Project 3 Physiologically-based pharmacokinetic/pharmacodynamic modeling of C60

摘要 项目3的最终目标是为预测这些材料可能对母体、胎儿或新生儿心血管系统产生影响的人体暴露条件提供坚实的基础。本项目的研究方法基于一个假设，即一个适当的基于生理学的药代动力学和药效学（PBPK/PD）模型，用于工程药物的处置和作用。 一个物种中的纳米颗粒（ENM）可以用于为另一个物种（包括人类）提供定量预测。在这种情况下，将使用项目1和2的大鼠数据开发PBPK/PD模型，并使用项目2的小鼠数据测试模型的预测能力。通过纳入项目1的人类生物学和人类细胞数据，该模型将提供定量外推动物实验结果的能力，以表征人类毒性的可能性。纳米颗粒的PBPK模型的开发将以严格的，逐步的 方法，首先使用项目1期间收集的上皮细胞和内皮细胞（具体目标1）的体外数据，对与细胞摄取、定位和纳米颗粒清除相关的过程进行建模。在具体目标2中，细胞剂量测定模型将嵌入妊娠和哺乳期生理时间过程的PBPK描述中。项目2期间收集的体内处置数据将 用于确定模型的全身PK参数。我们认为，从体外数据开发的细胞剂量学模型将准确地描述在体内情况下的细胞剂量学。我们将使用来自项目2的体内组织处置数据来检验这一假设。将使用类似的逐步方法开发特定目标3中纳米颗粒暴露的各种直接和间接组织反应的PD模型。PD模型将被设计用于检验关于纳米材料心血管毒性的两个备选假设：1）直接诱导 纳米颗粒本身在靶细胞中的炎症反应和毒性，或2）由响应于纳米颗粒暴露于入口而产生的循环细胞因子介导的对血管内皮细胞的间接作用（例如，肺泡上皮细胞）。我们假设这两种机制都有助于纳米颗粒在不同靶组织中的毒性作用。 该项目的前两年将专注于开发大鼠PBPK/PD模型，以提供纳米材料在多种暴露途径（即，静脉内[i. v.]，口腔和吸气）和生命阶段（即，非妊娠成年动物、妊娠母鼠和胎仔、哺乳母鼠和幼鼠）。在这些实验条件下对靶组织剂量测定的比较将允许评价直接和间接毒性机制的相对贡献，并识别敏感的生命阶段。在第3年至第5年，将开发小鼠和人的PBPK/PD模型参数（具体目标4）。此外，我们的模型结构将为其他中心的主要研究者（PI）提供工具，以评估其他纳米颗粒的潜在全身分布和毒性。

Abstract The ultimate goal of Project 3 is to provide a firm basis for predicting exposure conditions in the human under which these materials could elicit effects in the maternal, fetal, or neonatal cardiovascular system. The research approach for this project is based on the hypothesis that an appropriate physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the disposition and effects ofthe engineered nanoparticles (ENMs) in one species can be used to provide quantitative predictions for another species, including the human. In this case, a PBPK/PD model will be developed using rat data from Projects 1 and 2, and the predictive power ofthe model will be tested using mouse data from Project 2. By incorporating human biology and data from human cells from Project 1, the model will provide a capability for quantitative extrapolation ofthe results of animal experiments to characterize the potential for human toxicity. The development ofthe PBPK model for nanoparticles will be conducted in a rigorous, step-wise manner, beginning with modeling ofthe processes associated with cellular uptake, localization, and clearance of nanoparticles using the in vitro data collected during Project 1 for epithelial and endothelial cells (Specific Aim 1). In Specific Aim 2, the cellular dosimetry model will be embedded in a PBPK description of the physiological time-course for gestation and lactation. The in vivo disposition data collected during Project 2 will be used to identify the whole-body PK parameters for the models. We posit that the cellular dosimetry model developed from in vitro data will accurately describe cellular dosimetry in the in vivo situation as well. We will test this hypothesis using in vivo tissue disposition data from Project 2. A similar step-wise approach will be used for the development of PD models of the various direct and indirect tissue responses to nanoparticle exposure in Specific Aim 3. The PD models will be designed to test two alternative hypotheses regarding cardiovascular toxicity of nanomaterials: either 1) direct induction of inflammatory responses and toxicity in target cells by the nanoparticles themselves, or 2) an indirect effect on vascular endothelial cells mediated by circulating cytokines produced in response to nanoparticle exposure in the portal of entry (e.g., alveolar epithelial cells). We hypothesize that both of these mechanisms contribute to the toxic effects of nanoparticles in different target tissues. The first 2 years of the project will focus on the development of the PBPK/PD model for the rat to provide a consistent description ofthe disposition and cardiovascular effects ofthe nanomaterials across multiple routes of exposure (i.e., intravenous [i.v.], oral, and inspirafion) and life stages (i.e., non-pregnant adult, pregnant dam and fetus, lactafing dam and pup). Comparison of target tissue dosimetry across these experimental condifions will allow evaluation ofthe relafive contribution ofthe direct and indirect mechanisms of toxicity and identification of susceptible life stages. In Years 3 through 5, PBPK/PD model parameterizations for the mouse and human will be developed (Specific Aim 4). In addition, our model structures will provide tools for Principal Investigators (Pis) in other centers to evaluate the potential systemic distribution and toxicity of other nanoparticles.