Relevance of Transcriptomics for Mode of Action Assessment.

Recently, we reported an toxicogenomics comparison approach to categorize chemical substances according to similarities in their proposed toxicological modes of action. Use of such an approach for regulatory purposes requires, among others, insight into the extent of biological concordance between and findings. To that end, we applied the comparison approach to transcriptomics data from the Open TG-GATEs database for 137 substances with diverging modes of action and evaluated the outcomes obtained for rat primary hepatocytes and for rat liver. The results showed that a relatively small number of matches observed were also observed , whereas quite a large number of matches between substances were found to be relevant solely or . The latter could not be explained by physicochemical properties, leading to insufficient bioavailability or poor water solubility. Nevertheless, pathway analyses indicated that for relevant matches the mechanisms perturbed are consistent with those perturbed . These findings support the utility of the comparison approach as tool in mechanism-based risk assessment.