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

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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.