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CHAPTER 3 INFORMATION NEEDED TO ASSESS AND QUANTIFY HEALTH EFFECTS Repeated attempts in recent years to assess the health impacts of environmental factors have been hampered by the fragmentary state of present knowledge. Public Law 95-623 specifically lists cancer, birth defects, genetic damage, emphysema, asthma, bronchitis and other respiratory diseases, heart disease, stroke, and mental illness and impairment as examples of health problems to be considered by the ongoing study. However, environmental agents may also damage the skin, kidneys, immune system, and other organs of the body, and the committee believes that these and other effects should not be neglected. Appendix C contains tables of known and suspected environment-related health effects. This chapter continues the discussion of information needed to carry out the ongoing study, with particular reference to the methods used to ascertain the health effects of environmental hazards (Boxes 4 and 4a in Figure l-l).* Viewed in modern perspective, the development of virtually all diseases may be presumed to involve an interaction between genetic and environmental determinants.] The contribution of a given environmental risk factor can be expected to vary, depending on the conditions under which it is encountered, the presence of other factors in the environment that may modify its effects, and the susceptibility of the exposed population. Although adverse effects of various environmental factors have been well documented when such effects have occurred promptly in a high proportion of exposed individuals, effects have been more difficult to document when they have been delayed in their appearance, have occurred in only a small proportion of exposed individuals, or have resulted from the combined effects of two or more factors.2 Yet, it is the effects that occur under the latter conditions that are of greatest concern in assessing the impact of the environment on the health of the population as a whole. . Although this committee suggests that the ongoing study focus on the health effects resulting from involuntary exposure to physical and chemical pollutants, it will often be necessary to consider additional factors such as life-style factors and socioeconomic status. -49-

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Three types of studies provide evidence about whether a substance or exposure may lead to health problems o short-term experimental in vitro tests* and animal studies o clinical studies, particularly studies using human volunteers o epidemiologic studies, which provide data on the distribution and determinants of disease and illness in human populations. Each of these methods has strengths and weaknesses, and there is a great need to integrate data obtained by the three methods.3 Short-term tests and animal studies can predict potential toxicity before actual human exposure occurs. Short-term tests primarily detect substances that interact with genetic material,4~8~9 but animal studies can detect a wide range of toxic effects, including behavioral effects and damage to liver, skin, the nervous system, and other organs. With animals, acute effects, as well as those with long latent periods, can be studied. Dose/response curves can be derived, and the effects of substances on target organs analyzed. However, difficulties arise in applying data from short-term or animal studies to people. In some cases, evidence of health problems resulting from exposure to hazards noted by clinicians can provide a link between animal and short-term experimental studies on one hand, and epidemiologic studies on the other. Controlled experiments with toxic agents on human beings are constrained by practicality and ethics, so that they are rarely used today and usually involve relatively few (1-10) volunteers exposed to agents whose physiologic effects are easily measured and reversible, such as sulfur oxides.5 Epidemiologic studies provide statistical associations between the factors of concern and health effects in the population. They provide information on real people in a real environment and, therefore, are particularly useful for purposes of the ongoing study. The necessary use of observational investigation in most human epidemiologic studies means that such studies generally are not useful for predicting health effects before chemical or physical agents are introduced. There are major difficulties in detecting or estimating health effects for large populations at low levels of exposure. Estimation of risks at low doses requires either large population samples or extrapolation of effects at high doses to effects at low doses, with all the uncertainty such extrapolation procedures entail. The *Short-term tests refer to a group of tests, using bacteria or other biological systems, that detect substances that are potentially . mutagenic or carcinogenic. —SO—

