National Academies Press: OpenBook

Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes (1991)

Chapter: 7. Biological Markers in Studies of Hazardous-Waste Sites

« Previous: 6. Soil and Food as Potential Sources of Exposure at Hazardous-Waste Sites
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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-

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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.

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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)

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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-

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

ticular sequences, with a gene, that are mutated (Thilly et al., 1982). This capability may allow for the differentiation of the mutational changes that occur spontaneously in a person's cells from those gene changes that might be induced by environmental exposures (Marx, 1989).

Markers of exposure, because of their accessibility and relative ease of interpretation, have been used more often than have markers of effect. In a number of studies markers of exposure have been used to show internal doses of such substances as lead, TCE or its metabolites, or PCBs in serum. No direct studies on persons living near hazardous-waste or Superfund sites have thus far used more sophisticated cellular and biochemical markers, such as DNA or protein adducts, to assess exposure in epidemiologic studies. However, a number of studies have detected adducts to chemicals that may also be found at such sites (see discussion of Hemminki et al., 1990, below). No epidemiologic studies have been found involving hazardous-waste sites that use biologic markers of susceptibility.

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. This latter use requires understanding of the natural history, persistence, background levels, variability, and confounding factors for candidate markers. Also, cost considerations may be pivotal, insofar as some of the techniques involve expensive and time-consuming instrumentation. New technologies will offer some exciting options, which will be discussed further in Report 2.

The Centers for Disease Control (CDC) and the Agency for Toxic Substances and Disease Registry (ATSDR) Subcommittee on Biomarkers of Organ Damage has assessed the potential of markers for use in screening populations near hazardous-waste sites (CDC/ATSDR, 1990). The subcommittee 's report discusses markers for the renal, hepatobiliary, and immune systems. It distinguishes tests that are performed routinely in clinical laboratories from those that are used in epidemiologic population studies. The criteria for the usefulness of markers will vary according to their purpose. The report concludes that the ideal marker should be relatively specific to a narrow range of toxicants and that it should be relatively absent or constant in unexposed controls. It should be possible to measure by minimally invasive means that are acceptable to the subject, and it should be inexpensive to

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

measure, especially for intervention programs and epidemiologic studies. The ideal marker should be measurable with high sensitivity, specificity, and reproducibility, and it should yield predictive values with high probability. Changes in the marker caused by exposure to the toxicant should be larger than the normal variation in unexposed populations, and changes caused by possible confounding factors (such as diet, age, gender, and lifestyle) should be known and understood by those who interpret test results. It is important to know the extent to which a marker signals relatively recent or past exposure, the extent to which it indicates peak as opposed to integrated (chronic) exposures, and the extent to which it shows cumulative rather than noncumulative effects. Rarely does any marker meet these objectives completely (CDC/ATSDR, 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. Even though they wear protective equipment, their exposures are qualitatively similar to those that may be encountered by residents before an area has been certified as a hazardous-waste site. Studies on these workers are relevant to the environmental epidemiologic study of waste sites. The hazardous-waste disposal industry is burgeoning (Gochfeld et al., 1990), and it is covered by an Occupational Safety and Health Administration standard that requires medical surveillance of workers. Site owners and unions already conduct health monitoring, and their experience could be applicable to groups in the community. Like community exposures, occupational exposures often will be to unknown mixtures that can react to form new substances.

The use of biologic markers of exposure generally has been limited to studies that monitor the health of hazardous-waste workers, generally for exposure to heavy metals and pesticides, and the yield of these efforts has been low to date, reflecting the evolving nature of the field (Gochfeld, 1990). Biologic markers of effect also have been identified in occupational studies (Hodgson et al., 1990). Traditional liver injury tests provide insensitive measures of overall liver function and cannot reflect specific chemical exposures. The liver is a target organ for many toxicants found at waste sites. Newer techniques that detect urinary excretion of metabolites and other specific abnormalities need to be validated, so that they can be incorporated into biologic monitoring (Hodgson et al., 1990). The interpretation of liver injury in hazardous-waste workers with potential exposure to

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

hepatotoxins is difficult for several reasons: The true predictive value of the tests for liver injury is not known, the long-term prognosis of transient or minor elevation of liver function is undefined or poorly developed, the mathematic foundations of surveillance are poorly developed, and competing causes of nonspecific liver disease (such as viral illness, alcohol consumption, and minor exposure to hepatotoxins) are undefined (Hodgson et al., 1990).

Although other markers of effect, such as cytogenetic effects, have been used in populations near hazardous-waste sites, they have not been generally reported for workers. One impressive exception is a number of studies that use proteins that show mutated or overexpressed oncogenes in pilot studies of workers in the hazardous-waste and foundry industries. A study of 16 municipal workers engaged in hazardous-waste cleanup showed a serum oncoprotein (ras p21) abnormality not found in unexposed controls, in half the workers (Brandt-Rauf and Niman, 1988). Brandt-Rauf (1988) demonstrated the predictive utility of using protein products of oncogenes as potential markers of cancer risk. Abnormal patterns of oncogene-related protein products were detected both in the biologic fluids of individuals who had contracted cancer and in an individual who later developed a premalignant colonic polyp. At the time of the evaluation of oncogene-related proteins, all the workers surveyed were clinically healthy. Within 18 months, the individual with the abnormal ras oncogene product, who had workplace exposures to PCBs, asbestos, and pesticides and also smoked 20 cigarettes a day, had developed the colonic polyp (Brandt-Rauf et al., 1990a). The ras oncogene can be activated by two mechanisms: point mutations or overexpression of protooncogene. The authors speculate that asbestos exposure in this case may have produced oncogene activation by the latter process, in that asbestos fibers are capable of transfecting exogenous DNA segments, such as oncogenes and promoter sequences. Following removal of the colonic polyp, ras-encoded p21 protein was no longer detected in the patient's serum. This case points out the potential utility of oncogene protein products as markers for the early detection of cancer. Additional studies are underway to assess this possibility (Brandt-Rauf et al., 1990a).

