Comparative Quantitative Toxicology and QSAR Modeling of the Haloacetonitriles: Forcing Agents of Water Disinfection Byproduct Toxicity

The haloacetonitriles (HANs) is an emerging class of nitrogenous-disinfection byproducts (N-DBPs) present in disinfected drinking, recycled, processed wastewaters, and reuse waters. HANs were identified as primary forcing agents that accounted for DBP-associated toxicity. We evaluated the toxic characteristics of iodoacetonitrile (IAN), bromoacetonitrile (BAN), dibromoacetonitrile (DBAN), bromochloroacetonitrile (BCAN), tribromoacetonitrile (TBAN), chloroacetonitrile (CAN), dichloroacetonitrile (DCAN), trichloroacetonitrile (TCAN), bromodichloroacetonitrile (BDCAN), and chlorodibromoacetonitrile (CDBAN). This research generated the first quantitative, comparative analyses on the mammalian cell cytotoxicity, genotoxicity and thiol reactivity of these HANs. The descending rank order for HAN cytotoxicity was TBAN approximate to DBAN > BAN approximate to IAN > BCAN approximate to CDBAN > BDCAN > DCAN approximate to CAN approximate to TCAN. The rank order for genotoxicity was IAN approximate to TBAN approximate to DBAN > BAN > CDBAN approximate to BDCAN approximate to BCAN approximate to CAN approximate to TCAN approximate to DCAN. The rank order for thiol reactivity was TBAN > BDCAN approximate to CDBAN > DBAN > BCAN > BAN approximate to IAN > TCAN. These toxicity metrics were associated with membrane permeability and chemical reactivity. Based on their physiochemical parameters and toxicity metrics, we developed optimized, robust quantitative structure activity relationship (QSAR) models for cytotoxicity and for genotoxicity. These models can predict cytotoxicity and genotoxicity of novel HANs prior to analytical biological evaluation.