liat ion,

6, 2.5(;ongrcss

acts of (see I.egisla t ion )Ji(lusc (;ommittcr on Srif~l](’f~ iind ‘l’ f’chnolog:, .5, 23, 181olltions for [see Polirj o p t i o n s )

(:(]tton dust, 121(:~togenetir studies (sf’f~ ah (knetics ], 1()

on atomic homh surl’i~ors, 70-71associat ions hf;t~t”een rh romosoma 1 aberrations and

disease, 68-69chromosomal studies on groups, 6:)-70c o r r e l a t i o n lx3t\$’eerl (’llr-onlosor]]~il il})f’[’l’il t i(jns, sistt)r

chromatid exrhanges, i] nd (’ii rrinog(’n icit~ , 69economic ek’aluation of, 1.59-160in exposure to chronic iofI’ radia t ion 71purpose of, 28significance of sister rhromatid e~changrs, 47on unexposed populations, 70i n t h e ~~’orkplac[), 3S, 37

239


Diseasesassociation with certain genetic traits, 11association with human leukocyte antigens (HLA), 19detection of increased risk, 27-29differential susceptibility to, 27economic costs of occupational, 5genetic damage and risk of, 10, 18-19health hazards in the workplace, 24-26use of genetic testing for prevention of, 7-8, 27-29

DNA (deoxyribonucleic acid)cietection of damage in, 10, 18, 37, 78-79, 171diseases of repair of, 11, 96-97role in protein synthesis, 48-49structure of, 48unscheduled svnthesis of, in lvmphocvtes, 78

Down’s syndrome, 46

Economic issues, 5, 13-14benefits and risks, 29biases and value judgments, 153-154cost-benefit analyses, 151-152cost-effectiveness analyses, 152elements of economic ei’aluation, 154-156wraluation of cytogenetic monitoring, 159-160evaluation of genetic screening, 156-159idcntif}ling and measuring consequences, 152-153

EEOC (see Equal Employment Opportunity Commission)Ehnpbyserna, 19, 93-94, 101Environmental Protection Agency (EPA)

estimate of workplace exposure to ionizing radiation, 25federally funded data bank for epidemiologic studies,

19, 172(jene-Tox Program, 19, 69, 172inirentorj’ of hazardous chemicals, 6research to develop better genetic tests, 18, 171

EPA (we Environmental Protection Agency)Epidemiologic studies (see Research, epidemiologic studies

in occupational settings)Equal Employment opportunity Commission (EEOC), 123, 125Erythrocyte catalase deficiency, 98Ethical issues, 13

autonomy principle, 142-143Code of Ethics for Physicians Providing Occupational

hledical Services, 117, 147compensation of geneticall~’ disadvantaged workers, 146dubious tests, 144-145high correlation between genetic endpoints and disease

risk, 145-146informed consent, 145, 148justice, 143-144in medical research, 145nonmaleficence and beneficence, 143

Fortune 500” companies, 37, 38, 39

G-6 P-D kwe Glucose-6-phosphate dehydrogenase deficiencjr)(;cnetics (see also C}’togenetic studies)

and ability to detoxif~v chemicals, 50alleles, 49, .50, 51, 52as basis of human iariabilit}, 49-.50

body fluids used in detection of traits or abnormalities,53-54

of cancer, 52-53cell division, 45chromosome] aberrations, 46-47chromosome] instability diseases, 52DNA damage, 47, 51DNA repair, 53Down’s syndrome, 46of erythrocyte catalase deficiency, 98genotype, 52heterozygosity, 51-52homozygosity, 51immunoglobulin A deficiency, 97interaction with physiological processes, 89karyotyping, 45-46metabolism of chemical agents, 53mutations, 51, 52-53, 68-69paraoxanase polynorphisrn, 97phenotype, 52polygenic traits, 52pseudocholinesterase variants, 98of red blood cell traits, 89-93of sickle cell anemia, 51single gene traits, 51-.52sister chromatics, 4.5, 47of superoxide dismutase, 97of Ta~’-Sachs disease, 51\ariant genes, 49-50

