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ICCVAM Biennial Report 2018-2019

Biennial Progress Report 2018-2019 Interagency Coordinating Committee on the Validation of Alternative Methods

Optimization of Pharmacokinetic Models for In Vitro to In Vivo Extrapolation of Estrogenic Activity

NIEHS scientists evaluated and optimized IVIVE approaches using in vitro estrogen receptor activity to predict estrogenic effects measured in rodent uterotrophic studies. This work (Casey et al. 2018) evaluated the use of three PK models with varying complexities to extrapolate in vitro to in vivo dosimetry for 29 estrogen receptor agonists using data from validated in vitro and in vivo methods. In vitro activity values were adjusted using mass-balance equations to estimate intracellular exposure via an enrichment factor, and steady-state model calculations were adjusted using fraction of unbound chemical in the plasma to approximate bioavailability. Accuracy of each model-adjustment combination was assessed by comparing model predictions with lowest effect levels from guideline uterotrophic studies. The comparison found little difference in model predictive performance based on complexity or route-specific modifications. Simple adjustments, such as using the enrichment factor to account for in vitro intracellular exposure or fraction of unbound chemical to account for chemical bioavailability, resulted in significant improvements in the predictive performance of all models. The resulting computational IVIVE approaches accurately estimated chemical exposure levels that elicit positive responses in the rodent uterotrophic bioassay. Such studies are important for establishing confidence in the quantitative extrapolation of in vitro activity to relevant end points in animals or humans.