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. Nine of the municipal workers had positive findings for fes, ras, or sis oncoproteins compared with two of the state workers. Some of these findings may have been attributable to smoking, but the investigators conclude than an exposure related effect was also present (Brandt-Rauf et al.,

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

1989). A related study of foundry workers used a new technique for detecting oncogene activation based on immunoblotting for oncogene proteins in serum. 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 (Brandt-Rauf et al., 1990b). This approach has promise because it uses only a small amount of serum, and appears to be a general signal for the oncogenic process (Brandt-Rauf et al., 1989).

While the risk of cancer provides a central focus for much research on markers, risks to human reproduction offer another focal point, for which much shorter time periods between exposure and evidence of a related health effect are involved (NRC, 1989). Several studies have revealed that workplace exposures to males influence their ability to reproduce, as well as the health of their offspring. After a group of workers exposed to the pesticide dibromochloropropane (DBCP) had determined that they had all been unable to father children (Whorton et al., 1977), researchers confirmed that the exposed workers had abnormal sperm morphology and motility (Babich et al., 1981). Earlier studies revealed similar effects in multiple species, including testicular atrophy (Torkelson et al., 1961).

A series of studies using refined and automated measures of sperm concentration and sperm head morphology have recently found significant effects on male reproductive capacity related to exposures to pesticides or to general environmental exposures. DeStefano et al. (1989) conducted studies of reproductive effects in Vietnam veterans and reported that those who served in Vietnam were twice as likely to have lowered sperm concentrations and significantly reduced sperm morphology, with longer axis length and head circumference. The number of children fathered in both groups were comparable. However, whether the children of Vietnam veterans may have incurred other teratospermic or genetic defects has not been determined. In this context, it is noteworthy that Silbergeld et al. (1990) report that rats exposed to low levels of lead fathered defective offspring when mated with unexposed females. Thus, male mediated exposures may allow fertilization, but nonetheless convey hazards to offspring. The possibility of germ cell mutation needs to be carefully assessed in these circumstances.

Whatever the mechanism may be, a variety of characteristics of sperm have been detected and found to change with exposures to pesticides and other chemicals, such as those encountered at hazardous-waste sites or through other channels. Markers of exposure or effect can include changes in sperm shape, concentration, pH, viability, velocity, and motility. In addition, protamine adducts have been

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

studied in exposed animals (NRC, 1989), and adducts may also be found for other important sperm proteins. Welch et al. (1988) report that painters with exposures to ethylene glycol ethers had increased rates of sperm abnormalities, such as oligospermia and azoospermia, along with lower sperm counts. Ratcliffe et al. (1989) similarly find that workers with long term exposure to 2-ethoxyethanol, a known animal reproductive toxin, have significantly reduced sperm count, when compared to unexposed workers. Studies of pesticide exposures show similar effects in workers. Ratcliffe et al. (1987) investigated men who had long term exposures to ethylene dibromide (EDB) a now banned pesticide, known to cause reproductive dysfunction in animals. Exposed workers had significant impairments in a number of measures of sperm, including sperm count, the percentage of viable and motile sperm, and increases in the proportion of sperm with physical abnormalities (such as missing heads and abnormal tails), even though their exposures were well below the existing federal safety standard. Further work on EDB-exposed workers confirmed this finding and noted that long-term and short exposure produced distinct effects. Longer-term exposure resulted in decreased sperm motility and viability, and increased cell death, while short-term exposure slowed sperm velocity (Schrader et al., 1988).

Biologic markers of effect, such as alterations in sperm, can be used in studies of hazardous-waste workers and community residents even if the effects have not been related to specific diseases. Such markers show various routes of exposure to a multiplicity of substances and provide an indicator of total mutagenic load, which could have direct implications for reproductive or carcinogenic diseases. In this regard, such markers of effect also can be considered markers of exposure.

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. (1987) reviewed papers published in nine environmental and occupational health journals between 1981 and 1985. The articles are described according to trends (by year and journal) for type of markers, substances monitored, study design, biologic media sampled, and the studies' goals.

In all, 3738 articles were listed, of which 585 (15.6 percent) involved biologic monitoring. This percentage was relatively constant

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

over the period; the highest percentage (18 percent) appeared in 1983, and the lowest (12 percent) appeared in 1985. When the articles were grouped into three categories suggested by Zielhuis (1984, 1985) it was shown that 69 percent of the studies measured a toxin, 19 percent of the studies measured a metabolite, and 12 percent measured an agent-specific nonadverse effect (a reversible biologic change that is related to a specific exposure).

Then the articles were grouped into six categories, the three previously mentioned and three others. The most frequent topics were measurements of biologic substances that were not agent-specific but that caused nonadverse biological effects. This group, exemplified by changes in routine clinical chemistries, could be termed ambiguous effects, and it accounted for 26 percent of studies. Another group of measures of health effects, such as abnormal urine cytology, made up 14 percent of the studies. A third group of studies constituted 31 papers (5.3 percent) involving genetic monitoring and 4 papers (0.6 percent) involving genetic screening. Overall, it was found that 41 percent of the studies measured a toxic substance, 11 percent measured a metabolite, and 7 percent measured an agent-specific nonadverse effect.

