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首页> 外文期刊>Journal of Environmental Science and Health. A, Toxic/Hazardous Substances & Environmental Engineering >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
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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

机译：与软亲电子试剂混合毒性的时间依赖性：2.相对反应性水平对时间依赖性毒性的影响以及所选迈克尔受体的综合作用

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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.
机译：有机化学混合物的毒性评估通常被描述为近似可加性的。最近对软性亲电试剂的混合物研究表明，在相同系列浓度下，具有小于完全时间依赖性毒性（TDT）的药物实际上可以通过一种以上的毒性作用方式诱导毒性。为了进一步评估这个概念，我们分别使用假装组合（假装组合测试一种化学药品，就像它是二元混合物），对四种具有不同化学反应速率和不同水平的TDT的Michael受体亲电试剂进行了测试。 Microtox系统。对于每种二元组合，每种试剂均单独或混合测试，毒性评估为在暴露15分钟，30分钟和45分钟时抑制生物发光。每个单一试剂和混合物测试均包含七个重复浓度和一个重复对照处理。为了评估相对反应性，还用模型亲核试剂谷胱甘肽（GSH）测试了每种试剂。化学反应性更高的药物（平均RC_（50）mM）显示出更大的毒性（平均45分钟EC_（50）-mM），但这些与药物的TDT水平成反比。通过混合物的EC_（50）的加和商值来量化的伪装组合的组合效果趋于接近1.00（即剂量加法EC_（50）-AQ）。对于真正的二元组合（即，两种化学物质一起测试），当混合物中试剂的TDT水平更加不同时，EC_（50）-AQ趋于逐渐高于1.00。这项与迈克尔受体有关的研究结果表明：（ⅰ）当反应性较快时，最有可能出现单一的显着毒性作用模式，即亲核电反应性，从而导致全剂量或全时间毒性。高水平，（for）当化学物质的反应速率较慢时，两种作用模式，即亲核（亲核）反应性和麻醉作用很明显，因此随时间变化的毒性水平也较低，（ⅲ）混合物前一种药物显示出严格的剂量加和效应，而包含一种（或多种）反应速率较低的药物的（ⅳ）混合物具有近似于加和而不是严格的剂量加成效应。

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