Supplementary data for: 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
(HTS) assays and other new approach methodologies (NAMs) 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 a 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 to in
vivo PoDs, MRLs, and predicted human exposure levels. Although variations
existed depending on the 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.