Refining in vitro and in silico neurotoxicity approaches by accounting for interspecies and interindividual differences in toxicodynamics

Abstract

Introduction: The process of chemical risk assessment traditionally relies on animal experiments and associated default uncertainty factors to account for interspecies and interindividual differences. To work toward a more precise and personalized risk assessment, these uncertainty factors should be refined and replaced by chemical-specific adjustment factors (CSAFs). Areas covered: This concise review discusses alternative (in vitro/in silico) approaches that can be used to assess interspecies and interindividual differences in toxicodynamics, ranging from targeted to more integrated approaches. Although data are available on interspecies differences, the increasing use of human-induced pluripotent stem cell (hiPSC)-derived neurons may provide opportunities to also assess interindividual variability in neurotoxicity. More integrated approaches, like adverse outcome pathways (AOPs) can provide a more quantitative understanding of the toxicodynamics of a chemical. Expert opinion: To improve chemical risk assessment, refinement of uncertainty factors is crucial. In vitro and in silico models can facilitate the development of CSAFs, but still these models cannot always capture the complexity of the in vivo situation, thereby potentially hampering regulatory acceptance. The combined use of more integrated approaches, like AOPs and physiologically based kinetic models, can aid in structuring data and increasing suitability of alternative approaches for regulatory purposes.