(;ene-’I’ox Program (see lh~ironmenta] Protection Agency,Gene-Tox Program)

(;erm cell damage, 79G]ossary, 237-238Glucose-6-phosphate dehydrogenase (G-6P-D) deficiency,

7, 11characteristics of, 90-91frequency of testing for, in industry, 34hypothetical distribution of, 58 (figure)research on, 100tests for, 233and worker susceptibility, 27, 90-91

Health hazardscontrol of, 25-26t~’pes found in the workplace, 24-26

Hemoglobinalkylated, 18, 171mutations, 18, 171

HGPRT mutation in lymphocytes, 18HI. A (see Human leukocyte antigens)Human leukocyte antigens (HLA), 11

and risk of disease, 19, 96, 172tests for, 233

I]~]x~l~]I~oglot~ulin A deficiency, 97industrial companies, 33Insecticides, 98Ionizing radiation

diseases caLIsed by, 19, ,25effects in atomic bomb sur~’i~’ors, 70-71

Index ● 2 4 1

genetir damage from, 10-1 ], 18, 46orrupationa] exposure to, 6, 2 5 , 71

I.artic [i[~h}(iI(]g[’niist;-X (I,l)H-X)

automat f~(i testing for, 79, 171I ,I)H-X (SW I,ii(t ir (it’il~r(il-clg[?ll;is(J-X 1IJra(i (,wf; (:iwmicais)I,e,+il issurs (sfw also I,itif+ition), 11-13husiness necessitj’ and jot) rel:ite(inrss of genetir testingl

124-125, 128-130(’onfi(icni i:iiit~ of me{iirtii reror(is, 117-118disclosure of heaith risks, 117{iu[~ to conduct rne(i ical or genetic testing, 116mplo\’w arccss to I’rcor’(is , 117, 123

empio~’er iiahiiit\, 113-114eJIIp]O\r~r rights ami duties, 11, 112, 119geneti~’ testing anci thr ~rnerdi (iutj (iiiuse Oi’ the

os1{ A(’t , 120genetir testing and OSIiA st:in(i~ir[is, 121informe(i c o n s e n t , 1 1 6 - 1 1 7

medicai remmtii protert ion :ind r:ite retention, 122-123ra(’idi anci ethnic (iistrihution of tcstahie genetic traits, 124rr:isonahif’ a(’(’orllnl(](i:itiorl” ff)r susceptihie fmlpio}rf?f’s, 130rf;gulation of compdnf’ mmiical and emplownent practices,

118-130rf’iationship of compifnj doctor-s to empioyer-s anci

emplowx?s , 11.5right to refuse rx:iminitt ion, 116, 12.5-126right to refuse hazarxious \\r)r. k, 119St:ite an(i Federal anti(iiscrimination laws on hiring the

iuin(iirapped, 1 2 6 - 1 3 0

testing solrij i’or rese:irch, 116

\ a ri:ii]lf’ suscf:ptihilit}’ of empio}~fm in stami:irxis sf?tt ing,1 Z(). ] ~ 1

t~rork[~r’s compensation ia~t’s, 1 12?-113i,egisiation

BiinkruptcJ’ .\(’t , 23(;i\ii Rights Art, 1 ~ 11 ] , 1 ] ~, 1 Yj. I ‘1~(:onfi(ientialit} of hlmiiciil Information Art ((:;ilif. ), 118N’:ition;il I,iihoi’ Reiations Act (NI,RAJ, 1 1 1X:ition;i] Resciirrh Act, 116()(’rL]p;iti()niii Siifet~7 ;in(i Health Act K)SH Act), 11-12, 111,

