Implementing AOPs use for pesticide neurotoxicity assessment

Due to the unique characteristics of the nervous system, chemical exposures pose significant challenges in establishing definitive links to neurological adverse health effects. The key obstacles to neurotoxicity assessment include the complexity of the nervous system, species differences, extended developmental time, and cumulative exposure risks. Regulatory agencies have long required neurotoxicity testing, which has relied primarily on animal models. With increased mechanistic understanding and technological progress, other approaches become possible that could address some of the limitations of traditional neurotoxicity testing (e.g. high cost, ethical concerns, low precision, or human relevance). Recent international efforts to develop adverse outcome pathways (AOPs) and AOP-informed Integrated Approaches to Testing and Assessment offer new possibilities for neurotoxicity testing and assessment. This mini review highlights the advances, while addressing limitations, in the development and application of AOPs for both adult and developmental neurotoxicity as a way to address shortcomings in regulatory neurotoxicity assessment. Case studies are provided to illustrate the recent successful integration of AOPs into regulatory decision-making for pesticide risk assessment.