CHEMICAL DISPOSITION IN MAMMALS SRI INTERNATIONAL

本合同的目的是每年从选定的环境污染物或模型化合物的若干研究中获得详细的化学品处置数据。这类研究的目的是为国家毒理学计划进行的毒性测试提供关于完整动物体内化学物质命运的应用知识，以及关于化学毒性机制的基本知识。这些数据将有助于更准确地预测在动物生物检测中要研究的化合物的正确剂量。开发有关化学结构-活性关系的基本信息将使人们能够更准确地预测具有类似结构或物理性质的化学品的命运和毒性。大多数这些研究是在完整的实验室大鼠和/或小鼠身上进行的，尽管一些研究可能需要使用人和啮齿动物肝脏切片的体外孵育，以更准确地推断啮齿动物对人类的结果，并进行机制研究。工业中间体环氧环己烷的处置和代谢研究正在进行中。正在研究甲基苯乙烯酮，以提供数据，以确定亚慢性和慢性毒性试验的适当暴露途径。四种过氧化体增殖剂，邻苯二甲酸二丁酯，惠氏14,643，2，4-二氯苯氧乙酸和吉非罗齐，正在大鼠、小鼠和人的肝和肾切片上进行研究。这些数据将为人类接触这些化学品的风险评估提供数据。为了进行风险比较，正在将丁香酚、异丁香酚、甲基亮丁香酚和肉豆蔻素在啮齿动物和人类肝细胞中的比较生物转化与已知的致癌物质黄樟素进行比较。这一类研究的其他研究包括计划外DNA合成、DNA结合和加合物分析，以及对人类和啮齿动物肝细胞的毒性。

The purpose of this contract is to procure detailed chemical disposition data from a number of studies of selected environmental contaminants or model compounds per year. Such studies are designed to provide both applied knowledge of the fate of chemicals in the intact animal in support of toxicity tests conducted by the National Toxicology Program and basic knowledge of mechanisms of chemical toxicity. These data will help to predict more accurately the correct doses for compounds to be studied in animal bioassays. Developing fundamental information on chemical structure-activity relationships will permit a more accurate prediction of the fate and toxicity of chemicals that have similar structural or physical properties. Most of these studies are performed in intact laboratory rats and/or mice although some studies may require the use of human and rodent liver slice incubations in vitro for more accurate extrapolation of results from rodents to humans and for mechanistic studies. Disposition and metabolism studies are being conducted on the industrial intermediate cyclohexene oxide. Methyl styryl ketone is being studied to provide data to determine the appropriate route of exposure for the subchronic and chronic toxicity tests. Four peroxisome proliferators, dibutyl phthalate, Wyeth 14,643, 2,4-dichlorophenoxyacetic acid, and gemfibrozil, are being studied in rat, mouse and human liver and kidney slices. These data will provide data for risk assessments from human exposure to these chemicals. The comparative biotransformation in rodent and human hepatocytes for eugenol, isoeugenol, methyleugenol and myristicin are being compared to the known carcinogen safrole for risk comparison purposes. Additional studies on this class study include unscheduled DNA synthesis, DNA binding and analysis of adducts, and toxicity to human and rodent hepatocytes.