TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS

这个项目旨在描述剂量的参数， 外来物质的分布、代谢和消除。这 信息可以帮助设计和解释毒理学 研究和加强低剂量外推的科学基础 对人类的威胁。此外，生物现实的生物数学 模型提供了一种严密的结构来制定和测试假设 环境危害的作用机制。毒物动力学模型可以 也要适应不同的暴露途径和给药方案 可以适应导致个体间差异的因素。 在上一财年，创建了毒物动力学模型或 国家开发局正在研究的近20种化学物质的部分开发 毒理学计划(NTP)。更深入的生理学基础 建立了药物摄取、代谢和代谢的动力学模型。 1，3-丁二烯(BD)及其主要代谢物的清除 1，2-环氧丁烯(EB)。这一模型表明，组织中的差异 电子束的剂量学不够大，不足以解释 BD染毒大鼠和小鼠的肿瘤反应。最新型号 展示对更大的解剖现实主义和更完整的需求 所涉及的酶学和辅因子变化的特征 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.