Adverse outcome pathway networks as the basis for the development of new approach methodologies: Liver toxicity as a case study

The fields of toxicology and risk assessment are witnessing a paradigm shift moving away from animal testing towards the use of nonanimal and human-based new approach methodologies (NAMs). NAMs are fed by mechanistic information captured in adverse outcome pathway (AOP) networks, which are being developed and optimized at high pace. The present paper demonstrates this (r)evolution for the case of liver toxicity induced by pharmaceutical drugs. NAMs, in casu designed to predict hepatotoxicity, are composed of an in vitro system linked with a suite of assays mechanistically anchored in relevant AOP networks. These NAMs allow tiered testing at the transcriptional, translational and functionality level at high predictive capacity. Although promising, however, several challenges in NAM development still need to be tackled and are discussed in this paper.