Environmental Epidemiology, Volume 1 Public Health and Hazardous Wastes (1991) / Chapter Skim
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7. Biological Markers in Studies of Hazardous-Waste Sites
7. Biological Markers in Studies of Hazardous-Waste Sites
Pages 219-255
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From page 219... ...
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.
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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.
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, 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)
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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.
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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 oresent in a ch~micn1 rUSE 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)
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. 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.
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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.
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226 TABLE 7-1 Neuropsychological Test Battery ENVIRONMENTAL EPIDEMIOLOGY Test Description Function 1. Wechsler Adult Intelligence Scale, Wechsler Adult Intelligence Scale Revised Subtests: Information Questions of an Basic academic academic nature verbal skills Digit span Digits forward Attention and backward Vocabulary Word definitions Verbal concept formation Arithmetic Oral calculations Attention, calculation Comprehension Questions involving Verbal concept problem solving, formation judgment, social knowledge, proverb interpretation Similarities Deduction of Verbal concept similarities between formation nouns Picture completion Identification of Visuospatial missing parts of (analysis)
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BIOLOGIC MARKERS IN STUDIES OF HAZARDOUS-WASTE SITES TABLE 7-1 Continued 227 Test Description Function 2. Weschler Memory Scale, Weschler Memory Scale Revised Information Personal information and political names Orientation Time and place Mental control Count backwards 20-1; Cognitive recite alphabet; tracking, count by 3's beginning attention with 1 Digit span Digits forward and Attention backward Visual spans Pointing Span Attention on visual array (visual)
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Difficult Paired Learning 15. Albert's Famous Faces Test 10 paired associates Verbal memory low in associative value Recall of famous faces Retrograde from past decades memory
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Cytogenetic markers, sister chromatic 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.
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For the most part, biologic markers have not been extensively used in epidemiologic studies of hazardous-waste sites because research has not yet linked cellular and molecular biochemical tests with specific disease risks and with other biologic markers (Heath, 1983~. There appears to be no impetus for performing the preparatory studies necessary to take a marker at the laboratory development stage and adequately characterize it for use in field studies of waste-site populations.
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Rarely does any marker meet these objectives completely (CDC/ATSD1l, 1990~. BIOLOGIC MONITORING OF HAZARDOUS-WASTE AND OTHER WORKERS One of the first opportunities for extensive use of biologic markers will be in monitoring the health of workers at hazardous-waste sites.
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. Similar findings were obtained in a comparison of 16 municipal hazardous-waste cleanup workers handling PCBs and 17 more protected employees of a state agency, with those exposed showing higher frequencies of various serum oncogene proteins.
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In this study, 3 of 18 foundry workers with exposures to known carcinogens, such as polycyclic aromatic hydrocarbons, exhibited abnormal expression of the proteins of the ras and fes oncogenes, in contrast to none of the unexposed workers (BrandtRauf et al., l990b)
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GENERAL ENVIRONMENTAL AND OCCUPATIONAL HEALTH RESEARCH A broader picture of the use of biologic markers can be gleaned by reviewing the general environmental and occupational health literature, especially the few reports that involve exposure to materials commonly found at hazardous-waste sites. Schulte et al.
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GOAL OF BIOLOGIC MONITORING STUDIES Bernard and Lauwerys (1986) observe that most biologic monitoring studies focus on the relationships between internal dose and external exposure rather than between internal dose and adverse effect.
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For example, several studies involving biologic monitoring of heavy metals relate blood and urine levels to job classifications and length of employment or to historical air monitoring records in company personnel information (Hesley and Wimbish, 1981; Hassler et al., 1983; Piikivi et al., 1984~. VALIDATION Few biologic markers have been validated as tools for environmental epidemiology.
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Finally, how well does the marker indicate what exposure has occurred? The validity of biologic markers can be assessed in terms of sensitivity, specificity, event frequency, and predictive value.
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As a result, the data available in the early stages are likely to be biased or opportunistic (fate, 1983~. To avoid this, it is important that the design of marker studies, particularly at the validation stage, be oriented toward controlling for selection or other biases and that the studies be "blinded." The validation of biologic markers for use in epidemiologic research requires extensive laboratory work prior to testing in humans.
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. MARKERS OF EXPOSURE, EFFECT, AND SUSCEPTIBILITY This section reviews examples of the three broad categories of biologic markers exposure, effect, and susceptibility- to identify some of the methodologic issues that pertain to using markers in epidemiologic studies of people exposed to hazardous wastes.
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Develop Method of Measurement Prioritize based on occurrence, significant human exposure, potential for adverse human health effects. Identify logical consequence of chemical exposure that might serve as a useful measure of exposure.
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Important in the type of analysis was the need to adjust the mean adduct level for age and smoking. In addition to variability in the frequency and rate of repair of DNA adducts, there is a question of the extent to which DNA adducts in lymphocytes represent the historic exposure of an individual and the biologically effective dose.
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(1986a) have shown that the amount of hemoglobin adducts is proportional to that of DNA adducts.
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have used immune-system markers to indicate biologic response to low doses of toxic substances (Burger et al., 1987~. One study illustrates some of the strengths and limitations in using markers of effect in immune activation and autoantibodies in persons who have had long-term inhalation exposure to formaldehyde.
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When compared with the control group of students, the four patient groups had higher antibody titers to HCHO-HSA and increases in Tal+; IL2+, B cells, and autoantibodies were observed. The biologic markers used in this study in some instances lack appropriate standardization and preparatory testing for human field studies.
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From page 245... ...
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-l-antitrypsin ZZ allele, has been found to be associated with emphysema.
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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.
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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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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.
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l990b. Serum oncogene proteins in foundry workers.
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2:427-442. CDC/ATSDR (Center for Disease Control/Agency for Toxic Substances and Disease Registry Subcommittee on Biomarkers of Organ Damage and Dysfunction)
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1989. Biochemical and biological markers: Implications for epidemiologic studies.
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1987. Biologic markers in environmental health research.
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1987. DNA adducts, protein adducts and sister chromatic exchange in cigarette smokers and nonsmokers.
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1987. Methodologic issues in the use of biologic markers in epidemiologic research.
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Pp. 373-385 in Biological Monitoring of Workers Exposed to Chemicals, A
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