Approximately half of the studies involved sampling blood for biologic monitoring. There appears to be an increasing trend in the use of blood specimens for monitoring. Urine was monitored in 28.3 percent, lung tissue in 4.3 percent, expired air in 2.3 percent, hair in 2.2 percent, adipose tissue in 1.2 percent, and saliva in 1.1 percent. Other media, such as breast milk, teeth, semen, bone, feces, liver, conjunctival fluid, and skin, were 14.9 percent of the media evaluated. Each of these other media was examined in 1-2 percent of the studies. Except for blood, the trends in all other media were fairly constant.

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. Schulte et al. (1987) confirmed this observation—74 percent of the studies reviewed in their paper evaluate the relationship between the level of environmental exposure and the biologic level of the toxicant or metabolite. Typical among this type of study was the correlation of lead measured in air and the concentration of lead in blood. Approximately 21 percent of studies attempt to link the results of biologic monitoring done concurrently with the assessment of a health outcome. Similarly, but to a lesser degree, approximately 3 percent

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

of studies attempt to link historical biologic monitoring data with a subsequent health outcome. One example is a study that links past levels of mercury in urine with current evidence of neurotoxicity (Williamson et al., 1982).

In 2 percent of the studies (Schulte et al., 1987), biologic monitoring was used to supplement or confirm indirect data on exposures. 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. The validity of a biologic marker can be viewed in terms of “measurement validity” as used in epidemiology (Last, 1983). Three aspects of measurement validity have been defined: construct validity, content validity, and criterion validity. The construct validity of a biologic marker is its ability to correspond to theoretical constructs under study. For example, if kidney function changes with age, then a biologic marker of kidney function with construct validity should change as well. A biologic marker has content validity if it incorporates the domain of the phenomenon under study. For example, a DNA adduct for aromatic amines will represent exposure from various routes and from occupational and lifestyle exposures. A biologic marker will have criterion validity according to the extent to which the measurement correlates with an external criterion of the phenomenon under study. The two types of criterion validity that have been distinguished are concurrent validity and predictive validity (Last, 1983). A marker has concurrent validity if it and the criterion refer to the same point in time. For example, ambient air measures of occupational exposure to TCE could be validated against breath analysis of TCE. Predictive validity indicates the ability of a marker to predict a criterion. For example, detection of the immunologic marker HLA B27 can be validated against the appearance of ankylosing spondylitis, a degenerative joint disease.

Validation of the relationship between various components of the continuum from exposure to disease involves four levels of effort, as adapted from Gann (1986): (1) the determination of an association between a marker and a preceding exposure or subsequent effect; (2) the location, shape, and slope of the exposure-marker or marker-effect relationship; (3) the threshold of “no observed effect level” if it

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

exists; and (4) the positive predictive value of the marker for exposure or disease. For example, in validating a marker of exposure, the first step would be to see whether there is an association between exposure, such as by air, and the marker. The next step would be to seek the nature of that relationship: How much exposure produces how much marker? The third step is an amplification of the second. Are there levels of exposure that might not result in the appearance of a marker? 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. The relationship between these characteristics and the frequency with which a marker is found is exhibited by the equation m = bp + (1 - a)(1 - p); m is marker frequency, b is sensitivity, p is disease frequency, and a is specificity (Khoury et al., 1985). The positive predictive value (PPV) of a marker is the probability that persons with the marker will have experienced the event it represents. The ultimate criterion of the utility of a marker is strong positive predictive value.

Ultimately, as discussed by Hatch and Stein (1987), an essential requirement for a biologic marker of effect is that it should identify from among all exposed individuals those most likely to become diseased. Ideally, we should be able to observe a considerable gradient proceeding from left to right in the continuum between exposure and early biologic change (Figure 7-1). If the numbers scored positive for the left-most markers do not include those positive for altered structure and function or clinical disease, the marker is of dubious value (Hatch and Stein, 1987).

It is useful to consider two other definitions of validity: laboratory validity and population validity. Laboratory validity is the characteristic of a marker assay or test system to be sensitive and specific (Griffith et al., 1989). To be able to measure a marker or declare it absent, laboratory validity depends on the characteristics of the test (reliability, accuracy, precision) and on the biologic characteristics of the marker. Population validity refers to how well the markers depict an event in a population. It does not matter how well you can measure a marker if there is too little to find among those being studied (i.e., in a particular sample from a population). Hence, in assessing the validity of a marker in a population, it is necessary to consider the prevalence of the marker in the population and the specificity of the test. Both affect the predictive value. Despite high test sensitivity, some markers will have little predictive value if they have a low prevalence in the study population, unless they also have perfect specificity.

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

Validation studies in humans should include determinations of sensitivity, specificity, predictive value, and the range of normal values of a marker (Schulte, 1987, 1989). Important aspects of such studies are adequate sample size; control for confounders such as age, sex, and race; and variability. It is also important that researchers understand the purpose of the marker, that is, why the marker is being considered and what aspect of the exposure-disease association it is supposed to indicate. It is also necessary to determine the extent that a marker reflects recent or past exposures, peak as opposed to integrated exposures, and cumulative rather than noncumulative biologic effects (Valanis, 1986).

Most validation studies proceed from laboratory evaluations of animals to experimental studies of small groups of humans to larger cross-sectional studies. The assessment of risk of disease or of the ability of a marker to predict disease, however, requires that temporal considerations be included in the design. Hence, retrospective or prospective studies that allow for evaluation of the presence of a marker and of a subsequent rate of disease development are necessary for true validation. Before instituting a large-scale study of the usefulness of a biologic marker, it is necessary to examine critically the initial research on the marker, including the milieu in which the research was done. Early research on tumor markers demonstrates the problems that can arise. Research on tests for tumor markers involves both the laboratory carrying out (and perhaps still developing) tests and the clinicians treating the patients. To generate mutual interest and enthusiasm, neither will have been “blind” to the findings of the other. As a result, the data available in the early stages are likely to be biased or opportunistic (Tate, 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. Key to the validation procedure is agreement on what constitutes a “ critical effect” (Hernberg, 1987; Perera, 1987b)—one that must occur in the progression between exposure and disease. Exposure to toxic substances results in a range of effects on biologic systems. There is a need to have general agreement on which of these effects are critical (that is, which indicate some aspect of a disease response) and which are merely adaptive. Subsequently, it is necessary to relate critical effects to dose estimates, to determine what factors affect dose and to define a level of exposure for which there is no discernible toxic effect (Hernberg, 1987; Perera, 1987b).

