In vitro data combined with human disease data to improve toxicological hazard assessment: the ASAT Knowledge Base

In line with the Assuring Safety Without Animal Testing (ASAT) principle, risk assessment may ultimately become feasible without the use of animals (Fentem et al., 2004). ASAT assumes that activation of human disease mechanisms in in vitro models can be used for toxicological assessment. Therefore, goal of the present research was to demonstrate the integration of public data from the human disease domain with in vitro toxicology. Two diseases, associated with chemical exposure, were concerned: hepatocellular carcinoma and allergic contact dermatitis (ACD). Data were retrieved from online sources (e.g., GEO, CTD) and expert knowledge. A Knowledge Base for curation, storage and modelling of the data was developed. Using the Knowledge Base for ACD, it was possible to discern sensitizing from non-sensitizing chemicals, as defined by enrichment of disease gene sets in in vitro toxicogenomics datasets. Interestingly, the strongest sensitizers most profoundly activated these gene sets. The ongoing incorporation of (reverse) PBPK models in the Knowledge Base to judge the relevance of in vitro concentrations, in relation to realistic in vivo exposure scenarios, will be presented. Finally, the expansion with models towards other disease areas (cholestasis) will be discussed.