3
Human Data

Human data generally are not a part of toxicity-testing strategies despite the importance of human responses to potentially toxic agents. Although animal toxicity studies and in vitro studies provide relevant information on potential adverse health effects of exposure to an agent, they can miss an effect relevant to the human population. As mentioned in Chapter 2, a famous example is thalidomide, to which rats are highly resistant but human fetuses are exquisitely sensitive. Studying the human population also provides an opportunity to evaluate the effects of the full variety of agents in the complex contexts of workplaces and daily lives. The large populations also provide an enormous sample size in which rare effects might be detected. If the human experience is not evaluated, animal-to-human extrapolations are tenuous (for example, some responses observed in animals may not be relevant to the human population). Human data provide a benchmark for those extrapolations.

Given the importance of human data, this chapter reviews the various types of human data, provides examples of the use of human data in regulatory analyses, and considers the challenges to and possible advances in studies of the human population. Regarding availability of human data, clearly, no population data will be available on a chemical newly introduced to the marketplace, although there may be controlled-exposure data, such as those from a clinical trial conducted on a pharmaceutical. Population data will be available only on chemicals that have been in production for some time, perhaps several decades. Thus, differences in data availability on new versus existing chemicals should be considered in developing the role of human data in any toxicity-testing strategy.



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Toxicity Testing for Assessment of Environmental Agents: Interim Report 3 Human Data Human data generally are not a part of toxicity-testing strategies despite the importance of human responses to potentially toxic agents. Although animal toxicity studies and in vitro studies provide relevant information on potential adverse health effects of exposure to an agent, they can miss an effect relevant to the human population. As mentioned in Chapter 2, a famous example is thalidomide, to which rats are highly resistant but human fetuses are exquisitely sensitive. Studying the human population also provides an opportunity to evaluate the effects of the full variety of agents in the complex contexts of workplaces and daily lives. The large populations also provide an enormous sample size in which rare effects might be detected. If the human experience is not evaluated, animal-to-human extrapolations are tenuous (for example, some responses observed in animals may not be relevant to the human population). Human data provide a benchmark for those extrapolations. Given the importance of human data, this chapter reviews the various types of human data, provides examples of the use of human data in regulatory analyses, and considers the challenges to and possible advances in studies of the human population. Regarding availability of human data, clearly, no population data will be available on a chemical newly introduced to the marketplace, although there may be controlled-exposure data, such as those from a clinical trial conducted on a pharmaceutical. Population data will be available only on chemicals that have been in production for some time, perhaps several decades. Thus, differences in data availability on new versus existing chemicals should be considered in developing the role of human data in any toxicity-testing strategy.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report CLINICAL OR CONTROLLED-EXPOSURE STUDIES Humans are often intentionally exposed to various agents to evaluate possible health effects. Most intentional exposures occur during the development of potential new medicines and are used to characterize their efficacy and safety. The clinical-trial process is subject to numerous regulations, guidance, monitoring, and reporting obligations that attach primary importance to patient well-being. Specifically, the trials are conducted under multiple federal regulations (21 CFR 21, 50, 54, 312 [2004]), good-clinical-practice guidelines, and technical requirements established by the International Conference on Harmonization (EMEA 2002). Such guidelines and regulatory requirements determine regulatory oversight processes, trial conduct, ethical review, informed consent, monitoring of drug supplies, adverse-event monitoring, and data integrity and quality assurance. Preclinical safety testing of investigational new drugs must satisfy the appropriate regulatory bodies that the first clinical trials in humans will pose minimal risk for subjects. The exhaustive nature of the preclinical assessment, which includes high-dose acute and multidose chronic studies in animals, means that only a few potential new drugs will be deemed sufficiently safe for administration to human volunteers. The trial process itself is separated into distinct phases, and the study protocol for each phase is subject to review by an institutional review board or ethics committee. The phases of clinical trials are as follows: Phase 1. This stage, typically performed in fewer than 100 healthy volunteers, is designed to establish dose-range tolerance. It may include a carefully controlled and monitored dose-escalation protocol. For some disease indications, such as cancer and HIV, the Food and Drug Administration supports an accelerated process in which efficacy and tolerance are assessed simultaneously in patients with the disease in question. Phase 2. For most indications, this stage is designed to refine dose ranges, establishing efficacy and safety in typically 100-500 selected patients who represent the target population. Drug tolerance is monitored. Parallel safety studies in animals are also run to characterize potential adverse effects that may be a consequence of high-dose or long-term exposure and to characterize specific end points, such as reproductive and developmental effects.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Phase 3. These studies, which are usually multicenter and possibly multinational, involve thousands of representative patients and enable assessment of the efficacy and safety of the proposed new drug at doses characterized in the previous phases. Successful completion of this stage, with demonstrated efficacy and manageable side effects, is necessary for approval to market the drug. Phase 4. Postmarketing surveillance, which may include further clinical trials, involves the collection of further data on drug efficacy and safety in the broader patient population. Some environmental agents, such as ozone and perchlorate, have been studied with controlled exposures of volunteers. Those studies have provided information on pharmacokinetics and pharmacodynamics at environmentally relevant concentrations. The ethical implications of such studies have been raised, and guidance on their conduct and their use for regulatory purposes is being debated (NRC 2004a). CASE REPORTS Many human toxicants were first recognized by astute clinicians who reported their suspicions that the occurrence of some rare disease in association with an unusual exposure was more than coincidence. Case reports include detailed medical information that has been collected on a single patient or a series of similar patients. Clinical information may be gathered from private physicians, hospitals, clinics, and ambulatory-care facilities to investigate and understand disease etiology. Some clinical information on acute exposures may be obtained from the Toxic Exposure Surveillance System, which contains data on over 36 million human poison-exposure cases compiled by the American Association of Poison Control Centers (Watson et al. 2004). Case reports are particularly useful in investigating exposures on which there is little or no reported human toxicity information. Some of the most informative case reports are derived from occupational settings. Workers in industrial settings are often the first to show adverse effects of an agent because of their high or chronic exposure. One example is the recognition of the causative link between vinyl chloride and hepatic angiosarcoma among polyvinyl chloride workers. Zymbal gland carcinomas, nephroblastomas, and hepatic angiosarcomas were observed in

