Assuring safety without animal testing concept (ASAT). Integration of human disease data with in vitro data to improve toxicology testing

According to the Assuring Safety Without Animal Testing (ASAT) principle, risk assessment may ultimately become possible without the use of animals (Fentem et al., (2004). Altern. Lab. Anim. 32, 617-623). The ASAT concept takes human disease mechanisms as starting point and tries to define if activation of these mechanisms by chemical exposure in in vitro models can be used for toxicological risk assessment. The goal of the present research was to study if integration of public data, from human diseases and in vitro toxicology, is possible at the data level. Two human diseases, associated with chemical exposure, were included: human hepatocellular carcinoma and allergic contact dermatitis (ACD). Data were retrieved from expert knowledge and different online sources (e.g. GEO, ArrayExpress) and a Knowledge Base for storage and modelling of the data was established. Using the Knowledge Base for ACD, it was possible to discern sensitizing from non-sensitizing compounds, as defined by enrichment of clinically defined disease gene sets in in vitro genomics datasets. In addition, the strongest sensitizers most profoundly activated these gene sets. During the presentation, the Knowledge Base will be shown. In addition, the ongoing incorporation of (reverse) kinetic modelling to judge the relevance of in vitro concentrations, in relation to realistic in vivo exposure scenarios, will be illustrated. Finally, the expansion towards the development of data models for other disease areas (cholestasis) will be discussed.