Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and...

A computational framework was developed to assist in screening and prioritizing chemicals based on their dosimetry, toxicity, and potential exposures. The overall strategy started with contextualizing chemical activity observed in high-throughput toxicity screening (HTS) by mapping these assays to biological events described in Adverse Outcome Pathways (AOPs). Next, in vitro to in vivo (IVIVE) extrapolation was used to convert an in vitro dose to an external exposure level, which was compared with potential exposure levels to derive an AOP-based margins of exposure (MOE). In this study, the framework was applied to estimate MOEs for chemicals that can potentially cause developmental toxicity following a putative AOP for fetal vasculogenesis/angiogenesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe chemical disposition during pregnancy, fetal, neonatal, and infant to adulthood stages. Using this life-stage PBPK model, maternal exposures were estimated that would yield fetal blood levels equivalent to the chemical concentration that altered in vitro activity of selected HTS assays related to the most sensitive vasculogenesis/angiogenesis putative AOP. The resulting maternal exposure estimates were then compared with potential exposure levels using literature data or exposure models to derive AOP-based MOEs.