Utility of in vitro assay data in read-across prediction of nongenotoxic carcinogenicity of pesticides for cytotoxicity-related rat tumors.

Developing alternative methods for rat carcinogenicity studies remains challenging. This study aimed to establish a read-across method to predict nongenotoxic carcinogenicity in rats using molecular descriptors and in vitro assays. Based on 2-year rat carcinogenicity study results of agrochemicals, 80 compounds that caused benign or malignant tumors in the liver, thyroid, testis, uterus, ovary, breast, nasal cavity, stomach, or bladder/urethra and 46 compounds that did not were selected and subjected to cell-based cytotoxicity assays. Here, we focused on tumors associated with epithelial cell injury (nasal cavity, stomach, and bladder/urethra tumors). The read-across prediction was performed using neighboring substances, which were selected based on the Euclidean distance between the substances calculated using molecular descriptors. In some cases, neighboring substances were further selected based on the concordance of the in vitro assay results. The selection of neighboring substances based on the carcinogenicity-relevant descriptors and then on the cytotoxicity assay data improved the prediction accuracy (balanced accuracy: 0.752-0.821) compared to the accuracy with substances selected based on unselected descriptors alone (balanced accuracy: 0.294-0.582). These results suggest that the combined use of carcinogenicity-relevant descriptors and in vitro assays related to carcinogenic mechanisms is useful for read-across prediction of cytotoxicity-related tumors in rats.