Exposure Science Digests: Demonstrating How …...on health hazards and exposure pathways for the...

Developed in partnership with the International Society of Exposure Science, the Journal of Exposure Science and Environmental Epidemiology, and leading exposure scientists. Individual digests available from http://www.nature.com/jes/webfocus/esdigests/index.html

Exposure Science Digests: Demonstrating How Exposure Science

Protects Us From Chemical, Physical, and Biological Agents

Judith A. Graham, PhD, Fellow ATSGuest Editor

Journal of Exposure Science & Environmental Epidemiology

ExposureScienceDigest

Journal of Exposure Science and Environmental Epidemiology (2011) 2


PREFACENearly every day there is a story in the media that demonstrates how knowledge of exposures empowers individuals to make more informed decisions regarding their health and the health of their families, and how societies and govern-ments can make health-protective decisions. There are celebrated successes, such as marked reductions in children’s exposures to lead or exposure to tobacco smoke, that have resulted in some of the most significant interventions in the history of public health management. And there are legacies, such as Superfund sites, that remain a challenge, particu-larly in communities that are economically disadvantaged. The H1N1 virus reminded us that health and disease are conditions narrowly separated by exposure, in particular for those who are susceptible.

Discovery of lead in children’s toys, the rush to use recycled construction materials, debates over the safety of nanotech-nologies, and the unabashed embrace of green chemistry as the panacea to chemical exposures caution us that lessons from history should not be forgotten. Exposure science can enable sustainable innovation and help avoid unintended conse-quences of new materials, applications, and policies. In 2010, the International Society of Exposure Science (ISES) marked the 20th anniversary of its formal establishment—an occasion to revisit and celebrate the successes of exposure science, evaluate lessons learned, and consider how these can inform future decisions.

ISES and the Journal of Exposure Science and Environmental Epidemiology (JESEE) partnered on a project to celebrate their genesis. As a result of this Anniversary Project, issues of JESEE in 2010 and 2011 contained Exposure Science Digests that showcase successes in exposure science that have had a broad impact on understanding exposures, improving public health, advancing risk management, informing other related disciplines, and impacting policy. While these reviews mostly celebrate historical successes, they also discuss their relevance to some of the most pressing public health issues we face to-day. Changes in the field of exposure have never been greater, and the pace of change will only accelerate in the future. The final Exposure Science Digest highlights future scientific directions that are expected to have a profound impact on the field of exposure science and related disciplines.

This Anniversary Project was designed to increase the understanding of the value, impact, and future viability of exposure science. It targets public health, regulatory, and legislative decision makers, many of whom recognize the importance of exposure science but are daunted by its technical complexity and the difficulty of incorporating exposure information into their decisions.

We deeply appreciate the outstanding contributions of all the exceptional scientists who wrote and peer-reviewed these Exposure Science Digests. We are also grateful to Dr. Judith A. Graham, who served as Guest Editor for the digests, and the editorial staff of JESEE who were with us all the way.

We are excited about this endeavor and hope you will enjoy this journey through history and across the bridge to the future of exposure science.

DANA BoyD BArr, PhD, ISES PrESIDENt AND JESEE EmErItuS EDItor-IN-CHIEf

tINA BAHADorI, DSc, ISES PASt PrESIDENt

ElAINE CoHEN HuBAl, PhD, CHAIr, ISES PuBlICAtIoNS CommIttEE

Parts of this Preface are reprinted from “Close Encounters: reflections on the Successes and Near misses of Exposure Science,” t. Bahadori and D.B. Barr, J Expo Sci Environ Epidemiol 2010: 20: 1. reprinted with permission from the publisher.



Exposure Science Digests: Demonstrating How Exposure ScienceProtects Us From Chemical, Physical, and Biological AgentsJournal of Exposure Science & Environmental Epidemiology

Contents

1 Superfund: is it safe to go home?PAUL J LIOY AND THOMAS BURKE

3 Out of the frying pan and out of the fire: the indispensable role of exposure science in avoiding risks from replacement chemicalsJUDY S. LaKIND AND LINDA S. BIRNBAUM

5 Targeting the components most responsible for airborne particulate matter health risksMORTON LIPPMANN

7 Protecting children from environmental risks throughout each stage of their childhoodMICHAEL FIRESTONE

9 MTBE: A poster child for expsure assessment as central to effective TSCA reformBERNARD D. GOLDSTEIN

11 Ensuring the safety of chemicalsPAUL ANASTAS, KEVIN TEICHMAN AND ELAINE COHEN HUBAL

13 The smoking gun: working to eliminate tobacco smoke exposurePATRICK N. BREYSSE AND ANA NAVAS-ACIEN

15 Exposure science can increase protection of workers and their families from exposure to asbestos and inform on the effects of other elongate mineral particlesJOHN HOWARD AND PAUL MIDDENDORF

17 Vehicle emissions: progress and challengesROBERT F. SAWYER

19 Anthrax: modern exposure science combats a deadly, ancient diseaseJOHN R. BARR, ANNE E. BOYER AND CONRAD P. QUINN

21 Better radiation exposure estimation for the Japanese atomic-bomb survivors enables us to better protect people from radiation todayHARRY M. CULLINGS AND KIRK R. SMITH

23 Getting the lead out: important exposure science contributionsLESTER D. GRANT

25 Exposure science for viral diseases: 2009 H1N1 pandemic influenza virusNANCY COX, RUBEN DONIS AND JOHN R. BARR

27 Oil spills and fish health: exposing the heart of the matterJOHN P. INCARDONA, TRACY K. COLLIER and NATHANIEL L. SCHOLZ

29 Protecting Children From Pesticides and Other Toxic ChemicalsPHILIP J. LANDRIGAN and LYNN R. GOLDMAN

30 The Promise of Exposure ScienceELAINE A. COHEN HUBAL, DANA B. BARR, HOLGER M. KOCH AND TINA BAHADORI


Exposure Science Digests: Demonstrating How Exposure ScienceProtects Us From Chemical, Physical, and Biological AgentsJournal of Exposure Science & Environmental Epidemiology



The Superfund law does not effectively address exposure of the residents surrounding a hazardous waste site before, during, and after cleanup.

Superfund: is it safe to go home?PAUL J LIOYa AND THOMAS BURKEb

aEnvironmental and Occupational Health Sciences Institute (EOHSI), UMDNJ–Robert Wood Johnson Medical School and Rutgers University, Piscataway, New Jersey, USAbBloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USAAddress all correspondence to [email protected]:10.1038/jes.2009.69

BACKGROUND

The Superfund process, from identification of sites through clean-up, deletion from the National Priority List (NPL) upon successful remediation, and reuse of the site, is very cumbersome and does not lead to a quick elimination of public health risks.

Hundreds of sites that were discovered and officially listed more than 20 years ago remain on the list at various stages of removal, remediation, and containment. Thus, people in some Superfund-site neighborhoods have lived with potential risks through several generations. As of December 2009, 1,270 sites were on the NPL, 340 had been delisted, and 63 new sites were proposed (US Environmental Protection Agency, 2009). Although the program has attained a number of milestones, restoration has proven to be an elusive goal.

The first step in the Superfund cleanup process is site discov-ery by various parties. As a result, the process is not consistent and includes no systematic evaluation of potential community exposures. This can lead to long delays in addressing hazards or, potentially, to an untold number of sites remaining undiscovered.

Once identified, a site is evaluated against certain criteria and, if the criteria are met, added to the official Superfund list. Investiga-tions are then conducted, and a cleanup plan established and im-plemented. Usually these efforts provide qualitative information on health hazards and exposure pathways for the local residents. In most cases, however, they are void of actual personal-exposure data that quantitatively define the magnitude of the potential exposures derived from exposure routes (inhalation, dermal, or ingestion) or pathways (air, water, or soil). As a result, several high-profile sites, including Woburn, MA (Costas et al., 2002), Toms River, NJ (Maslia et al., 2005), and Camp Lejeune, NC (National Research Council, 2009), have underscored the need for improved characterization of community exposure.

The cleanup plan typically centers on expert judgment decisions to remove or contain the contaminants and on the goal of sufficient cleanup to permit deletion from the list and safe reuse of the site. However, exposure science is rarely used to determine optimal mitigation steps and evaluation of whether the cleanup actually worked to prevent future exposures.

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCE

Improving exposure characterization of Superfund sites will substantially increase efficacy, as well as speed up the entire process. Combining exposure information with chemical hazard information is likely to have led to some sites not being listed and other sites being listed. However, high-quality information on community exposure pathways (e.g., air, water, house dust) can direct mitigation plans. Exposure science also identifies the exposed population groups. For example, knowing whether children or the elderly are exposed can improve protection of vulnerable people around a site. Having scientifically robust estimates of exposure before and after cleanup informs the community about the cleanup. Without such knowledge, covert risk will persist.

Superfund is the environmental program established by the federal government in 1980 to address abandoned hazardous waste sites (http://www.epa.gov/superfund/index.htm). It directs the US Environmental Protection Agency (EPA) to clean up such sites and to force responsible parties to perform cleanups or re-imburse the government for EPA-led cleanups. It is estimated that one in four Americans lives within 4 miles of a Superfund site; ap-proximately 10 million of these people are under 12 years of age (Browner, 1996). The photograph shows a site in New Jersey.Cleanups are slow, resulting in some people being at potential risk for many years. Increased application of the principles of exposure science before, during, and after cleanup would greatly reduce the time and costs required for cleanup and, more impor-tantly, determine whether the cleanup actually worked and the property can be safely reused by the public. (Photo courtesy of Eileen Murphy, NJ department of Environmental Protection.)

mailto:[email protected]

http://www.nature.com/doifinder/10.1038/jes.2009.69

http://www.epa.gov/superfund/index.htm

2 Journal of Exposure Science and Environmental Epidemiology (2010)2 Journal of Exposure Science and Environmental Epidemiology (2010)

This Exposure Science Digest is sponsored by the International Society of Exposure Science (www.isesweb.org) in celebration of its 20th anniversary.

Gathering high-quality exposure information has a cost in dollars and time, but that must be weighted against an in-crease in process efficiency. For example, a scientifically stronger process can reduce time- and cost-intensive litigation and elicit more community support. Knowing that public health goals were attained and reuse is safe is fundamental to Superfund’s goals.

The cleanup of residential chromium sites in Hudson County, NJ, provides one case example of how exposure characterization can make a difference. During the first half of the twentieth century, northern New Jersey was the chromite–chromate industrial capital of the world. Two to three million tons of chromite ore processing waste were produced in Hudson County alone (Burke et al., 1991), with a legacy of more than 200 chromium waste sites in the county. One form of chromium can cause cancer.

In the 1990s, the Environmental and Occupational Health Sciences Institute (EOHSI) at Rutgers University, in col-laboration with the state of New Jersey, performed exposure studies in Hudson County. The studies were conducted in two phases: residential areas prior to remediation and the same areas after remediation (Lioy et al., 1992). The EOHSI demonstrated that residential exposure to total chromium was caused by chromium that was resuspended outdoors and transported indoors from waste sites located in or near residential neighborhoods in Jersey City and Bayonne (Lioy et al., 1992; Stern et al., 1998). This information on pathways of exposure helped fine-tune the cleanup strategy. Urine screening before and after cleanup also identified exposure (Stern et al., 1998). The important conclusion was that the excavation and removal of chromium waste from these residential sites actually reduced chromium exposure in the previously sampled homes to background levels (Freeman et al., 2000). This clearly was a major success and is a guidepost for completion of such investigations.

Questions and concerns remain today regarding the adequacy and efficacy of interim remediation at the remaining sites in Hudson County. Although many of the sites are industrial, there is concern about their current state and the potential impact on future residential development. In 2006, the EOHSI repeated the first phase of the 1990s study at several of these locations to determine current exposures prior to permanent remediation. The results showed that in-terim remediation of industrial sites has not led to widespread high exposures, but that the land needs to be recovered for use by the community. Our current study provides a basis for comparison of exposures during and after cleanup.

The Hudson County experience demonstrated the value of community exposure characterization to site remedia-tion and the evaluation of community health risks. As we consider the future of Superfund and our national response to the challenge of hazardous waste remediation, we offer the following approach to improving exposure character-ization at Superfund sites:

1. Conduct exposure assessments during site discovery to better estimate the degree of health risk.2. Perform systematic exposure characterization throughout the entire cleanup process to direct remediation to the

most dangerous pathways.3. Consider appropriate biological monitoring of exposure to identify personal exposures before and after remediation.4. Develop historical community exposure characterization to help understand current health issues.5. Perform postremediation evaluation of exposure reduction to ensure the effectiveness of remedial action and

facilitate property reuse.

REFERENCESBrowner C. Environmental Health Threats to Children. EPA 175-F-96-001. US Environmental Protection Agency: Washington, DC, 1996.Burke T., Fagliano J., Hazen R., Iglewicz R., and McKee T. (1991). Chromite ore processing residue in Hudson County, New Jersey. Arch Environ Health 1991: 92: 131–137.Costas K., Knorr R.S., and Condon S.K. A case-control study of childhood leukemia in Woburn, Massachusetts: the relationship between leukemia incidence and exposure

to public drinking water. Sci Total Environ 2002: 30: 23–25.Freeman N.C.G., Lioy P.J., and Stern A.H.. Reduction in residential chromium following site remediation. J Air Waste Manage Assoc 2000: 50: 948–953.Lioy P.J., Freeman N.C.G., Wainman T., Stern A.H., Boesch R., Howell T., and Shupack, S.I. Microenvironmental analysis of residential exposure to chromium laden wastes

in and around New Jersey homes. J Risk Anal 1992: 12: 287–299.Maslia M.L., Reyes J.J., Gillig R.E., Sautner J.B., Fagliano J.A., and Aral M.M. Public health partnerships addressing childhood cancer investigations: case study of Toms

River, Dover Township, New Jersey, USA. Int J Hygiene Environ Health 2005: 208: 45–54.

National Research Council. Committee on Contaminated Drinking Water at Camp Lejeune. Contaminated Water Supplies at Camp Lejeune: Assessing Potential Health Effects. National Academics Press: Washington, DC, 2009.

Stern A.H., Fagliano J.A., Savrin J.E., Freeman N.C.G., and Lioy, P.J. The association of chromium in household dust with urinary chromium in residences adjacent to chromate production waste sites. Environ Health Perspect 1998: 106: 833–839.

US Environmental Protection Agency. National Priorities List, 28 December 2009. http://www.epa.gov/superfund/sites/npl/index.htm

http://www.isesweb.org

http://www.epa.gov/superfund/sites/npl/index.htm



Dramatic increase over time in levels of polybrominated diphenyl ether (PBDE) flame retardants in the breast milk of Swedish women. Adapted from Meironyté et al., 1999.

When a chemical poses an adverse human health or ecological risk, its use is typically reduced or discontinued. However, a replacement chemical is usually still needed, and the risks posed by the replace-ment chemical might be poorly understood. In fact, the replace-ment might be associated with greater risk than the original. We discuss the use of exposure science in the context of replacement chemicals using as a case study a group of flame retardants—poly-brominated diphenyl ethers (PBDEs)—that is being phased out and several other chemicals increasingly used as replacements.

The precipitous increase in concentrations of PBDEs in breast milk focused worldwide attention on this class of flame-retardant chemicals. On the basis of information showing increases in human and wildlife exposures in combination with evidence of develop-mental toxicity at low doses, many government agencies around the globe moved to ban PBDEs and manufacturers ceased produc-tion of two commonly used formulations (a third formulation has been banned in Europe, Asia, and several states in the United States). Thus, exposure science was a powerful tool in effecting change that resulted in reduced exposures to toxicants. However, new exposure data show that alternative and new flame retardants are appearing in household dust, wildlife, and humans. We need to improve and use our existing exposure tools to proactively evalu-ate exposures to alternatives to phased-out chemicals.

Exposure science can move us toward a more protective chemicals management policy by preventing human and ecological risks that may occur when existing “bad actors” are replaced with alternative chemicals that may not be as well studied.

