CHEMICAL DISPOSITION IN MAMMALS SRI INTERNATIONAL

哺乳动物中的化学处置 SRI International

• 批准号: 6079033
• 负责人: CAROL E GREEN
• 金额: $ 52.18万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-03 至 2004-05-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6079033
• 关键词: biotransformation; clearance rate; colorimetry; dosage; environmental contamination; environmental toxicology; gas chromatography; high performance liquid chromatography; laboratory mouse; laboratory rat; mass spectrometry; nuclear magnetic resonance spectroscopy; physical chemical interaction; toxicant screening; toxin metabolism; ultraviolet spectrometry

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.

该合同的目的是从每年对选定的环境污染物或模型化合物进行的若干研究中获取详细的化学处置数据。 这些研究旨在提供完整动物体内化学品命运的应用知识，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测定中研究的化合物的正确剂量。 开发化学结构-活性关系的基本信息将能够更准确地预测具有类似结构或物理特性的化学品的命运和毒性。这些研究中的大多数在完整的实验室大鼠和/或小鼠中进行，尽管一些研究可能需要使用体外人类和啮齿动物肝脏切片孵育，以更准确地将啮齿动物的结果外推至人类，并进行机制研究。正在对工业中间体环氧环己烷进行处置和代谢研究。 正在研究甲基苯乙烯基酮，以提供数据，确定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、Wyeth 14，643、2，4-二氯苯氧乙酸和吉非罗齐正在大鼠、小鼠和人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。 出于风险比较的目的，将丁香酚、异丁香酚、甲基丁香酚和肉豆蔻醚在啮齿动物和人肝细胞中的生物转化与已知致癌物黄樟素进行比较。 该类研究的其他研究包括非程序性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。