7

Biologic Markers in Studies of Hazardous-Waste Sites

THE EPIDEMIOLOGIC STUDY of hazardous-waste sites can benefit by incorporating into study designs analyses of biologic specimens collected from people potentially at risk. In accord with the framework in Figure 1-1, this chapter reviews studies of biologic markers in persons exposed to materials like those commonly encountered at hazardous-waste sites and the few studies of persons directly exposed at such sites. Examples of markers of exposure, effect, and susceptibility are provided, and methodologic or other important considerations in their use are presented. The final section discusses some of the ethical and legal issues in the use of biologic markers in studies at hazardous-waste sites.

TYPES OF MARKERS

As defined by the NRC Board on Environmental Studies and Toxicology, a “biologic marker” is any cellular or molecular indicator of toxic exposure, adverse health effects, or susceptibility (NRC, 1987).

It is useful to classify biologic markers into three types—exposure, effect, and susceptibility. A biologic marker of exposure is an exogenous substance or its metabolites or the product of an interaction between a xenobiotic agent and some target molecule or cell that is measured in a compartment within an organism. A biologic marker



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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 7 Biologic Markers in Studies of Hazardous-Waste Sites THE EPIDEMIOLOGIC STUDY of hazardous-waste sites can benefit by incorporating into study designs analyses of biologic specimens collected from people potentially at risk. In accord with the framework in Figure 1-1, this chapter reviews studies of biologic markers in persons exposed to materials like those commonly encountered at hazardous-waste sites and the few studies of persons directly exposed at such sites. Examples of markers of exposure, effect, and susceptibility are provided, and methodologic or other important considerations in their use are presented. The final section discusses some of the ethical and legal issues in the use of biologic markers in studies at hazardous-waste sites. TYPES OF MARKERS As defined by the NRC Board on Environmental Studies and Toxicology, a “biologic marker” is any cellular or molecular indicator of toxic exposure, adverse health effects, or susceptibility (NRC, 1987). It is useful to classify biologic markers into three types—exposure, effect, and susceptibility. A biologic marker of exposure is an exogenous substance or its metabolites or the product of an interaction between a xenobiotic agent and some target molecule or cell that is measured in a compartment within an organism. A biologic marker

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 of effect is a measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease. A biologic marker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability to respond to the challenge of exposure to a specific xenobiotic substance (NRC,1987). Biologic markers have been discussed extensively in the scientific literature in the past ten years but rarely with regard to hazardous-waste research (Perera and Weinstein 1982; Fowle, 1984; CEQ, 1985; Underhill and Radford, 1986; Harris et al., 1987; Perera, 1987a,b; Hatch and Stein, 1987; NRC, 1987; Schulte, 1987, 1989; Hulka and Wilcosky, 1988; Hulka et al., 1990). Biologic markers are not new. Markers such as blood lead, urinary phenol levels in benzene exposure, and liver function assays after solvent exposure have long been used in occupational and public health research and practice to indicate recent exposures to these compounds. What distinguishes the current generation of research on markers from previous markers is the greater degree of analytical sensitivity available to detect markers and the ability these markers offer researchers to describe events that occur all along the continuum between exposure and clinical disease. There are domains of biologic response and levels of resolution that were unknown 20 years ago (Schulte, 1990). For instance, within the past few years more than 400 proteins have been identified on sperm. In theory, chemical adducts to these can form and they have already been detected in protamine, hemoglobin, and other vital human proteins (NRC, 1987). Accompanying these advances in sensitivity is the requirement to consider that numerous factors can influence the appearance of biological markers. All people with similar exposures do not develop disease or markers indicative of exposure or disease. Various acquired and hereditary host factors are responsible for this variation in responses. Biologic markers may represent signals in a continuum or progression of events between a causal environmental exposure and resultant disease (NRC, 1987). Current technological advances and developments in basic sciences allow for detection of smaller signals at diverse points in the continuum. These markers are generally biochemical, molecular, genetic, immunologic, or physiologic signals of an event. The current method for estimating risks by relating exposure to clinical disease (morbidity and mortality) can now be supplemented by a fuller method, one that identifies intervening relationships more precisely or with greater detail than in the past. As a result, health events are less likely to be viewed as binary phenom-

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 ena (presence or absence of disease) than they are to be seen as a series of changes on a continuum—through homeostatic adaptation, dysfunction, to disease and death. The progression from exposure to disease has been characterized by a number of authors and scientific committees (NRC, 1987, 1991; Perera, 1987a,b; Hatch and Stein, 1987; Schulte, 1989) and is shown in Figure 7-1. Along the progression from exposure (E) in the environment to the development of clinical disease (CD), four generic component classes of biologic markers can be delineated: those that show the internal dose (ID), and those that show the biologically effective dose (BED), early biologic effects (EBE), and altered structure and function (ASF). Clinical disease also can be represented by biologic markers for the current disease as well as by markers for prognostic significance (PS). Internal dose (ID) is the amount of a xenobiotic substance found in a biologic medium; the biologically effective dose (BED) is the amount of that xenobiotic material that interacts with critical subcellular, cellular, and tissue targets or with an established surrogate tissue. A marker of early biologic effect represents an event that is correlated with, and possibly predictive of, health impairment. Altered structure and function (ASF) are precursor biologic changes more closely related to the development of disease. Markers of clinical disease (CD) and of prognostic significance (PS) show the presence and predict the future of developed disease, respectively. Markers of susceptibility are indicators of increased (or decreased) risk for any component in the continuum. FIGURE 7-1 Relationship between biomarkers of susceptibility, exposure, and effect.