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

The U.S. Environmental Protection Agency (EPA) has commissioned the development of a decision model for biologic markers of exposure. The objective of the program is to identify and test appropriate markers for use in conjunction with other environmental data to provide better measures of exposure, and ultimately of risk, to individuals and populations (Bull, 1989; Nauman et al., 1990). The 10 steps in the process, which uses a mix of laboratory and field studies, are shown in After confirmation in tests with animals, the markers will have been shown capable of reliably indicating exposure to a target chemical in a small population for which gradients of exposure are established. The final validation step will demonstrate that results are within the limits of variability defined by lifestyle, disease state, therapeutic agents, and genetic and environmental factors. This effort requires an epidemiologic design and will involve a population large enough to allow the variables to be evaluated (Bull, 1989).

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. For each type of marker, pertinent issues in the study of hazardous-waste sites will be identified. Not all of the markers discussed have been validated. In some cases, they represent potentially useful indicators. In other cases, they are included only to illustrate an issue.

Whether a marker is indicative of exposure, disease, or susceptibility will depend on the state of knowledge concerning the relationship between the marker and the conditions of exposure, disease, or susceptibility that the markers represent. The allocation of markers to one of three categories is subjective and could change.

DNA AND PROTEIN ADDUCTS, MARKERS OF EXPOSURE

DNA and protein adducts hold great promise as markers of exposure in environmental epidemiology because they allow for measurement of the amount of xenobiotic substances that interact with critical macromolecules. This is of major interest in the studies of mutagenesis and carcinogenesis in which DNA is involved. However, DNA and protein adducts also can be used to measure exposures that cause other diseases that do not have a genotoxic etiology. For example, albumin adducts could indicate a xenobiotic dose to the liver. The

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

TABLE 7-2 Steps in the Development of a Biomarker

Step

Action Required

Relative Importance a

1. Chemical Selection

Prioritize based on occurrence, significant human exposure, potential for adverse human health effects.

C

2. Conceptualization

Identify logical consequence of chemical exposure that might serve as a useful measure of exposure.

C

3. Confirmation of Concept

Experimentally confirm the validity of the basic concept.

C

4. Develop Method of Measurement

Identify method for detecting changes in biomarker at doses at or below those producing toxic effects.

C

5. Biomarker Practical for Field?

Develop plausible field methodology and develop sufficient sensitivity of biomarker to monitor existing exposures.

L

6. Establish DoseResponse Relationship

Characterize pharmacokinetics and metabolism of chemical. (Consistent relationship to systematic dose is critical; knowledge of effective dose is limiting.)

C,L

7. Identify Variables Affecting Relationship with Dose

Establish specificity of response and identify lifestyle, genetic, disease state, therapeutic, or occupational variables that modify the response.

C,L

8. Measures Toxic Effect?

Provides advantage only among biomarkers of equal ability as measures of exposure.

N

9. Validation of Applicability to Humans

Conduct pilot study in small groups of humans with defined exposure gradients to the chemical of interest.

C

10. Conduct Demonstration Study

Determine whether variation in response in larger population can be accounted for by known variables.

C

a C = Critical to the application of the biomarker; L = Limiting to the application of the biomarker, i.e., places limits on interpretation of results for secondary purposes, e.g., risk assessment; N = Nice to have, but not essential to the application of the biomarker.

Source: Bull, 1989.

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

key feature in adduct formation is that the substance binds covalently to DNA or protein.

If a macromolecular adduct is to be useful as a marker of exposure, it should meet the following criteria: Its formation should be able to be characterized by a linear dose-response curve; for single exposures over the dose range of interest, it must be stable enough to accumulate over a specific period; and it must be detectable by existing methods of analysis (Schnell and Chiang, 1990). These three requirements can be influenced by highly efficient DNA repair mechanisms. Rates of DNA repair have been shown to vary between adducts, tissues, and individuals (Perera et al., 1988). In addition, DNA adducts can be “diluted” by cell proliferation (i.e., hyperplasia), a common response to cytotoxic insult (Schnell and Chiang, 1990). Despite these limitations, DNA adduct levels for some classes of compounds have been found to correlate with genotoxic exposures (Törngvist et al., 1986a).

A study by Hemminki et al. (1990) illustrates some of the issues that must be addressed in using DNA adducts in environmental epidemiology. These investigators studied the effect of environmental pollution on DNA adducts in humans in a highly industrialized area of Poland. DNA adducts in peripheral lymphocytes were analyzed by P32-post-labeling and immunoassay. Specimens were collected from three populations: coke workers who were exposed occupationally to high levels of polycyclic aromatic hydrocarbons, residents of towns around the coke ovens (local controls), and residents from rural Poland (countryside controls). Overall, local controls exhibited adduct levels and patterns similar to those of coke workers, whereas the levels in rural controls were two to three times lower. Assays were performed in duplicate, by two different laboratories, and they showed extensive interindividual variations of approximately 10-fold among local and countryside controls and approximately 150-fold among coke workers. This indicates large interindividual variations in exposure to or metabolic activation of the hydrocarbons or in the repair of DNA. Although the results were correlated, there also were interlaboratory variations. The results from one laboratory were generally twice those in the other, but the patterns were similar. 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. Because lymphocytes are in contact with many body tissues, they can provide an integrated measure of

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

exposure (Perera et al., 1987; Golding and Lucier, 1990). The variable life span of lymphocytes makes the number of adducts that persist after a given amount of time extremely variable, even within the same person. However, any immune disturbance, such as a common cold, can profoundly affect the number and life span of lymphocytes, so controlling for these factors can be difficult (Golding and Lucier, 1990).

