The broad, long-term objective of this application is to assess the cancer risk posed by heterocyclic aromatic amines (HAAs), an important class of genotoxicants formed in cooked meats and tobacco smoke condensate. The recent Report on Carcinogens, Eleventh Edition, National Toxicology Program, concluded that HAAs may be reasonably anticipated to be human carcinogens. The frequent consumption of red meats leads to an increased risk for colon cancer. HAAs have been implicated as specific etiological agents in this disease, based upon epidemiological studies that have shown the highest risk for individuals to develop colon cancer is conferred in those subjects who frequently consume meats cooked well-done and who harbor elevated activities in enzymes that bioactivate HAAs. However, the reported associations of dietary factors and genetic polymorphism data can not confirm the relationships between specific chemical exposures and carcinogenesis. Stable, long-lived chemical markers of exposure and genetic damage are required to strengthen the evidence for a role of these genotoxicants in cancer risk. The difficulty of obtaining relevant tissues non-invasively to assess genetic damage and cancer development, as well as the paucity of analytical methods that unambiguously identify and quantitate stable, long-lived HAA biomarkers at trace levels, has severely impeded human risk assessment of HAAs. Hair, blood cells, and plasma are rich sources of material to measure HAAs, HAA-DNA and HAA-protein adducts, which may serve as long-lived biomarkers in surrogate tissues for risk assessment. We hypothesize that recent advances in the sensitivity of mass spectrometry (MS) instrumentation will permit the identification, characterization and quantification of HAA biomarkers in tissues of individuals exposed to HAAs through the diet: these analytical MS methods on biomarkers of HAAs will provide superior approaches for establishing a role of HAAs in carcinogenesis. This proposed research will establish noninvasive chemical markers of HAAs, by measuring HAAs in hair, blood protein adducts, and DNA adducts in long-lived white blood cells, as surrogate biomarkers for target sites of cancer risk in humans who frequently eat grilled meats. The DNA and protein adduct biomarkers derived from the genotoxic HAA metabolites can be used to determine exposure, the biologically effective dose, genetic damage, and to identify genetic polymorphisms in enzyme metabolism genes or DNA repair genes that modulate HAA genotoxicity. The proposed research has important impact on public health and will provide an essential tool for developing risk assessment methods for this class of genotoxicants, which are believed to contribute to human colorectal and other common human cancers. The health risk can potentially be controlled at a population level by identifying those at risk, i.e. through exposures, or genetic polymorphisms, and then intervening in this group using disease prevention and early detection strategies. ? ? ?
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