Triage of Developmental and Reproductive Toxicants using an In vitro to In Vivo Extrapolation (IVIVE)-Toxicokinetic Computational modeling Application

项目摘要 环境化学品的安全评估正在发生重大转变。这种转变包括减少， 或在某些情况下消除传统的动物毒性试验， 方法（NAMs）。虽然这些新兴的NAM为识别致畸剂提供了一种有吸引力的手段 和其他发育毒物，缺乏一个定量框架， 人体体内的等效接触限制了它们在公共卫生方面的使用。在这里，我们开发了一种分层方法， 将现有的妊娠药代动力学模型整合到可调整的计算应用程序中 目前和新出现的NAM的发育毒性。拟议项目的主要目的是提供 一个开箱即用的计算解决方案，用于预测可能的人类健康影响的剂量反应， 进行体外至体内外推（IVIVE）。在具体目标1中，我们将设计一个基于Web的计算 用于发育和生殖体外至体内外推的DRIIVE应用程序，将执行 在分层模型内使用基于生理学的药代动力学（PBPK）建模的正向或反向剂量测定 一个连接生物复杂性多个层次的框架。这一框架将使我们能够更好地解释 与环境毒物有关的化学品空间和接触途径。在具体目标2中， 最终通过案例研究，通过定义的IVIVE工作流程获取行业相关化合物， 将结果与活体数据进行比较。我们的建议将减少对目前体内发育的依赖， 这是一个非常重要的框架，为下一代化学品安全评估提供了一个非常需要的框架。 第一阶段项目的成功完成将产生一个模型，该模型将得到进一步的发展， 我们将在第二阶段进行商业化，最终目标是为我们的客户提供IVIVE计算模型。 这种发育毒性产品适合我们提供的现有NAM产品， 目前的体内动物模型。

PROJECT SUMMARY A significant shift in the safety assessment of environmental chemicals is ongoing. This shift includes a reduction, or in some cases elimination, of traditional toxicity testing in animals with the implementation of new approach methodologies (NAMs). Although these emerging NAMs provide an attractive means for identifying teratogens and other developmental toxicants, the absence of a quantitative framework for relating in vitro effects to equivalent in vivo human exposures limits their use for public health. Here, we develop a tiered approach that integrates existing pharmacokinetic models for pregnancy into a computational application that can be adapted to current and emerging NAMs for developmental toxicity. The primary aim of the proposed project is to deliver an out-of-the-box computational solution for predicting the dose-response of possible human health effects by performing in vitro-to-in vivo extrapolation (IVIVE). In Specific Aim 1, we will design a web based computational application, DRIIVE for the Developmental and Reproductive In Vitro to In vivo Extrapolation, that will perform forward- or reverse-dosimetry using physiologically based pharmacokinetic (PBPK) modeling within a tiered framework bridging multiple levels of biological complexity. This framework will allow us to better account for chemical space and exposure routes relevant to environmental toxicants. In Specific Aim 2, the work will culminate in a case study to take industry-relevant compounds through the defined IVIVE workflows and compare the outcomes to in-life data. Our proposal will reduce the reliance on current in vivo developmental toxicity and provide a much-needed framework for the next generation of chemical safety assessment. Successful completion of this Phase I project will result in a model that will undergo further development and commercialization in Phase II, with the ultimate goal of providing an IVIVE computational model to our customers. This developmental toxicity product fits into the existing NAM products that we offer that reduce reliance on current in vivo animal models.