Protein adducts could be better measures of dose than are DNA adducts for some purposes. Protein adducts are not repaired and they tend to persist for the life of the protein (about 18 weeks for hemoglobin). They also accumulate in a dose-related manner (Schnell and Chiang, 1990). At least 60 compounds, including examples of most of the important classes of mutagens and carcinogens, have been shown to form hemoglobin adducts (Calleman, 1986).

The ability to monitor exposure through hemoglobin adducts is limited by the presence in some cases of high background levels that tend to mask the effects of low levels of exposure. The background levels of some human hemoglobin adducts are listed in Table 7-3. As the data indicate, the problem is greatest for methylating agents (Schnell and Chiang, 1990). Compound exposures (different chemicals and different sources of the same chemical that can produce identical adducts) from unknown sources contribute to high background levels. Additional background levels of some adducts, such as those for ethylene oxide, can be produced by endogenous metabolic reactions. The role of genetic characteristics also could affect the formation of hemoglobin adducts. Vineis et al. (1990) report that the formation of 4-aminobiphenyl-hemoglobin adducts in smokers is associated with whether they are slow or fast acetylators, which is a genetically determined metabolic characteristic.

Despite these limitations, several investigators have established a relationship between exposure to toxicants and the formation of hemoglobin adducts and DNA adducts. For example, the studies of OstermanGolkar and Bergmark (1988) and Brugnone et al. (1986) demonstrate that the extent of in vivo hemoglobin alkylation is proportional to the concentrations of ethylene oxide in the blood, and Calleman et al. (1978) and T örngvist et al. (1986a) have shown that the amount of hemoglobin adducts is proportional to that of DNA adducts.

IMMUNE-SYSTEM MARKERS OF EFFECT

The sensitivity of the immune system to xenobiotic substances could mean that it produces biologic markers of effect that could indicate illness or other damage to health resulting from exposure to toxicants. The immune system reacts to the environment. One challenge

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

TABLE 7-3 Background Levels of Some Human Hemoglobin Adducts (Average Levels Expressed as nmol/g Hemoglobin or nmol/g Globin)

Adduct

Background Level

Reference

MeCys

16

Segerbäck et al. (1978)

 

16.4

Bailey et al. (1981)

 

13-34

Farmer (1982)

MeHis

12-42

Törnqvist et al. (1988)

MeVal

0.4-0.7

Törnqvist et al. (1988)

HOEtCys

1.5-4.3

Calleman (1986)

HOEtHis

1.41

Törnqvist et al. (1986a)

Nt-(2-HOEt) His

0.11-0.29

Calleman (1986)

 

0.53-1.6

Farmer et al. (1986)

 

0.02-4.7

Van Sittert and DeJong (1985)

 

0.17-1.5

Osterman-Golkar (1983)

Nt-(2-HOEt)His

0.06-0.30

Calleman (1986)

HOEtVal

0.12-0.72

Törnqvist et al. (1986b)

 

0.03-0.80

Törnqvist et al. (1986b)

 

0.03-0.53

Calleman (1986)

 

0.03-0.93

Farmer et al. (1986)

Nt-(2-HOPr)His

<0.1-0.38

Osterman-Golkar et al. (1984)

ABP-Cys

<0.001

Bryant et al. (1987)

 

<0.001

Perera et al. (1987)

 

<0.001

Skipper et al. (1986)

“Nt” refers to the tau nitrogen of the imidazole ring of histidine (also call “N3”). Source: Schnell and Chiang, 1990.

in using immune-system markers is to distinguish homeostatic changes from pathognomic ones (Weill and Turner-Warwick, 1981). Various investigators (Bekesi et al., 1987; Levin and Byers, 1987; Thrasher et al., 1990) 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. Thrasher et al. (1990) compared four groups of patients with controls who had short-term periodic exposure. The patients were residents of mobile homes where formaldehyde concentrations were measured that ranged from 0.05 to 0.5 parts per million (ppm); office workers with estimated exposures ranging from 0.01 to 0.77 ppm; patients removed for at least one year from the original sources of formaldehyde exposure,

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

where exposures had been measured at 0.14 to 0.81 ppm; and persons who were occupationally exposed but for whom no measure of exposure was given. The controls were anatomy students who had been exposed to ambient classroom concentrations of 0.43 ppm. For each group, they determined total white cells, lymphocyte and T-cell counts; T-helper/suppressor ratios; total Tal+, IL2+, and B-cell counts; antibodies to formaldehyde-human serum albumin (HCHO-HSA) conjugate; and autoantibodies. 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. The specificity of antibodies to HCHO-HSA has not been documented by reports of appropriate inhibition assays, and no assays have demonstrated that specific antibodies are formed after airborne exposures to formaldehyde. The assays for the autoantibodies are not sufficiently standardized to measure weak reactions reliably. There has been no independent verification of the findings of these assays.

