AUTHOR=Moreau Marjory , Mallick Pankajini , Smeltz Marci , Haider Saad , Nicolas Chantel I. , Pendse Salil N. , Leonard Jeremy A. , Linakis Matthew W. , McMullen Patrick D. , Clewell Rebecca A. , Clewell Harvey J. , Yoon Miyoung TITLE=Considerations for Improving Metabolism Predictions for In Vitro to In Vivo Extrapolation JOURNAL=Frontiers in Toxicology VOLUME=4 YEAR=2022 URL=https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2022.894569 DOI=10.3389/ftox.2022.894569 ISSN=2673-3080 ABSTRACT=

High-throughput (HT) in vitro to in vivo extrapolation (IVIVE) is an integral component in new approach method (NAM)-based risk assessment paradigms, for rapidly translating in vitro toxicity assay results into the context of in vivo exposure. When coupled with rapid exposure predictions, HT-IVIVE supports the use of HT in vitro assays for risk-based chemical prioritization. However, the reliability of prioritization based on HT bioactivity data and HT-IVIVE can be limited as the domain of applicability of current HT-IVIVE is generally restricted to intrinsic clearance measured primarily in pharmaceutical compounds. Further, current approaches only consider parent chemical toxicity. These limitations occur because current state-of-the-art HT prediction tools for clearance and metabolite kinetics do not provide reliable data to support HT-IVIVE. This paper discusses current challenges in implementation of IVIVE for prioritization and risk assessment and recommends a path forward for addressing the most pressing needs and expanding the utility of IVIVE.