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 The relationship among the markers that represent events in the continuum is influenced by various factors that reflect susceptibility for occurrence (such as genetic or other host characteristics). These can also be represented by markers. The definition of all the marked events has been elaborated elsewhere (NRC, 1987; Hulka and Wilcosky, 1988). Some biologic markers of exposure, such as DNA or protein adducts, can be specific. DNA adducts, hemoglobin adducts, and other directly altered proteins indicate both the presence of the xenobiotic substance and its interaction with a critical macromolecule or the macromolecule 's surrogate. Validated markers of effect also can be used to resolve questions of whether a constellation of signs and symptoms does or does not indicate a disease or early pathologic process. Moreover, recognition of markers of effect can allow for timely or prudent interventions. It now appears possible that where valid markers can be found in exposed persons it will not be necessary to wait for disease to occur before an association can be made between exposure and disease. If, for example, a preclinical change predictive of disease is identified, then the same clinical and epidemiologic methods used in traditional epidemiology can be used to determine an association between an exposure and a marker representing the disease. For instance, Hemstreet et al. (1988) found that DNA hyperploidy correlated with disease risk in workers exposed to 2-naphthylamine, a compound known to cause bladder cancer. Eventually, as an optimistic goal, it should be possible to identify markers of effect that appear very early in the exposure-disease continuum, that is, closer to the time of exposure. Similarly, exposure characterization no longer needs to be chiefly an ecologic assessment, that is, the lumping of subgroups of individuals into a single category or into a few categories of presumed exposure (Hulka and Wilcosky, 1988). For instance, with biologic markers of lead exposure, it is usually possible to distinguish workers and community residents by evaluating the dose to target tissues: This is the true “exposure ” that occurs in people with different lifestyles, work practices, physiologic and metabolic characteristics, and levels of exposure. Hence, from the exposure end of the continuum, using biologic markers of dose makes it possible to move forward in time toward the disease end. The classic epidemiologic paradigm of a dichotomous classification of exposure and disease (exposed or not, diseased or not) worked well in the past when exposures were large and effects were detectable by alert clinicians and epidemiologists. However, because it is difficult to characterize exposure accurately by using such categorical descriptors, epidemiologic analyses can misclassify

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 people in terms of exposure. Biologic markers encompass all the exposure that occurs by various routes and from various sources and are thus of great utility for environmental epidemiology. Exposures to complex mixtures and multiple substances are characteristic of hazardous-waste sites. Perera et al. (1990) have presented a stepwise approach for separating the effects of specific constituents of a mixture. First, external exposure is characterized as completely as possible through ambient or personal monitoring and questionnaires. This provides an estimate of the level and pattern of exposure both to the mixture and to its individual components. The next step is to analyze the relationship between integrated and specific exposure variables on the one hand and total genotoxic and procarcinogenic effect, the broad spectrum of DNA adducts (by the postlabeling assay), class-specific adducts (e.g., polycyclic aromatic hydro carbons by immunoassay), and individual chemical-specific adducts (e.g., 4-ABP-Hb or BP-DNA) on the other. For substances that do not form adducts, other indicators of biologically effective dose can be used. Correlations between biologic markers are also examined. Of interest is the proportion of the total genotoxic and procarcinogenic effect of exposure to complex mixtures that is attributable to specific constituents in the mixture. Also, there is need to know whether there is an interaction between individual constituents or whether the effects are to be additive. The answers could allow identification of the major pathogenic agents present in a chemical mixture. USE OF BIOLOGIC MARKERS IN STUDIES OF HAZARDOUS SUBSTANCES Biologic markers have been used occasionally in epidemiologic studies of hazardous-waste sites (Levine and Chitwood, 1985; Phillips and Silbergeld, 1985; Buffler et al., 1985; Upton et al., 1989), predominantly as indicators of effect. In a comprehensive review of the literature, Buffler et al. (1985) identified an array of dermatologic, behavioral, and neurological symptoms that might provide markers of exposure to toxic chemicals, or early indicators of effect. Not counting symptoms or frank signs of morbidity, changes in liver enzymes, which indicate liver function, are among the most commonly used, presumably because of their nonspecificity and ease of analysis. Sometimes these effects are transitory, as with a study of elevated liver function tests (alkaline phosphatase) in persons exposed to chlorinated chemicals in domestic water. After exposure ceased, liver function returned to normal in persons exposed to a variety of pollutants in