117, 118, 119-123, 143Rehahi]itiition Art, 12-13, 17, 126-130

i.fx]kt’mia, Eit!i n atomic homh surliiors, 70from bfmzf’ne f;,xposurw, 72f r o m ethjif:ne oxi(ie exposurf;, 72

1,it i,+it ion,4/t] f~nlarlf2 P:ipf~r Co. ~’. Aloo@\’j 124, 125, 129,4nlf>rican ‘l’f’.x tile .Ilall[ltil(’tt]re[’s lnstifute L’. DonoL’an

((htton msf ciise), 121, 122-123on iishwtos, 23Bednarski I. (Wmr:il ,tfofors, 113Brnzenf’ riisv (.sef; lrrdustrial 1 k1iof7 [kpartnwnt, .4 FL-[.’IO

L. ,4nwriran Petrf)lf?urn Institutf; )

Borel L. k’ibreboard Paper Produrts Corp. , 114

[.’otton D u s t case (see Ameriran I’extik ,}lan[lfa~’tur-f!t’.s

ln, stitutf: i. DonoLan)[;rigg’.s [, DukfI Pok~er Co,, 123-124

lnciustriai [ ‘nion L)epartmfJnt, , 4 F’L-{.’10 \ ,ln]elvi[’an

Pf’tJ’Ok’UIJl lnslitutp (Ik’nzf’nf’ (’asf’), 12 J,\landolidas t, E)kins hdus?rif~.s, lnr. 114(16KY.’P L’. F;. F;, Black, ltd., 1 2 7 - 1 2 8J1’hirfpoo] Corp. i, ,’tlarshall, 119

I,ol%-iirti!’it} piiriiokanasf’, 97[,~mi)imcytf; tr-iillsf[]l’lll~itiO1l ;issii~, 79

Nl(; tilf; lllogi{)t)irlf’ rlliii, 92-93}Ionitoring for genf?tic ch:in#’sas ai(i in idf’nt if ffing ixiz. a rxious suhtanrf’s, 1 ()- 1 1in :itornic bomh sur\ i\ors, 1()cjtogenf=t ic, 67-7.5, 1.59-160fwonomir fwaluation, 1 5 9 - 1 6 0f’l)ici[;lllioiogi[” stu(iifw using, 1 9f;thic:i] issues in, 14.5, 147\r gf;nct ic scr-f:rnin~, .5, 7.s, ~:;, J ~mf~tho(ioiogj’, 10-11, 26, 37none’,’togenet ir, 18, 75-80k’aii(iit}’ an[i rf:iiiibiiitl of, 28

hlLltagr3ns

hin(iing t o immogiohin, 77

i n hocil’ fiuicis, 18, 7.5-77in fecfw, 77monitoring of mutations from, 1()

A“A1)lf (iehj(ir-(~g~;rl:ise cieficien(~, 11rixir:icteristics of, 92-93tests for, 233

N~itionai Institute for Lnlirorlmf’nt;il f ~[’iilt 11 ,in(i Siiff’tJ’(N IEHS)

epidemioiogir stu(iies in ()(’(’Up:lt i()lliil sf’ttings, 171-172feder’aiij tun[ie{i ~iatii hank for f’])i(lf’r?~i(]l(]gi(’ stu(iies,

19, 172rfwarch to del’eiop bf;tter genetic tests, 18, 171

N:itionai Institute for occL]patiorx~i Safet~ ami fiwilth (NIOSH)f?pidemioiogic studif>s in orrupatiomii sf;ttings, 1 7 1 - 1 7 2estimate of w’orker exposure to hazardous chern i(’ii]s, 6

fe[ier:iliy funded diita txink for epi[iemioiogir stL](iies,19, 172

National ~~cL]patif)na] Hazard SUr\’f’}’ (Notfs) 24research to (iwwlop hetter genetir trots, 18, 171

