Application of non-animal methods to more effective neurotoxicity testing for regulatory purposes

Abstract

The identification of chemicals that have the potential to induce developmental or adult neurotoxicity is currently entirely based on animal testing. At the regulatory level, systematic testing of developmental (DNT) and adult (NT) neurotoxicity is not a standard requirement within the EU legislation of chemical safety assessment, except for pesticides where NT testing is required. Both DNT and NT evaluation are only performed when triggered based on structure-activity relationships or evidence of neurotoxicity in systemic adult, developmental, or reproduction studies. However, these triggers are rarely used as to date only a limited amount of chemicals have been tested for either DNT or NT effects. Furthermore, the animal-based regulatory DNT or NT studies are unsuitable for screening large number of chemicals, since they are low throughput and costly and use large number of animals. Therefore, new, reliable, and efficient screening and assessment tools are needed for better identification, prioritization, and evaluation of chemicals with potential to induce neurotoxicity. A new framework is proposed for the development of a mechanistically informed IATA (Integrated Approaches to Testing and Assessment) which would integrate various sources of information (e.g., in vitro approaches, in silico modeling, mechanistic knowledge built in the relevant adverse outcome pathways, etc.) as well as in vivo animal and human data, speeding up the evaluation of thousands of compounds present in industrial, agricultural, and consumer products that lack safety data on NT and DNT potential.