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Toxicity Testing for Assessment of Environmental Agents: Interim Report rats exposed to vinyl chloride by inhalation in August 1972. In December 1973, a case of malignant hepatic angiosarcoma in a polyvinyl chloride production worker was associated with occupational vinyl chloride exposure (Creech and Johnson 1974; Maltoni et al. 1981). Retrospective occupational cohort studies later confirmed the connection. Thus, researchers identified a new cause (exposure to vinyl chloride monomer) of a rare disease previously associated only with medical use of Thorotrast and occupational exposure to inorganic arsenic (Falk et al. 1981). EPIDEMIOLOGIC STUDIES Epidemiologic studies typically investigate the relationship between exposure to a substance and potential health effects in a human population. There are several study designs and different approaches to organizing and classifying them. Table 3-1 provides one perspective on defining epidemiologic study designs and their basic characteristics. TABLE 3-1 Examples of Epidemiologic Study Designs Study Design Characteristics Comments Cohort A study in which the individual is the unit of observation. A cohort (large group of people) is defined and evaluated over a particular period to determine the occurrence of a health-related outcome and its possible relationship to a given exposure. Prospective cohort studies monitor a disease-free population selected at the beginning of the study for the occurrence of health effects associated with a given exposure. Retrospective cohort studies evaluate a cohort after the outcome has occurred, and exposure information is estimated on the basis of historical records, subjects’ memories, or job descriptions. The primary purpose of a cohort study is to establish the incidence or occurrence of new cases of the health outcome among the exposed and unexposed groups to estimate a relative risk between two groups. An unbiased cohort study can reflect the cause-effect temporal sequence of events with regard to an exposure and an outcome.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Case-Control A study that involves the recruitment of a series of cases with a specific disease and a series of disease-free controls. Comparisons of exposure to the agent of interest are then made between the cases and control series. Higher exposure to a specific agent among the cases than among the controls suggests that the risk of the disease of interest may be increased as a consequence of exposure. Cross-Sectional A study in which disease prevalence and exposures are evaluated in a cohort at a single time (that is, people are not followed over time). An important distinction between cohort and cross-sectional studies is that a cohort study selects an at-risk population, but a cross-sectional study selects people who are then classified as having or not having the disease on the basis of information collected after selection. Ecologic A study that examines exposure and risk factors on a group level (generally studies of geographically defined populations). Cross-sectional ecologic studies compare aggregate exposures and outcomes in communities in the same period. Time-trend ecologic studies compare aggregate exposures and outcomes in the same community over time. An association observed between two variables on an aggregate level does not necessarily represent an association on an individual level (known as the ecologic fallacy). Causation cannot be established by such studies, but they can supply useful supporting information. Epidemiologic studies are often referred to as occupational or environmental depending on whether the study population is exposed in the workplace or through daily living, respectively. Because of higher exposures in some workplaces relative to the general environment, the occupational setting has provided valuable information on the potential adverse effects of various chemicals. Although occupational exposure monitoring is done primarily for purposes of industrial hygiene and compliance with occupational exposure guidelines, the resulting data are

