Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards

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