Out of the frying pan and out of the fire: the indispensable role of exposure science in avoiding risks from replacement chemicalsJUDY S. LaKINDa aND LINDa S. BIRNBaUMb

aLaKind associates, LLC, Catonsville, Maryland, USa; Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USa; Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania, USabNational Institute of Environmental Health Sciences and National Toxicology Program, Research Triangle Park, North Carolina, USaaddress all correspondence to [email protected]:10.1038/jes.2009.71

BACKGROUND

Advances in analytical chemistry have allowed us to detect chemi-cals in the environment and in people at increasingly low concentra-tions, enabling us to better explore multiple pathways of exposure by assessing concentrations in air, water, and soil, as well as dust, furniture, and household products. Large-scale biomonitoring stud-ies of chemicals in blood and urine, such as those by the Centers for Disease Control and Prevention, have provided snapshots of human exposure to a wide array of chemicals. This has “personalized” ex-posure science and increased awareness in the general population about chemical exposures. Research demonstrating that a chemical is unexpectedly bioaccumulating—e.g., polybrominated diphenyl ethers (PBDEs)—or appearing in humans—e.g., perfluorooctane sulfonate (PFOS)—often produces an intense response by the pub-lic, the media, manufacturers, and regulators. The responses range from voluntary phaseouts of the chemical to calls for restrictions on use to outright bans. However, actions taken to reduce exposures to those chemicals often result in increased use of existing alternative chemicals or new chemicals developed to fill the void. In some cases, we know less about the exposure potential and/or toxic-ity of the alternative/new chemicals. In other cases, we find that chemicals once banned for a specific use find their way back into the marketplace as replacement chemicals with new uses. The story of a class of flame retardants—PBDEs—illustrates the importance of holistic thinking in chemical use and the role of exposure science in facilitating this type of thinking.

Flame retardants have been employed to reduce fire incidence and fire-related death and property destruction. The use of two brominated flame retardants was restricted in the 1970s because of exposure and toxicity concerns: polybrominated biphenyls were inadvertently mixed with animal feed, resulting in livestock death and high human exposures, and tris(2,3-dibromopropyl)phosphate (tris-BP), used in clothing, including children’s pajamas, was reported to be mutagenic and a kidney toxicant. It was also discovered that children were exposed to tris-BP through skin contact with their pajamas. The use of tris-BP and tris-(1,3-dichloro-2-propyl)phosphate (chlorinated tris) in children’s clothing was banned in the late 1970s, but they are still used in textiles and polyurethane foam. Similarly, PBDEs and other flame retardants that were replacement chemicals in the late 1970s are still used in some textiles and hard plastics (Birnbaum and Staskal, 2004).

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PBDE levels in breast milk





ImpACt AND ImplICAtIONs fOR expOsURe sCIeNCe

In the late 1990s, a report on PBDEs in breast milk in Sweden showed that levels had increased exponentially since the early 1970s (see figure). Follow-up studies in the United States found that PBDE concentrations in breast milk were much higher than those in Sweden. Equally alarming were reports of widespread exposures to PBDEs in humans and ecosystems. Although people are exposed to PBDEs in food, household dust can be an even more important route of exposure. This exposure information, in combination with toxicity research, led to a series of voluntary phaseouts, restrictions, and outright bans from 2004 to 2009 on the production of two PBDE formulations (penta and octa), followed by restrictions on the third formulation (deca) beginning in 2009. It took about 5 years from the time of release of the Swedish study to the time of widespread restrictions on these compounds.

However, to maintain fire safety standards, existing alternative flame retardants are being used in greater volume and new replacement chemicals are being brought to market. These include brominated phthalates, chlorinated tris, and other chemicals (CIREEH, 2009). These chemicals have now been measured in household dust. Ironically, although chlorinated tris was banned in children’s pajamas more than 30 years ago, it is now one of the highest-volume flame retardants in use today. Current use of chlorinated tris results in human exposure from dust inhalation and ingestion.

Unfortunately, the story of brominated flame retardants is not an isolated one, nor is it one consigned to the history books. There are too many examples of chemicals taken off the market only to be replaced with chemicals that, in time, come to be considered “of concern.” We may be at such a juncture with replacement chemicals for bisphenol A (BPA) and PFOS. BPA, used mainly in the production of polycarbonates, has been measured in >90% of the general US population, prompting calls for bans, which have been enacted for certain uses in some parts of the United States and proposed in other countries. This has in turn resulted in a demand for alternatives to polycarbonate bottles, including glass and metal bottles and those made from a copolyester (C&EN News, 2009), which is marketed to both adults and children. Our literature search on some of the replacement copolyester chemicals revealed no exposure information. Years from now, will we be seeing exposure stud-ies describing certain BPA alternatives as emerging chemicals of concern?

A similar issue has arisen with the replacement of PFOS—a compound used as, among other things, stain repellants and coatings for food packaging—with other perfluorinated compounds (PFCs). Once considered stable and nontoxic, PFOS is now known to bioaccumulate and has been measured in people, wildlife, and the environment around the world. As was the case with PDBEs, this type of exposure information led to a move away from its use (through voluntary phaseouts and restrictions) and toward other PFCs. Recently published levels of PFCs in household dust suggest the possibility of wide-spread exposure to some of these replacement PFCs (e.g., Kato et al., 2009).

By using exposure tools in a more holistic fashion, we may be able to avoid déjà vu all over again. Our experience with PBDEs clearly shows the high-priority need for a proactive exposure science approach toward evaluating emerging chemi-cal constituents. We must break the cycle of introducing (or re-introducing) chemicals with potential for widespread human and ecosystem exposures without first understanding potential pathways and magnitude of exposure. Exposure scientists, including those conducting biomonitoring research, can influence this process by thoughtfully considering both existing and potential replacements and using state-of-the-science tools to help us evaluate the likelihood that future exposures to these chemicals will become widespread and/or increasing in concentration. This will enable us to make more informed decisions about the public and environmental health acceptability of replacement/new chemicals.

RefeReNCesC&EN News. Babies on board. 31 august 2009, p 20.Birnbaum L.S., and Staskal D.F. Brominated flame retardants: cause for concern? Environ Health Perspect 2004: 112: 9–17.CIREEH. Center for Interdisciplinary Research in Environmental Exposures and Health. Exposure to PBDEs—Research at Boston University School of Public Health, 2009. http://

www.cireeh.org/pmwiki.php/Main/ExposureToPBDEs.Kato K., Calafat a.M., and Needham L.L. Polyfluoroalkyl chemicals in house dust. Environ Res 2009: 109: 518–523.Meironyté D., Norén K., and Bergman a. analysis of polybrominated diphenyl ethers in Swedish human milk: a time-related trend study, 1972–1997. J Toxicol Environ Health A 1999:

58: 329–341.

The Research described in this article has been reviewed by the National Institute of Environmental Health Sciences, and approved for publication. Approval does not signify that the contents necessarily reflect the views of the Agency, nor does the mention of trade names or commercial products constitute endorsement or recommendation for use.


http://www.cireeh.org/pmwiki.php/Main/ExposureToPBDEs

http://www.cireeh.org/pmwiki.php/Main/ExposureToPBDEs



Exposure to ambient air particulate matter (PM) causes more mortality and morbidity than any other regulated environmental pollutant, but PM is ill defined (US Environmental Protection Agency, 2004). Although regulations to protect people from PM have progressively improved, the ultimate goal is to iden-tify the components most responsible for adverse effects so regulations can be more targeted.

Targeting the components most responsible for airborne particulate matter health risksMORTON LIPPMANNa

aDepartment of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USAAddress all correspondence to [email protected]:10.1038/jes.2010.1

BACKGROUND

In December 1952, a thermal inversion settled over London, England, keeping coal-smoke emissions at ground level for four days. Deaths and hospital admissions rose with the levels of black smoke and sulfur dioxide (SO

2) and began to drop,

along with the pollutant concentrations, when a cleaner air mass moved in. However, the death rate did not return to baseline levels for months. The increase in deaths over the first week was approximately 4,000, and the excess over several months was approximately 12,000. Excess mortality—attrib-uted mainly to cardiac causes—occurred largely in those less than 1 year of age and those older than 55 (Lippmann, 2009a). This and subsequent London episodes, combined with the findings of some US studies, provided a primary basis for set-ting the US National Ambient Air Quality Standards (NAAQS) for particulate matter (PM) in 1971 and again in 1987.

ImpACt AND ImplICAtIONs fOR expOsURe sCIeNCe

Recognition of the problems with continued use of “total suspended particles” (TSP) as an index of health risk led to a series of reanalyses of the London experience and new studies of exposure–health relationships in US populations. Notable among these was the “Harvard six-cities study,” which began as a long-term prospective study of both adults and children but expanded to include related epidemiology and exposure studies. Improved measurements of pollutant gases, particle size fractions, and sulfates were especially important in the 1987 and subsequent NAAQS reviews. Other analysts from the US Environmental Agency (EPA) and academe pioneered in the development of more sensitive statistical methods used in new and reexamined previous studies, to take fuller advantage of existing regulatory monitoring data as well as the growing Harvard data (Greenbaum et al., 2001). An explosion of scien-tific papers that began to emerge in the 1990s demonstrated

The US Environmental Agency (EPA) sets primary National Ambient Air Quality Standards (NAAQS) to protect people, including sensitive populations, from the adverse health effects of certain air pollutants, including particulate matter (PM). Airborne PM is a mixture of varying physical and chemical composition, but its regulatory limits are currently based only on weight (mass) concentrations, within two broad ranges of “aerodynamic” diameters measured in micrometers: <10 µm and <2.5 µm.

The figure shows the relative size and respiratory penetra-tion of PM regulated by the NAAQS. The original (1971) NAAQS for “total suspended particles” (TSP) also included much larger, noninhalable particles. By 1987, the focus was on the combi-nation of fine (<2.5 µm) and coarse (<10 µm) particles, all of which can be inhaled into the lower respiratory tract (Lippmann and Leikauf, 2009). Subsequent research using both PM

10 and

fine-particle monitors found effects at levels below those of the 1987 standards, leading to new standards for PM

2.5 and PM

10

(Bachmann, 2007). These size fractions have different chemis-tries and different exposure patterns, which can significantly in-fluence health effects. On the basis of the most recent scientific assessments, many experts agree that fine PM is more strongly associated with cardiovascular health effects, including mortal-ity, than coarse PM. Most experts agree that inhalable coarse particles are a risk factor for adverse pulmonary responses.

The initial focus on inhalable particle-size ranges (PM10

and PM

2.5) enabled the development of NAAQS that were effective

in reducing exposures known to cause adverse health effects. However, they are far from ideal in that we now know that some chemical components of PM are more toxic than other compo-nents. Advances in exposure science to better understand the components are fundamental to the next generation of NAAQS.


6 Journal of Exposure Science and Environmental Epidemiology (2010)


6 Journal of Exposure Science and Environmental Epidemiology (2010)

the significant influence of particle size and mass and suggested that some degree of effect occurred at all PM concentrations, even those that were extremely low—i.e., there is no evidence for a threshold (Lippmann, 2009a; US Environmental Protection Agency, 2004). Exposure studies played an important role in evaluating the credibility of epidemiology studies that used outdoor monitors to measure exposure to air of ambient origin.

Collectively, the large, growing, and generally consistent literature on the adverse health effects of PM exposure provided sound scientific rationales for the more stringent PM NAAQS promulgated in 1997 and 2006. The resulting reductions in PM have saved lives (Laden et al., 2006). While sharpening the focus of the PM NAAQS by particle-size characteristics is good and is consistent with the mandate of the Clean Air Act, this approach has, in my view, gone about as far as is reasonable to go. To serve the public needs and interests, it is now time for the EPA and the scien-tific community to generate the data needed to provide an adequate basis for chemical component–specific PM NAAQS that will target the PM components and/or sources that are most directly responsible for the adverse effects associated with PM mass concentrations.

To its credit, the EPA has taken significant steps to facilitate epidemiological studies that can associate PM com-ponents and sources with health effects. Unfortunately, the PM chemical composition data being generated are severely limited because there are only one or a few sites in each city, and PM samples are collected only every third or sixth day. For components that are fairly uniformly distributed over urban areas, such as sulfate, this problem is not very severe when considering long-term average concentrations. But for components associated with vehicular traffic, seaports, airports, and space heating with dirty fuels, the highly variable exposure distributions among the populations at risk are a severe limitation (Peltier and Lippmann, in press). Furthermore, the lack of daily data on concentrations makes it all but impossible to accurately study acute responses to peaks in exposure. These limita-tions, as well as potential solutions through the application of new exposure science technology, were addressed at a recent EPA workshop and provided a basis for research recommendations as reported by Lippmann (2009b).

The ability of targeted research to characterize the impact of PM chemistry has been reviewed by Lippmann and Chen (2009), who describe recent studies of the effects of chronic exposures to chemically analyzed PM

2.5 mixtures

on human populations and laboratory animals. Results show closer associations of effects with some metals and elemental carbon than with other components. In one animal study, trace amounts of nickel were implicated as a cause of changes in cardiac function. This demonstrates the urgent need for advances in exposure science that can be applied in routine detailed chemical analyses of PM

10 and PM

2.5, so that the most toxic components can be clearly

identified (Lippmann, 2009b). With this new knowledge, we will be able to develop future PM NAAQS that are more closely targeted on the most toxic components and are more efficiently implemented.

RefeReNCesBachmann, J. Critical Review: will the circle be unbroken: a history of the U.S. National Ambient Air Quality Standards. J Air Waste Manage Assoc 2007: 57: 652–697.Greenbaum D.S., Bachmann J.D, Krewski D., Samet J.M., White R., and Wyzga R.E. Particulate air pollution standards and morbidity and mortality: case study. Am. J. Epidemiol 2001:

154: S78–S90.Laden F., Schwartz J., Speizer F.E., and Dockery D.W. Reduction in fine particulate air pollution and mortality: extended follow-up of the Harvard Six Cities Study. Am J Respir Crit

Care Med 2006: 173: 667– 672.Lippmann M. Ambient particulate matter. In: Lippmann M. (ed). Environmental Toxicants: Human Exposures and Their Health Effects, 3rd edn. Wiley: New York, 2009a, pp 317–365.Lippmann M. Semi-continuous speciation analyses for ambient air particulate matter: an urgent need for health effects studies. J. Expos Sci Environ Epidemiol 2009b: 19: 235–247.Lippmann M., and Chen L.-C. Health effects of concentrated ambient air particulate matter (CAPs) and its components. Crit Rev Toxicol 2009: 39: 865–913.Lippmann, M., and Leikauf, G.D. Introduction and background. In: Lippmann M. (ed). Environmental Toxicants: Human Exposures and Their Health Effects, 3rd edn. Wiley: New York,

2009, pp 1–38.Peltier R.E., and Lippmann M. Residual oil combustion: 2. Distribution of airborne nickel and vanadium within New York City. J Expos Sci Environ Epidemiol (in press).US Environmental Protection Agency. Air Quality Criteria for Particulate Matter. Report no. EPA/600/P-99/002aF. National Center for Environmental Assessment–RTP Office

Research: Triangle Park, NC, October 2004.




Rapid, early-life developmental changes in physiology, metabo-lism, anatomy, and behavior can significantly alter exposure and risk to environmental hazards during childhood. It has long been noted that infants and children breathe, eat, and drink propor-tionally more than adults, resulting in a pollutant load that is concentrated in much smaller and rapidly developing organ sys-tems, including the nervous, respiratory, metabolic, and immune systems. Comparing children and adults on a body-weight basis, however, is a gross simplification—after all, infants are not small adolescents. Thus, a life-stage approach that incorporates age-related differences in exposure, dose, and how the body handles chemicals is crucial to assessing risk. Water ingestion (see figure) provides a good illustration. Intake on a body-weight basis is very high during infancy but decreases dramatically during the first few years of life. A goal of improving consistency and accuracy in exposure assessment led the US Environmental Protection Agency to develop childhood age grouping guidance (EPA, 2005) for post-birth life stages, as well as accompanying data on exposure factors to support implementation of a standard set of childhood age groups. These age groupings are shown in the figure. (From EPA, 2009.)

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Children’s susceptibility to environmental contaminants can vary significantly by life stage. The recent adoption by the US Environmental Protection Agency of a standard set of childhood age groups is proving instrumental in im-proving our ability to protect children by more consistently considering life-stage changes when assessing exposure, dose, and risk.

Protecting children from environmental risks throughout each stage of their childhoodMICHAEL FIRESTONEa

aOffice of Children’s Health Protection, US Environmental Protection Agency, Washington, DCAddress all correspondence to [email protected]

doi:10.1038/jes.2010.10

BACKGROUNDAlmost 500 years ago, Paracelsus (1493–1541) wrote “Dosis facit venenum,” or “the dose makes the poison.” This relation-ship between dose and response (effect) is still one of the most fundamental concepts of toxicology—but is it accurate and does it tell the whole story? When it comes to understanding children’s environmental health, the answer is no!

For developmental toxicants, the same dose that may pose little or no risk to an adult can have drastic effects in a developing fetus or a young child. For example, outbreaks of methylmercury poisonings in which mothers with no adverse symptoms gave birth to infants with severe nervous system damage made it clear that the developing nervous system of the fetus is significantly more vulnerable to methylmercury than is the adult nervous sys-tem. Similarly, exposure to secondhand tobacco smoke has been found to increase an infant’s risk of succumbing to sudden infant death syndrome. Thus, it is often critical to consider life stage in risk assessment. The term “life stage” refers to a distinguishable time frame in an individual’s life that is characterized by unique and relatively stable behavioral and/or physiological characteris-tics that are associated with development and growth.