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 Hardeman County, Tennessee (Clark et al., 1982). The possible long-term effects of temporary alterations in liver enzymes are unknown. Other multiphasic tests to find markers of exposure or effect in blood and urine also have been used, but to a lesser extent. For example, serum cholesterol, gamma-glutamyl transpeptidase level (an indicator of enzyme induction in the liver), and blood pressure have been studied as markers of effect in residents of Triana, Alabama who were exposed to polychlorinated biphenyls (PCBs) from eating fish (Kreiss et al., 1981). Eighty to ninety percent of the levels of PCB found in the Triana study population fell within the range found in other community groups. Results indicated that serum PCB levels were positively associated with all the preceding measures, independent of age, sex, body mass, and social class. Similar findings of an effect of PCB exposure on blood pressure have been reported in studies of workers exposed to PCBs from capacitor manufacturing (Fischbein et al., 1979). Other studies of environmental exposure to PCB have identified additional markers of effect in children exposed transplacentally (Rogan et al., 1988) or through nursing or eating contaminated foods (Jacobson et al., 1990a,b). Children born to mothers in Taiwan who previously consumed contaminated oil have characteristic skin lesions and pigmentation, lower birth weights, impeded neurobehavioral development, and reduced head circumference (Rogan et al., 1988). Children with PCB levels that fall in the range of background for the U.S. in their cord blood at birth were more likely to be developmentally retarded than children with lower PCB levels (Rogan and Miller, 1989). Jacobson et al. (1990a) found that the highest exposed children on average weighed 1.8 kg less than the least exposed. Follow up studies of these children at age 4 showed that serum PCB levels were associated with reduced activity and some decrements in neurobehavioral performance (Jacobson et al., 1990b). The development of markers of exposure and markers of effect is proceeding rapidly in the field of neurotoxicology (NRC, in press). Studies that use nerve conduction velocity as a marker of potential neurotoxic effects have been conducted on persons exposed to mixtures from some dump sites (Schaumburg et al., 1983); they found significant impedance of normal conduction linked to such exposures. More recently, researchers at Boston University have studied markers of neurological function in persons from Woburn, Massachusetts, six years after exposure ceased to trichloroethylene (TCE) (Feldman et al., 1990). TCE levels in domestic water had been from 30 to 80 times higher than the recommended EPA Maximum Contamination Levels (MCL) of 5 ppb. As Chapter 3 noted, TCE is one of the most common pollutants at Superfund sites and also is emitted by drycleaners, household

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 cleaning agents, and degreasers. Exposed and control subjects were studied with a neurobehavioral evaluation protocol that included clinical tests, nerve conduction studies, blink reflex measurements, and extensive neuropsychological testing. The blink reflex indicates the physiological integrity of the afferent and efferent circuitry of the Vth (trigeminal) and VIIth (facial) cranial nerves. A physician using electromyographic equipment, quantitatively evaluated reflex latency responses with an automated oscilloscope for several modalities of stimulation. Highly significant differences were detected between the two groups, with a level of significance of 0.0001. Feldman et al. (1990) conclude that the blink reflex measurement appears useful in evaluating a population group with a history of chronic low-dose exposure to TCE, providing a sensitive method for evaluating subclinical neurotoxic effects on the Vth-VIIth cranial nerve circuitry. While not commonly thought of as constituting markers, neurobehavioral tests can provide a diverse range of measures of toxic exposures and effects. A battery of neurobehavioral tests has been applied to the study of persons exposed to materials that occur at hazardous-waste sites (Table 7-1). This battery includes numerous expressions of neurotoxic central and peripheral neuropathy and covers a wide array of functions. A comprehensive review of developing techniques in neurobehavioral assessment found consistent and significant neurobehavioral effects and a range of other subtle neurological alterations in persons exposed to metals, solvents, and insecticides, with some indication of greater effects in those with greater estimated exposures (White et al., 1990). Animal studies reveal that TCE inhalation also induces a range of neurotoxic effects in rodents (Dorfmueller et al., 1979). As discussed in Chapter 6, biologic monitoring for neurotoxic chemicals such as TCE has also identified specific markers of exposure. Levels of metabolites of TCE in urine have been determined in persons exposed environmentally and in human volunteers. About 60 percent of TCE is metabolized and excreted in the urine as one of three compounds, di- and trichloroacetic acid, trichloroethanol, and trichloroethanol glucuronide; a small amount (about 10 percent) is exhaled by the lungs as TCE. The typical kinetics and compartments for excretion or uptake of the remaining 30 percent of TCE are unknown, according to studies that have used human volunteers (Monster et al., 1979). There is no evidence of saturation in humans, that is, an exposure above and beyond which there is no uptake; but studies in mice and rats exposed to TCE in water or air indicate metabolic saturation in those species (ATSDR, 1989). Dichloroacetic acid (DCA) is both a by-product of chlorine disinfection of water containing natural organic material and a key metabolite

