Time-dependence in mixture toxicity with soft-electrophiles: 2. Effects of relative reactivity level on time-dependent toxicity and combined effects for selected Michael acceptors.
ABSTRACT Toxicity assessments for organic chemical mixtures are often described as being approximately additive. Recent mixture studies with soft electrophiles have suggested that agents with less-than fully time-dependent toxicity (TDT) may actually induce toxicity by more than one mode of toxic action within the same series of concentrations. To evaluate this concept further, four Michael acceptor electrophiles, each with a different rate of in chemico reactivity and different level of TDT, were tested with each other and in sham combinations (a single chemical tested as if it were a binary mixture) using the Microtox system. For each binary combination, each agent was tested alone and in a mixture, with toxicity assessed as inhibition of bioluminescence at 15-, 30- and 45-min of exposure. Each single agent and mixture test included seven duplicated concentrations and a duplicated control treatment. To evaluate relative reactivity, each agent was also tested with the model nucleophile glutathione (GSH). Agents with greater in chemico reactivity (mean RC(50) mM) showed greater toxicity (mean 45-min EC(50) - mM) but these were inversely related to the TDT levels of the agents. Combined effects for the sham combinations, as quantified by additivity quotient values for the EC(50) of the mixture, tended to be close to 1.00 (i.e., the dose-addition EC(50)-AQ). For true binary combinations (i.e., two chemicals tested together), the EC(50)-AQ tended to be increasingly above 1.00 when TDT levels of the agents in the mixture were more disparate. The results of this study with Michael acceptors suggested that: (i) when reactivity was fast, there was most likely a single prominent mode of toxic action, i.e., electro(nucleo)philic reactivity, leading to time-dependent toxicity at the full or high levels, (ii) when the reaction rate for a chemical was slower, two modes of action, electro(nucleo)philic reactivity and narcosis, were apparent such that the time-dependent toxicity level was lower as well, (iii) mixtures of the former agents show a combined effect that was strictly dose-additive, whereas (iv) mixtures which included one (or more) agent with a lower reaction rate had a combined effect that was approximately additive rather than strictly dose-additive.
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ABSTRACT: Using abiotic thiol reactivity (EC50) and Tetrahymena pyriformis toxicity (IGC50) data for a group of halo-substituted ketones, esters and amides (i.e. SN2 electrophiles) and related compounds a series of structure-activity relationships are illustrated. Only the alpha-halo-carbonyl-containing compounds are observed to be thiol reactive with the order I > Br > Cl > F. Further comparisons disclose alpha-halo-carbonyl compounds to be more reactive than non-alpha-halo-carbonyl compounds; in addition, the reactivity is reduced when the number of C atoms between the carbonyl and halogen is greater than one. Comparing reactivity among alpha-halo-carbonyl-containing compounds with different beta-alkyl groups shows the greater the size of the beta-alkyl group the lesser the reactivity. A comparison of reactivity data for 2-bromoacetyl-containing compounds of differing dimensions reveals little difference in reactivity. Regression analysis demonstrates a linear relationship between toxicity and thiol reactivity: log (IGC(50)(-1)) = 0.848 log (EC(50)(-1)) + 1.40; n=19, s=0.250, r2=0.926, r2(pred)=0.905, F=199, Pr > F=0.0001.SAR and QSAR in Environmental Research 01/2007; 18(1-2):21-9. · 1.67 Impact Factor
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ABSTRACT: QSARs based upon the logarithm of the octanol-water partition coefficient, log P, and energy of the lowest unoccupied molecular orbital, ELUMO were developed to model the toxicity of aliphatic compounds to the marine bacterium Vibrio fischeri. Statistically robust, hydrophobic-dependent QSARs were found for chloroalcohols and haloacetonitriles. Modelling of the toxicity of the haloesters and the diones required the use of terms to describe both hydrophobicity and electrophilicity. The differences in intercepts, slopes, and fit of these models suggest different electrophilic mechanisms occur between classes, as well as within the diones and haloesters. In order to model globally the toxicity of aliphatic compounds to V. fischeri, all the data determined in this study were combined with those determined previously for alkanones, alkanals, and alkenals. A highly predictive two-parameter QSAR [pT15 = 0.760(log P) - 0.625(ELUMO) - 0.466; n = 63, s = 0.462, r2 = 0.846, F = 171, Pr > F = 0.0001] was developed for the combined data that models across classes and is independent of mechanisms of action. The toxicity of these compounds to V. fischeri compares well to the toxicity (50% population growth inhibition) to the ciliate Tetrahymena pyriformis (r2 = 0.850).SAR and QSAR in Environmental Research 01/2000; 11(3-4):301-12. · 1.67 Impact Factor
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ABSTRACT: The toxicity of 30 binary combinations of 10 soft electrophiles was examined in Microtox using dose-response curve (DRC) analysis. Chemicals from three groups of soft electrophiles-vinyl Michael acceptors (I--react with a thiol group), dicarbonyl reactive agents (II--react with a primary amine), and alpha-haloactivation compounds (III--react with a thiol group)--were selected for testing to evaluate the relationship between molecular site of chemical action and combined toxic effect. For each combination tested, each single agent was tested alone at six duplicated concentrations and three 1:1 mixtures of the agents were also tested, each at six duplicated concentrations. Exposure duration was 15 min for each single agent and mixture test. Sigmoid DRCs for each single chemical and mixture were constructed and the single chemical curves were used to develop a theoretical dose-addition DRC for the combination. Additivity quotient (AQ) values for slope and EC50 were calculated by dividing the actual mixture slope or EC50 for a given combination by the predicted slope or EC50, respectively, from the theoretical dose-addition DRC. Three criteria were selected for value in determining the combined effect obtained for each combination: (1) slope AQ 95% confidence interval (CI) overlap with 1.0 (1.0=dose addition), (2) EC50 AQ 95% CI overlap with 1.0, and (3) mean mixture data point 95% and 99% CI overlap with the theoretical dose-addition DRC. Each of three sham combinations showed combined effects consistent with dose addition for each criterion. Dose addition was expected for 15 nonsham combinations (nine within-group combinations and six group I:III combinations) and a nondose-additive effect was expected for 12 combinations (all I:II and II:III combinations). Actual combined effects obtained by incorporating all three criteria (noted above) showed only six instances of dose addition. Therefore, time-dependent toxicity (TDT) tests of each soft electrophile alone and for three nonpolar narcotic chemicals alone were conducted, using 15-, 30-, and 45-min exposure durations, to assess the time-dependent nature of the toxicity. Results of the TDT tests suggested that five had fully (or nearly fully) TDT (interpreted as an irreversible effect representing one molecular site of action), five of the soft electrophiles had partially TDT (i.e., representing two or more molecular sites of action for the agents, one irreversible and one reversible), and the three nonpolar narcotics had no TDT (i.e., a fully reversible toxic effect). With this TDT information, the combined effects for 25 of the 27 mixtures, although rather complex, could be explained. It is noteworthy that all combined effects obtained, whether concluded to be dose-additive or not, were close to dose-additive for hazard assessment purposes.Ecotoxicology and Environmental Safety 11/2006; 65(2):171-80. · 2.20 Impact Factor