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effects of radiation on human beings provide one of the better examples of an area where data on both exposure and health effects exist. Even in this example, however, controversy continues about estimating the health effects of low levels of radiation because of the need to extrapolate from results seen at higher doses.2 Epidemiologic studies have become more informative as researchers have learned to control for confounding factors, and to do intricate statistical analyses. Some difficulties can be overcome by study design and by collecting data on particular populations, such as workers or susceptible groups, and by taking advantage of accidental events that lead to high levels of exposure. RISK EXTRAPOLATION FROM NON-HUMAN DATA Most environmental hazards have been ;denti fled after they caused human illness or disease. However, recent efforts are directed at predicting substances likely to cause health problems, and at minimizing or preventing human exposure. Attention is directed particularly to the effects of chemicals, because expansion of chemical technology since World War II has vastly increased both the variety and volume of chemicals used in the United States. An inventory by the Environmental Protection Agency (EPA) lists more than 55,000 chemical substances that are used commercially and are subject to regulation by the Toxic Substances Control Act (TSCA).6 The inventory excludes chemical mixtures, foods, drugs, cosmetics, pesticides, and other substances regulated under authorities other than TSCA. With rare exceptions, these materials have not been demonstrated to be either safe or unsafe to humans. Short-term Tests An array of short-term tests has been developed to provide relatively rapid and inexpensive means for screening compounds for mutagenic or related effects.4~8~9, Current short-term tests involve a variety of biologic systems, including bacteria, yeast , fruit flies, and cultured mammalian cells. Conducting short-term tests on a compound takes a few days to a few months and costs from a few hundred to a few thousand dollars . Positive results in these tests are highly correlated with the ability of certain classes of subs Lances to cause cancer in animal tes ts, 4 ~ 7 ~ ~ ~ 9 a [though some materials that are carcinogenic. by other criteria do not give posi t ive resul ts in many of these tests . The methods have been reviewed, ~ and an international effort that recently compared results obtained for many of the standard tests in different laboratories concluded that further development and validation are needed.l° -51-

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Although short-term tests are used primarily for detecting mutagenic and other effects that are assumed to be related to carcinogenesis, it would be useful if there were quick tests for other types of effects--such effects could include problems with reproductive or nervous system, liver function, or lung function. Researchers now are attempting to develop such tests. Animal Tests Because there are basic similarities between human beings and other animals in the way their cells and tissues respond to toxic or hazardous agents, animal experiments can be helpful in evaluating the human health risks from many substances. For a number of compounds,12 such as vinyl chloride, aflatoxin, and diethylsti lbesterol (DES) ~ harmful effects were detected in animal studies before such effects were recognized in human beings. Animal tests are widely used for detecting acute effects of substances . More attention i s needed to develop and use anima1 studies to detect diseases with long latent periods, such as cancer, respiratory diseases, heart disease, and neurological problems. Requirements for adequate numbers of animals, appropriate controls, and sufficient length of time to allow the expression of health effects that have long latent periods make such experiments expensive. Even using small rodents, testing two species for carcinogenicity ordinarily requires more than SOD animals, exceeds $500,000 in cost, and takes up to three years.13 Pisk Extrapolation Tests that do not involve human beings raise questions of whether results from the test system apply to human beings, and, if so, how to express the relationships quantitatively. For example, although the reactivity of DNA is similar whether situated in a test bacterium or a human cell, there are large differences in the environments traversed by a chemical on its way to the target DNA and in the organization, regulation, and repair of DNA in the two cases. It is not possible at present to use short-term test results to estimate human risk quantitatively. In animal tests for carcinogens, animals receive high doses of the substance under study, so that a reasonable percentage of them will develop tumors if the substance is carcinogenic. Risk estimation depends on dose/response relationships, and many attempts have been made to develop models to extrapolate results from high doses in animals to the low doses to which people are more likely to be exposed .2 ,14-17 -52-