In addition to changes in toxicological sensitivity during devel-opment, there are important differences in exposure that occur from birth through adulthood (Firestone et al., 2007). For example, consumption of apple products by children less than 1 year old is about 19 g/kg-day, whereas consumption by adults 20 years and older is approximately 2 g/kg-day, a differ-ence in almost an order of magnitude. Young children play close to the ground and come into contact with contaminated soil outdoors and contaminated dust on surfaces and carpets indoors. They also display considerably more hand- and object-to-mouth activity than adults do. And exposure to chemicals in breast milk impacts only infants and very young children, yet exposure through this pathway may be among the most significant since many persistent hydrophobic pol-lutants, such as dioxin and polychlorinated biphenyls, are biomagnified through the mother.

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEIn recognition of the rapid changes that occur in childhood related to physiology, metabolism, anatomy, and behavior and that can impact exposure to and risk from environmental hazards, the US Environmental Protection Agency (EPA) began to

Total water ingestion (from all sources) by age, 95th percentile





view childhood as a sequence of life stages, rather than children as a single subpopulation (EPA, 2005a). Although life-stage differences in toxicity and exposure have led many to conclude that children are not merely small adults, it is clear that this simplification is inadequate to describe how rapid behavioral and physiological changes early in life can have a profound impact on risk and health outcomes—both those that occur during childhood and those that may be manifested much later, in adulthood (Barker, 2007).

Historically, one of the great difficulties in consistently factoring in life-stage differences in exposure and toxicity has been the lack of a standard set of childhood age groups or a common convention for defining age groups. Prior to 2005, each program within the EPA had its own—and often unique—definition of childhood age groups (EPA, 2005b). In 2005, the landscape changed when the agency published a recommended set of standard post-birth childhood age groups for use when assessing or monitor-ing exposure (EPA, 2005b):• Less than 12 months old: birth to <1 month, 1 to <3 months, 3 to <6 months, and 6 to <12 months• 12 months and older: 1 to <2 years, 2 to <3 years, 3 to <6 years, 6 to <11 years, 11 to <16 years, and 16 to <21 yearsAlso adopted was a standard age-group notation “X to <Y”; for example, the age group “3 to <6 years” is meant to span a 3-year

time interval from a child’s third birthday until the day before his or her sixth birthday.Matching information regarding age-dependent exposure, physiological, and behavioral factors is contained in the Child-Specific

Exposure Factors Handbook (EPA, 2008).Use of this standard set of childhood age groups allows for a major computational shift in how risk assessment is conducted.

The importance of considering early-life differences in exposure and risk was clearly demonstrated in the EPA’s “Drinking Water: Perchlorate Supplemental Request for Comments” (Federal Register, 2009). The document provides alternative health reference levels (an exposure level below which no significant noncancer risk is expected) for various life stages. The EPA found that young infants were at greatest risk when their relative exposure was considered, with health reference levels an order of magnitude lower than those based on the assessment methods for adults.

In its Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (EPA, 2005c), the EPA developed a second, complementary set of childhood age groups based on toxicological sensitivity to carcinogens acting through a mutagenic mode of action. When chemical-specific dose–response data are not available, the guidance recommends the use of life-stage-based adjustments to carcinogenic potency values (i.e., the potential to induce cancer) for the following age groups (note that, because of limited data, the EPA was forced to consolidate the more expanded set of age groups used when assessing childhood exposures):• 0 to <2 years: 10-fold increase in the potency calculated to cause cancer in adults• 2 to <16 years: 3-fold increase• 16 and older: no adjustmentAlthough there is no single “correct” set of age groups, adopting a common convention for defining age groups will enable

scientists to better understand differences in exposure and risk across life stages and the factors that may account for such dif-ferences, such as nutritional status, prevalence of certain diseases, ethnic/cultural norms regarding activity or behavior patterns, population genetic characteristics, meteorological conditions, geography, and social stress. There are other life stages beyond those of childhood that may be important to consider when assessing human exposure and risk, including pregnancy, nursing, and old age.

In conclusion, perhaps Paracelsus should have stated his maxim as “Dosis quod timidus patefacio facit venenum,” or “The dose and its timing make the poison.”

REFERENCESBarker D. The origins of the developmental origins theory. J Intern Med 2007: 261: 412–7.EPA. Risk Assessment Forum, US Environmental Protection Agency. Guidelines for Carcinogen Risk Assessment, sections 1.3.5 and 1.3.6. EPA/630/P-03/001F. Washington, DC,

2005a.EPA. Risk Assessment Forum, US Environmental Protection Agency. Guidance on Selecting Age Groups for Monitoring and Assessing Childhood Exposures to Environmental

Contaminants. EPA/630/P-03/003F. Washington, DC, 2005b.EPA. Risk Assessment Forum, US Environmental Protection Agency. Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens. EPA/630/R-

03/003F. Washington, DC, 2005c.EPA. National Center for Environmental Assessment, US Environmental Protection

Agency. Child-Specific Exposure Factors Handbook. EPA/600/R-06/096F. Washington, DC, 2008.

Federal Register. Drinking water: perchlorate supplemental request for comments. Federal Register 74: 41883 (19 August 2009).

Firestone M., Moya J., Cohen-Hubal E., Zartarian V., and Xue J. Identifying childhood age groups for exposure assessments and monitoring. Risk Anal 2007: 27:

Disclaimer: The views expressed in this paper are those of the author and do not necessarily reflect the views or policies of the US Environmental Protection Agency.




(Image from the Office of Underground Storage Tanks, US Environmental Protection Agency.)

The reform of the Toxic Substances Control Act (TSCA) is likely to be taken up by Con-gress next year. Among the driving forces for amending the TSCA is recognition of our current weakness in dealing with chemicals that were already on the market at the time of TSCA’s original passage in 1976 (Renn and Elliott, 2010). Among these grandfathered compounds is methyl tertiary-butyl ether (MTBE), an oxygenate previously used primar-ily as an anti-knock compound in gasoline. When use became widespread, more than 100 million Americans were exposed to MTBE before adequate knowledge of toxicity and exposure was available. The history of MTBE clearly demonstrates the need to avoid similar experiences in the future. The picture depicts one major exposure pathway by which MTBE can reach drinking water: a leaking underground gasoline storage tank.

Advanced exposure assessment is vital to improving the Toxic Substances Control Act.

MTBE: A poster child for exposure assessment as central to effective TSCA reformBERNARD D. GOLDSTEINa

aUniversity of Pittsburgh, Pittsburgh, Pennsylvania, USAAddress all correspondence to [email protected]:10.1038/jes.2010.17

BACKGROUNDMethyl tertiary-butyl ether (MTBE) provides a case study of the im-portance of exposure assessment to amending the provisions of the Toxic Substances Control Act (TSCA). MTBE had long been in use for a variety of different purposes prior to its being chosen to supply the oxygenate required for much of US gasoline. Under the 1990 Clean Air Act amendments, oxygenates were required in the parts of the United States that failed to meet the carbon monoxide (CO) health air standard, at a level in gasoline equivalent to 15% MTBE (by volume), primarily during the winter. In areas of the country failing to meet the ozone health air standard, oxygenates were also used as part of the summertime gasoline blend at a level equivalent to 11.1% MTBE. As a result, MTBE rapidly became one of the leading worldwide commodity chemicals.

The major investment to gear up MTBE production was made before all the essential toxicological studies had been reported. In 1992, initial industry-funded long-term laboratory animal studies required by the TSCA Interagency Testing Committee reported renal, hepatic, and testicular cancers in different species and sexes under study (Bird et al., 1997). A subsequent Italian study confirmed the testicular cancers and also showed an increase in rat lymphohematopoietic cancers (Belpoggi et al., 1997). The recent International Agency for Research on Cancer categorization of a major MTBE metabolite, formaldehyde, as a known human leukemogen is consistent with this animal finding. Nonspecific symptoms were also attributed to MTBE, a phenomenon that was partially replicated in controlled human exposure studies, but only in individuals claiming to be symptomatic (Fiedler et al., 2000). In addition, significant groundwater contamination occurred, which was a deciding factor in the eventual Environmental Protection Agency decision to phase out MTBE usage, particularly because cleanup of MTBE-contam-inated groundwater is costly. But the proposal to phase out MTBE occurred only after a recurrent series of expert panels convened by the EPA, the National Academies of Science, the Office of Science and Technology Policy, various states, and the Health Effects Institute, all of which requested additional information (Davis and Farland, 2001; Erdal and Goldstein, 2000).

Northern New Jersey and Alaska provide two examples of the failure to consider exposure in relation to potential risks and benefits. The allowable 8-hour CO exposure level was based primarily on avoiding effects in individuals with arteriosclerotic heart disease (ASHD) in whom exposure was likely to lead to an increased risk of anginal attacks. Northern New Jersey exceeded the 8-hour CO standard at one monitoring station near the Lincoln Tunnel, which resulted in a regulatory requirement to use MTBE. More than 4 million residents of northern New Jersey were exposed to MTBE, of whom few, if any, were likely to be exposed for 8 hours to CO at the Lincoln Tunnel. Similarly, in Anchorage no exposure estimates were made of the number of individuals with pre-existing ASHD who were outdoors for 8 hours during the Alaskan winter, specifically in the CO exceedance area. The absurdity of such a scenario, along with the great outcry over nonspecific symptoms attributed to MTBE, contributed to Alaska’s being of-ficially excused from the use of MTBE.

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEOne of the forces driving consideration of whether and how to amend the TSCA is the recent promulgation by the Europe-an Union of the Registration, Evaluation, Authorisation, and Restriction of Chemical Substances (REACH) legislation (http://


http://ec.europa.eu/environment/chemicals/reach/reach_intro.htm



ec.europa.eu/environment/chemicals/reach/reach_intro.htm). This comprehensive approach to regulating chemicals remains a work in progress. But its tiered methodology has a much greater reliance on exposure assessment than does the TSCA. Exposure is considered in multiple steps in the REACH registration process (Williams et al., 2009). The extent of expo-sure assessment varies, depending on the tonnage released and the hazard of the agent. Industry is required to develop exposure scenarios based on life-cycle phases, including for uses recommended or anticipated by downstream purchasers. Exposure levels are estimated for different populations and for different potential environmental targets.

The “precautionary principle,” which served as a rationale for REACH and is part of the argument for amending the TSCA, is highly pertinent to the MTBE issue. A major tenet of the precautionary principle is shifting of the burden of proof such that safety must be shown by the manufacturer prior to marketing, rather than requiring governmental agencies to demonstrate that the agent is harmful after its use. In the case of MTBE, had the burden of proof been on the manufacturer to demonstrate safety under all exposure scenarios, it is unlikely to have been marketed. However, once the investment had been made, the forces at work under a regulatory approach that was particularly weak for existing chemicals made it difficult to remove the agent from the gasoline supply. If MTBE had been a new chemical, it is unlikely that it would be accepted for marketing to the general public if premarketing tests showed cancer in both rats and mice in multiple organs and in multiple studies. Putting any substance in gasoline is the most effective means of causing the maximum number of Americans to be exposed. Hence, such a pathway requires a cautious early assessment.

MTBE also provides a good example of the value of using exposure scenarios to predict potential problems. Drinking-water contamination was eminently predictable given the frequency of leaking underground gasoline storage tanks, the greater solubility in groundwater of an oxygenate as compared with usual gasoline hydrocarbons, the lack of natural bac-terial decomposition, and the exceptional extent to which trace levels of MTBE make water unpalatable. In retrospect, a rig-orous approach to analysis of exposure across all pathways and routes would probably have hindered the rapid adoption of MTBE as a major additive to gasoline. Delay until at least the full toxicological appraisal was completed not only would have protected public health and the environment but would also have been beneficial to the petrochemical industry, which has had to write off major investments.

Key to improving the TSCA is better predictive toxicology and exposure science as part of a holistic assessment of all uses and exposure pathways. It has been disappointing that two major initiatives to increase the toxicological and expo-sure data base—the High Production Volume Initiative and REACH—have led to relatively little governmental investment in improving toxicological or exposure science despite the imposition of major costs to perform the required studies. To achieve better protection of the public against the threat to the environment and to human health posed by chemicals, it is necessary to have both laws that force a comprehensive approach to assessing risks and science that can readily predict and detect the potential for adverse exposures and effects.

REFERENCESBelpoggi F., Soffritti M., Filippini F., and Maltoni C. Results of long-term experimental studies on the carcinogenicity of methyl tert-butyl ether. Ann NY Acad Sci 1997: 837: 77–95.Bird M.G., Burleigh-Flayer H.D., Chun J.S., Douglas J.F., Kneiss J.J., and Andrews L.S. Oncogenicity studies of inhaled methyl tertiary-butyl ether (MTBE) in CD-1 mice and F-344

rats. J Appl Toxicol 1997: 17(Suppl 1): S45–S55.Davis J. M., and Farland W.H. The paradoxes of MTBE. Toxicol Sci 2001: 61: 211–217.Erdal S., and Goldstein B.D. Methyl tert-butyl ether as a gasoline oxygenate: lessons for environmental public policy. Annu Rev Energy Environ 2000: 25: 765–802.Fiedler N., Kelly-McNeil K., Mohr S., Lehrer P., Opiekun R.E., Lee C. et al. Controlled human exposure to methyl tertiary butyl ether in gasoline: symptoms, psychophysiologic and

neurobehavioral responses of self-reported sensitive persons. Environ Health Perspect 2000: 108: 753–763.Renn O., and Elliott D.D. Chemicals regulation. In: Wiener J.B., Rogers M.D., Hammitt J.K., and Sand P.H. (eds). The Reality of Precaution: Comparing Risk Regulation in the United

States and Europe. RFF Press: Washington, DC, 2010.Williams E.S., Panko J., and Paustenbach D.J. The European Union’s REACH regulation: a review of its history and requirements. Cri Rev Toxicol 2009: 39: 553–557.









In September 2009, the administrator of the US Environmental Protection Agency announced White House–backed principles for modernizing the Toxic Substances Control Act (TSCA), the US legislation that regulates potentially toxic chemicals. This request for lawmakers to give the EPA authority to require manufactur-ers to provide sufficient exposure, hazard, and use data to allow meaningful risk characterization was a very important, and bold, step toward ensuring the safety of chemicals. Another major step in this direction has been the innovation that researchers have demonstrated by modifying molecules—by design—so that they manifest no hazards while in use and then degrade safely. Taken together, these steps signal the beginning of a new era of chemical risk management. Advanced exposure science is critical to the efficient and effective prevention and management of chemical risks. Fundamental exposure research in this area is transforming not only the pace of our analyses but the depth of our insights.

We now have the scientific tools to begin a new era of chemical management, an era in which exposure science will be more critical than ever.

Ensuring the safety of chemicalsPAUL ANASTASa, KEVIN TEICHMANa AND ELAINE COHEN HUBALa

aOffice of Research and Development, US Environmental Protection Agency, Washington, DC, USAAddress all correspondence to [email protected]:10.1038/jes.2010.28

BACKGROUNDWell over 10,000 chemicals are currently in commercial use, and hundreds more are introduced each year. Of these, only a small fraction has been assessed adequately for potential risks. Existing chemical testing and exposure measurement protocols are expen-sive and time consuming. Furthermore, the specific nature of the Toxic Substances Control Act (TSCA) led to many existing chemi-cals being deemed safe despite little knowledge of their exposure and toxicity. As a result, federal regulators have not had adequate information to fully evaluate chemical safety. Our challenges in the United States are not unique. As recognized by the European Union’s Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) legislation, there is a critical global need to better understand and manage risks to human health and the en-vironment that arise from the manufacture and use of chemicals.

In September 2009, in remarks made to the Commonwealth Club of San Francisco, US Environmental Protection Agency (EPA) Administrator Lisa Jackson announced principles for modernizing the TSCA. These principles highlight the need to review all manu-factured chemicals against safety standards protective of human health and the environment, with special consideration of expo-sures and effects on vulnerable groups, including children. Under these principles, policy reform will encourage innovation in green chemistry and sustainable chemical design. We are witnessing this innovation today as researchers modify molecules, by design, so that they do not manifest hazards; i.e., chemical and physical properties of chemicals are being modified to realize important benefits while minimizing undesired exposures. These advances are leading us down the road to safer and more sustainable chemi-cals and processes.

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEEPA research in chemical risk assessment provides the foundation for policy decisions and regulatory actions that facili-tate management of hazardous chemicals. Creative advances in exposure science are required for efficient and effective evaluation, prevention, and management of chemical risks (Sheldon and Cohen Hubal, 2009).

