Heat processing and pyrolysis of protein-rich foods along with standard American cooking practices such as broiling, frying and barbecuing of meats induce the formation of potent mutagenic and carcinogenic heterocyclic amines. These same compounds produced tumors at multiple organ sites in both mice and rats. Nonhuman primates fed one of these heterocyclic amines have developed hepatocarcinomas after a very short latency. Furthermore, epidemiology studies suggest a good correlation of meat consumption with cancer in humans. Because of these findings, it is important to determine whether these mutagens/carcinogens contribute to human cancer incidence. This proposal will attempt to do so by: 1) Identifying and quantifying dietary exposure to these heterocyclic amines; 2) Exploring practical methods of reducing exposure by preventing mutagen formation; 3) Understanding the chronic toxicology of these compounds by analysis of DNA binding, cytogenetic damage and mutational effects following long-term feeding of rodents; 4) Studying the importance of individual human differences in repair and metabolism by assessment in CHO cells having genetic differences in DNA repair and metabolic activation; 5) Characterizing important metabolic pathways with the goal of understanding the nature of the tissue-specific carcinogenesis induced by these heterocyclic amines in rodents and in nonhuman primates; 6) Understanding the biological dosimetry related to the low-dose exposures from the ingestion of these potent mutagens; 7) Subjecting data generated from this project and data from the literature to cancer-risk assessment. At the conclusion of this study, basic mechanisms of cytogenetic damage, metabolism and DNA adduction caused by these compounds will be more thoroughly understood. In addition, a risk assessment based on exposure, dosimetry, and pharmacokinetics will be developed.
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