Mixture toxicity of SN2-reactive soft electrophiles: 3. Evaluation of ethyl α-halogenated acetates with α-halogenated acetonitriles.

Abstract

Mixture toxicity for each of four ethyl α-halogenated acetates with each of three α-halogenated acetonitriles (xANs) was assessed. Inhibition of bioluminescence in Vibrio fischeri was measured after 15, 30, and 45 min of exposure. Concentration-response curves were developed for each chemical at each exposure duration and used to develop predicted concentration-response curves for the dose-addition and independence models of combined effect. Concentration-response curves for each mixture and each exposure duration were then evaluated against the predicted curves using three metrics per model: (1) EC50-based additivity quotient (AQ) or independence quotient (IQ) values; (2) mean AQ (mAQ) or mean IQ (mIQ) values, which were calculated by averaging the EC25, EC50, and EC75 AQ or IQ values; and (3) deviation values from additivity (DV-A) or independence (DV-I). Mixture toxicity for ethyl iodoacetate was dose-additive with each of the xANs at all exposure durations and was also often consistent with independence. The same was true for mixture toxicity of ethyl bromoacetate with each xAN. However, for the two more slowly reactive chemicals, ethyl chloroacetate (ECAC) and ethyl fluoroacetate (EFAC), mixture toxicity with each xAN only became consistent with dose-addition on increasing exposure duration. Consistency with independence for both ECAC and EFAC with the xANs was essentially limited to the EC50-IQ metric, thereby showing the utility of calculating the mean quotient (mAQ, mIQ) and deviation value (DV-A, DV-I) metrics. On review of these findings with those from the first two studies in the series, the results suggest that instances in which mixture toxicity was not consistent with dose-addition relate (1) to differences in the capability of the chemicals to form strong H-bonds with water; and (2) to differences in relative reactivity and time-dependent toxicity levels of the chemicals.