One of the greatest challenges is how to screen chemicals for potential risks so that scarce resources can be devoted to the chemicals of greatest concern. The EPA is conducting research to identify and address gaps in required exposure information to meet this challenge. For example, the agency’s Office of Research and Development recently implemented its ExpoCast program, which aims to develop novel approaches and metrics to efficiently screen and evaluate chemicals on the basis of biologically relevant human exposures, i.e., exposures that can be directly linked to key events leading to toxic response (Cohen Hubal, 2009). Combining information from ExpoCast with information from ToxCast—a battery of rapid screens being studied by the EPA to determine whether they can predict toxicity (Dix et al., 2007)—will help the agency to identify priority chemicals for evaluation based on the potential to harm human health.

“Wish I could always keep their environment safe!”





The properties of a chemical, whether naturally occurring or manufactured, that confer a useful function may be the same properties that can be harmful under the wrong conditions. Important industrial sectors, including energy, agri-culture, plastics, cosmetics, electronics, and pharmaceuticals, require the manufacture of chemicals. The challenge is to understand how best to develop, manufacture, use, and dispose of chemicals in order to manage risks and minimize, if not eliminate, harm. To minimize dangerous exposures, products should be engineered to break down into innocuous compounds that do not persist in the environment beyond the useful life cycle of the product. Simply put, we must man-age chemical risks by design.

To address society’s need for safe and effective chemicals, a transformation is occurring in the framework for design, manufacture, and management of chemicals (Anastas, 2009). Principles of green chemistry require holistic consideration of integrated environmental, economic, and social factors. Here, too, exposure science is critical. Exposure is the contact between an individual or group and an environmental chemical. Prediction of potential exposures across the product life cycle for all chemical classes and use scenarios is required under green engineering principles to minimize potential health risks to all vulnerable groups.

Why do we need innovative, quality exposure science to assure chemical safety?• Exposure information is critical to preventing, minimizing, and managing risks—by creative design—without forgoing

the important benefits of chemicals. Understanding exposure sources and pathways will facilitate green chemical and product design, safe use, and prevention of adverse health consequences to people and to the environment.

• A systems-level understanding of how humans interact with environmental chemicals is required in order to predict unin-tended consequences. Fundamental knowledge of exposure is essential to an understanding of how chemicals end up in unanticipated places. By collecting and evaluating detailed exposure data on existing chemicals, we can develop metrics that can be used to predict use and behavior of proposed and emerging chemicals.

• Exposure surveillance is required to proactively identify potential risks from chemicals in commerce. Chemicals show up in unexpected places long before their impact on health and the environment is understood or evaluated. As we manu-facture and release new chemicals, or existing substances are used in new ways, exposure monitoring will provide an early indication of a chemical’s behavior in our homes, communities, and environment. For example, small-scale biosensors can be developed to detect specific sets of environmental agents in air, water, and food, and even in our bodies. In this way, intervention to prevent or eliminate unexpected sources of exposure can be implemented prior to the identification of potential health consequences.

• Clear exposure information is required to make educated personal decisions. Good exposure information on chemicals found in the products we use and in our communities enables us, as individuals, to make educated decisions to pro-tect our health and the environment. Publicly available and accessible exposure science will empower individuals and communities to choose chemical-based products and services that are safe and effective.

We now have the scientific tools to begin a new era of chemical management, an era in which exposure science will be more crucial than ever. Exposure research, combined with green chemistry and new computational toxicity approaches, offers us the opportunity—through innovative design—to maximize chemical benefits while minimizing chemical risks. We owe the American people, and people around the world, no less.

REFERENCESAnastas P.T. The transformative innovations needed by green chemistry for sustainability. ChemSusChem 2009: 2: 391–392.Cohen Hubal E.A. (2009) Biologically relevant exposure science for 21st century toxicity testing. Toxicol Sci 2009: 111: 226–232.Dix D.J., Houck K.A., Martin M.T., Richard A.M., Setzer R.W, and Kavlock R.J. The ToxCast program for prioritizing toxicity testing of environmental chemicals. Toxicol Sci 2007: 95:

5–12.Sheldon L.S., and Cohen Hubal E.A. Exposure as part of a systems approach for assessing risk. Environ Health Perspect 2009: 117: 1181–1184.

Disclaimer: This paper has been subjected to Agency review through the Office of Research and Development and been cleared for publication by the US Environmental Protection Agency. Nonetheless, any opinions expressed are those of the authors and do not necessarily reflect EPA policy.




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The World Health Organization Framework Convention on Tobacco Control (FCTC) has set the stage for efforts to reduce smoking worldwide. Tobacco smoke exposure studies have made essential contributions to tobacco control efforts in the United States and worldwide.

In Baltimore, MD, smoking was allowed in bars and nightclubs before the enactment of comprehensive smoke-free legislation in February 2008. To objectively document secondhand smoke exposure levels in Baltimore bars, we measured nicotine concen-trations in the air as well as in the hair of nonsmoking employees in 11 bars. As shown in the figure, bars that allowed smoking had median airborne and hair nicotine concentrations 45 and 16 times higher, respectively, than bars that did not permit smoking. These findings were widely disseminated via advocacy groups and local media and were presented to local and statewide government entities in support of the smoke-free legislation that was subse-quently approved in the city of Baltimore and later in the state of Maryland (unpublished data).

“The scientific evidence indicates that there is no risk-free level of exposure to secondhand smoke” (US DHHS, 2006).

The smoking gun: working to eliminate tobacco smoke exposurePATRICK N. BREYSSEa AND ANA NAVAS-ACIENa

aDepartment of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USAAddress all correspondence to [email protected]:10.1038/jes.2010.34

BACKGROUNDThe 1972 US Surgeon General’s Report on smoking reported the first systematic examination of the impact of smoking on indoor environments (US DHEW, 1972). The report noted the lack of exposure data, concluding that the contribution to human disease of tobacco smoke components (e.g., particulate matter (PM) and oxides of nitrogen) was not well known.

By the early 1980s, evidence of the health consequences of sec-ondhand smoke (SHS) exposure was mounting. The literature suf-fered, however, from limited data characterizing the extent of SHS exposure. The recent report of the Surgeon General on the health consequences of involuntary smoking (US DHHS, 2006) relied heav-ily on the growing body of literature describing exposure to PM, nicotine, nitrosamines, and other tobacco compounds associated with SHS exposure.

SHS exposure is most commonly assessed by measuring PM and nicotine in the air. Measuring PM for this purpose began in the early 1980s, and determining vapor-phase nicotine concentra-tions dates back to landmark studies in the late 1980s (Spengler et al., 1981; Repace, 1980; Mattson et al., 1989). Biomonitoring offers important insights into internal dose by integrating multiple exposure sources and can thus provide information about expo-sure in different environments (e.g., home, work, and transporta-tion). Cotinine—the principal metabolite of nicotine—in biological samples (e.g., serum) is the biomarker that is used most often to assess short-term and ongoing SHS exposure.

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEMeasurements of airborne nicotine and PM in public places have contributed to the development and implementation of smoke-free legislation around the world by documenting the magnitude and extent of SHS exposure (Navas-Acien et al., 2004; Hyland et al., 2008; Jiang et al., 2010). While SHS concentrations range widely across locations and countries, elevated concentrations are consistently found in restaurants, bars, and casinos, raising major concerns about the health of the patrons and the employees in those environments. For example, SHS assessments have provided key evidence indicating that separate nonsmoking sections in public places are insufficient to protect nonsmokers from SHS exposure, and that such exposure is a significant occupational health problem for nonsmokers in workplaces that allow smoking. Overall, these and other studies have clearly documented that comprehensive smoke-free legislation is urgently needed to protect all people, including workers in the hospitality industry.

The World Health Organization Framework Convention on Tobacco Control (FCTC), developed in response to the global-ization of the tobacco epidemic, entered into force in 2005. Article 8 requires signatories to adopt legislative measures to

Airborne and hair nicotine concentrations in nonsmoking employees, by smoking status of bars, recruited in Baltimore, MD, before enactment of smoke-free legislation (median and 75th percentile of the distribution).





protect the population from exposure to tobacco smoke in all indoor public places and workplaces. According to Article 8, protection from tobacco smoke is grounded in fundamental human rights and freedoms.

In response to the FCTC, many countries and subnational entities are enacting comprehensive smoke-free laws that ban smoking in indoor public places. For example, in the United States and Canada, many states and provinces have passed comprehensive smoke-free legislation. Despite these successes, the World Health Organization estimated in 2009 that only 5% of the world’s population was covered by comprehensive smoke-free laws (WHO, 2009). In the United States, it was estimated that 41% of the population was covered by comprehensive laws as of April 2010 (Americans for Non-smokers’ Rights, 2010).

The FCTC also indicated that smoke-free legislation should be monitored and evaluated for compliance. Although ques-tionnaires and observation are useful tools for evaluating the implementation of smoke-free laws, airborne nicotine, PM, and other tobacco markers have the advantage of allowing precise, objective measures of SHS exposure at a reasonable cost.

Exposure measurement and biomonitoring have played a critical role in implementation and compliance with tobacco control efforts. First, they provide baseline measures in critical locations, including both public and private places, as well as overall levels of SHS exposure in the nonsmoking population. Detecting SHS is a powerful argument in support of compre-hensive smoke-free initiatives because it has been firmly established that there are no safe levels of SHS exposure. Second, they provide unquestionable evidence that some approaches to eliminating SHS exposure, such as mechanic ventilation systems and separated areas for smokers and nonsmokers, are ineffective. Third, they allow for comparisons between places where smoking is allowed and those that are comprehensively smoke-free. Similarly, biomonitoring allows for comparison of SHS exposure for individuals working or living in places where smoking is allowed with that for similar individuals working or living in comprehensively smoke-free places. Studies have shown dramatically higher SHS exposures in locations where smoking is allowed as well as in individuals spending time in those environments.

The fourth role of exposure measurement and biomonitoring is for dissemination and advocacy campaigns to audiences such as the media, policy makers, medical and public health providers, and the public at large. In most countries where SHS exposure assessments have been conducted, this information has been presented to legislative bodies debating tobacco control legislation. Local evidence of tobacco smoke exposure provides a powerful tool for policy development. Finally, SHS exposure data are critical to evaluate the implementation of tobacco control programs. For instance, in the United States, se-rum cotinine levels declined 70% from the late 1980s to the early 2000s (Pirkle et al., 2006), providing evidence of the impact of tobacco control measures implemented during the 1990s. These evaluations also identify opportunities for improvement. For example, serum cotinine data clearly showed that additional tobacco control efforts are needed among young children and black populations in the United States (Pirkle et al., 2006).

Assessment of SHS exposure has afforded a key evidence base needed to establish the associated risks, to drive policy ef-forts worldwide aimed at banning smoking in public places, and to assess compliance with smoking bans.

acknowledgementThe authors are supported by research grants from the Flight Attendant Medical Research Institute.

REFERENCESAmericans for Nonsmokers’ Rights. Percent of U.S. State Populations Covered by 100% Smokefree Air Laws (1 April 2010). http://www.no-smoke.org/pdf/percentstatepops.pdf.Hyland A, Travers MJ, Dresler C, Higbee C, and Cummings KM. A 32-country comparison of tobacco smoke derived particle levels in indoor public places. Tob Control 2008: 17:

159–165.Jiang RO, Cheng KI, Acevedo-Bolton V, Klepeis NE, Repace JL, Ott WR et al. Measurement of fine particles and smoking activity in a statewide survey of 36 California Indian

casinos. J Expo Sci Environ Epidemiol; e-pub ahead of print 17 February 2010.Mattson M.E., Boyd G., Byar D., Brown C., Callahan J.F., Corle D. et al. Passive smoking on commercial airline flights. JAMA 1989: 261: 867–872.Navas-Acien A., Peruga A., Breysse P., Zavaleta A., Blanco-Marquizo A., Pitarque R. et al. Secondhand tobacco smoke in public places in Latin America, 2002–2003. JAMA 2004:

291: 2741–2745.Pirkle J.L., Bernert J.T., Caudill S.P., Sosnoff C.S., and Pechacek T.F. Trends in the exposure of nonsmokers in the U.S. population to secondhand smoke: 1988–2002. Environ Health

Perspect 2006: 114: 853–858.Repace J.L., and Lowery A.H. Smoking rates among gamblers at Nevada casinos mirror US smoking rate. Science 1980: 208: 464–472.Spengler J.D., Dockery D.W., Turner W.A., Wolfson J.M., and Ferris B.G. Long-term

measurements of the respirable sulfates and particles inside and outside homes. Atmos Environ 1981: 15: 23–30.

US DHEW. Department of Health, Education, and Welfare. The Health Consequences of Smoking: A Report of the Surgeon General (1972). DHEW publication no. (HSM) 72-7516. http://profiles.nlm.nih.gov/NN/B/B/P/M.

US DHHS. Department of Health and Human Services. The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General (2006). http://www.surgeongeneral.gov/library/secondhandsmoke/index.html.

WHO. World Health Organization. WHO Report on the Global Tobacco Epidemic, 2009: Implementing Smoke-Free Environments. http://www.who.int/tobacco/mpower/2009/gtcr_download/en/index.html.


http://www.no-smoke.org/pdf/percentstatepops.pdf

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http://www.surgeongeneral.gov/library/secondhandsmoke/index.html

http://www.who.int/tobacco/mpower/2009/gtcr_download/en/index.html

http://www.who.int/tobacco/mpower/2009/gtcr_download/en/index.html



In the twentieth century, exposure science established that fibers of asbestos minerals, when inhaled, can cause serious diseases such as mesothelioma (cancer of the thin lining of organs and cavities, including the chest cavity), lung cancer, and asbestosis (irreversible scarring of the lungs). Despite minimal new uses of asbestos in the United States, severe illness and mortality from asbestos exposure continue to be a problem. The history of asbestos-related diseases clearly shows us the major impact of not knowing about exposures early enough to intervene to protect workers and their families. Ex-posure research is now even more necessary, to detect and prevent exposures and to understand the relative risks of mineral fibers, including asbestos and other “elongate mineral particles.”

Asbestos bodies in a human lung. Trichrome stain. Bar = 20 µm. (Courtesy of Health Ef-fects Laboratory Division, National Institute for Occupational Safety and Health.)

Exposure science is fundamental to refining our scientific un-derstanding about the health effects arising from asbestos and other elongate mineral particles, as well as helping im-prove our public health protection and regulatory efforts to safeguard workers, their families, and community residents.

Exposure science can increase protection of workers and their families from exposure to asbestos and inform on the effects of other elongate mineral particlesJOHN HOWARDa AND PAUL MIDDENDORFa

aNational Institute for Occupational Safety and Health, Washington, DC, USAAddress all correspondence to [email protected]:10.1038/jes.2010.40

BACKGROUNDAsbestos has been a topic in environmental and occupational health for nearly half a century. The generic term “asbestos” is typi-cally used to represent six naturally occurring mineral fibers. The asbestos minerals have been used in thousands of commercial products over many years. They can separate into very small fibers that can be inhaled and cause morbidity and mortality. As our knowledge increased, so did concern over other particles that share some (but not all) properties. This drew more attention to this larger class of “elongate mineral particles” (EMPs).

Even though asbestos no longer commands as much scientific attention as it once did, the public health burden from exposure continues. In fact, despite the facts that asbestos is no longer mined in the United States and imports are less than 3% of the peak in 1973, years of potential life lost (YPLL) due to asbestosis as a result of prior exposures are still increasing, from an average of 146.0 YPLL per year in 1968–1972 to 239.6 per year during 2001–2005 (CDC, 2008). Moreover, even though the number of deaths from all other forms of pneumoconiosis decreased from 1968 to 2000, asbestosis deaths increased from 77 deaths in 1968 (annual age-adjusted death rate: 0.54 per million population) to 1,493 deaths in 2000 (6.88 per million) (CDC, 2004). Because of reduced use of, and exposures to, asbestos in the United States since the 1970s, the incidence of new asbestosis cases may be at a peak.

As we close the first decade of the twenty-first century, there is still much more to learn about exposure to asbestos, especially to other EMPs. Efforts to understand, prevent, track, and eliminate related disease need to be updated and improved.

The very nature of occupational exposures to asbestos has changed over the past several decades. In the twentieth century, chronic exposures in textile mills, friction-product manufacturing, and cement-pipe fabrication dominated. Now, occupational exposures to asbestos in the United States occur primarily during maintenance activities or remediation of buildings contain-ing asbestos (HEI, 1991). These current occupational exposure scenarios frequently involve intermittent short-term exposures. In addition, there are exposures to other asbestiform minerals, such as those found at the Libby vermiculite mine, and to “naturally occurring asbestos.” The large number of potentially exposed workers, these altered exposure scenarios, and new types of expo-sure give rise to the need to better understand whether appropriate protection is provided by the current occupational exposure recommendations and regulations.

Awareness of secondhand exposure has increased (McDonald, 1985). Mesothelioma and possibly lung cancer and structural changes in the lungs have been observed in family contacts of asbestos workers. For example, if a worker comes home with





contaminated clothing, others in the family may be exposed. Questions have been asked about more general public exposures resulting from maintenance and remediation activities.