The Thrasher et al. (1990) study illustrates the problems in assessing biologic markers of effect. First, all of the cases were self-selected; the subjects had sought medical attention because of multiple symptoms that involved the central nervous system (headache, memory loss, difficulty with completing tasks, dizziness), the upper and lower respiratory tract, and the skeleton and muscles. They also had symptoms of gastroenteritis. Three common symptoms were expressed: An initial flulike illness from which the subjects had not fully recovered, chronic fatigue, and a sensitivity to odors produced by low concentrations of chemicals. Hence, the case definition is broad and consists of a range of diverse symptoms.

Second, despite the fact that the controls were 5 to 15 years younger than the patients were (and the group contained a greater percentage of males), the investigators report no effect for age or gender, but no data are presented to support the conclusion. Studies of markers of effect are of little use when data are not provided to allow the reader to rule out confounding factors.

Similarly, no mention is made of other confounding factors, such as race; whether all assays were performed blind to the laboratory personnel; whether all assays were performed on blood collected during the same season; and whether the study subjects received more medications than did controls. Third, the study groups each had longterm exposures, whereas the students in the control group had periodic exposures that generally were as high as the exposures of one

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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.

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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.

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
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.

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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.

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

studies of populations exposed to chemicals from waste disposal sites Environ. Health Perspect. 62: 423-456

Bull, R.J. 1988. Decision Model for the Development of Biomarkers of Exposure. U.S. EPA 600/X-89/163. Las Vegas: Environmental Monitoring Systems Laboratory, U.S. Environmental Protection Agency.

Burger, E.J., R.G. Tardiff, and J.A. Bellanti, eds. 1987. Environmental Chemical Exposures and Immune System Integrity. Princeton, N.J.: Princeton Scientific.

Calleman, C.J. 1986. Monitoring of background levels of hydroxyethyl adducts in human hemoglobin Pp. 261-270 in Genetic Toxicology of Environmental Chemicals, Part B, Genetic Effects and Applied Mutagenesis New York: Alan K. Liss

Calleman, C.J., L. Ehrenberg, B. Jansson, S. Osterman-Golkar, D. Segerback, K. Svensson, and C.A. Wachtmeister. 1978. Monitoring and risk assessment by means of alkyl groups in hemoglobin in persons occupationally exposed to ethylene oxide J. Environ. Pathol. Toxicol. 2: 427-442

CDC/ATSDR (Center for Disease Control/Agency for Toxic Substances and Disease Registry Subcommittee on Biomarkers of Organ Damage and Dysfunction) 1990. Summary Report. August 27. Atlanta, Ga.

Clark, C.S., C.R. Meyer, P.S. Gartside, V.A. Majeti, B. Specker, W.F. Balistreri, and V. Elia. 1982. An environmental health survey of drinking water contamination by leachate from a pesticide waste dump in Hardeman County, Tennessee Arch. Environ. Health 37: 9-18

Cole, R.B., N.C. Nevin, G. Blundell, J.D. Merrett, J.R. McDonald, and W.P. Johnston. 1976. Relation of alpha-1-antitrypsin phenotype to the performance of pulmonary function tests and to the prevalence of respiratory illness in a working population Thorax 31: 149-157

CEQ (Council on Environmental Quality, Executive Office of the President) 1985. Report on Long-Term Environmental Research and Development. Washington, D.C.: Executive Office of the President.

DeStefano, F., J.L. Annest, M. Kresnow, S.M. Schrader, and D. Katz. 1989. Semen characteristics of Vietnam veterans. Reprod. Toxicol. 3: 165-173

Dorfmueller, M.A., S.P. Henne, R.G. York, R.L. Bornschein, and J.M. Manson. 1979. Evaluation of teratogenicity and behavioral toxicity with inhalation exposure of maternal rats to trichloroethylene Toxicology 14: 153-166

Farmer, P.B. 1982. The occurrence of S-methylcysteine in the hemoglobin of normal untreated animals Pp. 169-175 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.

Farmer, P.B., E. Bailey, S.M. Gorf, M. Törngvist, S. Osterman-Golkar, A. Kautiainen, and D.P. Lewis-Enright. 1986. Monitoring human exposure to ethylene oxide by the determination of haemoglobin adducts using gas chromatography-mass spectrometry Carcinogenesis 7: 637-640

Feldman, R.G., J. Chirico-Post, and S.P. Proctor. 1988. Blink reflex latency after exposure to trichloroethylene in well water Arch. Environ. Health 43: 143-148

Fischbein, A., M.S. Wolff, R. Lilis, J. Thornton, and I.J. Selikoff. 1979. Clinical findings among PCB exposed capacitor manufacturing workers Ann. N.Y Acad. Sci. 320: 703-715

Fowle, J.R. III. 1984. Workshop Proceedings: Approaches to Improving the Assessment of Human Genetic Risk—Human Biomonitoring Report No. EPA/60019/84-016. Washington, D.C.: Office of Health and Environment Assessment, U.S. Environmental Protection Agency.

Gann, P. 1986. Use and misuse of existing data bases in environmental epidemiology:

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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-

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

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.

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

289-298 in Developments in the Science and Practice of Toxicology, A.W. Hayes, R.C. Schnell, and T.S. Miya, eds. New York: Elsevier Science.

Osterman-Golkar, S., and E. Bergmark. 1988. Occupational exposure to ethylene oxide. Relation between in vivo dose and exposure dose. Scand. J. Work Environ. Health 14: 372-377

Osterman-Golkar, S., E. Bailey, P.B. Farmer, S.M. Gorf, and J.H. Lamb. 1984. Monitoring exposure to propylene oxide through the determination of hemoglobin alkylation. Scan. J. Work Environ. Health 10: 99-102

OTA (U.S. Congress, Office of Technology Assessment). 1983. The Role of Genetic Testing in the Prevention of Occupational Disease OTA-BA-194. Washington, D.C.: U.S. Government Printing Office.

