Prioritizing chemicals for developmental neurotoxicity by integrating data from a new approach methods (NAMs) battery...

Thousands of chemicals have not been assessed for developmental neurotoxicity (DNT) despite potential human exposure, prompting efforts to screen chemicals for possible DNT hazard using in vitro approaches. Ninety-five chemicals were screened in in a battery including in vitro assays covering the key neurodevelopmental processes (KNDPs) of proliferation, apoptosis, cell migration, neuronal differentiation, neurite outgrowth, neuronal maturation and synaptogenesis, oligodendrocyte differentiation, and network formation using human and rat (primary cortical) cells. An in vivo assay of zebrafish neurobehavior was also included. This assay battery was sensitive enough to detect effects in the neurodevelopmental processes modeled. The chemicals comprised negative controls and several use classes: drugs, flame retardants, fungicides, herbicides, industrial chemicals (including PFAS), and insecticides. A data analysis pipeline was developed using a benchmark concentration approach and included multi-objective optimization (Pareto) and ToxPi analysis to integrate data from the individual assays to evaluate DNT hazard and prioritize chemicals, ranking them for further evaluation. Although the zebrafish assay was the most sensitive for detecting potency, selectivity varies significantly by assay and chemical class with neurite outgrowth assays and fungicides exhibiting the highest percentage of selective hits. Chemicals from the fungicide, drug, and insecticide use classes had higher priority in the Pareto and ToxPi analysis based on having the most potent and selective activity in the assays. These prioritization methods represent a novel and useful approach for comparative evaluation of potential developmental neurotoxicity hazard in large groups of chemicals.