TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS

工作总结：该项目旨在描述外来生物材料的剂量、分布、代谢和消除参数。这些信息可以帮助设计和解释毒理学研究，并加强低剂量外推对人类风险的科学基础。此外，生物现实的生物数学模型提供了一个严密的结构来制定和测试关于环境危害的作用机制的假设。毒代动力学模型还可以适应不同的暴露途径和给药方案，并可以适应导致个体间差异的因素。已建立、部分开发或扩展了几种化学物质的毒代动力学模型，包括蒽醌、甲基亮酚、萘、二氯二苯砜(DDS)、萘、异戊二烯、1，3-丁二烯、TCDD、艾滋病药物单独和组合，以及吸入汞蒸气在孕鼠和新生儿中的处置。建立的基于生理学的萘毒性动力学(PBTK)模型表征了萘在大鼠和小鼠体内的处置，包括估计在两年致癌性研究中使用的暴露浓度下两种物种吸入的萘量，以及暴露期间大鼠和小鼠的肺(小鼠的靶器官，而不是大鼠)和肝脏中的代谢率。亚硝酸钠模型表征了亚硝酸盐的剂量依赖的口服吸收和消除，以及暴露大鼠高铁血红蛋白血症的诱发率和亚铁血红蛋白的恢复。甲亮酚模型表明，这种制剂在大鼠和人类口服后很快就被吸收了，肝脏发生了很大的首过代谢效应。用于拟合大鼠血浆浓度数据的模型结构也模拟了人类的血浆数据，人类的新陈代谢速度慢于大鼠。这个模型是用来描述大鼠和小鼠口服的蒽醌的处置情况的，它需要一种独特的吸收途径。这种高度亲油的化学物质很可能被包装在乳糜粒中，被吸收到排出小肠的淋巴中，并进入混合静脉血液，以避免肝脏的首过代谢。由单次静脉和口服给药的血浆时程数据发展而来的蒽醌模型，被扩展到慢性饲料暴露。DDS在大鼠和小鼠体内的处理模型表明，DDS经口给药后吸收迅速，肝脏首过代谢很少，母体化合物和代谢产物通过胆汁排泄，DDS诱导参与其代谢的酶。后者的观察结果与在喂食含DDS的饲料13周或2年的大鼠和小鼠中观察到的肝脏肥大一致。

Summary of Work: This project is designed to characterize parameters of dose, distribution, metabolism, and elimination ofxenobiotic materials. This information can aid in the design and interpretation of toxicology studies and to strengthen the scientific basis for low-dose extrapolation of risk to humans. Furthermore, biologically realistic biomathematical models provide a rigorous structure to formulate and test hypotheses on mechanisms of action of environmental hazards. Toxicokinetic models can also be adapted to different routes of exposure and dosage regimens and can accomodate factors that contribute to interindividual variabilities. Toxicokinetic models have been created, partially developed, or expanded upon for several chemicals, including anthraquinone, methyleugenol, naphthalene, dichlorodiphenyl sulfone (DDS), naphthalene, isoprene, 1,3-butadiene, TCDD, AIDS drugs singly and in combinations, and the disposition of inhaled mercury vapor in pregnant rats and neonates. The physiologically based toxicokinetic (PBTK) model developed for naphthalene characterized the disposition of naphthalene in rats and mice, including estimates of the amount of naphthalene inhaled by both species at the exposure concentrations used in the 2-year carcinogenicity studies and the rates of metabolism of naphthalene in the lung (target organ in mice but not in rats) and liver of rats and mice during exposure. The model for sodium nitrite characterized the dose-dependent oral absorption and elimination of nitrite, as well as the rates of induction methemoglobinemia and recovery of ferrous hemoglobin in exposed rats. The methyleugenol model indicates that this agent is rapidly absorbed following oral exposure in rats and humans and that a large first-pass metabolic effect occurs in the liver. The model structure used to fit the rat plasma concentration data also simulates human plasma data, with metabolism being slower in humans than in rats. The model that was created to describe the disposition of orally administered anthraquinone in rats and mice required a unique absorption pathway. This highly lipophilic chemical is likely packaged in chylomicrons, taken up into the lymph that drains the small intestine, and passed into the mixed venous blood avoiding first-pass liver metabolism. The anthraquinone model, which was developed from from single intravenous and oral dose plasma-time course data, was extended to chronic feed exposures. The model on the disposition of DDS in rats and mice indicated that this agent is rapidly absorbed following oral exposure, there is little first pass liver metabolism, the parent compound and metabolites are excreted via the bile, and DDS induces enzymes involved in its metabolism. The latter observation was consistent with liver hypertrophy observed in rats and mice fed diets containing DDS for 13 weeks or 2 years.