TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS

工作概要：本项目旨在描述剂量、分布、代谢和生物外源性物质消除的特征参数。这一信息可有助于毒理学研究的设计和解释，并加强低剂量推断对人类的风险的科学依据。此外，生物现实的生物数学模型提供了一个严格的结构，制定和测试的环境危害的作用机制的假设。毒代动力学模型也可以适用于不同的暴露途径和给药方案，并可以适应导致个体间变异性的因素。已经建立、部分开发或扩展了若干化学品的毒代动力学模型，包括蒽醌、甲基丁香酚、萘、二氯二苯砜（DDS）、萘、异戊二烯、1，3-丁二烯、四氯二苯并对二恶英、艾滋病药物的单独和组合，以及怀孕大鼠和新生儿吸入汞蒸气的处置。针对萘开发的基于生理学的毒代动力学（PBTK）模型表征了萘在大鼠和小鼠中的处置，包括在2年致癌性研究中使用的暴露浓度下两种物种吸入的萘量估计值，以及暴露期间萘在大鼠和小鼠肺（小鼠靶器官，但非大鼠靶器官）和肝脏中的代谢速率。亚硝酸钠模型的特点是剂量依赖性的口服吸收和消除的亚硝酸盐，以及在暴露大鼠的高铁血红蛋白血症的诱导率和亚铁血红蛋白的恢复。甲基丁香酚模型表明，大鼠和人类经口接触该药剂后会迅速吸收，并在肝脏中产生较大的首过代谢效应。用于拟合大鼠血浆浓度数据的模型结构也模拟了人血浆数据，人体代谢比大鼠慢。 为描述大鼠和小鼠口服蒽醌的处置而创建的模型需要独特的吸收途径。这种高度亲脂性的化学物质可能包装在乳糜微粒中，被吸收到排出小肠的淋巴中，并进入混合静脉血，避免首过肝脏代谢。蒽醌模型，这是从单次静脉注射和口服剂量的血浆时间过程数据，扩展到慢性饲料暴露。DDS在大鼠和小鼠体内的分布模型表明，该药物在口服暴露后被迅速吸收，几乎没有首过肝脏代谢，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。 后一观察结果与在喂食含DDS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.