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.
Startdatum: 21 september 2010
Prof. dr. G.M.M. Groothuis
Projectleider en penvoerder, Rijksuniversiteit Groningen
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