MOLECULAR DOSIMETRY OF INGESTED PAHS AND HETEROCYCLIC AMINES

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Project II: A major route of exposure to environmental carcinogens is through the diet. Epidemiological studies indicate that 20 to 50% of all human cancers can be attributed to dietary causes. The frequent consumption of animal fat, red meats, or barbequed/smoked meats has been associated with increased risk for cancers of the gastro-intestinal tract and pancreas. However, in contrast to the strong association between aflatoxin and liver cancer described in other projects in this program, the specific etiologic agents responsible for causing many diet- associated human cancers remain undetermined. Two classes of chemical carcinogens, polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HAs), have been identified in cooked meats. These chemicals produce a variety of cancers in animal models including colon, stomach, breast, and liver cancers. The overall goals of this project are to investigate the molecular dosimetry of ingested PAHs and HAs from cooked meats in humans, and identify susceptibility factors (effect modifiers) that modulate the formation of DNA and protein adducts due to these dietary carcinogens. These studies will utilize controlled feeding protocols. Individual differences in the formation and persistence of carcinogen-DNA adducts in peripheral white blood cell fractions and carcinogen metabolites in urine will be investigated following ingestion of char-broiled meat. Relevant metabolic phenotypes (P450IA2, P450IIIA4 and acetyltransferase) will be assessed to determine their role in adduct and metabolite kinetics. A pilot case-control colon polyp study will also be initiated to examine selected biomarkers as indicators of cancer risk. This study will develop and evaluate biomarkers of exposure to cooking- induced dietary carcinogens. The study should yield insight into the biological basis for inter-individual variation in response to carcinogens associated with cooked meats. The identification of critical metabolic and dietary determinants of DNA and protein damage could provide methodologies for assessing increased susceptibility to cancer from ingested carcinogens. Ultimately, molecular biomonitoring may allow quantitation of biological dose from ingested carcinogens, thereby accounting for variation in exposure, cooking processes, and metabolism.