TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS

危险物质的毒代动力学和生化模型

• 批准号: 6290095
• 负责人: RONALD L MELNICK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290095
• 关键词: biotransformation; chemical models; chemical structure function; drug /agent; drug adverse effect; drug metabolism; model design /development; pharmacokinetics; toxicology

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

工作总结：本项目旨在表征生物外源性物质的剂量、分布、代谢和消除参数。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、部分开发或扩展了几种化学品的毒代动力学模型，包括蒽醌、甲基丁香酚、扑米酮及其代谢物苯巴比妥、异戊二烯、异丁烯、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、褪黑激素以及吸入汞蒸气在怀孕大鼠和新生儿中的处置。蒽醌剂量测定模型的一个独特特征是其不寻常的吸收途径，其特征是从下肠道吸收，包装在乳糜微粒中，转运到淋巴中并转移到混合静脉血中，避免了首过肝脏代谢。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。对于甲基丁香酚，为大鼠和人类创建了基于生理学的药代动力学模型。人体模型在结构上与大鼠模型相似，基于从志愿者获得的血液甲基丁香酚数据，这些志愿者食用了含有甲基丁香酚的免费饼干。- 毒代动力学建模、靶器官剂量测定、消毒副产物、蒽醌、硼、异戊二烯、甲基丁香酚、扑米酮、羟甲烯龙-人类受试者