The National Institute for Occupational Safety and Health (NIOSH) believes that a twenty-first-century “road map for research” is needed to resolve the existing scientific uncertainties and policy controversies surrounding asbestos and other EMPs and seeks to involve partners from government, academia, labor, and industry (NIOSH, 2010). When finalized, the “Roadmap” will set out a strategic research framework that encompasses activities in exposure assessment, epidemiology, toxicology, mineralogy, and analytical exposure-assessment methods.

We hope you will read the Roadmap and support its call for focused research efforts to expand our fund of knowledge about asbestos and EMPs and human health.

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEImproving the characterization of exposure to asbestos fibers and other EMPs is critical. Limited information is currently avail-able on exposures to, and health effects of, other EMPs. The similarities to asbestos cause us to be concerned, but the differences cause us to be uncertain. Hence, additional knowledge is needed to develop accurate risk assessments and protection strategies. The NIOSH Roadmap presents recommendations for improving the science of asbestos and EMP exposure assessment.• Improved sampling and analytical methods are required to characterize exposures to asbestos fibers and other EMPs. For example,

the current analytical methods used for routine exposure assessment lack the capability to accurately count, size, and identify all EMPs collected on airborne samples.

• The rich source of occupational exposure information should be mined to inform scientific understanding of exposures to EMPs. This would include taking opportunities to (re)analyze (historically) collected samples using enhanced analytical methods to better characterize the exposures.

• Ongoing characterization and surveillance of occupational exposures to EMPs should be systematically designed and implemented to protect workers’ health throughout US industry. Such exposure assessments should include workplaces in which a fraction of the dust is composed of EMPs (i.e., mixed-dust environments) and occupational environments in which EMPs may not meet the current regulatory criteria to be counted (e.g., “short” fibers). The resultant findings could lead to representative EMP expo-sure data that could help identify worker populations or particular types of EMPs warranting further study (i.e., more in-depth exposure assessment, medical surveillance; epidemiology studies of particular types of EMPs, processes, job tasks, occupations, or industries; toxicity studies of particular EMPs).

• Occupational exposure data should be collected and stored in a comprehensive database. Information similar to that described by Marchant et al. (2002) should be incorporated into the database to support these efforts. This could be accomplished in paral-lel with efforts to develop an occupational exposure database for nanotechnology (Miller et al., 2007) or efforts to develop a national occupational exposure database (Middendorf et al., 2007).

Advances in asbestos exposure science research can lead to better understanding of the health effects caused by exposures to other EMPs and to new elongate materials such as nanofibers. Engineered nanomaterials are being rapidly introduced into the workplace and into our homes. As a society, we need to apply lessons we have learned, and continue to learn, from the asbestos experience to be health protective as we engineer and use new elongate materials.

REFERENCESCDC. Changing patterns of pneumoconiosis mortality—United States, 1968–2000. MMWR 2004: 53: 627–632.CDC. Asbestosis-related years of potential life lost before age 65 years—United States, 1968–2005. MMWR 2008: 57: 1321–1325.HEI (Health Effects Institute)–Asbestos Research. Asbestos in Public and Commercial Buildings: A Literature Review and Synthesis of Current Knowledge (1991). http://www.

asbestos-institute.ca/reviews/hei-ar/hei-ar.html.Marchant G.E., Amen M.A., Bullock C.H., Carter C.M., Johnson K.A., Reynolds J.W. et al. A synthetic vitreous fiber (SVF) occupational exposure database: implementing the SVF

health and safety partnership program. App Occup Environ Hyg 2002: 17: 276–285.McDonald J.C. Health implications of environmental exposure to asbestos. Environ Health Persp 1985: 62: 319–328. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1568700/pdf/

envhper00445-0306.pdf.Middendorf P., Graff R., Keller L., and Simmons C. National Occupational Exposure Database: AIHA-NIOSH alliance efforts to develop a pilot. American Industrial Hygiene

Conference and Exhibition, Philadelphia, PA, 2007.Miller A.L., Hoover, M.D., Mitchell D.M., and Stapleton B.P. The Nanoparticle

Information Library (NIL): a prototype for linking and sharing emerging data. J Occup Environ Hyg 2007: 4: D131–D134.

NIOSH (2010). Asbestos Fibers and Other Elongate Mineral Particles: State of the Science and Roadmap for Research (Draft 4, January 2010). http://www.cdc.gov/niosh/topics/asbestos.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.


http://www.asbestos-institute.ca/reviews/hei-ar/hei-ar.html

http://www.asbestos-institute.ca/reviews/hei-ar/hei-ar.html

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1568700/pdf/envhper00445-0306.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1568700/pdf/envhper00445-0306.pdf

http://www.cdc.gov/niosh/topics/asbestos/

http://www.cdc.gov/niosh/topics/asbestos/



Exposures to vehicle-related air pollutants depend on a complex relationship among vehicular emissions per mile, vehicle miles traveled, fate and transformation of emissions in the air, and prox-imity to traffic. Over the past 40 years, relentless growth in vehicle miles traveled (now 3 trillion miles a year in the United States, a 170% increase since 1970) (US Department of Transportation) has eroded the impact of the impressive reductions in vehicle emis-sions. The drop in ambient levels of all these pollutants is smaller, but still impressive. In the United States, the current low ambient carbon monoxide and lead levels are success stories, the result of stringent regulation and effective, durable vehicular control technology plus fuel improvements. Ozone and fine particulate matter (aerodynamic size <2.5 μm) present the greatest public health concern, and attainment of tightened air-quality standards for these pollutants remains elusive in many areas. Worldwide, urbanization and traffic growth combine to impact the health of increasing numbers of people. Determining how to better protect public health from vehicular exposures requires far more detailed knowledge of exposure.

US highway vehicle fleet emissions reductions since 1970. CO, carbon monoxide, NOx,

oxides of nitrogen; PM2.5

, fine particulate matter; VOC, volatile organic compounds. (Data from US EPA, 2009.)

Understanding exposures to vehicular emissions is funda-mental to characterizing health risks and developing regula-tory approaches that effectively reduce that risk.

Vehicle emissions: progress and challengesROBERT F. SAWYERa

aDepartment of Mechanical Engineering and Energy and Resources Group, University of California, Berkeley, California, USAAddress all correspondence to [email protected]:10.1038/jes.2010.44

BACKGROUNDRoad-vehicle emissions continue to dominate urban air pollution. The most important pollutant emissions from light-duty, gasoline-pow-ered vehicles are volatile organic compounds (VOCs), carbon monox-ide (CO), and oxides of nitrogen (NO

x), whereas for heavy-duty, diesel

vehicles, NOx and fine particulate matter (PM

2.5) are of the greatest

concern. VOCs and NOx react in the presence of sunlight to form ozone

and photochemical aerosols. Control technology applied to light-duty vehicles using precise, computer-based fuel–air mixture control and three-way catalyst aftertreatment combined with improved fuel qual-ity have reduced the emissions of VOCs, CO, NO

x, and PM from new

vehicles by more than 99%, as compared with 1970. The effectiveness of this control technology allows some vehicles to have exhaust that is lower in these compounds than the ambient air! As the light-duty fleet has turned over, on about a 15-year cycle, emissions of VOCs and CO from highway vehicles have fallen significantly.

The current interest in electric-drive vehicles, which include hybrid electric, plug-in hybrid, battery electric, and fuel-cell hybrid designs, arises from concerns about energy security and greenhouse gas levels. While their further reduction of air pollutant emissions will be welcome, these reductions will be small. But other mobile sources, with combus-tion engines, do require continuing attention. As compared with the low emissions and durability of new vehicles, the emissions from a few, generally older, “high emitters” present an important control challenge.

Emissions regulation of heavy-duty vehicles has lagged behind that of light-duty vehicles, and, combined with the slower turnover of the heavy-duty fleet, the reduction in highway emissions of NO

x and PM

2.5 has trailed that of CO and VOCs. Diesel control technology

capable of achieving nearly the reductions seen in light-duty vehicles appeared only recently. Heavy-duty vehicles with traps, which are very effective in reducing PM

2.5 and ultrafine particles (<100 nm in diameter), result in particulate mass emissions that are more

than 98% below those from uncontrolled vehicles. The first half of this reduction comes from improved combustion; the second from the trap. Selective catalytic reduction technology introduced this year, combined with previous combustion improvements and exhaust-gas recirculation, delivers similar levels of control of NO

x.

As emissions from on-road vehicles have been reduced, more attention is being given to reducing pollutant emissions from non-road mobile sources. Most important are locomotives, ships, and construction and farm equipment, all powered primarily by diesel engines to which now existing control technology can be applied. Even longer turnover times in this sector point to an increasing relative importance of their emissions. The relative importance of aircraft emissions will grow as the fleet size increases, and technology to yield substantial emissions reductions is not yet available.

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEBetter exposure assessment has been key to the development of strong epidemiological evidence for increased mortality and morbidity from PM

2.5. Resulting quantitative risk analyses that use these assessments provide the justification for aggressive

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reductions of both primary (emitted directly by motor vehicles) and secondary (formed in the atmosphere from gaseous pol-lutants emitted by motor vehicles) PM

2.5. In an extensive review of traffic-related air pollution and associated adverse health

effects, the Health Effects Institute (2010) identified the exposure zone within 300 to 500 meters of major roadways to be of particular health concern. The report notes the problematic nature of using traffic proximity as a surrogate for pollutant ex-posure in epidemiologic assessments. Traditionally, the locations of monitoring sites were chosen to avoid influence by local sources. As a consequence, the more than 700 PM

2.5-monitoring sites in the United States are not well suited to characterizing

regions of highest exposure to vehicular emissions. The new EPA National Ambient Air Quality Standard for nitrogen dioxide includes a requirement for near-roadway monitoring to characterize high exposures. The inclusion of some PM

2.5 and PM

10

monitoring at these sites would be valuable. This might help to better define another vehicular source of PM, re-entrained road dust.

The US National Ambient Air Quality Standard for PM2.5

is based on epidemiological assessments that relate both short- and long-term exposure, as measured by this metric, to increased morbidity and mortality. The role of particle composition and par-ticle size is not well understood, nor is it yet part of the regulatory mechanism. Geographical differences in particle potency seem to be related to particle composition, pointing to the need to better understand the vehicular contribution.

The likely role of particle size in determining toxicity is evident from the biophysics of ultrafine particles and their ability to cross cell walls and rapidly enter the bloodstream. Mass, composition, and size all appear to be important exposure metrics. Both the assessment of health effects and the design of regulations require advances in particle characterization and human exposure. As focus shifts to ultrafine particles, number and/or surface area may become more significant than mass, presenting new challenges in measurement and regulatory design. Possibly prematurely, the European Union is considering a particle-number-per-kilometer standard for motor vehicles.

The recent history of reducing health risks from vehicular emissions offers both good news and bad news. Diesel engine trap technology, designed to reduce PM

2.5 mass, is also very effective in reducing the mass and number of ultrafine particles by more

than an order of magnitude. This is an example of a problem being easier to solve than to understand, given the uncertainty about the most appropriate exposure metric. More somber is evidence of an increasing Northern Hemisphere background of both ozone and PM

2.5. This will make it extremely difficult to meet stringent air-quality standards and will most likely require a reconsideration

of the regulatory mechanism laid out in the Clean Air Act of 1970.The challenges for exposure scientists in characterizing human exposure to ambient particles and related gases are substantial.

Their findings will provide fertile data to be mined by epidemiologists, risk assessors, and policy makers who seek the most effec-tive ways to significantly reduce harmful exposures.

REFERENCESHealth Effects Institute. Special Report 17: Traffic-Related Air Pollution: A Critical Review of the Literature on Emissions, Exposure, and Health Effects, January 2010. http://pubs.

healtheffects.org/getfile.php?u=553US Department of Transportation. Federal Highway Administration. Quick Find: Vehicle Miles of Travel—Highway Statistics Series. http://www.fhwa.dot.gov/policy/ohpi/qftravel.

cfm.US EPA. National Emissions Inventory (NEI) Air Pollutant Emissions Trends Data. 1970–2008 Average Annual Emissions, All Criteria Pollutants (2009). http://www.epa.gov/ttn/

chief/trends/trends06/nationaltier1upto2008basedon2005v2.xls.US EPA. Our Nation’s Air—Status and Trends Through 2008. http://www.epa.gov/airtrends/2010.


http://pubs.healtheffects.org/getfile.php?u=553

http://pubs.healtheffects.org/getfile.php?u=553

http://www.fhwa.dot.gov/policy/ohpi/qftravel.cfm

http://www.fhwa.dot.gov/policy/ohpi/qftravel.cfm

http://www.epa.gov/ttn/chief/trends/trends06/nationaltier1upto2008basedon2005v2.xls

http://www.epa.gov/ttn/chief/trends/trends06/nationaltier1upto2008basedon2005v2.xls

http://www.epa.gov/airtrends/2010



Exposure science is now being used for the early diagnosis of anthrax and to assess the efficacy of medical countermeasures. Detection and quantification of deadly anthrax toxins are used to identify exposure to Bacillus anthracis spores and the develop-ment of clinical anthrax at very early stages of disease. In rabbits and nonhuman primates, anthrax lethal factor can be detected in serum or plasma 12 hours after inhalation exposure to B. anthracis spores, which provides much earlier diagnosis than is possible with traditional biochemical techniques. Data from human clinical and animal studies have indicated that anthrax lethal factor levels in serum and plasma are predictive of the severity of disease and effectiveness of treatment. Thus, monitoring anthrax toxin levels is a crucial tool that enables earlier medical treatments and guide both the course of treatments and the development of new medi-cal countermeasures. In the case of an anthrax attack by terrorists, such rapid identification would be invaluable in saving lives by enabling treatment of immediate contacts and preventing the spread of this highly infectious agent.

We now have the technology to detect and quantify anthrax toxin levels. This technology has tremendous promise for diagnosis at very early stages of disease and monitoring the efficacy of treatments, including those for disease aris-ing from anthrax-related terrorist events.

Anthrax: modern exposure science combats a deadly, ancient diseaseJOHN R. BARRa, ANNE E. BOYERa AND CONRAD P. QUINNa

aUS Centers for Disease Control and Prevention, Atlanta, Georgia, USAAddress all correspondence to [email protected]:10.1038/jes.2010.49

BACKGROUNDExposure to the spores of Bacillus anthracis causes the disease anthrax. Spores gain entry into the host through dermal abrasions, gastrointestinal lesions, injection (usually in intravenous drug use), and inhalation, which cause cutaneous, gastrointestinal, injection, and inhalation anthrax, respectively.

Anthrax is a naturally occurring disease in many parts of the world, and it remains a bioterrorism threat. Inhalation anthrax has a mortality rate higher than 90% if untreated and is often deadly even with antibiotic therapy. During the anthrax-letter attacks of 2001, mortality was 45%, even with antibiotics and aggres-sive supportive care (Jernigan et al., 2002). Additionally, there is a “point of no return” during anthrax infection after which all tradi-tional treatments may fail.

The lethal consequences of this disease are caused by the an-thrax toxins. “Lethal toxin” inactivates cell components central to the victims’ defense against infection. ”Edema toxin” causes mas-sive fluid retention and swelling (edema), as well as depressing some parts of immune defenses. Both of these toxins also cause bleeding late in the course of infection.

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEDiagnosis of anthrax in the early stages of disease is critical for effective treatment and thus to saving lives. Mass spec-trometric detection and quantification of anthrax toxins are highly selective and rapid diagnostic tools for early disease. The ability to quantify the toxins provides an additional benefit in understanding the course of disease and the efficacy of treatments and therapies. For the anthrax toxins to be detected early in the disease, they must be quantified at exqui-sitely low levels. Exposure science techniques have been developed to achieve this (Boyer et al., 2007).

Detection and quantification of the anthrax toxin lethal factor represent a major advancement in the diagnosis of an-thrax. The anthrax exposure science technology has the following important features:

Detects infection earlier. Monitoring lethal factor detects B. anthracis infection as early as 12 hours after exposure to anthrax spores and as much as 24 hours earlier than other technologies (Boyer et al., 2009). Anthrax can be detected even before symptoms such as fever are present.

Shorter time to the first result. Quantitative lethal factor measurements and analyses are completed within 4 hours. By comparison, traditional biochemical approaches to diagnosis anthrax may take several days to produce definitive results.

Analyzes many more samples per day. The new method to measure lethal factor has been automated and can analyze hun-dreds to thousands of samples per day. This throughput represents a significant advancement over previous techniques.

Colored scanning electron micrograph of anthrax bacteria (Bacillus anthracis), the cause of anthrax in humans and livestock. (From “Anthrax: From Lethal Factor to Life Extender,” Annual Report 2001–2002, Synchrotron Radiation Department: Warrington, UK, 2002.)





