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Tissue architecture and hepatic cell morphology reflect the functional differentiation of the liver. In vivo, differentiated functions of hepatocytes, depend on complex, heterotypic cell-cell/cell-matrix interactions. The development of in vitro organotypic human hepatic models which mimic these aspects of the liver will prove invaluable for preclinical toxicology and chemical safety studies. Here I will present a brief overview of our work highlighting approaches for in vitro modelling for safety assessment of drugs (such as paracetamol) and nanomaterials (such as ZnO) – using human HepaRG cells - a unique intrinsic co-culture of hepatocytes and cholangiocytes derived from hepatic progenitor cells.