This project will explore the practical, health-related implications of data obtained in the other program projects by using these and other data to develop quantitative estimates of potential cancer risks associated with consuming heterocyclic amines (HAs) in cooked foods. This project will generate new quantitative information and analysis currently needed to determine whether HAs may cause a substantial fraction of diet-related cancer in the United States, where new epidemiological studies might shed additional light on this issue, and what kinds of dietary cancer-prevention strategies might be used to reduce intake of HAs. The study will consist of four methodological components. (1) Exposure Assessment for the U.S. Population. A detailed, quantitative analysis will be undertaken to determine age- and sex-specific intakes of HAs in cooked-food products present in the U.S. diet. (2) Dose Assessment (Pharmacokinetic Modeling). Empirically based models of pharmacokinetic relationships between cooked- food ingestion, HA intake, and effective genotoxic and/or cytotoxic doses of HA metabolites in relevant target organs will be developed based on in vitro and in vivo data from the other program projects and from the literature. These models will be used to describe and predict effective dose as a function of ingested dose for humans and bioassay animals. (3) Dose-Response Modeling. Two alternative dose-response models will be selected and parameterized for use in extrapolating increased cancer risk as a function of plausibly relevant measures of biologically effective HA dose, based on information from task (2) and from available animal-bioassay and epidemiological data. One of these models will be a biologically based one that accounts for both mutational cell-proliferative processes linked to carcinogenesis. The other, a health-conservation model of the type typically used in regulatory risk assessment for environmental carcinogens, will be used for comparative purposes. (4) Integrated Risk Characterization. The information obtained in the exposure, pharmacokinetic/dose, and dose-response assessments will be integrated to form quantitative characterizations of estimated HA-related cancer risk to individuals and populations in the United States. These characterizations will be critically evaluated in light of available epidemiological data implicating dietary agents as potentially significant sources of human risk, and the relative importance of HAs among these potential sources will be assessed.
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