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Risk extrapolation estimates using various models give similar results at high doses where measurements are available, and give very different results at low doses. In one massive experiment, called the ED01 study, more than 24,000 mice received varying doses of a carcinogen so that low-dose effects would be detectable and dose/response models could be tested.15 The number of cancers observed were consistent with several different models and demonstrated the difficulties in risk extrapolation. At present there is not a good theoretical basis for extrapolating results of animal studies to estimate human risk.18 One of the systematic efforts to make quantitative comparisons of the carcinogenesis of chemicals in mice, rats, and human beings is that of Crouch and Wilson.l9 Their method has shown a high correlation for most of the compounds tested and begins to offer a basis of rational estimates of human risk from animal data. However, further study of compounds that show idiosyncratic reactions may lead to discovery of useful comprehensive principles for estimating human risk from experimental species. Pisk extrapolation is at a stage of conceptual development such that a wide range of data scattered among many different sources needs to be integrated. Quantitative judgments, although necessary, are particularly difficult. Much medical research is needed--from fundamental molecular biology to more immediately applicable medical and public health practices--in order to develop a theoretical basis for predicting possible human health effects from studies on non-human test systems. Improved understanding of the ways in which environmental agents affect different biological systems should provide a basis for developing less costly and more rapid tests to estimate human risk. CLINICAL STUDIES Clinical studies may provide data to help detect and quantify the health effects of environmental hazards in at least two ways. First, the medical care system, either by observations of individuals or by analyses of records, can detect the occurrence of unusual health problems or identify cases of disease associated with exposure to an environmental hazard. This will be discussed further in the following section on epidemiology. Second, in some circumstances, clinical studies can be carried out to evaluate health effects after exposure to a pollutant under rigorously controlled conditions.5 However, these studies are sharply limited by ethical concerns; exposures must be limited to those that cause only temporary effects and do not cause volunteers undue discomfort or pain. Clinical observations, whether they are case reports associated with exposures or the result of data collected in controlled studies, can help relate data obtained in animal studies to those obtained in -53-

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epidemiologic studies. is similar to an animal from animal studies. Clinical documentation of human disease that disease permits more secure generalization EPIDEMIOLOGIC STUDIES The relevance of epidemiologic principles and methods to the ongoing study is evident from the common definition of epidemiology--the study of the distribution and determinants of disease frequency in human populations. The unit of study--human populations--is emphasized. In principle, given the congressional charge in P.L. 95-623, all the health consequences of exposures to all the hazards deriving from the man-made environment should be assessed in all residents of the United States, and monitored over time. Although this is an impossible task, it is desirable to retain the concept, in order to discuss the types of epidemiologic studies that are or should be carried out and their limitations. The major strength of epidemiology is that it provides a direct measure of risk in human beings. However, the technique has limitations, especially for conditions that have long latent periods and occur after low levels of exposure to hazardous agents. Studies in these instances require large populations, adequate exposure data, and careful analysis of confounding factors.* The necessary use of the observational mode of investigation in most human environmental epidemiologic studies imposes limitations on the causal inferences derivable directly from relationships between exposures and diseases. Types of Studies Epidemiologists often classify studies according to the purpose of the study and the research designs employed to achieve the purpose. Descriptive studies can be used to monitor and to document the burden of illness and disease from known hazards, and to generate hypotheses for future testing in situations where the adverse health consequences of substances found in the environment are not yet known. Analytic studies can be used to test specific hypotheses about environment-health relationships. The major types MA confounding factor is a factor that contributes to a disease incidence, and to which exposure frequently occurs under the same conditions as exposure to the substance whose effects are being studied. An incorrect estimate of the risk attributable to the substance under study will be made if confounding factors are present but ignored. For example, if respiratory illness is attributed to the air pollutant sulfur dioxide but is in reality due primarily to asbestos exposure that occurred in association with sulfur dioxide, then asbestos is a confounding factor. -54-

