Evaluating applicability domain of acute toxicity QSAR models for military and industrial chemical risk assessment

Abstract

Quantitative Structure-Activity Relationship (QSAR) models can be used to predict the risk of novel and emergent chemicals causing adverse health outcomes, avoidance of which is crucial for military operations. While QSAR modeling approaches have been proposed for military and industry risk assessment, the applicability of peer-reviewed tissue-specific QSAR models in military and industrial contexts remain largely unexplored, particularly with respect to specific organ toxicity. We investigated the applicability domain (AD) of acute and sub-chronic tissue-specific QSAR models to evaluate the coverage of military- and industrial-relevant chemicals. Our analysis reveals that military-relevant compounds occupy a similar chemical space as industrial compounds. However, published models for acute target organ toxicity had minimal coverage of the military and industrial chemicals. The published Collaborative Acute Toxicity Modeling Suite (CATMoS) acute oral toxicity model was the notable exception, as it covers a broad range of military and industrial chemicals. Our study underscores the urgent need for development of novel tissue-specific QSAR models, or modification of existing models, to improve chemical risk prediction in both industrial and military applications.