Not subject to antibiotic interference. Quantitative lethal factor monitoring can be used to identify and track infection even if antibiotic treatment has started, unlike with historical methods, which cannot consistently detect infection in people undergoing treatment.

Quantifies toxin to track course of infection and responses to treatment. Quantification of lethal factor is an excellent measure of treatment effectiveness by tracking changes in toxin levels. This capability could be helpful in the clinical management of patients who are not progressing well. For example, such information could help doctors determine whether additional or alternative therapeutics are necessary.

Monitoring anthrax lethal factor levels in animal and clinical studies has already yielded insights into the course of infection and responses to treatment. The animal study data show that the progression of infection can occur in three stages, during which traditional diagnostic tests can be at first positive but then transiently revert to negative, only to become positive again later in infection. In contrast to these traditional tests, quantification of anthrax lethal factor is detected throughout all stages of infection (Boyer et al., 2009). In addition, the animal studies have shown that lethal factor levels may be predictive of the stage or severity of illness, and they have been used to establish a potential toxin-related point of no return, when mortality is very likely. This would indicate that additional therapeutics are required to remove high toxin levels from the blood. Quantification of lethal factor levels on a daily basis during a clinical case would allow physicians to monitor changes and adjust treatment accordingly.

The application of exposure science to detect and quantify anthrax lethal factor levels has recently been used to respond to clini-cal cases of inhalation (Walsh et al., 2007), cutaneous, injection, and gastrointestinal anthrax. A great deal has been learned about the course of B. anthracis infection in humans and the efficacy of treatments. The information gained can be used to evaluate therapeutics and help guide medical intervention. The use of exposure science to detect and quantify toxins produced by human pathogens can have a major impact on the diagnosis and treatment of an even wider range of infectious diseases.

REFERENCESBoyer A.E., Quinn C.P., Woolfitt A.R., Pirkle J.L., McWilliams L.G., Stamey K.L. et al. Detection and quantification of anthrax lethal factor in serum by mass spectrometry. Anal Chem

2007: 79: 8463–8470.Boyer A.E., Quinn C.P., Hoffmaster A.R., Kozel T.R., Saile E., Marston C.K. et al. Kinetics of lethal factor and poly-D-glutamic acid antigenemia during inhalation anthrax in rhesus

macaques. Infect Immun 2009: 77: 3432–3241.Jernigan D.B., Raghunathan P.L., Bell B.P., Brechner R., Bresnitz E.A., Butler J.C. et al. 2002. Investigation of bioterrorism-related anthrax, United States, 2001: epidemiologic findings.

Emerg Infect Dis 2002: 8: 1019-1028Walsh, J.J., Pesik N., Quinn C.P., Urdaneta V., Dykewicz C.A., Boyer A.E. et al. A case of naturally acquired inhalation anthrax: clinical care and analyses of anti-protective antigen

immunoglobulin G and lethal factor. Clin Infect Dis 2007: 44: 968–971.

Disclaimer: The information included in the text of this article is the opinion of the authors and does not necessarily reflect the official position of the Centers for Disease Control and Prevention.




Ionizing radiation is defined in physics as radiation with enough energy to remove electrons from atoms, resulting in an ionized atom. Many sources of ionizing radiation exist; examples include atomic or hydrogen bombs, X-ray machines, some types of radia-tion therapy, the sun, and Earth’s crust (e.g., radon). High doses of radiation have been known to cause acute effects for more than a century. As with other environmental hazards, however, the long-term risk of radiation exposure—particularly for lower doses typical of occupational and environmental exposures (in this case, mainly excess cancer)—are much more difficult to assess. Such risk infor-mation is needed to protect workers and the public from radiation sources found in industry, medical care, and the environment, as shown in the figure, as well as to estimate the risks posed by nuclear power plants and nuclear weapons. Perhaps surprisingly, a large proportion of our knowledge of radiation’s dose–response relation-ship comes from continuing studies of the atomic-bomb survivors in Japan. Over time, advances in exposure science were creatively applied to obtain increasingly precise dose estimates, which in turn allowed us to understand the health implications of radiation and to estimate the probability of harmful effects at a given dose.

This knowledge has led to regulations and guidance to protect tens of millions of workers in several occupations, medical patients, and the general public. For example, workers wear radiation do-simeter badges to limit their exposure within guidelines based on scientific estimates of the probability that they might later develop cancer or other adverse health effects, newer generations of X-ray machines deliver lower doses to patients, and more homes are now evaluated for the presence of radon gas as it has become clear that radon increases cancer risk.

The development of radiation dose estimates for the Jap-anese atomic-bomb survivors illustrates the value of ex-posure science in greatly increasing the precision of risk estimates and, as a result, global confidence in the details of the health impacts from ionizing radiation and the develop-ment of health-protective regulations and guidance.

Better radiation exposure estimation for the Japanese atomic-bomb survivors enables us to better protect people from radiation todayHARRY M. CULLINGSa AND KIRK R. SMITHb

aRadiation Effects Research Foundation, Hiroshima, JapanbSchool of Public Health, University of California Berkeley, Berkeley, California, USAAddress all correspondence to [email protected]:10.1038/jes.2010.48

BACKGROUNDAt the time of the Manhattan Project during World War II, relatively little was known about the effects of ionizing radiation—particularly the late effects, as opposed to acute injury at high doses. Much was learned about the physics of exposures in the Manhattan Project it-self, but most of the development of radiation protection standards would come later, and much of it would be based on studies of the Japanese atomic-bomb survivors.

After the establishment in 1947 of the Atomic Bomb Casualty Commission (ABCC) in Hiroshima and Nagasaki (Neel and Schull, 1956), several early studies were conducted. In the earliest of these, because of the lack of knowledge of a relevant exposure metric, parents were classified in terms of distance from the hypocenters of the bombs as a surrogate for radiation dose.

In 1956, the ABCC set up several large, fixed cohorts for prospective studies of radiation effects. The largest of those, the Life Span Study, has essentially complete follow-up of mortality data through death certificates on a national level, and encompasses 120,321 individu-als. The questionnaire used for gathering exposure data on members of the cohorts showed remarkable foresight. Dose estimates for the survivors have come from a series of systems that evolved over half a century by incorporating the most current technical and scientific methods available at the time (Cullings et al. 2006).

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEAn important aspect of the dosimetry systems is their validation by measurements of materials that were exposed to the penetrating radiation of the bombs in known locations. By a few days after the bombings, Japanese physicists were in the cities, collecting samples and making measurements. They devised clever and insightful methods for some measurements. Measurement technology has continued to develop up to the present day (Young and Kerr, 2005; Gasparro et al., 2010).

All the dosimetry systems calculate survivor doses on the basis of survivors’ reported locations, body positions, and shielding—information obtained from interview data. Methods in the realm of biodosimetry, which do not depend on the accuracy of sur-

Sources of radiation exposure to the US population (Reprinted with permission from NCRP, 2009 (National Council on Radiation Protection and Measurements, http://NCR-Ponline.org).

Terrestrial(background)

(3%)

Computed tomography

(medical) (24%)

Nuclear medicine(medical) (12%)

Interventional fluoroscopy(medical) (7%)

Conventional radiography/fluoroscopy(medical) (5%)

Consumer (2%)

Occupational (<0.1%)

Industrial (<0.1%)

Radon and thoron(background) (37%)

Space(background)

(5%)Internal(background)

(5%)



http://NCRPonline.org

http://NCRPonline.org



vivor recall in regard to location and shielding, are an important adjunct. Such methods include measurements of chromosomal aberrations and isotopes and carboxyl radicals created by neutron and gamma radiation exposure to tooth enamel (Kodama et al., 2001; Wallner et al., in press).

Biodosimetry is hampered by large uncertainty and the existence of artifacts. Nevertheless, biodosimetric results can, in princi-ple, contribute to analyses of the relationship between dose and health outcomes, particularly when available physical dosimetry is prone to error. Statistical treatment of dose uncertainty remains an important topic of research with wide implications (Pierce et al., 2008).

RERF maintains a repository of biosamples from the Adult Health Study, a cohort of more than 20,000 survivors who undergo bi-ennial medical examinations—an invaluable resource for exposure science, as are archival records about survivors. RERF continues to improve these records. In addition, new technologies, such as geographical information systems and photogrammetry using pre-bombing aerial photographs of the cities, allow improved data to be extracted from archival records.

Thus, the estimation of doses received by the atomic-bomb survivors continues to be refined and to be a subject of scientific inquiry even 65 years after the bombings took place. None of this would be possible without the foresight of early Japanese and US researchers in collecting and preserving data, as well as the participation of survivors and their children. By greatly reducing exposure error (“misclassification”), better estimates of the dose received by each person allowed increasingly sensitive and precise estimates of the health impact of ionizing radiation per unit exposure.

The scientific development of dosimetry underlies the credibility of health-effects studies that quantify risk of cancer and other late health effects of ionizing radiation. Such studies are summarized in the recommendations of major international advisory bodies and are the basis for risk estimation, not only for occupational exposures but also for exposures such as those from medical procedures and nuclear power plant accidents.

Although stemming from great tragedy, the ABCC/RERF studies represent a triumph of exposure science in which “true” doses were pinned down with greater and greater accuracy by integrated application of increasingly sophisticated questionnaire, physi-cal, statistical, chemical, spatial, and biological methods.

ACKNOWLEDGEMENTThe Radiation Effects Research Foundation, Hiroshima and Nagasaki, Japan, is a private, nonprofit foundation funded by the Japanese Min-istry of Health, Labor, and Welfare and the US Department of Energy, the latter in part through the National Academy of Sciences.

REFERENCESCullings H.M., Fujita S., Funamoto S., Grant E.J., Kerr G.D., and Preston D.L. Dose estimation for atomic bomb survivor studies: its evolution and present status. Radiat Res 2006: 166:

219–254.Gasparro J., Hult M., Marissens G., Hoshi M., Tanaka K., Endo S. et al. Measurements of 60Co in Massive Steel Samples Exposed to the Hiroshima Atomic Bomb Explosion (EUR 24146

EN). European Commission Joint Research Centre Institute for Reference Materials and Measurements: Luxembourg, 2010.Kodama Y., Pawel D., Nakamura N., Preston D., Honda T., Itoh M. et al. Stable chromosome aberrations in atomic bomb survivors: results from 25 years of investigation. Radiat Res

2001: 156: 337–346.NCRP. National Council on Radiation Protection and Measurements report 160, Ionizing Radiation Exposure of the Population of the United States, 2009. http://www.

ncrppublications.org/Reports/160.Neel J.V., and Schull W.J. The Effect of Exposure to the Atomic Bombs on Pregnancy Termination in Hiroshima and Nagasaki. Atomic Bomb Casualty Commission: Hiroshima,

Japan, 1956.Pierce D.A., Vaeth M., and Cologne J.B. Allowance for random dose estimation errors in atomic bomb survivor studies: a revision. Radiat Res 2008: 170: 118–126.Wallner A., Rühm W., Rugel G., Nakamura N., Arazi A., Faestermann T. et al. 41Ca in tooth enamel. Part I: a biological signature of neutron exposure in atomic bomb survivors. Radiat

Res 2010: 137–145.Young R.W., and Kerr G.D. (eds). Report of the Joint US–Japan Dosimetry Working Group, Reassessment of the Atomic-Bomb Radiation Dosimetry for Hiroshima and Nagasaki:

DS02. Radiation Effects Research Foundation: Hiroshima, Japan, 2005.


http://www.ncrppublications.org/Reports/160

http://www.ncrppublications.org/Reports/160



Exposure to lead has long been known to exert toxic effects on the nervous system as a key target, with the greatest concern typi-cally being for unborn fetuses, infants, and young children. It is now recognized, however, that people of all ages can be affected (including geriatric populations) and that lead impacts virtually all organ systems. Since the 1960s, as research revealed adverse effects of lead at lower and lower exposure levels, views regard-ing “unacceptable” lead concentrations have been repeatedly revised downward to prevent or reduce human lead exposures. This has led to remarkable progress in reducing exposures, as well illustrated by the graph above showing decreased percentages of blood lead levels in US children. These dramatic decreases in lead exposure are attributable mostly to the phase-out of the use of leaded gasoline in the United States. The ongoing decline also reflects success in reducing other major lead sources (e.g., house paint, soil, house dust, drinking water from leaded pipes, and food). Exposure science has been essential to showing the need for reducing lead exposure, pathways of exposure, and the suc-cess of implementing laws aimed at exposure reduction, e.g., the Lead Contamination Control Act of 1988. As sources of lead are further elucidated, exposure science will continue to play a crucial role in enabling protection of public health.

Lead is a highly useful metal, but it has long been feared because of the risks it poses to human health. The char-acterization of human lead-exposure pathways and internal lead burdens is an important exposure science advance that has contributed to an impressive public health success story that is not yet finished.

Getting the lead out: important exposure science contributionsLESTER D. GRANTa

aRetired from National Center for Environmental Assessment, RTP Division, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina, USAAddress all correspondence to [email protected]:10.1038/jes.2010.47

BACKGROUNDBoth ancient and modern societies have used lead in diverse ways (e.g., in water distribution systems, paints, fuel additives, and electri-cal and electronics applications). This has led to widespread environ-mental dispersal of the metal, elevated lead exposures among many human populations, and increased public health risks. Over the past 50 years or so, major exposure science advances have contributed notably to the characterization of human lead exposures and conse-quent public health threats. Of special note are advances in two key areas: (i) characterizing lead-exposure pathways and contributions of various sources (e.g., gasoline) and media (e.g., air, water, soil) to human exposures and internal lead body burdens and (ii) computer modeling of relationships between external exposures and impacts on internal lead burdens. These advances, coupled with paral-lel health science findings of toxic lead effects at lower and lower exposure levels, have led to worldwide recognition of the need to reduce human lead exposures and associated public health threats, with much progress having been made toward this goal. Numerous reviews of the extensive literature documenting the above advances have been published (e.g., EPA, 1986, 2006; Grant, 2009).

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCECharacterization of lead-exposure pathways has enabled identifica-tion of effective approaches to reduce lead health risks. As reviewed by the US Environmental Protection Agency (EPA, 1986, 2006) and Grant (2009), exposure science has identified modern sources of lead, quantified associated emissions, delineated dispersal path-ways (e.g., via air, soil, water, or food) leading to exposures, quantified lead levels encountered in such exposure pathways, and estimated impacts of lead exposures via various pathways on internal lead burdens (as indexed by lead levels in blood, bone, and other tissue or by effects on blood hemoglobin or other lead-exposure biomarkers) in pediatric and adult popula-tions. Of much importance has been development of computational exposure models by academic and government scien-tists. For example, the EPA’s Integrated Exposure Uptake Biokinetic model is widely used to predict effects of lead exposure via varying pathways on the internal lead burdens of young children. That model is being expanded to create the All-Ages Lead Model to estimate exposure impacts on human lead burdens for people up to 90 years of age, as well as to predict impacts of maternal lead exposures on lead burdens in fetuses or newborns.

Multiple sources and pathways of lead exposure exist (EPA, 1986, 2006). Reduction of air pollution from the use of leaded gaso-line, and of consequent human lead exposure, is a classic example of successful regulation (see figure). The phase-out of leaded

Percentage of children 1–5 years old in the US population with elevated blood lead levels (≥10 μg/dl). (From CDC, 2010a; data from the CDC National Health and Nutrition Examination Survey.)

100908070605040302010

0

1976

–198

0

1988

–199

1

1991

–199

4

1999

–200

4

%




gasoline has led to substantial reductions of US urban airborne lead levels, often from more than 1.0 μg/m3 to more usual current values below 0.2 μg/m3. Also, as other significant exposure pathways have been identified, additional mitigation steps have been taken. For example, in the United States lead is banned from house paint, lead solder is no longer used in manufacturing food cans, and the use of leaded solder in indoor plumbing to carry drinking water has been discontinued. These regulations have been effective, but exposure continues, sometimes raising health concerns. For example, increased tap water lead levels have been found in some homes with older lead-soldered plumbing following changes in drinking water treatment procedures in some cities. Also, lead persists in soil from past deposition of airborne lead from gasoline and the weathering of old lead-based house paint. Children may play in such dirt, and re-entrainment into air and dispersal of leaded soil from Superfund sites is sometimes a concern. Both older and recent exposure science studies highlight the importance of house dust contaminated by lead from soil or air as a vector for exposure in young children. Several studies have shown the effectiveness of certain cleaning approaches for removal of house dust and of lead-contaminated soil around residential structures in reducing blood lead levels in young children. Higher average blood lead levels typically seen in the United States for urban children versus those in rural areas were partly attrib-utable to large numbers of children being exposed to weathering lead-based house paint used (especially prior to 1978) in or on residential structures in urban areas. Guidance now exists for safer renovation of homes with old leaded paint, but not everyone seeks out and implements it.