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of study designs used for these purposes are described below.* With few exceptions, the greater the analytic power of the design, the more complex the study and the more resources will be needed to carry it out. (1) Ecologic studies look at patterns of morbidity and mortality in aggregates or groups of individuals in relation to information collected on an environmental. characteristic. There is no direct measure of individual exposure or other individual characteristics. An example is a comparison of cancer in counties of the United States according to the presence of selected industries. Because the individuals with cancer in such a study are not classifiable according to how near they live to the industry or whether they work in that industry, no firm association between cancer and the industry can be made. The hypothesized relationship needs further testing. (2) Case-series studies start with individual cases of a disease, often identified by an alert physician who suspects or discovers a common factor associated with the cases.22~23 The discovery that vinyl chloride is associated with angiosarcoma is an example of a case-series study. A surgeon noted that three patients with hepatic angiosarcoma worked in the same factory and were exposed to vinyl chloride. Vinyl chloride has since been shown to cause that rare cancer. (3) Cross-sectional studies evaluate differences in health status at a specified time among individuals in two or more groups exposed to different levels of the environmental factor or factors in question. In the Community Health and Environmental Surveillance System (CHESS) and in the Six City Study, a group of communities was selected to represent an exposure gradient for designated pollutants so as to use the cross-sectional design as one of the study strategies.24-26 The surveys on health status of the U.S. population carried out by the National Center for Health Statistics, for example, the 1980 National Natality and National Fetal Mortality Surveys, are good examples of cross-sectional epidemiologic studies. These classifications are flexible. In some cases, a complex study might fit into more than one category. In addition, these studies are described in terms of exposure to hazardous substances, but the studies could look for relationships to life-style factors well. -55-

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(4) Case-control studies begin with two groups of individuals that differ according to whether or not they have a specific disease or illness. The individuals with the disease or illness (cases) are compared with those who are free of the disease (controls) for past exposures to factors that might be associated with the illness or disease. This type of study can estimate the relative risk of disease associated with exposure, but cannot give information on the absolute risk for a population. As an example of a case-control study, Newhouse used this design to show that inhalation of asbestos particles increased the chances of contracting - mesothelioma, a rare cancer of the lining of the chest or abdomen.27 (5) Cohort studies evaluate the differences in health status emerging over time among specified groups. The groups, or individuals within the groups, may be classified according to the level of past exposures to specific agents and by other characteristics, such as age, occupation, or residence. Health status and further exposures are followed over time. This study design is more powerful than a case-control or cross-sectional study.- It provides information on the absolute risk associated with exposure, as well as the relative risk among the different exposure groups. Cohort studies require long-term commitment of resources. One example of a cohort study is the Atomic Bomb Casualty Commission's study of the Japanese populations exposed to radiation in Hiroshima and Nagasaki, a study that has continued for more than 35 years.28 a less expensive technique that can be used to establish a cohort involves linking data that have already been collected on individuals for other purposes. For example, in England a 1 percent sample of the population is followed longitudinally by linking various records of individuals in order to study occupational health.29~30 Establishing Causal Relationships If~associations are demonstrated by rigorous unbiased epidemiologic studies, then the problem is to demonstrate a cause and effect relationship between a particular entity in the environment and a particular health effect. Epidemiologists establish causality, with greater or lesser certainty, by fulfilling as many as possible of the following rules of evidence for establishing causality (1) Strength of association The stronger the association between a definable environmental agent and the presence of an -56-

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observable adverse health effect, the more likely it is that the relationship is causal and not attributable to known or unknown confounding factors. (2) Dose/response gradient The finding of increased incidence of disease with increasing exposure to the substance in question suggests a biologic effect. When the environmental agent or substance is removed, the effect should diminish or disappear. For the purposes of the ongoing study, it would be important to quantify the dose/response gradient. (3) Confirmation of the study Confirmation of the study's finding by other researchers in other populations under different circumstances decreases the chance the association is an artifact. (4) Biological plausibility Are the effects in humans consistent with laboratory findings? (5) Temporal sequence Because cause must precede effect, studies that record exposure and disease status without regard to which came first may be less reliable for inferring causal relationships than studies that have a clear time frame and collect data over a long period of time. (5) Consistency with animal experimentation When the results of animal experiments agree with those found in epidemiologic studies, the likelihood that there is a cause and effect relationship is increased. (7) Specificity of response The finding that exposure to a particular substance always results in a particular disease would be strong evidence of a causal relationship (the one-cause, one-disease concept). However, this criterion is rarely available to epidemiologists studying environmental health effects and, in addition, must be used with care. Almost all diseases of interest have multiple causes, and specific exposures generally are accompanied by a multiplicity of health consequences. ~ slightly different but similar approach to that above for establishing causality for environment-related health effects has been proposed by Hackney and Linn.31 They updated Koch's postulates to apply to modern problems of environmentally caused health effects. Even if ~ causal relationship is established, the fact that many health problems have multiple causes must be considered in projecting the results of epidemiologic studies to anticipated costs and savings in reducing these problems with control measures. Not only are the responses of individuals conditioned by genetic fac tars, but antecedent life experiences, including nutrition, exposure to —5 7—