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Toxicity Testing for Assessment of Environmental Agents: Interim Report often useful in occupational epidemiologic studies. Large industries may also have disease surveillance programs, which can be used to provide health-outcome data for occupational studies. However, occupational data may be biased because of the healthy-worker effect, which is defined as a population bias resulting from reduced recruitment or early withdrawal of less-healthy persons from the worker population. That bias diminishes the possibility of observing a significant increase in risk. Other factors that may affect the reliability of occupational, as well as environmental, studies are poor or no control for confounding factors, nonrandom sampling of study subjects, exposure and disease measurement error, and missing data due to subject nonresponse or losses to followup. Regardless of the possible study limitations, occupational and environmental epidemiologic studies can provide a systematic evaluation of human exposures and possible outcomes, are valuable in the risk-assessment process, and are relevant in determining the adequacy of regulatory standards for chemicals that are already widely used. USE OF HUMAN DATA FOR REGULATORY ANALYSES Human data have been used to estimate risk and to establish standards for environmental and occupational exposures. Table 3-2 provides TABLE 3-2 Examples of Risks or Standards Derived from Human Data For Drinking-Water Standards and Advisories Arsenic Cancer risks estimated from studies of bladder and other cancers in populations consuming arsenic-contaminated water (EPA 1984; NRC 1999; OEHHA 2004a) Benzene Cancer risks estimated from studies of leukemia in workers in the Pliofilm industry in the United States and a large cohort of workers from various industries in China (EPA 1998; OEHHA 2001) Nitrate Reference levels estimated from studies of infants exposed to nitrate at >20 mg of nitrate-nitrogen per liter in drinking water used to prepare their formula (Bosch et al. 1950; Walton 1951) Perchlorate Reference levels estimated from controlled-exposure studies of inhibition of thyroid iodide uptake in perchlorate-exposed humans (OEHHA 2004b; NRC 2005)

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Toxicity Testing for Assessment of Environmental Agents: Interim Report For Air-Pollutant Standards and Advisories Arsenic Cancer risks estimated from studies of lung cancer in workers in the smelter and pesticide manufacturing industries (Roth 1958; Ott et al. 1974; Tokudome and Kuratsune 1976; Rencher et al. 1977; Axelson et al. 1978; Mabuchi et al. 1979; Matanoski et al. 1981; Enterline and Marsh 1982; Lee-Feldstein 1983) Benzene Cancer risks estimated from studies of leukemia in workers in the Pliofilm industry (Rinsky et al. 1981, 1987) Cadmium Cancer risks estimated from studies of lung cancer in workers in the cadmium smelter industry (Thun et al. 1985) Diesel exhaust Cancer risks estimated from studies of lung cancer in rail workers (Crump 2001; OEHHA/ALA 2001) Hexavalent chromium Cancer risks estimated from studies of lung cancer in workers in the chromate production industry (Mancuso and Hueper 1951; Mancuso 1975, 1997) Ozone Criteria standard derived from controlled human chamber studies of lung-function decrements and respiratory symptoms after ozone exposure (EPA 2005a) or epidemiologic studies of premature mortality, respiratory hospitalization, and asthma exacerbation (OEHHA 2004c) Particulate Matter Criteria standard derived from studies of correlations of premature mortality and fine-particle exposure in various U.S. cities (EPA 2005b) Vinyl chloride Risks estimated from studies of hepatic angiosarcoma and other cancers in workers in the U.S. polyvinyl chloride industry (Feron et al. 1981) For Food Residues Aflatoxin Widely recognized as a known human carcinogen on the basis of numerous studies of populations in China and Africa consuming contaminated foods (IARC 1993; FDA 2003); risks estimated from data in studies of Chinese populations controlled for confounding by hepatitis infection (Wu-Williams et al. 1992 ) Methyl-mercury Reference exposure levels initially established from studies of poisoning incident in Iraq where people consumed grain treated with organomercurial pesticides and currently established from studies of associations of developmental effects and hair concentration in populations consuming large amounts of seafood (NRC 2000; EPA 2001)

