Application of an Accessible Interface for Pharmacokinetic Modeling and to Extrapolation.

Regulatory toxicology testing has traditionally relied on methods to inform decision-making. However, scientific, practical, and ethical considerations have led to an increased interest in the use of and in silico methods to fill data gaps. While experiments have the advantage of rapid application across large chemical sets, interpretation of data coming from these non-animal methods can be challenging due to the mechanistic nature of many assays. to extrapolation (IVIVE) has emerged as a computational tool to help facilitate this task. Specifically, IVIVE uses physiologically based pharmacokinetic (PBPK) models to estimate tissue-level chemical concentrations based on various dosing parameters. This approach is used to estimate the administered dose needed to achieve bioactivity concentrations within the body. IVIVE results can be useful to inform on metrics such as margin of exposure or to prioritize potential chemicals of concern, but the PBPK models used in this approach have extensive data requirements. Thus, access to input parameters, as well as the technical requirements of applying and interpreting models, has limited the use of IVIVE as a routine part of testing. As interest in using non-animal methods for regulatory and research contexts continues to grow, our perspective is that access to computational support tools for PBPK modeling and IVIVE will be essential for facilitating broader application and acceptance of these techniques, as well as for encouraging the most scientifically sound interpretation of results. We highlight recent developments in two open-access computational support tools for PBPK modeling and IVIVE accessible the Integrated Chemical Environment (https://ice.ntp.niehs.nih.gov/), demonstrate the types of insights these tools can provide, and discuss how these analyses may inform in vitro-based decision making.