Comparison of physiologically based pharmacokinetic modeling platforms for developmental neurotoxicity in vitro to in vivo extrapolation

An extensive battery of 17 in vitro assays has been developed for assessing developmental neurotoxicity (DNT), with the aim of replacing or supplementing traditional in vivo guideline studies for risk assessment, as these mechanistic assays provide advantages over costly, lengthy in vivo studies. However, 1 major challenge in employing in vitro assays is the translation of in vitro bioactive concentrations into in vivo doses that can be compared with human exposures. This study describes an in vitro to in vivo extrapolation (IVIVE) approach to derive human-relevant administered equivalent doses based on chemical partitioning into DNT target organs during the critical period of brain development. We used data from chemicals previously found to elicit bioactivity in a subset (7 of 17) of the in vitro DNT battery assays conducted at the US Environmental Protection Agency. Three physiologically based pharmacokinetic modeling platforms were evaluated for their suitability for this DNT-IVIVE approach. Chemical predictions for administered equivalent doses were compared against in vivo effect levels, where available, and found to be within 3-fold for 78% of chemicals. To provide metrics for risk assessment considerations, administered equivalent doses were compared with predicted human exposures. Overall, this DNT-IVIVE approach was found to be relatively transferable among modeling platforms, albeit with varying limitations and considerations that should be taken into account for specific contexts of use.