In vitro and in silico testing strategies for predicting human liver toxicity

Increasing numbers of chemicals are registered at federal agencies of which most of them have little or lack any toxicity data at all. Their potential impact on human health is therefore not well investigated. With the widely acknowledged incentive of reducing and replacing animal studies in toxicity testing, sophisticated in vitro and in silico model are needed to perform hazard screening of thousands of chemicals. As the liver is a major organ exposed to xenobiotics and its metabolites, it makes it susceptible for chemically induced liver disease. Nonalcoholic fatty liver disease (NAFLD) is a global burden affecting about 25% of the general adult population. Drugs and environmental chemical exposure (e.g. pesticides) is an emerging risk factor of NAFLD, besides the most common one including obesity, type 2 diabetes and genetics. With its link to obesity and metabolic disorders, food-related chemical exposure is suggested to contribute to NAFLD risk. However, due to limited in vitro and in silico models, a systematic assessment of the risk of chemicals to induce NAFLD is lacking. The work summarized in this thesis described the development of a systems toxicology platform to predict the risk of chemicals to induce NAFLD. The obtained knowledge provided a proof-of-concept for the use of in vitro and in silico models in hazard identification and toxicity testing in the context of chemically induced NAFLD.