CHEMICAL DISPOSITION IN MAMMALS SRI INTERNATIONAL

该合同的目的是每年从一些选定的环境污染物或模型化合物的研究中获得详细的化学处置数据。这些研究的目的是提供有关化学物质在完整动物体内的命运的应用知识，以支持国家毒理学计划进行的毒性试验，并提供有关化学物质毒性机制的基本知识。这些数据将有助于更准确地预测用于动物生物测定的化合物的正确剂量。发展关于化学结构-活性关系的基本资料，将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。这些研究大多是在完整的实验室大鼠和/或小鼠中进行的，尽管有些研究可能需要使用人类和啮齿动物的肝片体外孵育，以便更准确地推断从啮齿动物到人类的结果，并进行机制研究。目前正在对工业中间体环氧环己烯进行处理和代谢研究。正在对甲基苯乙烯酮进行研究，以提供数据，以确定进行亚慢性和慢性毒性试验的适当接触途径。四种过氧化物酶体增殖剂，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，小鼠和人类肝脏和肾脏切片中进行研究。这些数据将为人类接触这些化学品的风险评估提供数据。丁香酚、异丁香酚、甲基丁香酚和肉豆蔻素在啮齿动物和人类肝细胞中的生物转化与已知致癌物黄樟醇进行了比较，以进行风险比较。这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.