Derivation, characterisation and analysis of an adverse outcome pathway network for human hepatotoxicity

Adverse outcome pathways (AOPs) and their networks are important tools for the development of mechanistically based non-animal testing approaches, such as in vitro and/or in silico assays, to assess toxicity induced by chemicals. In the present study, an AOP network connecting 14 linear AOPs related to human hepatotoxicity, currently available in the AOP-Wiki, was derived according to established criteria. The derived AOP network was characterised and analysed with regard to its structure and topological features. In-depth analysis of the AOP network showed that cell injury/death, oxidative stress, mitochondrial dysfunction and accumulation of fatty acids are the most highly connected and central key events. Consequently, these key events may be considered as the rational and mechanistically anchored basis for selecting, developing and/optimising in vitro and/or in silico assays to predict hepatotoxicity induced by chemicals in view of animal-free hazard identification