Abstract
Mixture and time-dependent toxicity (TDT) was assessed for a series of mono-halogenated acetonitrile-containing combinations. Inhibition of bioluminescence in Aliivibrio fischeri was measured after 15, 30 and 45-min of exposure. Concentration-response (x/y) curves were determined for each chemical alone at each timepoint, and used to develop predicted x/y curves for the dose-addition and independence models of combined effect. The x/y data for each binary mixture was then evaluated against the predicted mixture curves. Two metrics of mixture toxicity were calculated per combined effect model: (1) an EC50-based dose-addition (AQ) or independence (IQ) quotient and (2) the mixture/dose-addition (MX/DA) and mixture/independence (MX/I) metrics. For each single chemical and mixture tested, TDT was also calculated. After 45-min of exposure, 25 of 67 mixtures produced curves that were consistent with dose-addition using the MX/DA metric, with the other 42 being less toxic than predicted by MX/DA. Some mixtures had toxicity that was consistent with both dose-addition and independence. In general, those that were less toxic than predicted for dose-addition were also less toxic than predicted for independence. Of the 25 combinations that were consistent with dose-addition, 22 (88%) mixtures contained chemicals for which the individual TDT values were both >80%. In contrast, of the 42 non-dose-additive combinations, only 2 (4.8%) of the mixtures had both chemicals with individual TDT values >80%. The results support previous findings that TDT determinations can be useful for predicting chemical mixture toxicity.
Highlights
Determining and predicting the effects of toxic substances in combination has been a focal point of recent mixture toxicity research
In using the 5-parameter logistic minus 1-parameter (5PL-1P) function for fitting all x/y data presented the maximum effect constraint was set to equal 100% (MAX = 100). This was done to provide a consistent basis for determining time-dependent toxicity (TDT) values and the combined effect
After 45-min of exposure the results showed that when both chemicals of the combination had individual TDT values >80%, toxicity of the mixture was more likely to be consistent with that predicted for dose-addition (i.e., >85% frequency)
Summary
Determining and predicting the effects of toxic substances in combination has been a focal point of recent mixture toxicity research. Via exposure profiling of reactive mixtures [1], docking-based receptor library [2] or toxicogenomics [3] studies, or examining aquatic toxicity [4], mammalian reproductive effects [5] or endocrine disruptors [6] such research efforts can improve the ability to predict mixture toxicity. Conceptual studies and efforts to develop and evaluate mixture toxicity models [15,16,17,18,19,20] have provided approaches for improving toxicity assessment of mixtures. For other chemicals toxicity continues to progress over exposure time such that bioluminescence decreases throughout exposure. These features allow the assay to be used effectively for assessing changes in toxicity over exposure time (i.e., time-dependent toxicity)
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