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 TABLE 7-1 Neuropsychological Test Battery Test   Description Function 1. Wechsler Adult Intelligence Scale, Wechsler Adult Intelligence Scale—Revised   Subtests:   Information Questions of an academic nature Basic academic verbal skills   Digit span Digits forward and backward Attention   Vocabulary Word definitions Verbal concept formation   Arithmetic Oral calculations Attention, calculation   Comprehension Questions involving problem solving, judgment, social knowledge, proverb interpretation Verbal concept formation   Similarities Deduction of similarities between nouns Verbal concept formation   Picture completion Identification of missing parts of pictures Visuospatial (analysis)   Picture arrangement Sequencing pictures to tell a story Sequencing, visuospatial (reasoning)   Block design Replicating designs of red & white blocks Visuospatial (organization)   Object assembly Puzzle assembly Visuospatial (organization)   Digit symbol (with incidental learning tast) Coding Motor speed (visual short-term memory)

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 2. Weschler Memory Scale, Weschler Memory Scale—Revised   Information Personal information and political names     Orientation Time and place     Mental control Count backwards 20-1; recite alphabet; count by 3's beginning with 1 Cognitive tracking, attention   Digit span Digits forward and backward Attention   Visual spans Pointing Span on visual array Attention (visual)   Logical memories with delayed recall Recall of narrative material presented in 2 paragraphs Verbal memory acquisition, retention   Visual reproductions with delayed recall Drawing visual designs from immediate recall Visual memory acquisition, retention   Verbal paired associates Learning of 10 paired associates Verbal memory acquisition, retention   Visual paired associates Recognition memory for colors paired with designs Visual memory   Figural memory Multiple-choice memory for visual designs Visual memory 3. Continuous Performance Testing Subject sees rapidly presented letters, must press button when X appears Attention reaction time

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 4. Trails Connecting numbered dots, then alternating between numbered and lettered dots Attention, tracking sequencing 5. Wisconsin Card Sorting Test Categorical sorting of cards Concept formation 6. FAS-Verbal Fluency Production of words with F, A, and S in 1 each Language (fluency) 7. Boston Naming Test Naming objects depicted in line drawings Language 8. Reading Comprehension Subtest, Boston Diagnostic Aphasia Examination Screening test of reading comprehension Language (reading) 9. Wide Range Achievement Test Reading, spelling, arithmetic Basic academic skills 10. Boston Visuospatial Quantitative Battery Drawing objects spontaneously and to copy, clocks, U.S. map locations Visuospatial 11. Santa Ana Form Board Test Turn pegs 90 degrees with each hand separately and both hands Motor speed 12. Milner Facial Recognition Test Matching and remembering similar unknown faces Visual memory, visuospatial (analysis) 13. Benton Visual Retention Test Multiple choice recall of visual designs Visual memory 14. Difficult Paired Learning 10 paired associates low in associative value Verbal memory 15. Albert's Famous Faces Test Recall of famous faces from past decades Retrograde memory

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 16. Profile of Mood States Mood testing on 6 dimensions: anger, vigor, tension, depression, fatigue, confusion Affect 17. Minnesota Multiphasic Personality Inventory, MMPI-R Personality test Personality, affect 18. Interview Extensive clinical interview re: medical and cognitive symptoms, psychiatric symptoms, personal background, and work and educational history   Source: Adapted from draft of White et al., 1990, with permissionof the authors. of TCE. DCA exposure of pregnant Long-Evans rats by oral intubation produced dose-related cardiac malformations in fetuses (Smith et al., 1990). Other studies of environmental exposures to TCE have found significant associations between exposures to TCE in workers in chemical or paint manufacturing facilities plants and levels of TCE in exhaled breath (Wallace et al., 1986). There is a growing literature on cytogenetic changes and somatic mutations as markers that indicate either exposures to carcinogens or as potential early effects predictive of cancer (Albertini, 1982; Marx, 1989). Cytogenetic markers, sister chromatid exchanges, and chromosome aberrations were assessed in residents of Love Canal, New York (Heath et al., 1984), but otherwise use of these markers in epidemiologic studies of hazardous-waste sites has been limited. One potentially useful marker is the T-cell assay for the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene as a mutation indicator. This assay has been shown to detect HPRT mutations in human T-cells of atomic bomb survivors 40 years after the explosion (Hakoda et al., 1988). To assess the mutational impact of various types of environmental exposures, an HPRT Mutational Spectra Repository has been established (Marx, 1989). This could assist in assessing hazardous-waste exposures. In addition to determining whether there has been an HPRT mutation, it is now possible to identify par-