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Toxicity Testing for Assessment of Environmental Agents: Interim Report examples of the use of human data to set water, air, and food standards or advisories. In March 2004, the Environmental Protection Agency (EPA) Risk Assessment Task Force reviewed a sample of EPA’s Integrated Risk Information System database to estimate how often human data were used in developing reference concentrations (RfCs), reference doses (RfDs), or cancer risk assessments (EPA 2004). Of the 15 RfC determinations reviewed, eight included human data, and four of the eight used the human data as the principal basis for determining the RfCs. Of the 42 RfD determinations reviewed, nine included human data, and five of the nine used the human data as the principal basis to derive the RfDs. Of the 27 classifications of carcinogenicity reviewed, 10 identified human data, and four of the 10 used the human data to make the classification of carcinogenicity. When human data were available but not used as the principal data, a variety of reasons were provided, including the questionable relevance of the exposures, concurrent exposure to other chemicals, imprecise measurements of exposure and duration, inadequate consideration of confounding factors, inadequate statistical power, insufficient time after exposure to observe outcome, and the difficulty of using null results from epidemiologic studies. Epidemiologic studies have played a particularly important role in the assessment of population health risks associated with air pollutants. Two kinds of epidemiologic studies have shown that pollutants in ambient air are associated with adverse health outcomes (Cohen et al. 2003; Samet and Krewski 2005). Adverse health effects of short-term exposures to air pollutants have been consistently demonstrated in studies that relate daily fluctuations in pollutant exposure to hospital admissions, mortality (Samet et al. 2000), and perinatal health outcomes (Liu et al. 2003). Long-term cohort mortality studies, most notably the Harvard six-cities study (Dockery et al. 1993) and the American Cancer Society (ACS) study (Pope et al. 1995), have shown that long-term exposure to particulate air pollution is associated with increased cardiopulmonary and possibly lung-cancer mortality (Pope et al. 2002). Recent analyses of the ACS cohort conducted by Pope et al. (2003) have suggested that cardiovascular mortality associated with particulate air pollution is consistent with pathophysiologic mechanisms of accelerated atherosclerosis. That hypothesis is supported by toxicologic data suggesting that particulate air pollution may lead to the induction of endothelins and cytokines, which may in turn lead to atherosclerosis (NRC 2004b).