National I,abor Reiations Bmirci, 12Nationai occLlpationa] ]~iiz:]r-d SuJ’\’f?j’ (NOIIS), 2431atioJ]ai o p i n i o n Reswirrh (:enter (NOR(:)

sL]r\w} of genetic tf+sting h~ in(iLlstrJ, 9, 33 175-226NIEHS (see Nationai InstitL]te for E:r~\ir-or~l~l[;J~tiii Iieaith and

safety),NIOSIi (see Nationai Institute for ()[’(’Ll]>:iti()rl:ii Siiff’tJ’ :ind

Heaith)N’OHS Lsee National occupat ional Haz:ir{i Sur\w}r), ~-lNOR(: (SW N;itiona] opinion Research Center)NL1ciear’ indLlstry, 6

Occupatimlal Safet3 and Health Administration (OSHA),12, ~J

,Arrms to i+:mplo~tee Exposure and hleciiciti RecordsSt;irrdard, 117, 118

f>xposure st:in(iard for ethkiene oxki[”, 72ti~reshoici limit standar[is ;(iopted h~, 1 Z()


office of Technolo~v Assessment (OTA)assessment of occupational studies, 60-61contributors and contractors (this report), 235-236surtrey of genetic testing by industry, 9, 23, 33-40, 175-226

OSHA (see Occupational Safety and Health Administration)(MH (see Legislation, occupational Safety and Health Act)()-llA (MW Office of Technology Assessment)

Paraoxanase polymorphism, 97Parathion (see Chemicals)Policy options

adopt Federal regulations on protection of human researchsubjects, 170

constrain emplo~mlent actions based on genetic testing,169-170

employers to disclose nature and purpose of medicalprocedures, 170-171

(?mp]o.vers to dwnonstrat[! predictilw abilit}’ of tests, 170encourage troluntar’v guidelines, 16Federal funding of ;esearch, 171-172m a i n t a i n t h e s t a t u s qL]o, 14, 1 6 7p r o h i b i t genetic testing in the ~vorkplace, 1 . 5 - 1 6 , 1 6 8 - 1 6 9

rqjulate g e n e t i c t e s t i n g , 1 6 - 1 8 , 1 6 9 - 1 7 1

s t i m u l a t e g e n e t i c t e s t i n g technolo~}~, 15, 18-19, 167-168

Poljqclic ~iromatic h@rocarbons ( s e e C h e m i c a l s )

P r e d i c t a b i l i t y ’ (see \’alidit}, re l iab i l i ty , predictil’e \alue)

P r o t e i n sj~thesis, 48-49

Pseuclocholinesterase Yariants, 98

Purposes of genetic testing, .27-28, 35, 36, 38-39

Radiation Effects Research Foundation, 70Radiation (see Ionizing Radiation)Red cell phosphatase distribution, 99 (figure)Regulation (sf?e Policy options)Rt?]iabi]it~~ (see t’alidit}, reliability, predicti~’e \ralue)Researrb

to d[?~wlop I)etter genetic tests, 18by employers on enlplo~rees, 17epiciemiologic studies in occupational settings, 18-19,

171-172ft?derall~~ funded data bank for epidemiologic studies,

19, 172priorities, ] $), r~.:~, 80, 100-101, 1 ~~

Respiratorjf tract infections, 97Risk (it?tf;[’I~~ir~ ~itiol~, 7-8, 27-28, 59-60

SArl’ !stw? Serum alph:i ,-antitrypsin cieficiencj)S(:E: (see Sister chromiitid exchanges)Screening for genetic traits

ar(w racy and reliabil it~’ of tests in, 11aret}~]ation and susceptibilit~’ to ar’~~lamine-ill(iuced bladder

cancer, 95-96~id~’erse drug reactions and risk of disease from

occupational exposures, 11ar}~l h~d rocarbon huvdrox~lwe inducibility and susceptibilit~’

to lung’ cancer, 94-95carbon oxidation abilit~~l 96II[;r’rlliitologi(’iii” ll~p[:l’s~ls(;epti t}ilitJ~, 96diseases of DNA repair, 96-97worwmk [?lraluation of, 156- 15Y

