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ICCVAM Biennial Report 2018-2019

Biennial Progress Report 2018-2019 Interagency Coordinating Committee on the Validation of Alternative Methods
https://ntp.niehs.nih.gov/go/892662

Predictive Modeling of Developmental Toxicity with Human Pluripotent Stem Cells

FDA and NICEATM scientists applied IVIVE to evaluate the impact of pharmacokinetics and different modeling approaches on predicting relevant external exposure from in vitro developmental toxicity potential concentrations derived from an in vitro human iPSC-based assay. Previous work showed that the devTOX quick Predict assay ranked the developmental toxicity potential of valproate analogues in a manner that was consistent with observed developmental toxicity potency in vivo. The IVIVE analysis in this project estimated equivalent administered doses that would result in maternal blood concentrations equivalent to the developmental toxicity potential and cytotoxic in vitro concentrations. The estimated equivalent administered doses were compared to published lowest effect levels from in vivo developmental toxicity studies. Preliminary results of this analysis showed close agreement between equivalent administered doses and in vivo rat lowest effect levels for two valproate analogues. This suggested that the devTOX quick Predict assay and IVIVE approaches can quantitatively predict in vivo developmental toxicity potential. An abstract describing this work (Chang et al.) was accepted for a presentation at the Society of Toxicology 2020 annual meeting.

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