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 group of patients. Hence, in comparing study subjects and controls, the marker levels could have been the result of the disease status or differences in exposure, but it is not clear which was responsible. Finally, the lower titers in most cases (1:4 was the most prevalent) make these findings difficult to interpret clinically. In contrast, the patterns of these changes were consistent between groups for most of the markers and generally correlated with putative exposure to formaldehyde. It is much better to use a collection of immune-system markers than to use single markers because no single marker will accurately reflect the state of the immune system as a whole. ALPHA-1-ANTITRYPSIN, MARKER OF SUSCEPTIBILITY Emphysema and other chronic obstructive pulmonary diseases (COPDs) are often studied as end points in environmental or occupational epidemiology. These conditions can result from exposure to ambient air pollution, cigarette smoke, or occupational substances, but not all similarly exposed persons will develop COPDs. A biologic marker of susceptibility, the alpha-1-antitrypsin ZZ allele, has been found to be associated with emphysema. Kueppers (1978, 1984) estimates that the risk of emphysema developing in people with the genetic ZZ homozygote is about 30 times higher than it is in the general population. The ZZ homozygote has approximately 10-15 percent the normal concentration of alpha-1-antitrypsin, and the prevalence for the trait is 1/4000 to 1/8000. The risk for individuals with the heterozygous allele is less clear. Kueppers (1978) reports that despite considerable variation, the prevalence of heterozygous MZ and FZ individuals among patients with COPD is increased. In an industrial community in northern Sweden in which the major pollutants were sulfur dioxide and chlorine from a sulfite pulp factory, persons with COPD were more likely to be heterozygotic for alpha-1antitrypsin (MS, MZ, or MF alleles) or to have other rare allele types. Ninety-one percent of the 3466 residents of this town responded to a questionnaire about their respiratory problems and were tested for serum alpha-1-antitrypsin. Eight percent of the 3466 reported symptoms were connected with COPD (Beckman et al., 1980). Persons with the heterozygote have 55-60 percent of the normal concentrations alpha-1-antitrypsin. Other, larger controlled studies show no risk of emphysema from one allelic state, the MZ heterozygote (Cole et al., 1976; McDonagh et al., 1979). The population sizes of these two studies were small and hence there was a limitation in the ability to detect an association of heterozygotes with emphysema, which might occur in only 10 percent of heterozygotes.

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 Available studies do not adequately address the presence or absence of coexisting factors, such as environmental exposures that could be necessary to cause emphysema. In fact, because emphysema is a disease that has several causes, the heterozygous state—although not itself predisposing—could combine with multiple environmental factors (for example, exposure to cadmium, ozone, or cigarette smoke) to present an increased risk. Other genetic abnormalities might increase a person's susceptibility to emphysema, such as mutations in the structural gene for elastin, those that lead to increased protease activity in the alveolar macrophages, those that produce decreased antiprotease in bronchial secretions, and those that alter the structure of the chest wall (Kazazian, 1976; Koenig and Omenn, 1988). The use of markers of susceptibility in environmental epidemiology has the potential to increase both the precision and the strength of putative exposure-disease associations by avoiding the dilution effect that occurs in populations with a large proportion of nonsusceptible persons ( Brain, 1988; Hulka et al., 1990). However, certain practical limitations will affect whether determining a genetic marker in a population is warranted (Mattison and Brewer, 1988). When the prevalence of a particular genetic marker, such as with some of the alpha-1-antitrypsin alleles, is low in a population, even a highly specific test will give a relatively large number of false positives, resulting in nondifferential misclassification, that is, the inaccurate classification of groups to be compared in terms of some characteristic such as exposure (OTA, 1983). This can lead to the mistaken impression that the difference between two groups is less than it actually is. If, however, there is differential misclassification, it can bias in either direction (toward or away from a conclusion of no difference between study groups). The predictive value of a screening test will vary from 0 percent to 92 percent as the frequency of the genotype varies between 1 per 100,000 (0.001 percent) and 10,000 per 100,000 (10 percent) of the persons screened (OTA, 1983). This should be considered in the use of markers of genetic susceptibility in epidemiologic studies. In some instances the limitation to using biological markers is the absence of markers. For example, the paucity of validated markers for reproductive events and toxic effects is likely to result in extensive misclassification with respect to reproductive performance and xenobiotic exposure (Mattison and Brewer, 1988). Since these types of studies involve both the individual (i.e., male and female) as well as couple specific factors, there is a need for sensitive measures that define the wide variation in characteristics and responses.

