Applying Chemical Engineering Concepts to Toxicology

将化学工程概念应用于毒理学

• 批准号: 6524834
• 负责人: MICAELA B REDDY
• 金额: $ 3万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6524834
• 关键词: bioengineering /biomedical engineering; biotransformation; carcinogenesis; chemical kinetics; chemical models; chemical related neoplasm /cancer; dosage; drug metabolism; environmental toxicology; human tissue; inhalation drug administration; laboratory rat; model design /development; pharmacokinetics; polymers; silicon compounds

Octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (DS) are common additives in personal care products. Both D4 and D5 are volatile, lipophilic chemicals that can be absorbed through the skin and lungs. Exposure to D4 has resulted in enzyme induction in the liver similar to that resulting from exposure to phenobarbital. Exposure to D5 has resulted in toxicity in the lung of the rat. However, it is not clear if these compounds will have similar effects in humans. To determine if these health effects are likely to occur in humans as well as rats, the mode of action of the compounds and the relationship between dose at the target tissue and response must be determined. As a first step to determining the mode of action and dose-response relationship, the major goal of this research project is to use chemical engineering methodolgies to develop physiologically based pharmacokinetic (PBPK) models for estimating D4 and D5 concentrations at the target tissue in both rats and humans. To achieve this goal, existing pharmacokinetic data for D4 and D5 distribution in the rat from the literature will be used in combination with PBPK model parameters measured experimentally (i.e., tissue:air and blood:air partition coefficients and kinetic constants for biotransformation). The resulting PBPK models for D4 and D5 distribution in humans can be used to assess the risk these compounds pose to humans.

八甲基环四硅氧烷(D4)和十甲基环戊基硅氧烷(DS)是个人护理产品中常见的添加剂。D4和D5都是挥发性、亲脂性化学物质，可以通过皮肤和肺部吸收。暴露于D4可导致肝脏中的酶诱导，与暴露于苯巴比妥的结果相似。暴露于D5对大鼠的肺部有毒性。然而，目前还不清楚这些化合物是否会对人类产生类似的影响。为了确定这些健康影响是否可能在人类和大鼠身上发生，必须确定化合物的作用模式以及目标组织剂量和反应之间的关系。作为确定作用模式和剂量-反应关系的第一步，本研究项目的主要目标是利用化学工程方法建立基于生理的药代动力学(PBPK)模型，以估计D4和D5在大鼠和人类靶组织中的浓度。为了实现这一目标，将使用文献中现有的D4和D5在大鼠体内的药代动力学数据，并结合实验测量的PBPK模型参数(即组织：空气和血液：空气分配系数和生物转化的动力学常数)。由此得到的人体内D4和D5分布的PBPK模型可用于评估这些化合物对人类构成的风险。