Reexamining the acute toxicity of chloropicrin: Comprehensive estimation using in silico methods

Abstract

Chloropicrin, historically infamous as a chemical warfare agent during World War I, has recently resurfaced in global conflicts, prompting a reevaluation of its acute toxicological significance. This study addresses the historical knowledge gap surrounding chloropicrin by employing in silico toxicology methods to estimate toxicophores and predict acute toxicity across various exposure routes. Allegations of its use in recent conflicts necessitate a deeper understanding of its toxicological profile, particularly in modern warfare scenarios. Qualitative analysis (STopTox and admetSAR) revealed chloropicrin to be toxic for oral, dermal, and inhalation administration, with the nitro group attached to the carbon atom identified as a significant contributor to its toxic profile. Quantitative in silico estimates, using multiple methods (TEST, ProTox-II, ADMETlab, ACD/Labs Percepta and QSAR Toolbox), indicated t-LD₅₀ values of 48.71 mg/kg bw for oral exposure, 130.16 mg/kg bw for dermal exposure, and an inhalation t-LC₅₀ of 0.022 mg/L. However, method inconsistencies and variability in dose conversion guidance highlight the importance of a cautious approach to interpreting results. Furthermore, the study explores the potential of in silico methods to reduce reliance on animal testing, providing a more efficient and humane alternative for toxicity assessments. The findings contribute to a comprehensive understanding of chloropicrin's acute toxicity, emphasising the relevance of in silico methods in guiding future toxicological studies and informing safety assessments in agricultural and wartime scenarios.