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 ETHICAL AND LEGAL ISSUES In addition to the scientific concerns noted above, many ethical and legal issues arise in the use of biologic markers (Schulte, 1987, 1990; Samuels, 1988; Ashford et al., 1990). The major ethical issues involve what to tell individuals with “abnormal” marker results about their disease risk, and then how society should treat such people. The CDC/ATSDR subcommittee concludes that when a biologic marker is included in a study, it must be evaluated against established batteries of tests. A separate, statistically valid evaluation of the new marker must be conducted. The marker assay results produced in this evaluation should be used only for marker description and evaluation, and they should not be presented to the study subjects as individual marker assay results until all relevant data have been compiled and reviewed. Results released before the physiologic significance of the marker is thoroughly assessed could cause unnecessary public alarm and spur demand for the test before the meaning of the results is fully understood (CDC/ATSDR, 1990). The CDC/ATSDR subcommittee also concludes that the evaluation process to find new markers should be conducted anonymously, with informed consent of the subjects and coding of specimens to delete identification of all study subjects. Before a test for a marker is considered to have completed the investigative phases, the biochemical or physical abnormality associated with the marker should be identified, and the probability that the abnormality will progress to disease and the nature of the disease should be known (CDC/ ATSDR, 1990). One suggestion for handling uncertainty about the meaning of markers with regard to health risk is to couple such research with conventional screening of high-risk groups (Schulte, 1986). This offers the opportunity at least to provide study subjects with some information (from the conventional screening) that can be interpreted with a known degree of certainty. The societal response to people with “abnormal” levels of markers can involve ethical issues pertaining to discrimination, the need for medical follow-up, and the removal of workers or residents from areas of imminent danger (Schulte, 1987, 1990; Ashford et al., 1990). Do people with a certain biologic marker of susceptibility have the same right to be protected against discrimination as do people with other, more visible disabilities? Increasingly, these types of questions will be asked by residents and workers who live or work near hazardous-waste sites and who receive biologic monitoring as part of epidemiologic studies or routine medical surveillance.

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 Biologic monitoring data can also have an effect on litigation over alleged health effects that result from exposure to hazardous wastes. Ashford et al. (1990) maintain that human monitoring has the potential to bring about a change in the nature of evidence used in such cases. Typically, the evidence offered to prove causation in chemical exposure cases is premised on a statistical correlation between disease and exposure. Whether the underlying data are from epidemiologic studies, from toxicological experiments, or from the results of a complicated risk assessment model, they usually are population-based. As markers become refined, it will eventually be possible to use them to assess the probability that an individual's exposure is linked to disease. CONCLUSIONS The developing science of human monitoring and research on biologic markers offer methods to improve the characterization of exposure to hazardous wastes and detect relevant pathologic changes earlier. Conceivably, the data generated by various human monitoring procedures will Increase our knowledge of the “subclinical” effects of toxic substances, thus permitting us to track the effect of a chemical exposure over time and expanding the universe of “ medical conditions” for which compensation may be provided. Eventually enable us to establish that a particular person has been exposed to a particular chemical (or class of chemicals). Eventually enable us to establish that a particular person's medical condition (or subclinical effect) was caused by exposure to a particular chemical (or class of chemicals). Although epidemiologists could use biologic markers to reduce misclassification or to obviate the need for long periods of study, markers also could be used for purposes that are inappropriate or unethical. For example, the screening of workers for the appearance of “unvalidated” markers and the development of job placements on the basis of results have been vigorously denounced (Lappe, 1982; Murray, 1983). Screening residents who live near waste dumps also can be problematic because it can produce uninterpretable information, promote unfounded anxiety, and initiate reckless litigation —all without a strong scientific basis. Researchers and public health practitioners need to consider these ethical and legal questions before embarking on studies that use biologic markers. A concerted effort should be made to validate biologic markers of exposure, effect, and susceptibility as applied to hazardous wastes.

