Relevance of <i>In Vitro</i> Transcriptomics for <i>In Vivo</i> Mode of Action Assessment

Recently, we reported an in vitro 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 in vitro and in vivo 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 in vitro were also observed in vivo, whereas quite a large number of matches between
substances were found to be relevant solely in vivo or in vitro. 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 in vitro are consistent with those perturbed in vivo. These
findings support the utility of the comparison approach as tool in
mechanism-based risk assessment.