Applying Chemical Engineering Concepts to Toxicology

八甲基环四硅氧烷（D4）和十甲基环五硅氧烷（DS）是个人护理产品中常见的添加剂。D4和D5都是易挥发的亲脂性化学物质，可以通过皮肤和肺部吸收。暴露于D4导致肝脏酶诱导，类似于暴露于苯巴比妥导致的酶诱导。接触D5会导致大鼠肺部中毒。然而，目前尚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中发生，必须确定化合物的作用方式以及作用于目标组织的剂量与反应之间的关系。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使用化学工程方法建立基于生理的药代动力学（PBPK）模型，用于估计大鼠和人靶组织中的D4和D5浓度。为了实现这一目标，将文献中已有的D4和D5在大鼠体内分布的药代动力学数据与实验测量的PBPK模型参数（即组织：空气和血液：空气分配系数和生物转化动力学常数）相结合。由此得出的D4和D5在人体内分布的PBPK模型可用于评估这些化合物对人类构成的风险。

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.