TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS

工作总结：该项目旨在描述外来物质的剂量、分布、新陈代谢和消除参数。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、扑草酮及其代谢物苯巴比妥、异戊二烯、异丁烯、1，3-丁二烯、TCDD、艾滋病药物单独和组合、褪黑素以及吸入汞蒸气在孕鼠和新生儿中的处置。蒽醌剂量学模型的一个独特特征是其不寻常的吸收途径，其特征是从低位肠道吸收，包装在乳糜粒中，运输到淋巴，转移到混合静脉血液，避免第一次通过肝脏代谢。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。对于甲基亮丁香酚，建立了大鼠和人类的基于生理的药代动力学模型。人体模型在结构上与大鼠模型相似，是基于从志愿者那里获得的血液甲基亮酚数据，这些志愿者食用了商业上可获得的含有甲基亮酚的饼干。-毒代动力学模型、靶器官剂量测定、消毒副产物、蒽醌、硼、异戊二烯、甲基亮酚、扑热息痛、羟甲醇酮-人类受试者

Summary of Work: This project is designed to characterize parameters of dose, distribution, metabolism, and elimination of xenobiotic 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, primidone and its metabolite phenobarbital, isoprene, isobutene, 1,3-butadiene, TCDD, AIDS drugs singly and in combinations, melatonin, and the disposition of inhaled mercury vapor in pregnant rats and neonates. A unique feature of the anthraquinone dosimetry model is its unusual absorption pathway characterized by absorption from the lower intestine, packaging in chylomicrons, transport into the lymph and transfer 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. For methyleugenol, physiologically based pharmacokinetic models were created for rats and humans. The human model, which was structurally similar to the rat model, was based on blood methyleugenol data obtained from volunteers who consumed commericially available cookies containing methyleugenol. - toxicokinetic modeling, target organ dosimetry, disinfection byproducts, anthraquinone, boron, isoprene, methyleugenol, primidone, oxymetholone - Human Subjects