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 This would involve interdisciplinary collaboration on a range of laboratory and field studies to ascertain not only the association between a marker with the event it indicates, but also the factors that affect the marker, the range of normal, and variability. REFERENCES Albertini, R. 1982. Studies with T-Lymphocytes and approach to human mutagenicity monitoring Pp. 393-410 in Indicators of Genotoxic Exposure, B.A. Bridges, B.E. Butterworth, and I.B. Weinstein, eds. Banbury Report 13. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. Ashford, N.A., C.J. Spadafor, D.B. Hattis, and C.C. Caldart. 1990. Monitoring the Worker for Exposure and Disease: Scientific, Legal and Ethical Considerations in the Use of Biomarkers Baltimore: Johns Hopkins University Press. ATSDR (Agency for Toxic Substances and Disease Registry). 1989. Toxicological Profile for Trichloroethylene. Atlanta, Ga.: Agency for Toxic Substances and Disease Registry. Babich, H., D.L. Davis, and G. Stotzky. 1981. Dibromochloropropane (DBCP): A review. Sci. Total Environ. 17: 207-221 Bailey, E., T.A. Connors, P. B. Farmer, S. M. Gorf, and J. Rickard. 1981. Methylation of cysteine in hemoglobin following exposure to methylating agents. Cancer Res. 1: 2514-2517 Beckman, G., L. Beckman, B. Mikaelsson, O. Rudolphi, N. Stjernberg, and L.G. Wiman. 1980. Alpha1-antitrypsin types and chronic obstructive lung disease in an industrial community in northern Sweden Hum. Hered. 30: 299-306 Bekesi, J.G., J.P. Roboz, A. Fischbein, and P. Mason. 1987. Immunotoxicology: Environmental contamination by polybrominated biphenyls and immune dysfunction among residents of the State of Michigan Cancer Detect. Prev. Suppl. 1: 29-37 Bernard, A., and R. Lauwerys. 1986. Present status and trends in biological monitoring of exposure to industrial chemicals J. Occup. Med. 28: 558-562 Brain, J.D. 1988. Introduction. Pp. 1-5 in Variations in Susceptibility to Inhaled Pollutants, J.D. Brain et al., eds. Baltimore: Johns Hopkins University Press. Brandt-Rauf, P.W. 1988. New markers for monitoring occupational cancer: The example of oncogene proteins J. Occup. Med. 30: 399-404 Brandt-Rauf, P.W., and H.L Niman. 1988. Serum screening for oncogene proteins in workers exposed to PCBs Br. J. Ind. Med. 45: 689-693 Brandt-Rauf, P.W., S. Smith, H.L. Niman, M.D. Goldstein, and E. Favata. 1989. Serum oncogene proteins in hazardous-waste workers. J. Soc. Occup. Med. 39: 141-143 Brandt-Rauf, P.W., H.L. Niman, and S.J. Smith. 1990a. Correlation between serum oncogene protein expression and the development of neoplastic disease in a worker exposed to carcinogens J Royal Soc. Med. 83: 594-595 Brandt-Rauf, P.W., S. Smith, F.P. Perera, H.L. Niman, W. Yohannan, K. Hemminki, and R.M. Santella. 1990b. Serum oncogene proteins in foundry workers. J. Soc. Occup. Med. 40: 11-14 Brugnone, F., L. Perbellini, G.B. Faccini, F. Pasini, G.B. Bartolucci, and E. DeRosa. 1986. Ethylene oxide exposure: Biological monitoring by analysis of alveolar air and blood Int. Arch. Occup. Environ. Health 58: 105-112 Bryant, M.S., P.L. Skipper, S.R. Tannenbaum, and M. Maclure. 1988. Hemoglobin adducts of 4-aminobiphenyl in smokers and non-smokers Cancer Res. 47: 602-608 Buffler, P.A., M. Crane, and M.M. Key. 1985. Possibilities of detecting health effects by

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 The case of air pollution. Pp. 109-122 in Environmental Epidemiology, F.C. Topfler, and G.F. Craun, eds. Chelsea: Lewis. Gochfield, M. 1990. Biological monitoring of hazardous waste workers: Metals. Occup. Med. 5: 25-31 Gochfield, M., V. Campbell, and P.A. Landsbergis. 1990. Demography of the hazardous waste industry. Occup. Med. 5: 9-24 Golding, J.M., and G.W. Lucier. 1990. Protein and DNA adducts. Pp. 78-104 in Biological Markers in Epidemiology, B.S. Hulka, T.C. Wilcosky, and J.D. Griffith, eds. New York: Oxford University Press. Griffith, J., R.C. Duncan, and B.S. Hulka. 1989. Biochemical and biological markers: Implications for epidemiologic studies Arch. Environ. Health 44: 375-381 Hakoda, M., M. Akiyama, S. Kyoizumi, A.A. Awa, M. Yamakido, and M. Otake. 1988. Increased somatic cell mutant frequency in atomic bomb survivors. Mutat. Res. 201: 39-48 Harris, C.C., A. Weston, J.C. Willey, G.E. Trivers, and D.L. Mann. 1987. Biochemical and molecular epidemiology of human cancer: Indicators of carcinogen exposure, DNA damage, and genetic predisposition Environ. Health Perspect. 75: 109-119 Hassler, E., B. Lind, and M. Piscator. 1983. Cadmium in blood and urine related to present and past exposure. A study of workers in an alkaline battery factory Br. J. Ind. Med. 40: 420-425 Hatch, M.C., and Z.A. Stein. 1987. The role of epidemiology in assessing chemical-induced disease Pp. 303-314 in Mechanisms of Cell Injury: Implications for Human Health, B.A. Fowler, ed. New York: John Wiley and Sons. Heath, C.W., Jr. 1983. Field epidemiologic studies of populations exposed to waste dumps Environ. Health Perspect. 48: 3-7 Heath, C.W., Jr., M.A. Nade, M.M. Zack Jr., A.T.L. Chen, M.A. Bender, and J. Preston. 1984. Cytogenic findings in persons living near the Love Canal. J. Am. Med. Assoc. 251: 1437-1440 Hemstreet, G.P., P.A. Schulte, K. Ringen, W. Stringer, and E.B. Altekruse. 1988. DNA hyperploidy as a marker for biological response to bladder carcinogen exposure. Int. J. Cancer 42: 817-820 Hemminki, K, E. Grzybowska, M. Chorazy, K. Twardowska-Saucaha, J.W. Srozynski, K.L. Putman, K. Randerath, D.M. Phillips, A. Hewer, R.M. Santella, T.L. Young, and F.P. Perera. 1990. DNA adducts in humans environmentally exposed to aromatic compounds in an industrial area in Poland Carcinogenesis 11: 1229-1231 Hernberg, S. 1987. Validation of biological monitoring tests. Pp. 41-49 in Occupational and Environmental Chemical Hazards: Cellular and Biochemical Indices for Monitoring Toxicity V. Foa et al., eds. Chichester, Eng.: Ellis Horwood Ltd. Hesley, K.L., and G. H. Wimbish. 1981. Blood lead and zinc protoporphyrin in lead industry workers Am. Ind. Hyg. Assoc. J. 42: 42-46 Hodgson, M.J., B.M. Goodman-Klein, and D.H. van Thiel. 1990. Evaluating the liver in hazardous waste workers Occup. Med. 5: 67-78 Hulka, B.S., and T. Wilcosky. 1988. Biological markers in epidemiologic research. Arch. Environ. Health 43: 83-89 Hulka, B.S., T.C. Wilcosky, and J.D. Griffith, eds. 1990. Biological Markers in Epidemiology New York: Oxford University Press. Jacobson, S.L., S.W. Jacobson, and H.E.B. Humphrey. 1990a. Effects of exposure to PCBs and related compounds on growth and activity in children. Neurotox. Teratology 12: 319-326 Jacobson, J.L., S.W. Jacobson, and H.E.B. Humphrey. 1990b. Effects of in utero expo-