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infectious agents, and exposure to physical and chemical environmental agents other than the one under inquiry, also will modify the biologic response to the causal agent. Analysis of Data from Varied Sources Large bodies of data have been collected on various characteristics of the environment and on the health status of individuals. These data, although collected for other purposes, can be used in ecologic study designs to monitor for known hazards and to generate new hypotheses regarding presently unknown hazard-disease causal relationships for further testing. The strongest kind of evidence in establishing cause and effect relationships comes from data on individuals in cohort or case-control studies. Such studies are often done by linking records of various kinds, such as birth records, death records, social security and health records, to obtain information from different sources. One very successful example of linking data on individuals to study occupational health is the 1 percent sample studies in Britain which define the cohort to be followed over time.29~30 In the United States, linking data on individuals in one data set with information on the same individual in another data set would be greatly facilitated by the use of a "person number" or a unique personal identifier. For example, it would be possible to link health, medical, and census records to seek new insights into factors associated with illness. People could be followed prospectively, or past records could be retrieved. Such personal identifiers are used in other countries; NCHS discussed their use recently. ~ recent study by NCHS related to locating, assessing, and treating individuals exposed to hazardous substances indicated the difficulty of tracking people in the United States, partially because existing statutes--including the 1974 Privacy Act (U.S.C.552a)--protect individuals against undue invasion of privacy by the federal government.32 Because the issues surrounding the use of a personal identifier in the United States-are complex, the planning committee observed that the subject deserves further study. When possible, the ongoing study should use existing data systems to obtain the necessary information. However, as noted earlier, ideal data systems are nonexistent, and the problem is one of adapting available information for the immediate purpose. Longitudinal studies, that is, studies carried out over extended time periods, are probably necessary for answering certain research questions. Notable examples of longitudinal studies of special populations include the National Academy of Sciences/Atomic Bomb Casualty Commission studies of persons exposed to radiation from atomic bomb explosions. These studies documented early effects on fetuses of exposed women, and decades later, excess rates of various cancers.28 The Framingham Heart Study, supported by the National -58-

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Heart, Lung, and Blood Institute, has provided much useful inflation about risk factors for heart attacks.33,34 Although the power of well-designed longi tud i nal studies is great, they require long-term commitment of personnel and resources. See Appendix E for approximate costs associated with some epidemiologic studies. Surveillance In addition to being able to use the various epidemiologic research designs for deriving causal relations, epidemiology can also be used for purposes of surveillance. Surveillance serves two purposes. The first of these is to monitor for known hazards and their health consequences, for example, to monitor the workplace. The second is to generate hypotheses that can be tested with further research. Complete Population and Integrated Environmental Surveillance The identification of all exposures and all disease episodes among all individuals would provide the totality of observational information available to identify environmental hazard-disease relationships. Although there are no instances of total surveillance, attempts have been made to implement portions of a general system through the use of population registries, disease registries, and environmental monitoring systems. Population registries have a wide range of objectives, from identifying all citizens of a country--their residences, family relationships and vital statistics--primarily for legal purposes, but also useful for health studies,35 to identifying an exposure cohort, such as the Japanese survivors of the atomic bombings, for follow-up to determine long-term health effects.28 Disease registries have been developed for objectives besides etiologic research; for instance, cancer registries have been developed to improve diagnostic and therapeutic practices, professional education, and assessment of treatment efficacy. When the community catchment areas and population at risk estimates are defined and case ascertainment and reporting are relatively complete and of good quality, the registries can serve several purposes. The cancer registry in Connecticut, for example, has been used to estimate-the incidence-of selected cancers and their relation to potentially hazardous environmental exposures, including those associated with industry and occupation.35 When the risk of a malignancy is known to be markedly increased upon exposure to a specific environmental agent--such as risk of mesothelioma and exposure to asbestos, 27 angiosarcoma and vinyl chloride,22 and bladder cancer and beta-naphthylamine36--combined exposure and disease registries may be used to identify populations previously not -59-

