In Vitro to In Vivo Extrapolation

A workflow for conducting in vitro to in vivo extrapolation (IVIVE) analyses is available in the Integrated Chemical Environment (ICE). Recent updates to ICE have improved the IVIVE tool. ICE now allows users to upload their own in vitro data for IVIVE analyses, as well as their own in vivo data for comparison to IVIVE outputs. Other improvements include help videos, an inhalation model from the EPA httk package, improved output graphics, selection of assays based on mode of action, and options to specify use of experimental or predicted data for certain input parameters.

A key issue with high-throughput in vitro testing methods is how to accurately relate concentrations of substances that induce in vitro responses to in vivo exposure levels that could result in human or animal adverse effects. This relationship is established through IVIVE, the focus of a webinar series and following workshop presented by NICEATM and EPA during 2015 and 2016. Scientists interested in the use of IVIVE for substance screening and risk decision-making met at the 2016 workshop to develop best practices and identify areas for further research (Bell et al. 2018).

NICEATM's computational toxicologists developed methods for conducting IVIVE analyses (Chang et al. 2014). Subsequent work focused on understanding the impact of various parameters, such as using free plasma concentration as a surrogate for total plasma concentration, and comparing multiple modeling approaches (Casey et al. 2018).

NICEATM is applying IVIVE approaches to predict the potential of substances to cause developmental toxicity. Current work is evaluating the impact of pharmacokinetics and different modeling approaches on predicting relevant external exposure. Results using data from a specific in vitro stem cell-based assay as input for IVIVE suggest that these approaches could quantitatively predict in vivo developmental toxicity potential of valproate analogues (Chang et al. 2022a); more recent work in this area was presented at the 2024 Society of Toxicology annual meeting (Chang et al., Mathematical Modeling session; Kreutz et al., Neurotoxicity:Developmental II session).

NICEATM is also incorporating adverse outcome pathway information into an IVIVE approach to predict in vivo points of departure for sensitization endpoints that might be caused by inhaled substances. A poster presentation at the 12th World Congress on Alternatives and Animal Use in the Life Sciences (Chang et al., 21st Century Predictive Toxicology session) summarizes recent NICEATM investigations into using IVIVE for predicting inhalation toxicity.

ICCVAM established an IVIVE workgroup to catalog and evaluate currently available IVIVE approaches, to determine their suitability for specific research or regulatory purposes, and to assess whether additional tools or models are needed. A review produced by the workgroup (Chang et al. 2022b) proposes operational definitions for IVIVE, presents literature examples for several common toxicity endpoints, and highlights their implications in decision-making processes across various federal agencies, as well as international organizations.