Project: Risk assessment of liver toxicity without animal data: towards an integrated in vitro-in silico approach combining toxicogenomics, in vitro molecular toxicology and target tissue exposure modelling. A case study on paracetamol.

Risk assessment of liver toxicity without animal data: towards an integrated in vitro-in silico approach combining toxicogenomics, in vitro molecular toxicology and target tissue exposure modelling. A case study on paracetamol.

This is a summary of the request.

This pilot project will explore the feasibility for risk assesment for liver toxicity by xenobiotics, without the use of animal models, by deriving dose-response relations of human liver toxicity based on human in vitro data on exposure of the target cells as well as on mechanism-based hazard identification. By applying a toxicogenomic approach to elucidate the molecular mechanisms-of-action as obtained through transcriptomic and metabolomic technologies, and mechanism-based physiologically-based toxicokinetic (PBTK) modelling of the target organ exposure to the toxicant, quantification of the risk of liver toxicity upon oral intake of normal/therapeutic doses is explored. Integration of kinetic data on intracellular generation of toxic metabolites and phase II metabolism and transporters with 'omics-based molecular response pathways, is a novel approach that is crucial for accurate human risk assessment. Paracetamol, as a well-known human hepatotoxicant, will be used for this exploration.

This combination of prediction of exposure, mechanism of action and dose-effect relationships using metabolomics and transcriptomics, will generate a powerful tool for closing the gaps between in vitro toxicity testing and prediction of in vivo toxicity in man at target organ level without animal use.