Commonly measured pharmacokinetic values can also be used as markers of exposure, for example, the presence of parent compound or metabolites in exhaled breath, blood, or urine or the appearance of macromolecular adducts or their degradation products in urine. Some markers of chemical exposure, such as the hematological changes that accompany high levels of exposure to lead or benzene, have been measured for decades. As early as 1976, hemoglobin adducts were being used as internal dosimeters of exposure to ethylene oxide and were later used as internal exposure biomarkers for aromatic amines, nitrosamines, and polycyclic aromatic hydrocarbons (DeCaprio, 1997).

In essence, exposure biomarkers are useful for measurement of the actual absorbed dose and the extent of delivery of the exposure to the putative site. These measurements are superior to ambient monitoring and questionnaire data (DeCaprio, 1997). To understand the relationship of such markers to prior exposures, however, one must know the rates of formation and clearance of the marker and the factors that influence those rates. Because of safety concerns about determination of these rates in humans, historically these studies have been limited to those that use animal models (Henderson, 1995). Interspecies variations in absorption and uptake complicate extrapolation of results of studies with animal to human populations.

To address the issue of the nonspecificity of these biomarkers, more recent work has focused on early-effect markers, such as oncogenes and tumor suppressor genes. These markers not only serve as indicators of exposure, for example, in studies of aflatoxin and lung cancer in asbestos workers (Brandt-Raut et al., 1992; Hollstein et al., 1993), but they also provide insights into the mechanism of the disease process itself (Cullen and Redlich, 1995). However, the utility of these markers is limited as well because they cannot adequately account for variability in individual susceptibility factors; that is, the dose-response curve differs among individuals due to differences in metabolic pathways. Still, better biomarkers of exposure could be very useful in verifying claims of environmental exposure in communities of concern.

Biomarkers of Susceptibility

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an individual's ability to respond to the challenge of exposure to an environmental hazard. The variation in individual responses to environmental exposures is wide, even within racial or ethnic classifications (see discussion in Addressing Race below). Investigators have studied an extensive range of enzymes that are known to be important toxicologically and that also demonstrate substantial variation in activity levels within the population (e.g., N-acetyl-transferase or P-450 cytochromes). Such enzymes are likely to play an essential role in the activation or detoxification of potent carcinogens or other chemical exposures. Different susceptibilities are likely to account for at least some of the different responses to exposures such as metals, solvents, or pesticides (Bock,



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