Application of in vitro to in vivo extrapolation (IVIVE) to inform chemical health guidance value derivation—sample case studies comparing neuro-, hepato-, and developmental toxicities

Traditional chemical risk assessment is often based on published mammalian in vivo toxicity data, which are used to identify a point-of-departure (PoD) to derive the minimal risk level (MRL) and similar health guidance values. However, time and resource requirements prohibit efficient multi-target-organ toxicity assessments for a large number of environmental chemical pollutants. In vitro high-throughput screening assays and other new approach methodologies could address this problem by using reverse dosimetry to contextualize activity concentrations obtained from the in vitro assays to in vivo settings. In this study, we selected sample priority of diverse chemicals for which both curated high-throughput screening (cHTS) assay data and acute oral MRLs were available for neurotoxicity, hepatotoxicity, and developmental toxicity. We obtained in vitro activity concentrations for these chemicals and conducted in vitro to in vivo extrapolation (IVIVE) to estimate the daily equivalent administered dose (EAD) that would result in rat or human plasma concentrations equivalent to the in vitro activity concentrations. The range of EAD values across various cHTS assays was then compared with in vivo PoDs, MRLs, and predicted human exposure levels. Although variations existed depending on toxicity endpoints evaluated, our results showed that PoDs for a majority of chemicals can be predicted using such data. Our results also demonstrated that a majority of MRL and EAD values fall well below predicted human exposure levels. In summary, our findings demonstrate the usefulness and limitations of using cHTS data and IVIVE approaches for the derivation of health guidance values.