Probabilistic Reference and 10% Effect Concentrations for Characterizing Inhalation Non-cancer and Developmental/Reproductive Effects for 2,160 Substances.

Chemicals assessment and management frameworks rely on regulatory toxicity values, which are based on points of departure (POD) identified following rigorous dose-response assessments. Yet, regulatory PODs and toxicity values for inhalation exposure (i.e., reference concentrations [RfCs]) are available for only ∼200 chemicals. To address this gap, we applied a workflow to determine surrogate inhalation route PODs and corresponding toxicity values, where regulatory assessments are lacking. We curated and selected inhalation in vivo data from the U.S. EPA's ToxValDB and adjusted reported effect values to chronic human equivalent benchmark concentrations (BMC(h)) following the WHO/IPCS framework. Using ToxValDB chemicals with existing PODs associated with regulatory toxicity values, we found that the 25th %-ile of a chemical's BMC(h) distribution (PODp25BMCh) could serve as a suitable surrogate for regulatory PODs (Q(2) ≥ 0.76, RSE ≤ 0.82 log(10) units). We applied this approach to derive PODp25BMCh for 2,095 substances with general non-cancer toxicity effects and 638 substances with reproductive/developmental toxicity effects, yielding a total coverage of 2,160 substances. From these PODp25BMCh, we derived probabilistic RfCs and human population effect concentrations. With this work, we have expanded the number of chemicals with toxicity values available, thereby enabling a much broader coverage for inhalation risk and impact assessment.