Perera, F.P. 1987a. Molecular epidemiology: A novel approach to the investigation of pollutant-related chronic disease. Pp. 61-88 in Environmental Impacts on Human Health: The Agenda for Long-Term Research and Development, S. Draggan, J.J. Cohrssen, and R.C. Morrison, eds. New York: Praeger.

Perera, F.P. 1987b. The potential usefulness of biological markers in risk assessment Environ. Health Perspect. 76: 141-145

Perera, F.P., and I.B. Weinstein. 1982. Molecular epidemiology and carcinogen-DNA adduct detection. New approaches to studies of human cancer causation. J. Chronic Dis. 35: 581-600

Perera, F.P., R.M. Santella, D. Brenner, M.C. Poirer, A.A. Munshi, H.K. Fischman, and J. Van Ryzin. 1987. DNA adducts, protein adducts and sister chromatid exchange in cigarette smokers and nonsmokers. J. Natl. Cancer Inst. 79: 449-456

Perera, F.P., K. Herminki, T.L. Young, D. Brenner, G. Kelly, and R. Santella. 1988. Detection of polycyclic aromatic hydrocarbon-DNA adducts in white blood cells in foundry workers Cancer Res. 48: 2288-2291

Perera, F., A. Jeffrey, R.M. Santella, D. Brenner, J. Mayer, L. Latriano, S. Smith, T.L.Young, W.Y. Tsai, K. Hemminki, and P. Brandt-Rauf. 1990. Macromolecular adducts and related biomarkers in biomonitoring and epidemiology of complex exposures. IARC Sci. Publ. 104: 164-180

Phillips, A.M., and E.K. Silbergeld. 1985. Health effects studies of exposure from hazardous waste site—Where are we today? Am. J. Ind. Med. 8: 1-7

Piikivi, L., H. Hanninen, T. Martelin, and P. Mantere. 1984. Psychological performance and long-term exposure to mercury vapors Scand. J. Work Environ. Health 10: 35-41

Ratcliffe, J.M., S.M. Schrader, K. Steenland, D.E. Clapp, T.W. Turner, and R.W. Hornung. 1987. Semen quality in papaya workers with long term exposure to ethylene dibromide. Br. J. Ind. Med. 44: 317-326

Ratcliffe, J.M., S.M. Schrader, D.E. Clapp, W.E. Halperin, T.W. Turner, and R.W. Hornung. 1989. Semen quality in workers exposed to 2-ethoxyethanol. Br. J. Ind. Med. 46: 399-406

Rogan, W.J., and R.W. Miller. 1989. Prenatal exposure to polychlorinated biphenyls. Lancet 2(8673): 1216

Rogan, W.J., B.C. Gladen, K. L. Hung, S.L. Koong, L.Y. Shih, J.S. Taylor, Y.C. Wu, D.Yang, N.B. Ragan, and C.C. Hsu. 1988. Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science. 241: 334-336

Samuels, S.W. 1988. The arrogance of intellectual power. Pp. 113-120 in Phenotypic Variation in Populations: Relevance to Risk Assessment A.D. Woodhead, M.A.Bender, and R.C. Leonard, eds. New York: Plenum Press.

Schaumburg, H.H., P.S. Spencer, and J.C. Arezzo. 1983. Monitoring potential neurotoxic effects of hazardous waste disposal Environ. Health Perspect. 48: 61-64

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

Schnell, F.C., and T.C. Chiang. 1990. Protein Adduct-Forming Chemicals for Exposure Monitoring: Literature Summary and Recommendations. EPA 600/4-90/007. Las Vegas: Environmental Monitoring Systems Laboratory, U.S. Environmental Protection Agency.

Schrader, S.M., T.W. Turner, and J.M. Ratcliffe. 1988. The effects of ethylene dibromide on semen quality: A comparison of short-term and chronic exposure. Reprod. Toxicol. 2: 191-198

Schulte, P.A. 1986. Problems in the notification and screening of workers at high risk of disease. J. Occup. Med. 28: 1-7

Schulte, P.A. 1987. Methodologic issues in the use of biologic markers in epidemiologic research. Am. J. Epidemiol. 126: 1006-1016

Schulte, P.A. 1989. A conceptual framework for the validation and use of biological markers Environ. Res. 48: 129-144

Schulte, P.A. 1990. Contribution of Biological Markers to Occupational Health: Keynote Address, 23rd International Conference on Occupational Health, held 22-28 September in Montreal, Canada.

Schulte, P.A., W.E. Halperin, M. Herrick, and L.B. Coinnally. 1987. The current focus of biological monitoring. Pp. 50-60 in Occupational and Environmental Chemical Hazards, V. Foa et al., eds. Chichester, Eng.: Ellis Horwood.

Segerback, D., C.J. Calleman, L. Ehrenberg, G. Lofroth, and S. Osterman-Golkar. 1978. Evaluation of genetic risks of alkylating agents. IV. Quantitative determination of alkylated amino acids in hemoglobin as a measure of the dose after treatment of mice with methyl methanesulfonate Mutat. Res. 49: 71-82

Silbergeld, E., M. Akkerman, B. Fowler, E. Alberquerque, and M. Alkondon. 1990. Lead: Male Mediated Effects on Reproduction and Neurodevelopment. Paper presented at the Annual Meeting of the American Public Health Association, New York City, October 2, 1990

Skipper, P.L., M.S. Bryant, S.R. Tannenbaum, and J.D. Groopman. 1986. Analytical methods for assessing exposure to 4-aminobiphenyl based on protein adduct formation. J. Occup. Med. 28: 643-646

Smith, M.K., J.L. Randall, E.J. Read, J.A. Stober, and R.G. York. 1990. Developmental effects of dichloroacetic acid in Long-Evans rats. Teratology 39: 480

Tate, H. 1983. Assessing tumor markers. Stat. Med. 2: 217-222

Thilly, W.G., P-M. Leong, and T.S. Skopek. 1982. Potential of mutational spectra for diagnosing the cause of genetic change in human cell populations. Pp. 453-465 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.

