Investigating open access new approach methods (NAM) to assess biological points of departure: A case study with 4 neurotoxic pesticides

Open access new approach methods (NAM) in the US EPA ToxCast program and NTP Integrated Chemical Environment (ICE) were used to investigate activities of four neurotoxic pesticides: endosulfan, fipronil, propyzamide and carbaryl. Concordance of in vivo regulatory points of departure (POD) adjusted for interspecies extrapolation (AdjPOD) to modelled human Administered Equivalent Dose (AEDHuman) was assessed using 3-compartment or Adult/Fetal PBTK in vitro to in vivo extrapolation. Model inputs were from Tier 1 (High throughput transcriptomics: HTTr, high throughput phenotypic profiling: HTPP) and Tier 2 (single target: ToxCast) assays. HTTr identified gene expression signatures associated with potential neurotoxicity for endosulfan, propyzamide and carbaryl in non-neuronal MCF-7 and HepaRG cells. The HTPP assay in U-2 OS cells detected potent effects on DNA endpoints for endosulfan and carbaryl, and mitochondria with fipronil (propyzamide was inactive). The most potent ToxCast assays were concordant with specific components of each chemical mode of action (MOA). Predictive adult IVIVE models produced fold differences (FD)