TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS

该项目旨在表征剂量参数， 分布、代谢和消除异生物质。 这 信息可以帮助设计和解释毒理学 加强低剂量外推的科学基础 对人类有风险。 此外，生物现实主义生物数学 模型提供了一个严格的结构，以制定和测试假设， 环境危害的作用机制。 毒代动力学模型可以 还应适应不同的接触途径和剂量方案， 能够适应导致个体间差异的因素。 在上一财年，已创建毒代动力学模型，或 部分开发用于国家正在研究的近20种化学品 毒理学计划（NTP）。 一个更深入的基于生理学的 构建了摄取、代谢和 清除1，3-丁二烯（BD）及其主要代谢产物， 1，2-环氧-3-丁烯（EB）。 这个模型显示， EB的剂量测定不足以说明 暴露于BD的大鼠和小鼠之间的肿瘤反应。 最近的模型 展示了更大的解剖现实主义和更全面的需求， 涉及的酶学和辅因子变化的表征 在生物转化过程中。

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 accommodate factors that contribute to interindividual variabilities. During the past fiscal year, toxicokinetic models have been created or partially developed for nearly 20 chemicals under study by the National Toxicology Program (NTP). A more in-depth physiologically-based toxicokinetic model was constructed for the uptake, metabolism, and clearance of 1,3-butadiene (BD) and its principal metabolite, 1,2-epoxy-3-butene (EB). This model showed that differences in tissue dosimetry of EB are not sufficiently large to account for differences in tumor response between rats and mice exposed to BD. Recent models demonstrate the need for greater anatomical realism and fuller characterization of the enzymology and cofactor changes that are involved in the biotransformation processes.