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ENVIRONMENTAL EPIDEMIOLOGY: Volume 1 sure to polychlorinated biphenyls and related contaminants on cognitive functioning in young children. J. Pediatr. 116: 38-45 Kazazian, H.H., Jr. 1976. A geneticist's view of lung disease. Am. Rev. Respir. Dis. 113: 261-266 Khoury, M.J., C.A. Newill, and G.A. Chase. 1985. Epidemiologic evaluation of screening for risk factors: Application to genetic screening Am. J. Public Health 75: 12041-208 Koenig, J.Q., and G.S. Omenn. 1988. Genetic factors. Pp. 59-88 in Variations in Susceptibility to Inhaled Pollutants J.D. Brain et al., eds. Baltimore: Johns Hopkins University Press. Kreiss, K., M.M. Zack, R.D. Kimbrough, L.L. Needham, A.L. Smrek, and B.T. Jones. 1981. Association of blood pressure and polychlorinated biphenyl levels J. Am. Med. Assoc. 245: 2505-2509 Kueppers, F. 1978. Inherited differences in alpha1-antitrypsin. Pp. 23-74 in Genetic Determinants of Pulmonary Disease, S. Litwin, ed. New York: Marcel Dekker. Kueppers, F. 1984. The effect of smoking on the development of emphysema in alpha1-antitrypsin deficiency Pp. 345-358 in The Role of Genetic Predisposition in Responses to Chemical Exposures G.S. Omenn and H. Gelboin, eds. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. Lappe, M. 1982. Ethical and social aspects of screening for genetic disease. N. Engl. J.Med. 206: 1129-1132 Last, J.M., ed. 1983. A Dictionary of Epidemiology. New York: Oxford University Press. Levin, A.S., and V.S. Byers. 1987. Environmental illness: A disorder of immune regulation. Occup. Med. 2: 669-681 Levine, R., and D.D. Chitwood. 1985. Public health investigations of hazardous organic chemical waste disposal in the United States Environ. Health Perspect. 62: 415-422 Marx, J.L. 1989. Detecting mutations in human genes. Science 243: 737-738 Mattison, D.R., and D.W. Brewer. 1988. Computer modelling of human fertility: The impact of reproductive heterogeneity on measures of fertility. Reprod. Toxicol. 2: 253-271. McDonagh, D.J., S.P. Nathan, R.J. Knudson, and M.D. Lebowitz. 1979. Assessment of alpha-1-antitrypsin deficiency heterozygosity as a risk factor in the etiology of emphysema. Physiological comparison of adult normal and heterozygous protease inhibitor. J. Clin. Invest. 63: 299-309 Monster, A.C., G. Boersma, and W.C. Duba. 1979. Kinetics of TCE in repeated exposure of volunteers. Intl. Arch. Occup. Environ. Health 42: 283-292 Murray, T.H. 1983. Warning: Screening workers for genetic risk. Hastings Center Rep. 13: 5-8 NRC (National Research Council). 1987. Biologic markers in environmental health research. Environ Health Perspect. 74: 3-9 NRC (National Research Council). 1989. Biologic Markers in Reproductive Toxicology. Washington, D.C.: National Academy Press. NRC (National Research Council). 1991. Human Exposure Assessment for Airborne Pollutants. Washington, D.C.: National Academy Press. NRC (National Research Council). In press. Environmental Neurotoxicology. Washington, D.C.: National Academy Press. Nauman, C.A., J.N. Blancato, and R.J. Bull. 1990. Decision model for exposure biomarkers. Pp. 514-525 in Proceedings of the EPA/A & WMA specialty conference, Total Exposure Assessment Methodology. Pittsburgh: Air & Waste Management Association. Osterman-Golkar, S., 1983. Tissue doses in man: Implications in risk assessment. Pp.

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