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Toxicity Testing for Assessment of Environmental Agents: Interim Report CHALLENGES TO THE ADVANCEMENT OF EPIDEMIOLOGY Epidemiologic studies have been widely criticized on the grounds that their methodologic limitations make it difficult to draw clear associations between exposure and disease. Those limitations have made it difficult to use epidemiologic data in regulatory risk assessments. Three of the most common problems are that only uncertain or indirect estimates of human exposure are available; that epidemiologic studies may identify associations with chemical classes, such as organophosphate pesticides, or with consumer-product categories, such as insecticides, rather than specific chemicals; and that the indeterminate and often long latency period between exposure and disease creates logistical challenges for study design and adds to the uncertainty of results. Because of the complexity of epidemiologic datasets, there is a need to develop and refine statistical methods of analysis to address critical data issues, such as random and systematic exposure-measurement error, selection bias, the effects of residual confounding and unmeasured covariates, and errors in health-outcome ascertainment. Good exposure assessment is critical for population-based research in environmental health to reduce the likelihood of biased results and to provide information that is valid and useful for informing public-health decision-making. Adequate assessment of human exposure to an environmental agent includes determining the exposure intensity, frequency, and duration. A good exposure assessment should answer several questions: Are people exposed to the environmental agent? If so, what is the statistical distribution of exposures in the population? How do exposures depend on personal characteristics, such as age, place of residence, and work in a particular area of a factory? How have exposures changed over time? Through what pathways are people exposed? Evaluation of exposures of children and evaluation of exposures to mixtures are other exposure issues. Children often have exposure pathways that differ from those in adults because of their propensity for hand-to-mouth activities, and children may be exposed to a higher dose relative to their body weight than adults in the same setting. Mixtures typically are not addressed in exposure assessment; when exposures to mixtures are measured, incorporation of the results into a risk assessment is often impossible because of the lack of information about whether the combined exposures act in an additive, less than additive, antagonistic, or synergistic manner.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Despite all the complex issues, human studies are needed to determine actual exposures; laboratory investigations cannot do that. Most epidemiologic studies have estimated human exposure to suspected environmental toxicants by collecting questionnaire data on past behavior patterns related to exposure. Some studies have used job title or place of residence to categorize the exposure of study subjects. Those methods often result in simplistic exposure categorizations, such as exposed and unexposed, which are of limited use in quantitative risk assessment. Furthermore, the errors in such data can lead to misclassification of exposure, which can increase variances, introduce bias, or both. Nondifferential random exposure misclassification will bias studies toward a null result, and a study may fail to detect or adequately measure a true association. In contrast, systematic exposure-measurement error can lead to bias toward or away from a null result. Exposure assessment has improved in recent years. Environmental monitoring has provided useful data for exposure assessments. For example, testing foods and drinking water for contaminants has allowed scientists to create reasonable exposure estimates from the test results and data on food and water consumption patterns. Exposure modeling also has proved helpful in exposure assessment. Models can be constructed to estimate exposures to chemicals in food, water, and air and from various household scenarios, such as a toddler playing on a lawn or carpet. Exposure models gradually improve as they are tested against monitored data and can be useful for generating exposure assessments for regulatory risk assessments. Some models are not publicly available for scientific scrutiny and so cannot be assessed for validity. Such models should not be used in the development of regulations or advisories until they have been shown to be valid and reliable. The emerging fields that hold much promise for improving exposure assessment and other issues mentioned are discussed briefly below. CONTRIBUTIONS OF EMERGING FIELDS TO EPIDEMIOLOGY Improving the science of epidemiology so that it can improve the effectiveness of toxicity testing of environmental agents should have high priority. New fields are emerging that may help to overcome the issues discussed. Specifically, developments in biomonitoring, molecular and genetic epidemiology, and environmental health tracking hold

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Toxicity Testing for Assessment of Environmental Agents: Interim Report great potential for overcoming some of the major historical limitations of epidemiology and are discussed in the following sections. Biomonitoring Biomonitoring is the measurement of biomarkers in blood, urine, and tissues. A biomarker is defined as “any substance, structure or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease” (WHO 2001). Biomarkers should ideally be both specific to a particular environmental agent and sufficiently sensitive to reflect the effects of low-level exposure to that agent. The incorporation of biomarkers in epidemiologic research offers considerable potential to improve exposure estimates and detection of adverse health effects of environmental agents in population-based studies. In applying biomarkers of exposure, pharmacokinetic models are needed to define the relationship between exposure to a compound and the concentration of that compound or its metabolites in body tissues. Biomarkers of Exposure Biomarkers of exposure—such as lead in blood or deciduous teeth and polychlorinated biphenyls in blood or breast milk—have been in wide use for many years and have been critical in creating a large and robust epidemiologic database on a variety of toxicants. The Centers for Disease Control and Prevention (CDC) National Report on Human Exposure to Environmental Chemicals provides a continuing assessment of the U.S. population’s exposure to environmental chemicals based on a statistical sample of the general population. The first report (CDC 2001) presented biomonitoring data on 27 chemicals; the second report (CDC 2003) on 116 chemicals, including the original 27; and the third report (CDC 2005) on 149 chemicals, including the 116 from the second report. CDC’s work is one example of estimating population exposures with biomarkers of exposure. Examples of innovative uses of biomarkers of exposure in population studies include researchers sampling participants for residues of relevant contaminants (Nordstrom et al. 2000; Pavuk et al. 2003). By decreasing exposure misclassification, the studies have helped to overcome one of the major hurdles of epidemiology. However, biomonitoring does not fully overcome dose uncertainty and is applicable