erythrocu~e catalase deficiency and sensitivity to hydrogenperoxide producing agents, 96

ethical issues in, 144-145, 146\r. genetic monitoring, 5, 7-8, 23, 28, 57

@cose-6-phosphate dehydrogenase (G-6P-D) deficiencyand hemolytic anemia, 90-91

human leukocyte antigens (HLA) associated With diseasesusceptibility, 96

immunoglobulin A deficiency and risk of respiratory tractinfections, 97

lung disease, 93-95NADH dehydrogenase deficiency and methemoglobinernia,92-93

paraoxanase polymorphism and risk of parathiontoxicity, 97

pseudocholinesterase \ariants and sensitivity toinsecticidelike compounds, 98

red blood cell traits, 89-93, 100research on, 100-101reservations in application of, 99selection of emp]oyees for, 34-36serum alpha I-ant itrypsin deficiency}’ and susceptibility toemphysema, 93-94

sickle cell trait and sickle cell anerniti, 91superoxide disrnutase, !37tests in current use, 36-37, .233thalassemias and erjthroblastic anenlia, 91-92traits measured in, 11, 19, 89-101

%?cretary of Labor, 11, 12Sensitivity and specificity of tests, 58Serum alpha ,-antitrypsin (SAT) deficiency, 11, 19

characteristics of, 93-94cronomic ekraluation of testing for, 1.fi7-158frec~uenc~ of use in industr’~~, 34high prevalence of, 19, 172ll~p)thetical break-e~en number of cases alerted t~j~

testing for, 157 (table)research on, I (]1and susceptibility to emphysema, 93-!]4t(?sts for, 233

Sickle cell trait, 9, 34beta-S .g]obin and, sod incrimination based on, 12pre~’alence and distribution of, 91srreening for, 11, 34, 38, 91tf’sts for, 233

Sister chromatic exchanges (SCL)b:ickgrouod frequencies, 231 (table)and ca rcinogenicit.y, 69definition, 4 i’testing in industry, 35, 37in unexposed populations, 70

Spondylitis, ankylosing, 96State of’ the art (genetic testing), 9-10, 67-101Super’ oxide dismutase alleles, 97Sur~wy of genetic testing, 9, 23, 33-40

anal~~sis of nonrespondents, 205-208animal t(?sting, 196comments on questionnaire, 202-203”factors and criteria for test selection, 201 (t:ible)

—

I ndex ● 2 4 3

‘1’tlwr’rtical iolln(ii~tiorls (of genetic testing], 7, 27, 45-.54‘111. vr’oi(i ciisww, 96

c)

liter-atun~ review, 1 H.'i-l 1'11'1

met hodology, 1 H 1- 1 H~ missing data, 1~}1

qlH~stionnaire, 17!i-17n

ra t!~s of testing J'(~ported, EJ4, 195 (table) n~sponse patterns, 17n-17H, IH9-19(), 192-1!13 (table) response quality, 190

n~sults of testing n~port!~d, 199-20() SOlllTP of da ta, 17!i

stud,v conclusions, 2():~-2()4

su/,\,e,V materials, 209-22n

types of t!~sting rq)Orted, 197-1!1!1

Tay-Sachs disease, :i 1 Thalasspmias, 1 1

char';u:teristics of, !11-!12

tpsts for, 2:U

u

Theon~tical foundations (of mid disease, 9n

l'nions, 11, 3:~

University of Chicago, ~l, 33 llraniurn (set-' Chemicals) Utilities, :13

testing), 7, 27, 4:i-:i4

Validity, reliability, pr-edictivc \'alue (of gelwtic tests), 11, 21'1, :i7-:i9

calculation of predictive value, 59 (table) influence of genotype frequency on pJ'(~dicti\'(~ valup of

screening tests, ,'19 (table) Vinyl chloride (see Chemicals)

Zinc (see Chemicals)

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