Thasher, J.D., A. Broughton, and R. Madison. 1990. Immune activation and autoantibodies in humans with long-term inhalation exposure to formaldehyde. Arch. Environ. Health 45: 217-223

Torkelson, T.R., S.E. Sadek, V.K. Rowe, J.K. Kodama, H.H. Anderson, G.S. Loquvam, and C.H. Hine. 1961. Toxicologic investigations of 1,2-dibromo-3-chloropropane. Toxicol. Appl. Pharmacol. 3: 545-559

Törngvist, M., S. Osterman-Golkar, A. Kautiainen, S. Jensen, P.B. Farmer, and L. Ehrenberg. 1986a. Tissue doses of ethylene oxide in cigarette smokers determined from adduct levels in hemoglobin. Carcinogenesis 7: 1519-21

Törngvist, M., J. Mowrer, S. Jensen, and L. Ehrenberg. 1986b. Monitoring of environmental cancer initiators through hemoglobin adducts by a modified Edman degradation method. Anal. Biochem. 154: 255-266

Törngvist, M., S. Osterman-Golkar, A. Kautiainen, M. Naslund, C.J. Calleman, and L. Ehrenberg. 1988. Methylations in human hemoglobin. Mutat. Res. 204: 521-529

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×

Underhill, D.W., and E.P. Radford, eds. 1986. New and Sensitive Indicators of Health Impacts of Environmental Agents Pittsburgh: Center for Environmental Epidemiology, University of Pittsburgh.

Upton, A.C., T. Kneip, and P. Toniolo. 1989. Public health aspects of toxic chemical disposal sites. Annu. Rev. Public Health 10: 1-25

Valanis, B. 1986. Environmental and direct measures of exposure. Occup. Med. 1: 431-444

Van Sittert, N.J., and G. DeJong. 1985. Biomonitoring of exposure to potential mutagens and carcinogens in industrial populations. Food Chem. Toxicol. 23: 1, 23-31

Vineis, P., N. Caporaso, S.R. Tannebaum, P.L. Skipper, J. Glogowski, H. Bartsch, M. Coda, G. Taleska, and F. Kadlubar. 1990. Acetylation phenotype carcinogen-hemoglobin adducts, and cigarette smoking. Carcinogen Res. 13: 3002-3004

Wallace, L.A., E.D. Pellizzari, T.D. Hartwell, R. Whitmore, C. Sparacino, and H. Zelon. 1986. Total exposure assessment methodology (TEAM) study: Personal exposures, indoor-outdoor relationships, and breath levels of volatile organic compounds in New Jersey. Environ. Int. 12: 369-387

Weill, H., and M. Turner-Warwick, eds. 1981. Occupational Lung Diseases. New York: Deckker

Welch, L.S., S.M. Schrader, T.W. Turner, and M.R. Cullen. 1988. Effects of exposure to ethylene glycol ethers on shipyard painters: II. Male reproduction Am. J. Ind. Med. 14: 509-526

White, R.F., R.G. Feldman, and P.H. Travers. 1990. Neurobehavioral effects of toxicity due to metals, solvents, and insecticides. J. Clin. Neuropharmacology 13: 392-412

Whorton, M.D., R.M. Krauss, S. Marshall, and T. H. Milby. 1977. Infertility in male pesticide workers. Lancet 2: 1259-1261

Williamson, A.M., R.K.C. Teo, and J. Sanderson. 1982. Occupational mercury exposure and its consequences for behavior. Int. Arch. Occup. Environ. Health 50: 273-286

Zielhuis, R.L. 1984. Approaches in the development of biological monitoring methods: Laboratory and field studies. Pp. 373-385 in Biological Monitoring of Workers Exposed to Chemicals A. Aitio, V. Riihimaki, and H. Vainio, eds. Washington, D.C.: Hemisphere Publishing.

Zielhuis, R.L. 1985. Total exposure and workers' health. Ann. Occup. Hyg. 29: 463-475

Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 219
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 220
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 221
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 222
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 223
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 224
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 225
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 226
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 227
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 228
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 229
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 230
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 231
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 232
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 233
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 234
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 235
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 236
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 237
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 238
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 239
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 240
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 241
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 242
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 243
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 244
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 245
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 246
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 247
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 248
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 249
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 250
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 251
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 252
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 253
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 254
Suggested Citation:"7. Biological Markers in Studies of Hazardous-Waste Sites." National Research Council. 1991. Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes. Washington, DC: The National Academies Press. doi: 10.17226/1802.
×
Page 255
Next: 8. General Conclusions »
Environmental Epidemiology, Volume 1: Public Health and Hazardous Wastes Get This Book
×
Buy Paperback | $80.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

The amount of hazardous waste in the United States has been estimated at 275 million metric tons in licensed sites alone. Is the health of Americans at risk from exposure to this toxic material? This volume, the first of several on environmental epidemiology, reviews the available evidence and makes recommendations for filling gaps in data and improving health assessments.

The book explores:

  • Whether researchers can infer health hazards from available data.
  • The results of substantial state and federal programs on hazardous waste dangers.

The book presents the results of studies of hazardous wastes in the air, water, soil, and food and examines the potential of biological markers in health risk assessment.

The data and recommendations in this volume will be of immediate use to toxicologists, environmental health professionals, epidemiologists, and other biologists.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!