complex mixtures or the detection of exposures after time has elapsed, providing “fingerprints” of biologic responses to agents that are not retained in tissues, such as ionizing radiation.

This chapter focuses on applications of toxicogenomic technologies to measure environmental exposures in populations exposed to occupational and environmental agents, an important task in risk assessment and toxicology research. The related problem of exposure to pharmaceutical agents is not considered here. The relevance of toxicogenomics to risk assessment modeling is discussed after a description of the state of the art.

CONVENTIONAL BIOMARKERS OF EXPOSURE AND RESPONSE

The term biomarker has been widely applied to describe quantifiable molecular species that reflect biologic states, exposures, and disease. Under this broad heading, two biomarker subcategories can be distinguished: biomarkers of exposure, reflecting the occurrence of an exposure; and biomarkers of response, which indicate the response of an organism to an exposure.

Biomarkers of exposure may be specific modifications of specific molecules, such as the adducts formed on hemoglobin due to exposure to benzene or pyrolysis products (Skipper et al. 1994; Medeiros et al. 1997; Alexander et al. 2002), the DNA adducts produced by exposure to vinyl chloride or urethane (Skipper et al. 1994), or the polycyclic aromatic hydrocarbons from cigarette smoke (Shugart et al. 1983; Perera et al. 1986). Although xenobiotics and the metabolites that persist in tissues (for example, polychlorinated biphenyls, dioxins) are used as exposure biomarkers, adducts are the most commonly used biomarkers of exposure. Adducts can persist detectably in the organism, constituting biomarkers of a past exposure. Exposure biomarkers such as hemoglobin adducts might not be involved in toxic effects, but others (for example, mutagenic DNA damage) may be.

Single-molecule species have been most commonly used as biomarkers, and traditionally they have been measured by conventional approaches such as gas chromatography and high-performance liquid chromatography. However, a collection of biomarkers may also be used as a fingerprint of exposure. Monitoring multiple biomarker molecules could boost the sensitivity of detection as well as its specificity in reporting a particular exposure type. One reason is that different agents can produce overlapping profiles of adducts, so that measuring multiple types of adducts could distinguish related but different exposures. Such distinctions can help define exposures associated with different disease risks. For example, weakly carcinogenic methylating agents such as methyl methanesulfonate produce N7-methylguanine as the predominant DNA adduct, which is also the main DNA lesion formed by potent carcinogens such as N-methyl-N'-nitro-N-nitrosourea. The key mutational and carcinogenic effects of these compounds, however, are mainly due to differences in the levels of relatively minor lesions: the strongly mutational adduct O6-methylguanine accounts for only



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