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The primary responsibility of this team would be to go rapidly to the sites of acute environmental events in order to conduct studies that would document and measure a) the extent and severity of the environmental insult b) the number of people actually or potentially at risk c) the immediate health effects resulting from the exposure. Tf adverse health effects were found, or if potential future effects were strongly suspected, further study might be required. For example a) cross-sectional evaluation of the entire population at risk or of a statistical sample of the population with additional intensive monitoring of exposures b) establishment of a registry for the prospective longitudinal follow-up of the exposed group. A population-at-risk registry would require the collection of identifying data, information on exposure dose (by environmental, biological, or proxy monitoring), information on baseline health status, and possibly information on potentially confounding life-style factors. Future follow-up of such registries, including follow-up through the National Death Index, would enable future estimation of the incidence of delayed disease resulting from acute environmental exposures. For both the acute and long-term phases of these evaluations, appropriate comparisons must be made to unexposed control groups.50 The results of too many acute environmental studies have been vitiated by failure to employ adequate epidemiologic methodology of this kind. The systematic collection of data on the acute and chronic health consequences of population exposures to acute environmental episodes will constitute an important component of the ongoing data collection activity mandated under P.L. 95-623. These evaluations would provide data, available from no other source, that are necessary to elucidating the high-dose range of the dose/response curves predicting health effects from environmental exposure. Susceptible Populations Many, if not most, factors that contribute interaction between the which the individual is that will determine the well understood illnesses have environmental to their occurrence.] However, it is the environmental components and the degree to susceptible or resistant to these factors severity and outcome of the health effect. -56-

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Individuals may be more susceptible or resistant to particular environmental factors because of heredity; their particular developmental stage of life; sex; or acquired conditions, such as nutritional status, pre-existing disease conditions, and, to some extent, personal habits and behavior. Identifying those individuals susceptible to environmental factors can be important in developing occupational and environmental health policies and practices and in interpreting environment-related health statistics. However, the mechanisms responsible for differential susceptibility to toxic environmental agents are known for only a few predisposing conditions and substances. Moreover, attempts to estimate the costs of environment-related health effects for a population usually are based on data derived from studies that assume homogeneous populations. Accordingly, consideration of the effect of various characteristics being evaluated on particularly susceptible groups should be bui It into the ongoing study. Acauired SusceDtibi litY Hei ghtened suscept i hi 1 i ty to envi ronmental a gents may be acquired. 51, 52 For example, suppression of the body's immune system results in an increase in susceptibility to some kinds of microbial agents. Certain chronic diseases, such as bronchitis and asthma, may make some people increasingly liable to the irritating effects of photochemical smog or chemical exhausts in the atmosphere. There are instances in which people develop hypersensitivity to substances to which they are exposed. The phenomenon of acquired susceptibility needs further study to determine its incidence. Inherited Individual Susceptibility - Many of the best known and understood examples of heightened susceptibility are inherited, or probably inherited, and involve changes in single genes. However, other cases of inherited susceptibility are controlled by two or more genes that interact with one or more environmental factors. A mutant gene may have little or no significant effect on well-being until the person is in an environment that stresses a biochemical system influenced by the gene. If this stress is great enough, the cellular integrity of target tissues may be disrupted or damaged badly enough to cause an illness that may be acute or chronic. Some inherited conditions already have been identified and -67-

