Applying httk and in vitro data to estimate acute neurotoxicity risk
Neurotoxicity is of particular concern for the military due to the potential for cognitive, behavioral, and physiological effects. With an ever-evolving operational landscape, de novo generation of in vivo data for all potential neurotoxicants is not feasible. USAF Predictive Risk Team (PRT) evaluated the utility of high-throughput new approach methodologies (NAMs) for rapid risk assessment of 220 potentially neurotoxic chemicals. Chemical-specific point-of-departure (PODs) were derived from novel in vitro neuronal assay data and ToxCast bioactivity concentrations. The AC50 (concentration with 50% maximum activity) was derived for each chemical/assay combination and PODs were calculated from the 5th percentile of the AC50 values. In vitro to in vivo extrapolation (IVIVE) was performed using the EPA httk model to estimate the equivalent administered dose (EAD) for each POD. Monte Carlo calculations from httk were modified to reflect USAF active-duty demographics. Neurotoxicity-associated endpoints produced higher PODs compared to all CompTox in vitro endpoints combined. In vitro-derived EADs were lower than in vivo-derived PODs for most of the chemicals in both the U.S. and USAF populations. In vitro-derived EADs were also lower than 45% of provisional reference doses calculated using one-year Military Exposure Guideline procedures. An uncertainty factor of 1000 results in conservative estimated exposure limits (vs. Military Exposure Guidelines) for almost all the chemicals. This case study supports the use of NAMs to derive conservative PODs for risk assessment. A manuscript is currently being prepared for publication in 2024.