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Toxicity Testing for Assessment of Environmental Agents: Interim Report mostly to chemicals with long biologic half-lives and to disease end points with relatively short latency periods. Some researchers have successfully used biomarkers of exposure for relatively short-lived toxicants in prospective cohort studies (Whyatt et al. 2004; Murray et al. 2004). Such an approach can allow clearer demarcation of the exposure status of members of the cohort, although it does not necessarily allow extrapolation to dose. Biomarkers of exposure are critically important for strengthening epidemiologic research, but they can be used for other purposes. Population-based exposure surveys can be used to determine the distribution of exposure to specific toxicants, to identify groups with high exposures, and to track trends. Such data can be useful in setting priorities when there is a need to determine whether exposure is widespread and in the risk-assessment process when there is a need to identify highly exposed populations. Agencies can also use biomarkers of exposure to track the effectiveness of regulatory efforts or identify a need for regulatory attention. Biomarkers of Effect Epidemiologic studies of such outcomes as cancer and chronic disease are particularly difficult because years or even decades may elapse between an exposure and the manifestations of symptomatic disease. In some cases, the mechanism of action of an environmental toxicant is sufficiently well understood that biomarkers of effect have been developed and used in human health risk assessment. For example, perchlorate, a drinking-water contaminant, is known to inhibit the uptake of iodide by the thyroid and thus possibly decrease the production of thyroid hormones. Inhibition of radioiodide uptake measured in a human clinical study has been used as a biomarker of effect in risk assessments performed by state environmental agencies and by the National Research Council (OEHHA 2004b; NRC 2005). Markers of airway inflammation (such as nitric oxide in exhaled breath; inflammatory cells, cytokines, and chemokines in bronchoalveolar-lavage fluid; and RANTES gene activation) have been used in studies of the effects of ozone, diesel exhaust, and other air pollutants on rodents and humans (Pandya et al. 2002). Clinical tests of effect, such as forced expiratory volume in 1 sec (FEV1), have been used in risk assessments that have formed the basis of regulation of pollutants, including ozone (Gauderman et al. 2000).

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Some biomarkers appear to be markers of both exposure and effect. For example, polycyclic aromatic hydrocarbon (PAH) DNA adducts in biologic samples can be used to assess exposure to PAHs, evaluate the potential for an early event in a multistep process of carcinogenesis, and perhaps even predict cancer risk in some groups (Peluso et al. 2005). Such biomarkers might be useful in risk assessment in which prevention of an early effect would protect human health. Molecular and Genetic Epidemiology Molecular epidemiology and genetic epidemiology identify molecular biomarkers of exposure and effect and incorporate them into study designs to investigate gene-environment interactions and their associations with the etiology and distribution of disease. Studies incorporating biomarkers have demonstrated that genetic consequences of human exposure are measurable and definable in tissues from exposed people (Schroeder et al. 2003; Perera et al. 2005). For example, spontaneous chromosomal aberrations detected in peripheral blood lymphocytes have been shown to identify humans at increased cancer risk (Bonassi et al. 2000; Chien et al. 2004; Shao et al. 2004). The use of other biomarkers, such as DNA adducts and urinary hydroxypyrene, in epidemiologic studies has shown that exposed groups have considerable increases in DNA-associated damage or excreted metabolites (Wiencke et al. 1995; Siwinska et al. 2004; Peluso et al. 2005). Those studies have been useful in helping to understand the relative risks associated with different routes of exposure (for example, dermal vs inhalation) and in providing evidence to support the mechanistic understanding of relationships between exposure, disease, and potential modifiers of absorbed dose (Schurdak and Randerath 1989; Turteltaub et al. 1993; McClean et al. 2004). Delineation of genetic variation is also proving important in defining potential differences in susceptibility to environmental toxicants. Genetic variation is well known to give rise to heritable disease states, and recent work suggests that common normal genetic polymorphisms may in some cases be associated with an increase in susceptibility to toxicants (Caporaso and Goldstein 1997; Singh 2003). It is critical to remember that once a genetic polymorphism has been identified, it is not a simple task to determine its mechanism of action. For example, it is not always clear whether a particular variant itself has a biologically distinct

