EXAMINING ORGANOPHOSPHATE POINTS OF DEPARTURE COMPARING DEVELOPMENTAL NEUROTOXICITY VERSUS ACETYLCHOLINESTERASE INHIBITION CONSIDERING TRADITIONAL, NEW APPROACH METHODOLOGIES AND PBPK-PD MODELS

Acephate, malathion and dimethoate (ACE/MAL/DIM) Organophosphate (OP) risk assessments have regulatory points of departure (POD) based on acetylcholinesterase inhibition (AChEI) in rat studies reported as Benchmark Dose analyses (BMD10) or PBPK-PD models using human parameters. The purpose of this study is to compare PODs among: 1) the rat developmental neurotoxicity (DNT) study; 2) the rat AChEI; 3) the open access in vitro acute neuroactive, DNT and neuronal toxic new approach methodologies (NAM-CompTox Chemicals Dashboard: CTCD) converted by Integrated Chemical Environment (ICE) by in vitro to in vivo models with Administered Equivalent Dose in Humans (AEDHuman) endpoints to see which method of assessment and which PODs are the most sensitive. The rat DNT PODs were the most sensitive for all three OPs. The ICE modeled PODs were more sensitive than the AChEI and PBPK-PD PODs for all but DIM, where the PBPK-PD model was the most sensitive POD. This was of interest because based on an older version of the CTCD the USEPA determined that DNT NAMs were less sensitive than AChEI as the major POD. This conclusion rationalized the reduction of child- protective safety factors based on a lack of neurotoxic evidence. This study examined newer NAM neuroactivity assays on the CTCD to obtain ICE modeled POD predictions to support a weight of evidence for DNT at values lower than the AChEI for each OPs. OP exposures in early development can negatively impact neurobehavioral functioning throughout life.