Cell Painting and chemical structure read-across can complement each other for rat acute oral toxicity prediction in chemical early de-risking

Early de-risking decisions in the development of new chemical compounds, enable the identification of novel chemical candidates with improved safety profiles. In vivo studies are traditionally conducted in the early assessment of acute oral toxicity of crop protection products to avoid compounds which are considered "very acutely toxic", with an in vivo Lethal Dose of 50% (LD50) [≤] 60 mg/kg bodyweight. Those studies are lengthy, costly, and raise ethical concerns, catalyzing the use of non-animal alternatives. The objective of our analysis was to assess the predictive efficacy of read-across approaches for acute oral toxicity in rats, comparing the use of chemical structure information, in vitro biological data derived from the Cell Painting profiling assay on U2OS cells or the combination of both. Our findings indicate that the classification of compounds as very acute oral toxic (LD50 [≤] 60 mg/kg) or not is possible using a read-across approach, with chemical structure information, morphological profiles, or a combination of both. When classifying compounds structurally similar to those in the training set, chemical structure was more predictive (balanced accuracy of 0.82). Conversely, when the compounds to be classified were structurally different from those in the training set, the morphological profiles were more predictive (balanced accuracy of 0.72). Combining the two models allowed for the classification of compounds structurally similar to those in the training set, to slightly improve the predictions (balanced accuracy of 0.85). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/591123v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@d7d4fcorg.highwire.dtl.DTLVardef@1e00a92org.highwire.dtl.DTLVardef@1d60fccorg.highwire.dtl.DTLVardef@a72961_HPS_FORMAT_FIGEXP M_FIG For Table of Contents Only C_FIG