DETERMINANTS OF DIETARY RISK OF HETEROCYCLIC AMINE

富含蛋白质食品的热加工和热解沿着标准 美国的烹调方法，如烤肉、煎和烧烤 诱导形成强诱变和致癌杂环 胺。 这些相同的化合物在多个器官部位产生肿瘤， 小鼠和大鼠。 非人灵长类动物喂食这些杂环胺中的一种 在很短的潜伏期后发展成肝癌。 此外，委员会认为， 流行病学研究表明，肉类消费与 人类的癌症 由于这些发现，确定 这些诱变剂/致癌物是否有助于人类癌症发病率。 本提案将尝试通过以下方式做到这一点：1）确定和量化 饮食暴露于这些杂环胺; 2）探索实际的 通过防止诱变剂形成减少暴露的方法; 3） 通过DNA分析了解这些化合物的慢性毒性 结合、细胞遗传学损伤和突变效应 啮齿动物的饲养; 4）研究人类个体的重要性 通过评估CHO细胞中修复和代谢的差异， DNA修复和代谢活化的遗传差异; 5） 表征重要的代谢途径，目的是了解 这些诱导的组织特异性致癌作用的性质 啮齿类动物和非人灵长类动物中的杂环胺; 6）了解 与低剂量暴露有关的生物剂量学 摄入这些强效诱变剂; 7）将由此产生的数据 项目和数据从文献到癌症风险评估。 在 本研究的结论，细胞遗传学损伤的基本机制， 由这些化合物引起的代谢和DNA加合将更多 彻底理解。 此外，根据接触情况进行风险评估， 将开发剂量测定和药代动力学。

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.