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首页> 外文期刊>Archives of Environmental Contamination and Toxicology >Time Dependence in Mixture Toxicity with Soft Electrophiles: 1. Combined Effects of Selected SN2- and SNAr-Reactive Agents with a Nonpolar Narcotic
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Time Dependence in Mixture Toxicity with Soft Electrophiles: 1. Combined Effects of Selected SN2- and SNAr-Reactive Agents with a Nonpolar Narcotic

机译：与软亲电子试剂混合毒性的时间依赖性：1.选定的SN 2-和SN Ar反应剂与非极性麻醉剂的联合作用

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Frequently the toxicity of an organic chemical mixture is close to dose-additive, even when the agents are thought to induce toxicity at different molecular sites of action. These findings appear to conflict with the hypothesis that a strictly dose-additive combined effect will be observed for agents sharing a single molecular site of toxic action within the organism. In this study, several SN2-reactive (α-halogen) or SNAr-reactive (halogenated dinitrobenzene) soft electrophiles were tested with a model nonpolar narcotic (NPN) to determine the toxicity of the combinations. A sham combination of the model NPN (3-methyl-2-butanone) was also tested as a positive control. The study design incorporated time-dependent toxicity (TDT) determinations at 15, 30, and 45 minutes using a Microtox (Vibrio fischeri) protocol that included testing seven duplicated concentrations for each single agent and mixture per combination. Additionally, in chemico reactivity was determined for each compound using thiol in glutathione as a model nucleophile. The model NPN alone lacked reactivity and TDT. The SN2-reactive agents individually showed varying levels of both reactivity and TDT alone, while the SNAr-reactive chemicals alone were reactive and had toxicity that was fully time-dependent between 15 and 45 minutes of exposure. Data analyses indicated that the sham combination was dose additive, as expected, whereas three of four SN2:NPN combinations showed effects close to that predicted for dose addition but with some differences. The fourth SN2:NPN combination, which included an α-halogen with full TDT, showed a less-than-dose-additive combined effect as did both of the SNAr:NPN pairings. By incorporating TDT values, shapes of the dose-response curves, chemical reactivity data with thiol, reactive mechanisms for the soft electrophiles, and quantitative structure activity relationship information on whether the toxicity of the individual soft electrophiles did or did not exceeded that predicted for baseline narcosis, the results suggested that the α-halogens elicited two toxic effects at the concentrations tested (reactivity and narcotizing effects), whereas toxicity induced by the halogenated dinitrobenzenes was essentially limited to reactive effects. Collectively, these results provide experimental evidence consistent with previous explanations as to why binary mixtures of industrial organic chemicals often show combined effects that are close to dose additive, even when the chemicals are thought to induce toxicity at different molecular sites of action.
机译：通常，即使认为化学试剂在不同的分子作用位点会诱导毒性，有机化学混合物的毒性也接近剂量加和的。这些发现似乎与以下假设相抵触：对于在生物体内共享单个分子毒性作用的药剂，将观察到严格的剂量加和联合作用。在这项研究中，使用模型非极性麻醉剂（NPN）测试了几种SN 2-反应性（α-卤素）或SN 反应性（卤化二硝基苯）软亲电试剂，以确定组合的毒性。还测试了模型NPN（3-甲基-2-丁酮）的假组合作为阳性对照。该研究设计采用了Microtox（Vibrio fischeri）方案，在15、30和45分钟时测定了时间依赖性毒性（TDT），其中包括测试每种组合物中每种单一药剂和混合物的七个重复浓度。另外，在化学反应中，使用谷胱甘肽中的硫醇作为模型亲核试剂测定每种化合物的反应性。仅模型NPN缺乏反应性和TDT。单独的SN 2-反应剂分别显示出不同的反应性和TDT水平，而单独的SN 反应性化学品则具有反应性，并且毒性在15-45分钟内完全依赖时间接触。数据分析表明，假手术组合具有预期的剂量加成作用，而四种SN 2：NPN组合中的三种显示出的效果接近于预期的添加剂量，但有一些差异。第四个SN 2：NPN组合包括一个具有完整TDT的α卤素，与两个SN Ar：NPN配对一样，显示出小于剂量加成的组合效应。通过合并TDT值，剂量反应曲线的形状，与硫醇的化学反应性数据，软亲电试剂的反应机理以及有关各个软亲电试剂的毒性是否超过或超过基线预期的定量结构活性关系信息结果表明，α-卤素在所测试的浓度下会引起两种毒性作用（反应性和麻醉作用），而卤代二硝基苯诱导的毒性基本上仅限于反应性作用。总的来说，这些结果提供了与以前的解释一致的实验证据，即为什么工业有机化学物质的二元混合物通常会显示出接近剂量加和的联合作用，即使认为该化学物质在不同的分子作用部位会引起毒性。

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    E. M. Gagan; M. W. Hull; T. W. Schultz; G. P?ch; D. A. Dawson;

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    Department of Biology/Toxicology Ashland University Ashland OH 44805 USA;

    Department of Biology/Toxicology Ashland University Ashland OH 44805 USA;

    Department of Comparative Medicine College of Veterinary Medicine The University of Tennessee Knoxville TN 37996-4543 USA;

    Department of Pharmacology and Toxicology University of Graz A-8010 Graz Austria;

    Department of Biology/Toxicology Ashland University Ashland OH 44805 USA;

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