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In Silico Prediction of Chemical-Induced Hepatocellular Hypertrophy Using Molecular Descriptors

In silico prediction for toxicity of chemicals is required to reduce cost, time, and animal testing. However, predicting hepatocellular hypertrophy, which often affects the derivation of the No-Observed-Adverse-Effect Level in repeated dose toxicity studies, is difficult because pathological findings are diverse, mechanisms are largely unknown, and a wide variety of chemical structures exists. Therefore, a method for predicting the hepatocellular hypertrophy of diverse chemicals without complete understanding of their mechanisms is necessary. In this study, we developed predictive classification models of hepatocellular hypertrophy using machine learning-specifically, deep learning, random forest, and support vector machine. We extracted hepatocellular hypertrophy data on rats from 2 toxicological databases, our original database developed from risk assessment reports such as pesticides, and the Hazard Evaluation Support System Integrated Platform. Then, we constructed prediction models based on molecular descriptors and evaluated their performance using independent test chemicals datasets, which differed from the training chemicals datasets. Further, we defined the applicability domain (AD), which generally limits the application for chemicals, as structurally similar to the training chemicals dataset. The best model was found to be the support vector machine model using the Hazard Evaluation Support System Integrated Platform dataset, which was trained with 251 chemicals and predicted 214 test chemicals inside the applicability domain. It afforded a prediction accuracy of 0.76, sensitivity of 0.90, and area under the curve of 0.81. These in silico predictive classification models could be reliable tools for hepatocellular hypertrophy assessments and can facilitate the development of in silico models for toxicity prediction.