As new information has emerged on exposure and health effects over the past few decades, designations of “unacceptable” lead levels have been repeatedly revised downward. For example, the earlier prevailing view that blood lead levels should be kept below 40 μg lead/dl of blood to avoid unacceptable health risks for young infants and children less than 6 years old was revised downward in the late 1970s to 30 μg/dl. By the late 1980s, this had been reduced to 10 μg/dl, and within the past decade or so was reduced to 1–5 μg/dl. Even with these lower action levels, set by EPA, Centers for Disease Control and Prevention, and World Health Organization authorities, questions persist as to how safe still lower levels might or might not be. Defining safe exposure levels is complicated by the fact that many different organ systems and physiological functions (neurological, hematological, cardiovascu-lar, renal, immune, and other functions) are affected by lead, even at extremely low exposure levels, for both children and adults (EPA, 2006).

The lead story is not finished yet. Consideration of a need for further downward revision of the designated “unacceptable” lead-exposure levels will probably ultimately hinge not only on new health findings but also on exposure research. Extensive informa-tion already exists regarding lead toxicity, even at rather low exposure levels. Therefore, improved knowledge of modern lead-exposure pathways and levels is critical for characterizing and reducing adverse exposures. New sources and pathways are being identified through exposure research (e.g., disposal of computers and other electronic devices containing lead components). Some older sources are becoming more recognized through exposure research (e.g., imported toys and other products contami-nated by lead, and leaded dust in some artificial turf (CDC, 2010b)). Also, lead may come to be used in novel nanoparticle applica-tions. Exposure research is crucial to pointing the way for future protection strategies.

REFERENCESCDC. Centers for Disease Control and Prevention. CDC’s Childhood Lead Poisoning Prevention Program, 2010a. http://www.cdc.gov/nceh/lead/about/program.htm.CDC. Centers for Disease Control and Prevention. Artificial Turf, 2010b. http://www.cdc.gov/nceh/lead/tips/artificialturf.htm.EPA. US Environmental Protection Agency. Air Quality Criteria for Lead, EPA/600/8-83/028aF-dF (NTIS PB87-142386), 1986.EPA. US Environmental Protection Agency. Air Quality Criteria for Lead (2006) Final Report, EPA/600/R-05/144aF-bF, 2006. http://cfpub.epa.gov/ncea/cfm/recordisplay.

cfm?deid=158823.Grant, L.D. Lead and compounds. In: Lippmann M. (ed). Environmental Toxicants: Human Exposures and Their Health Effects, 3rd edn. John Wiley and Sons: Hoboken, NJ, 2009, pp

763–815.


http://www.cdc.gov/nceh/lead/about/program.htm

http://www.cdc.gov/nceh/lead/tips/artificialturf.htm

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=158823

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=158823



Historically, exposure science has taught us how individuals can prevent transmission of infections using such simple measures as properly washing hands and coughing into one’s sleeve, and it has also been used for evaluating exposure to infectious diseases. More current exposure science enables early detection of novel influenza viruses, which is critical in controlling rapid and wide-spread infection that could result in heightened morbidity and mortality and overwhelm health-care systems. A new H1N1 influ-enza virus (see figure) that emerged in Mexico was first detected in California in mid-April of 2009. Laboratory testing at the Centers for Disease Control and Prevention confirmed that this virus had not previously been detected in humans. Exposure science could be applied to improve future flu vaccines.

Early detection of novel influenza viruses can enable interven-tions to reduce their transmission, thereby reducing morbidity and mortality through deployment of antivirals and vaccines.

Exposure science for viral diseases: 2009 H1N1 pandemic influenza virusNANCY COXa, RUBEN DONISa AND JOHN R. BARRb

aInfluenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USAbDivision of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USAAddress all correspondence to [email protected] of Exposure Science and Environmental Epidemiology published online 24 November 2010; doi:10.1038/jes.2010.52

BACKGROUND

The 2009 H1N1 virus, which caused this century’s first pandemic (an epidemic over a very large geographic area), is a genetically novel influenza A virus. Virologists call it a “reassortant” virus because gene segments of the virus originated from different influenza virus sources (from pigs in Europe and Asia and from North American influenza viruses infecting birds, pigs, and humans). Initially, the press called it “swine flu”; the scientifically proper name of H1N1 is derived from proteins on the outer surface of the virus. The first diagnosis of a novel 2009 H1N1 infection in the United States was made on 15 April 2009 in a 10-year-old child who was enrolled in a Centers for Disease Control and Prevention (CDC)-sponsored clinical study. Two days later, laboratory testing at the CDC confirmed a second infection with this novel virus in another patient, an 8-year-old child living in California about 130 miles away from the first patient. There was no known con-nection between the two patients and no exposure to pigs. Labora-tory analysis at the CDC determined that the viruses obtained from these two patients were almost identical to each other and different from any influenza virus previously seen in either humans or animals. Testing showed that these two viruses were resistant to certain influ-enza antiviral drugs (called M2 ion channel inhibitors) but susceptible to a class of antiviral drugs called neuraminidase inhibitors.

Infection with a new swine-origin influenza virus in two patients living 130 miles apart raised concern that a novel swine-origin influenza virus had made its way into the human population and was spreading. There had previously been sporadic reports of human infection with North American–lineage swine influenza viruses in the United States, most often associated with close contact with infected pigs. However, human-to-human spread of swine influenza viruses is rare, and these viruses had not caused large community, regional, or global outbreaks. In June 2009, the World Health Organization declared that the novel 2009 H1N1 viruses were causing a pandemic. By the end of 2009, an estimated 57 million people worldwide had been infected with 2009 H1N1, and over 14,000 people had died (Bell et al. 2009; Reed et al., 2009). Within the United States alone, 22 million had contracted the disease, resulting in about 4,000 deaths, including those of 500 children (Reed et al., 2009).

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEEarly detection and identification of emerging influenza viruses are critical for the implementation of appropriate public health interventions. In addition, identification of variant viruses is crucial for the selection of seasonal influenza viruses to be included in the influenza vaccines that are necessary to prevent influenza epidemics and pandemics. Exposure science plays

H1N1 influenza virus. Courtesy of the US Department of Health and Human Services.



http://www.cdc.gov/flu/swineflu/

http://en.wikipedia.org/wiki/World_Health_Organization

http://en.wikipedia.org/wiki/Pandemic_H1N1/09_virus

http://en.wikipedia.org/wiki/Pandemic_H1N1/09_virus

http://en.wikipedia.org/wiki/2009_flu_pandemic



an essential role in both efforts. Several laboratory diagnostic tests can be used to detect the presence of influenza viruses in respiratory specimens (Boggild and McGeer, 2010). However, these tests differ in their sensitivity and specificity in detect-ing influenza viruses as well as in their commercial availability, the amount of time needed between specimen collection and availability of results, and their ability to distinguish between different influenza virus types (A versus B) and influenza A subtypes (e.g., novel H1N1 versus other seasonal H3N2 viruses). Blood tests can help to establish a diagnosis of influenza virus infection for research studies, but such testing is not routinely available through clinical laboratories. More advanced methods were rapidly developed for diagnosis of 2009 pandemic influenza H1N1 viruses. Further characterization of novel influenza 2009 H1N1 infection may be necessary for surveillance purposes and for special situations, e.g., for analyzing specimens from severely ill patients and immunocompromised patients.

Seasonal influenza vaccines typically include three influenza viruses selected on the basis of early evaluation of the antigenic and genetic characteristics of viruses circulating globally. The vaccine manufacturing process takes approximately 6–8 months, and vaccination campaigns now require about 3 months to complete. Hence, the predictions of variant viruses must be made nearly one year prior to the deployment of the vaccine, occasionally leading to a suboptimal antigenic match between circulating viruses and vaccine antigens. Most of the evaluation process of the vaccine involves laborious and time-consuming laboratory and animal studies. The techniques to standardize the amount of a critical component (hemagglutinin) in vaccines are slow and imprecise, causing sporadic delays in the vaccine production process. A new laboratory technique based on mass spectrometry has been developed that could significantly shorten some of these testing steps and accelerate the delivery of a vaccine to the population. Shortening the time required for production and testing of the influenza vaccines would potentially enable the selection of candidate viruses for updating the composition of vaccines to be made closer to the time of vaccination, allowing for more accurate selection of the appropriate vaccine viruses. This new science could be applied to the development of the seasonal influenza virus vaccines, to ensure that they are highly effective.

To summarize:• Early detection and isolation of novel influenza viruses can allow implementation of control measures to delay widespread trans-

mission and ultimately reduce morbidity and mortality.• Exposure science helps in the accurate identification of new influenza strains.• Using exposure science to detect variant seasonal influenza strains early will facilitate production of more efficacious influenza

vaccines.

REFERENCESBell D.M., Weisfuse I.B., Hernandez-Avila M., Del Rio C., Bustamante X., and Rodier G. Pandemic influenza as 21st century urban public health crisis. Emerg Infect Dis 2009:15:

1963–1969.Boggild A.K., and McGeer AJ. Laboratory diagnosis of 2009 H1N1 influenza A virus. Crit Care Med 2010: 38: e38–e42.Reed C., Angulo F.J., Swerdlow D.L., Lipsitch M., Meltzer M.I., Jernigan D., et al. Estimates of the prevalence of pandemic (H1N1) 2009, United States, April–July 2009. Emerg Infect

Dis 2009: 15: 2004–2007.

Disclaimer: The contents of this digest are the opinions of the authors and do not necessarily reflect CDC’s official opinion.




As we learn more about exposure and effects of oil spills, many assumptions are being proven wrong and more unknowns are being identified. Beyond the widely documented physical effects of oil spills on seabirds and marine mammals, scientific studies are increasingly finding that the “invisible” components of oil are also toxic to the developing hearts of fish. The figure shows magni-fied views of the head region of hatching-stage fish embryos. The heart is indicated by arrows. Zebrafish (Danio rerio) are a small tropical fish used as a model system for laboratory studies, much like mice or rats. Pacific herring (Clupea pallasi), which are native to cold northern Pacific waters, are among the species affected by the Exxon Valdez oil spill. When zebrafish or Pacific herring are incubated in clean water, the heart fills a compact space. When the embryos of these species (and others) are incubated in water contaminated with low levels of polycyclic aromatic hydrocarbon (PAH) compounds from crude oil, the heart fails to pump properly and fluid accumulates in this space (a condition called edema), “inflating” the overlying skin and displacing the yolk mass.

The chemical complexity of crude oil and its fuel products poses many important challenges for exposure science in marine ecosystems that support productive fisheries throughout the world. Meeting these challenges will enable better decisions on approaches to protecting and restoring these ecosystems.

Oil spills and fish health: exposing the heart of the matterJOHN P. INCARDONAa, TRACY K. COLLIERb AND NATHANIEL L. SCHOLZa

aEnvironmental Conservation Division, Northwest Fisheries Science Center, National Oceanic and Atmospheric Administration, Seattle, Washington, USAbOceans and Human Health Initiative, National Oceanic and Atmospheric Administration, Silver Spring, Maryland, USAAddress all correspondence to [email protected] of Exposure Science and Environmental Epidemiology published online 10 November 2010; doi:10.1038/jes.2010.51

BACKGROUNDMajor oil spills typically trigger heightened public concern for highly visible species such as birds and marine mammals. However, because these events do not occur every day and are difficult to study, we know much less about the unseen and more subtle ef-fects of oil exposure in marine ecosystems. Consequently, academic and government scientists alike have had great difficulty predicting the impacts of an event like the blowout of the Deepwater Horizon–MC252 well in the Gulf of Mexico. Moreover, the lack of knowledge required to measure the impacts of large oil spills hinders our ability to determine whether multiple small oil spills, which occur almost daily, have effects on our coastal ecosystems. The chemicals in crude oil that we know are toxic to fish enter waterways not only via large oil spills but also every day in smaller quantities, as “fallout” from motor vehicle exhaust and through stormwater runoff from streets and parking lots. The frequency of such smaller events is likely to increase worldwide with rising automobile ownership and coastal population growth. The number of small spills of “bunker” fuel, which powers large ships, is also likely to increase with the expan-sion of container shipping in worldwide trade.

Exposure of marine organisms to oil-derived chemicals is usually assessed by two means. One approach uses analytical chemistry to detect oil compounds in tissues; the other uses biological markers to indicate oil exposure, i.e., measurable changes in a physi-ological or other biological parameter in response to oil. Both approaches have important limitations that stem from two major information gaps. The first is incomplete characterization of the thousands of chemicals that may be present in a particular oil. The second is a limited understanding of what biomarkers mean for the health of oil-exposed organisms. Moreover, neither approach is perfectly diagnostic for pinpointing oil exposure in habitats with overlapping sources of petroleum pollution, such as urban stormwater runoff. This is problematic for apportioning exposure sources along urbanized bays and coasts (e.g., San Francisco Bay and Puget Sound) and in regions such as the Gulf of Mexico that receive smaller, chronic inputs from oil explora-tion and extraction.

Key advances in understanding the effects of oil on fish followed the 1989 Exxon Valdez oil spill in Alaska’s Prince William Sound—to date, the most intensively studied case of a large, one-time input of crude oil into a relatively pristine aquatic ecosys-tem. Intensive environmental monitoring and research following the spill engendered a new understanding of the near- and long-term impacts of oil spills on individual organisms, populations, and communities that extended well beyond the visible physical effects of oil-covered birds and sea otters (Peterson et al., 2003). In the 1990s, field and laboratory studies of fish such as Pacific herring and pink salmon that spawn (deposit eggs) near oiled shorelines discovered important toxic effects of “invisible” dissolved





oil components on fish embryos and larvae. More recent studies have built on these findings, with the goal of further sorting out which specific chemicals in complex oil mixtures are causing this early-life-stage toxicity in fish (Incardona et al., 2004, 2005, 2009). This more refined understanding is needed to develop next-generation biomarkers for oil exposure and to more accurately esti-mate the potential decline and recovery of fish populations that spawn in future spill zones.

IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEThe studies following the Exxon Valdez spill narrowed the search for chemicals in oil that are toxic to fish to a family of com-pounds containing a few hundred chemicals. Some members of this family—polycyclic aromatic hydrocarbons (PAHs)—were known to be toxic, but published research revealed little about how they might cause developmental defects in fish. One rea-son for this is that more than 60% of the published papers on PAH toxicity are on a single carcinogenic compound (benzo[α]pyrene) that typically makes up only 0.02% of the total PAH content of crude oil. Suspect PAHs that are more abundant in crude oil have received almost no attention from the scientific community because they are only weakly carcinogenic.

We recently found that these more abundant chemicals in crude oil target the heart and can cause heart failure in developing fish embryos (Incardona et al., 2004, 2005, 2009; see figure in box). This implies that most of the conventional tools for assessing oil exposure have limited usefulness for understanding effects on fish at vulnerable early life stages. New cardiac-specific biomarkers that are diagnostic of both oil exposure and cardiovascular injury are needed. In addition, we have begun to address the related is-sue of smaller but more frequent spills. Large oceangoing vessels are fueled by tens to hundreds of thousands of gallons of refined bunker oil. Although the volume of a spill of bunker oil would most likely be small as compared with that from a crude-oil tanker or a burst wellhead, bunker oil is the concentrated remains of the overall oil-refinement process. Thus, on a mass basis, residual fuel oils have higher concentrations of many uncharacterized chemicals, with novel and lethal forms of toxicity to fish embryos that we and others are only just beginning to study (Hatlen et al., 2010).

At the current pace of research, our ability to predict the effects of oil spills—large and small—on marine ecosystems will ad-vance in only small steps, with punctuated bursts of progress in reaction to major spill events. Research focused on understanding the consequences of oil exposure in our oceans continues to be needed in order to support more scientifically robust decisions about preventing spills and how to assess their impacts when they occur.

ACKNOWLEDGEMENTSThe authors thank Sandie O’Neill and Mark Myers for their critical reviews of the manuscript.

REFERENCESHatlen K., Sloan C.A., Burrows D.G., Collier T.K., Scholz N.L., and Incardona J.P. Natural sunlight and residual fuel oils are an acutely lethal combination for fish embryos. Aquat

Toxicol 2010: 99: 56–64.Incardona J.P., Collier T.K., and Scholz N.L. Defects in cardiac function precede morphological abnormalities in fish embryos exposed to polycyclic aromatic hydrocarbons. Toxicol

Appl Pharmacol 2004: 196: 191–205.Incardona J.P., Carls M.G., Teraoka H., Sloan C.A., Collier T.K., and Scholz N.L. Aryl hydrocarbon receptor–independent toxicity of weathered crude oil during fish development.

