Gene expression analysis in human cells as cornerstone of an integrated testing strategy in genetic toxicology

Genotoxicity is a key endpoint in the hazard assessment of any chemical as damage to the genetic material might lead to detrimental effects on human health. To assess the potential of chemicals to induce genotoxicity many in vitro and in vivo tests have been developed. Regulatory bodies worldwide recommend, in a first tier, to apply a battery of in vitro tests to cover the most important genotoxicity endpoints. If needed, this is followed up by in vivo genotoxicity studies. By the introduction of an animal testing and marketing ban in the European cosmetic sector, in vitro tests - backed-up by in chimico and in silico data - had to become the sole predictor of possible genotoxic properties of cosmetic compounds. Yet over the years discrepancies were noticed between the in vitro and in vivo genotoxicity results. The multitude of positive results found in the in vitro tests could often not be confirmed in vivo. In this dissertation we present the development of a qPCR-array, based on an 84-gene fingerprint subtracted from gene expression analyses on microarrays. This allows to identify genotoxic compounds based on mechanistic information. Furthermore, we investigated how this qPCR array and other non-animal-based strategies can be integrated in a testing strategy to improve the overall genotoxicity hazard assessment.