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characterized in which the response to environmental factors and subsequent severity of disease vary according to the type of mutant.^ It is conceivable and even likely that every individual in the population is especially susceptible to some environmental factors. The overwhelming majority of genetic factors or the environmental factors that may contribute to differences in susceptibility are not known. Appendix F lists some inherited conditions that may directly or indirectly influence an individual's risk of developing an illness related to environmental factors. Age and Sex During pregnancy the mother and fetus are particularly susceptible to a variety of environmental factors.53-56 Experiments with rodents indicate that the fetus is more sensitive than the adult to certain carcinogens by several orders of magnitude. Further, the newborn rodent is also more susceptible than the adult, and possibly even than the fetus, to some carcinogens, because it is no longer protected by the maternal body. Various stages in the human life span are associated with increased susceptibility. The developing embryo in the first eight weeks has been reported to have a high susceptibility to certain environmental influences, especially drugs.-53 This is a time when a great majority of birth defects are induced, and the conditions of exposure to certain types of agents are of particular concern in relation to such structural defects. Other groups subject to *For example, a large number of mutations of the gene controlling production of the enzyme glucose-5-phosphate dehydrogenase (G6PD) have been described.! Two of these, an African and a Mediterranean variant, are associated with limited breakdown of red blood cells when males affected by this deficiency take certain drugs, e.g. antimalarial drugs, such as primaquine, or ingest certain chemicals, e.g. naphthalene (the major ingredient in moth balls). However, the severity of red blood cell damage is much greater in those who have the Mediterranean variant than in those who have the African variant. Furthermore, ingestion of the fava bean will damage red blood cells in males who carry the Mediterranean variant of C~5PD deficiency, but will generally have no detectable clinical effect on males who have the African variant. This mutation is quite common, with, for example, in the United States approximately 12 percent of black males of African descent having G6PD deficiency. The proportion of whites of Mediterranean ancestry who have the more severe form varies with different ethnic groups. -68-

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increased susceptibi lity because of their age include the young, during the perinatal and breast feeding periods, and the elderly. The issue of individual susceptibility will become more important as information increases. For accurate risk estimates and quantification of costs, groups with special susceptibility need to be considered. Observations often are based on effects seen at relatively high doses in a small population without adequate representation of possibly susceptible groups. Low doses will have their greatest effects on the susceptible groups. Therefore, effects extrapolated from high doses may underestimate or miss effects on susceptible populations. Questions of individual susceptibility raise many additional issues, such as the cost of surveillance of high risk groups, costs of worker's compensation, confidentiality, and the setting of priorities for funding. This committee recognizes that these issues exist and notes that they deserve study and consideration. Effects of Environmental Agents on Human Reproduction The planning committee singled out the effects of environmental agents on human reproduction for special attention. There is growing concern about such effects and a broader range of effects is being noted than in the past, but the kinds of data that are available do not readily lend themselves to studying reproductive effects. Environmental agents may affect reproduction in males and females in many ways. They could affect fertility, diminish libido or sexual function, promote impotence, or otherwise impair reproductive ability by adversely affecting the reproductive cycle or contri but i ng to de fec t ive or i nsu fficient spermatogenesis or oogenesi s . Environmental agents may increase pregnancy . wastage by inducing implantation defects, spontaneous abortions, or stillbirths; they could act as mutagens or teratogens, producing structural, functional, or metabolic defects; they can act as transplacental carcinogens, influence behavioral development, or increase susceptibility to disease. Examples of environmental exposures leading to reproductive effects include abnormalities in sperm and cases of sterility after exposure to dibromochloropropane (~BCP),57 decreased libido after occupational exposure to synthetic estrogens,58 and transplacental carcinogenesis due to in utero exposure to diethylstilbesterol (DES).59 Despite a large accumulation of scientific literature concerning the reproductive effects of environmental agents such as are found in the computerized files of the Environmental Mutagen Information —69—

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Center (EMIC)* and the Environmental Teratogen Information Center (ETIC),* the effects of environmental factors on reproduction are not well understood or quantified. In order for the ongoing study to be able to calculate the costs of reproductive effects of environmental agents, a great deal more information will be needed.60 High risk populations, including occupational cohorts, should be identified and monitored for point mutations, chromosome aberrations, abortions, stillbirths, birth weight, and congenital malformations. It would be useful to have sentinel indices and in vitro tests for assessing different levels of reproductive failure and for predicting the pathogenetic potential of environmental agents. *EMIC and ETIC systems are located in Oak Ridge, Tennessee, and they are operated by Union Carbide Corporation under a contract from the U.S. Department of Agriculture. -70-

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