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Toxicity Testing for Assessment of Environmental Agents: Interim Report action or if it is linked to another variation that is functionally important. Phenotypic characterization of genotypic variation is critical to the application of such data in population studies. Environmental-Health Tracking New efforts to collect data relevant to environmental health in human populations systematically may hold promise for improving the quality and quantity of data available for epidemiologic studies. The Institute of Medicine has stated that “every public health agency [should] regularly and systematically collect, assemble, analyze, and make available information on the health of the community, including statistics on health status, community health needs, and epidemiologic and other studies of health problems” (IOM 1988). That recommendation has been implemented for some types of diseases but poorly developed for others. Many infectious diseases, such as rabies and influenza, are intensively tracked in the United States to facilitate public-health responses. Birth defects and cancer are tracked in some states, and the data are centrally compiled at CDC and the National Cancer Institute, respectively. However, hospital-discharge data and medical-billing data, which are sometimes useful for developing disease patterns, are not centralized, are of mixed quality, and are not useful for many chronic diseases. Because most diseases are multifactorial, elucidation of the environmental causes of human disease requires data on exposure to environmental agents that can be linked to specific adverse health outcomes. However, few systems at the state or national level track many of the exposures and health effects that may be related to environmental hazards. The existing tracking systems are usually not compatible with each other, and data linkage is extremely difficult. Over the last 5 years, there has been an effort to create a nationwide environmental public-health tracking (EPHT) program in up to 20 states and local regions with a coordinating center at CDC. The national EPHT program was established in 2002 with low funding, and its future is in some doubt. EPHT is defined as the “ongoing collection, integration, analysis, and interpretation of data about environmental hazards, exposure to environmental hazards, and human health effects potentially related to exposure to environmental hazards” (CDC 2004). An integrated EPHT system includes three components: hazard tracking, exposure

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Toxicity Testing for Assessment of Environmental Agents: Interim Report tracking, and disease tracking. The components are designed to be maintained in electronic files that can be linked to facilitate hypothesis generation and research. There are at least four reasons to create an integrated environmental health surveillance system: tracking of environmental hazards, exposures, and disease can help to identify areas or groups in which exposure to an environmental hazard may be excessive and require reduction; trends can help to evaluate the success of environmental-protection and public-health measures; linkage of environmental-hazard information and disease information can help to generate hypotheses that require investigation; and a tracking network provides the foundation that researchers need to do scientific studies to identify the causes of disease. REFERENCES Axelson, O., E. Dahlgren, C.D. Jansson, and S.O. Rehnlund. 1978. Arsenic exposure and mortality: A case referent study from a Swedish copper smelter. Br. J. Ind. Med. 35(1):8-15. Bonassi, S., L. Hagmar, U. Stromberg, A.H. Montagud, H. Tinnerberg, A. Forni, P. Heikkila, S. Wanders, P. Wilhardt, I.L. Hansteen, L.E. Knudsen, and H. Norppa. 2000. Chromosome aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. Cancer Res. 60(6): 1619-1625. Bosch, H.M., A.B. Rosefield, R. Huston, H.R. Shipman, and F.L. Woodward. 1950. Methemoglobinemia and Minnesota well supplies. J. Am. Water Works Assoc. 42:161-170. Caporaso, N., and A. Goldstein. 1997. Issues involving biomarkers in the study of the genetics of human cancer. Pp. 237-250 in Application of Biomarkers in Cancer Epidemiology, P. Toniolo, P. Boffetta, D. Shuker, N. Rothman, B. Hulka, and N. Pearce, eds. IARC Science Publications No. 142. Lyon, France: IARC. CDC (Centers for Disease Control and Prevention). 2001. National Report on Human Exposure to Environmental Chemicals. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA [online]. Available: http://www.noharm.org/details.cfm?ID=745&type=document [accessed March 25, 2005]. CDC (Centers for Disease Control and Prevention). 2003. Second National Report on Human Exposure to Environmental Chemicals. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA [online]. Available: http://www.serafin.ch/toxicreport.pdf [accessed October 25, 2005].

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