In Silico Assessment of Acute Oral Toxicity for Mixtures

While exposure of humans to environmental hazards often occurs with complex chemical mixtures, the majority of existing toxicity data are for single compounds. The Globally Harmonized System of chemical classification (GHS) developed by the Organization for Economic Cooperation and Development uses the additivity formula for acute oral toxicity classification of mixtures, which is based on the acute toxicity estimate of individual ingredients. We evaluated the prediction of GHS category classifications for mixtures using toxicological data collected in the Integrated Chemical Environment (ICE) developed by the National Toxicology Program (United States Department of Health and Human Services). The ICE database contains in vivo acute oral toxicity data for ∼10,000 chemicals and for 582 mixtures with one or multiple active ingredients. By using the available experimental data for individual ingredients, we were able to calculate a GHS category for only half of the mixtures. To expand a set of components with acute oral toxicity data, we used the Collaborative Acute Toxicity Modeling Suite (CATMoS) implemented in the Open Structure-Activity/Property Relationship App to make predictions for active ingredients without available experimental data. As a result, we were able to make predictions for 503 mixtures/formulations with 72% accuracy for the GHS classification. For 186 mixtures with two or more active ingredients, the accuracy rate was 76%. The structure-based analysis of the misclassified mixtures did not reveal any specific structural features associated with the mispredictions. Our results demonstrate that CATMoS together with an additivity formula can be used to predict the GHS category for chemical mixtures.