Develop an in vitro test battery to test for metabolic clearance rates and hepatotoxicity of industrial chemicals for different species and use the data as input parameters in corresponding PBPK models as an alternative for toxicity testing on animal models.

To set-up a liver cell assay test battery, the metabolic capacity of the new human liver cell line, HepaRG, is optimized using different culturing methods. The cell line is then used in conjunction with canine and rat liver progenitor cells in a hepatotoxicity test battery with model drugs and industrial organic chemicals. Results are compared to those obtained from test batteries with primary hepatocytes and liver slices. The test battery is also used to derive species specific intrinsic clearance input data for PBPK models.

Chemical-induced liver injury remains a significant issue in pharmaceutical development and chemical safety testing. One reason for this is that toxicological and pharmacological assessments of hepatotoxic risks of chemicals in humans rely on the extrapolation from rodent and non-rodent studies. However, xenobiotic biotransformation enzymes patterns and pathways vary across species and within populations leading to differences in metabolite formation and rates. Translational research models are therefore emerging which begin to bridge the gap between animal studies and human risk assessment. Major breakthroughs in this area include the advancement of organotypic in vitro models and the integration of in vitro data with in silico modeling to provide insight into species and individual specific chemical disposition and metabolism.

A-Cute-Tox, Predict-IV, CEllSens