Environ Health Perspect 2005: 113: 1755–1762.Incardona J.P., Carls M.G., Day H.L., Sloan C.A., Bolton J.L., Collier T.K., et al. Cardiac arrhythmia is the primary response of embryonic Pacific herring (Clupea pallasi) exposed to

crude oil during weathering. Environ Sci Technol 2009: 43: 201–207.Peterson C.H., Rice S.D., Short J.W., Esler D., Bodkin J.L., Ballachey B.E., et al. Long-term ecosystem response to the Exxon Valdez oil spill. Science 2003: 302: 2082–2086.

Disclaimer: The views and opinions expressed herein are solely those of the authors and should not be taken or construed as positions or policy of their agency.




Parents have long understood that children are sensitive to hazards in the world around them, and pediatricians have studied children’s susceptibilities since the specialty was established in 1860. But it was only in 1993, following publication of a National Academy of Sciences (NAS) report—Pesticides in the Diets of Infants and Children (National Research Council, 1993)—that children’s unique vulner-abilities to chemicals came to be understood in policy circles. This marked a paradigm shift and has had profound impacts on expo-sure science, toxicology, risk assessment, and regulation.

Before then, virtually all exposure science, toxicology, and risk assessment had focused on the “average adult.” The NAS report changed that. It resulted in major legislative and regulatory actions to better protect infants and children from environmen-tal hazards. It catalyzed new research—notably, the National Children’s Study, a prospective epidemiologic study of 100,000 US children. The NAS report, and numerous scientific findings since then, suggests that the time has come to update Paracelsus’ axiom that “the dose makes the poison,” with the corollary that “in early development, timing makes the poison.”

A key 1990s breakthrough in exposure science was the first recognition by policy makers of the unique exposures and exquisite vulnerabilities of fetuses, infants, and children to pesticides and other toxic chemicals. The result was legisla-tion and other actions that significantly improved protections for children against environmental hazards.

Protecting Children From Pesticides and Other Toxic ChemicalsPHILIP J. LANDRIGANa AND LYNN R. GOLDMANb

aDepartment of Preventive Medicine, Mount Sinai School of Medicine, New York, New York, USAbSchool of Public Health and Health Services, George Washington University, Washington, DC, USAAddress all correspondence to [email protected] of Exposure Science and Environmental Epidemiology published online 12 January 2011; doi:10.1038/jes.2011.1

BACKGROUNDPesticides in the Diets of Infants and Children, a report issued by the National Academy of Sciences in 1993, outlined four principles that characterize children’s vulnerability:

Children have greater exposures to toxic chemicals on a body-weight basis than that of adults. As compared with an adult, a 6-month-old formula-fed infant drinks seven times more water. Children have three to four times more caloric intake. Moreover, children have unique food preferences; for example, an average 1-year-old drinks 21 times more apple juice and 11 times more grape juice than an adult does. The air intake per pound of a resting infant is two times greater than that of an adult. The consequence is that children have proportionately greater intake of toxic chemicals in water, food, and air. Children’s hand-to-mouth behavior and their play close to the ground further magnify their exposures.

Children’s metabolic pathways are immature. Children’s ability to metabolize and excrete toxic chemicals is different from adults’. In some instances, infants are at lower risk because they cannot convert chemicals to their toxicologically active forms. More commonly, how-ever, they are more vulnerable.

Children are undergoing rapid growth and development. Research in pediatrics has identified “windows of vulnerability,” i.e., critical stages in early development when toxic exposures can cause devastating injury. Examples include phocomelia (from thalidomide), vaginal adenocar-cinoma (from diethylstilbestrol), and brain injury (from methylmercury). More recently, prenatal exposures to certain endocrine-disrupting chemicals have been shown to produce profound effects on the developing brain at very low doses. These windows of susceptibility exist only in early development. They have no counterpart in adult life.

Children have more time than adults to develop chronic diseases that may be triggered by harmful exposures in the environment. Many diseases triggered by toxic chemicals are now understood to evolve through multistage, multiyear processes. Because chil-dren have more future years of life, they are at greater risk of developing disease resulting from early exposures.

ImpACt AND ImplICAtIONs fOR ExpOsURE sCIENCEThe core insights and recommendations of the NAS report were incorporated into the 1996 Food Quality Protection Act (FQPA), the federal pesticide law. It was the first national environmental statute to contain explicit provisions for protecting children.

Children today are surrounded by toxic chemicals

Boys bathing in a recycled pesticide drum. (Courtesy of Donald C. Cole, Dalla Lana School of Public Health, University of Toronto.)




In the regulatory arena, the FQPA forced reexamination of pesticide standards (“tolerances”). It reduced agricultural use of or-ganophosphates. It also led to bans on residential applications of two very widely used organophosphate insecticides: chlorpyrifos and diazinon. These bans were triggered by recognition of the compounds’ neurodevelopmental toxicity and documentation of their long residence time in indoor environments.

The FQPA changed risk assessment. It forced development of child-protective approaches that explicitly consider children’s ex-posures and susceptibilities. It also requires the use of child-protective safety factors. It was the first legislation to mandate realistic consideration of exposures to multiple pesticides via multiple routes, including diet and drinking water, in order to assess poten-tially synergistic effects. In addition, it mandates consideration of exposures to chemicals that impact the endocrine system. The challenge before the US Environmental Protection Agency (EPA) today is to use these approaches rigorously and frequently.

The FQPA enabled the EPA to mandate a new assay that permits accurate assessment of the toxicity of carbamate pesticides such as aldicarb, a potent insecticide used in agriculture since 1970. With this test, the concentration of aldicarb legally allowed in food was found to be 1.2 times greater than the adult limit for acute toxicity and 3.2 times higher than the limit for acute toxicity in children. When drinking-water exposures were considered, the legally permitted levels were found to be 5 times the adult toxicity limit and 16 times the pediatric limit (EPA, 2010). The result was that the EPA announced a phaseout of aldicarb in 2010, a significant benefit for the health of all Americans, especially for children.

The recognition of children’s exposures and susceptibilities embodied in the FQPA has had consequences that extend beyond pesticide regulation. It led to establishment of the Office of Children’s Health Protection within the EPA. It catalyzed a Presidential Ex-ecutive Order requiring agencies of the federal government to consider children’s special exposures and susceptibilities in all policy and rule making (Clinton, 1997). It stimulated creation of a White House Task Force on Children’s Health and Safety, and it led to pas-sage in 2002 of the Best Pharmaceuticals for Children Act, which requires that drugs labeled for use in children undergo scientific studies to specifically examine children’s susceptibilities.

Recognition of children’s susceptibility has stimulated substantial increases in research in exposure science and children’s environ-mental health. These initiatives include:• A national network of federally funded Centers for Children’s Environmental Health and Disease Prevention Research and a

global network of Pediatric Environmental Health Specialty Units (Spivey, 2007; Wilborne-Davis et al., 2007)• Fellowship training programs in environmental pediatrics in leading medical institutions (Landrigan et al., 2007)• The National Children’s Study, a prospective epidemiologic study that will follow a nationally representative sample of 100,000

children from early pregnancy to age 21 to assess environmental influences on health and development (Landrigan et al., 2006)These new initiatives may be expected to increase still further our knowledge of children’s unique susceptibilities to toxic chemi-

cals in the environment and thus to guide the future of risk assessment and exposure science.

REfERENCEsClinton W.J. Presidential Executive Order 13045: Protection of Children from Environmental Health Risks and Safety Risks, 21 April 1997. http://yosemite.epa.gov/ochp/ochpweb.

nsf/content/whatwe_executiv.htm.EPA. US Environmental Protection Agency Office of Chemical Safety and Pollution Prevention. Aldicarb: Revised Acute Probabilistic Aggregate Dietary (Food and Drinking Water)

Exposure and Risk Assessment Incorporating Revised FQPA Factor. Washington, DC, 4 August 2010.Landrigan P.J., Trasande L., Thorpe L.E., Gwynn C., Lioy P.J., D’Alton M.E., et al. The National Children’s Study: a 21-year prospective study of 100,000 American children. Pediatrics

2006: 118: 2173–2186.Landrigan P.J., Woolf A.D., Gitterman B., Lanphear B., Forman J., Karr C., et al. The ambulatory pediatric association fellowship in pediatric environmental health: a 5-year

assessment. Environ Health Perspect 2007: 115: 1383–1387.National Research Council. Pesticides in the Diets of Infants and Children. Washington, DC: National Academy Press; 1993.Spivey A. Children’s health centers: past, present, and future. Environ Health Perspect 2007: 115: A192–A194.Wilborne-Davis P., Kirkland K.H., and Mulloy K.B. A model for physician education and consultation in pediatric environmental health—the Pediatric Environmental Health

Specialty Units (PEHSU) program. Pediatr Clin North Am 2007: 54: 1–13, vii.


http://yosemite.epa.gov/ochp/ochpweb.nsf/content/whatwe_executiv.htm

http://yosemite.epa.gov/ochp/ochpweb.nsf/content/whatwe_executiv.htm

http://www.ncbi.nlm.nih.gov/pubmed/17938724

http://www.ncbi.nlm.nih.gov/pubmed/17938724



Exposure science empowers sustainable development, disease prevention, and risk analysis. It is fundamental to protecting vulner-able people and ecosystems from environmental dangers. Exposure information provides a foundational element for understanding the interactions among the environment, genetics, and health. Efficient and effective public health policy requires a better understanding of key environmental risk factors and a renewed focus on health protection and disease prevention. Long-term solutions to improve global environmental health require a shift toward sustainable design and development. Meeting these fundamental scientific challenges will require innovation and transformation of exposure science. Ultimately, a cohesive contribution of intellectual and finan-cial resources will be required from the entire environmental health community of scientists, regulators, and policy makers for more informed public policy and health protection.

Exposure science is the bedrock for protection of pub-lic health. It fundamentally informs decisions that relate to smart and sustainable design, prevention and mitigation of adverse exposures, and ultimately health protection.

The Promise of Exposure ScienceELAINE A. COHEN HUBALa, DANA B. BARRb, HOLGER M. KOCHc AND TINA BAHADORId

aNational Center for Computational Toxicology, US Environmental Protection Agency, Research Triangle Park, North Carolina, USAbDepartment of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USAcInstitute for Prevention and Occupational Medicine of the German Social Accident Insurance Institute of the Ruhr-Universität Bochum (IPA), Bochum, GermanydAmerican Chemistry Council Long-Range Research Initiative, Washington, DC, USAAddress all correspondence to [email protected] of Exposure Science and Environmental Epidemiology advance online publication 12 January 2011; doi:10.1038/jes.2010.55

BACKGROUNDThere has recently been unprecedented convergence among leaders of several research agencies about the critical role of exposure science in public and environmental health protection. Many have incorpo-rated key exposure considerations into visions and strategies for their agencies. The timing is ripe to harness this collective energy, mobilize resources, and innovate the field.

In describing his vision for science and research at the US Environ-mental Protection Agency (EPA), Paul Anastas, the EPA’s science adviser, highlights innovation and prevention and supports promotion of a “safe by design” approach. This requires a seismic shift to viewing challenges in a systems-based way rather than chemical by chemical, air toxic by air toxic, or water contaminant by water contaminant (Anastas et al., 2010).

Similarly, the National Institute for Occupational Safety and Health recently released Prevention Through Design: Plan for the National Initiative. These strategies for preventing work-related illnesses by de-signing occupational hazards out of work environments are important steps in addressing challenges posed by the changing nature of work. John Howard, director of the agency, notes that prevention through design is in many respects a “transformative concept” for the 21st century and that it “views investments in worker safety and health as an integral part of business efficiency and quality” (NIOSH, 2010). This shift in the framework for design, manufacture, and manage-ment to address principles of sustainability requires holistic consideration of integrated environmental, economic, and social factors.

Linda Birnbaum, director of the National Institute of Environmental Health Sciences (NIEHS), recently made a compelling case for the need to increase the understanding of health impacts of low-level exposures to environmental stressors (Kang, 2010). Emphasizing the institute’s focus on public health and prevention, she highlighted the importance of considering the full complexity of the ways in which genetics, epigenetics, and environmental exposures combine to affect health at both the individual and the population level across the course of development and even across generations.

Despite the success in sequencing the human genome, underlying causes of common diseases remain elusive. It has become evident that elucidating these causes requires commensurate efforts to map markers of environmental exposures and their contribution to health and to the onset or exacerbation of disease. In February 2010, the National Academies of Science (NAS) organized a workshop, “The Exposome: A Powerful Approach for Evaluating Environmental Exposures and Their Influences on Human Disease,” to examine the concept of the exposome (Rappaport and Smith, 2010) and its importance for illuminating the etiology of human diseases. This concept involves accounting for the life course of environmental exposures from all sources, includ-ing lifestyle factors.

This trans-agency and trans-disciplinary call for an increase in relevant, high-quality exposure information demands a transfor-mation in exposure science. Creative contributions from scientists with a wide range of expertise are required in order to fulfill the vision of understanding the life course of environmental exposure and to provide the evidence base for public health decisions regarding environmental health.





IMPACT AND IMPLICATIONS FOR EXPOSURE SCIENCEExposure science fundamentally informs decisions that relate to smart and sustainable design, prevention and mitigation of adverse exposures, and, ultimately, health protection. It shifts the focus of public health and clinical medicine from diagnosis and treatment to elucidation of cause and prevention. Some of the areas of critical need for exposure information to support the interdependent pillars of sustainability, prevention, and risk analysis are examined below.

Sustainability: Sustainable decisions and actions are those that improve the current health of individuals and communities without compromising the health and welfare of future generations. Such decisions are supported by comprehensive environmental assess-ments so that, for example, risk is not merely shifted from water to air or from one population to another. Exposure information is required to support this holistic approach to addressing emerging trends and strengthening public health policies.• What exposure science is required to analyze linked social-environmental systems?• How do global pressures on the environment and human health (e.g., development, population growth, climate change) impact

the potential for exposures to chemical, physical, and biological agents?• What key exposure metrics are required to evaluate alternatives and ensure safe products and processes across their life cycles?Prevention: To shift focus from treating to protecting health and preventing disease, we require an advanced understanding of

the roles of environmental factors in impairing health status and in the etiology of diseases. Environmental factors include the full spectrum of biological, physical, chemical, and psychosocial stressors. Innovation in exposure-measurement technologies is required to provide rapid, efficient, and effective methods for characterizing these environmental factors (exposures) at all levels of biological organization and to supplement traditional biomonitoring.• Over the developmental time course, from conception through old age, what is the potential for disease and other adverse

impacts from exposure to multiple stressors?• What key metrics are required to characterize critical aspects of these combinations of stressors, and how are these likely to

interact and impact susceptibility and response?• What are the most effective ways to reduce adverse exposures?Risk analysis: Risk-based decision making calls for strong, science-based exposure analysis. Real-time exposure measurements

integrated into public health and environmental-surveillance platforms will provide data critical to identifying, managing, and mitigating risks to susceptible and vulnerable groups. Reliable prediction of exposures in order to assess and prevent risks requires models grounded by measured data spanning the full range of environmental factors. These exposure-analysis tools are essential for understanding the current risks of our built, indoor, and workplace environments as well as the potential for risks from emerging technologies and products.• How can emerging methods in molecular biology and advanced sensor technologies be developed to measure exposure?• What are biologically relevant exposures?• What exposure measurements and models are required to understand risks of built, indoor, and workplace environments?• What is the potential for exposure to and risk from emerging technologies and products such as newly manufactured chemicals,

engineered nanomaterials, and products of biotechnology?In light of high-visibility calls for dramatic innovation in exposure science, there is great potential for the NAS committee tasked

with a major new study cosponsored by the EPA and the NIEHS—Human and Environmental Exposure Science in the 21st Century—to provide the vision to guide research in our field.

Realizing the promise of exposure science to support public health requires a fundamental cultural shift toward the following:• Trans-disciplinary collaborations that provide the linkages between exposure and health sciences• A suite of scientifically based tools and approaches to support public health decisions• Policy making based on holistic approaches• Commitment of resources to trans-disciplinary long-term research and trainingTogether, the state of technology and our understanding of biology create fertile opportunities to revolutionize exposure science.

This transformation is no longer an optional scientific luxury; rather, it is our obligation if we are to enhance the public health pillars to support the well-being of our children and future generations.

REFERENCESAnastas P, Teichman K, Cohen Hubal E. Ensuring the safety of chemicals. J Expo Sci

Environ Epidemiol 2010: 20: 395–396.Kang E. Birnbaum unveils strategic vision for NIEHS. Environmental Factor, June 2010.

http://www.niehs.nih.gov/news/newsletter/2010/june/spotlight-strategic.cfm.NIOSH. NIOSH Releases Prevention Through Design (PtD) Plan: Transformative

Goals, Strategies for Job Safety and Health, 19 November 2010. http://www.cdc.gov/niosh/updates/upd-11-19-10.html.

Rappaport SM, Smith MT. Epidemiology: environment and disease risks. Science 2010: 330: 461–461.

Disclaimer: This digest represents the opinions of the authors and does not necessarily represent the views of their organizations.


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