Department of Biology/Toxicology, Ashland University, Ashland, OH 44805, USA.
Arch Environ Contam Toxicol. 2010 Nov;59(4):532-41. doi: 10.1007/s00244-010-9518-1. Epub 2010 Apr 20.
The concept of multiple modes of toxic action denotes that an individual chemical can induce two or more toxic effects within the same series of concentrations, for example, reactive toxicity and narcosis. It appears that such toxicity confounds the ability to develop precise predictions of mixture toxicity and makes it more difficult to clearly link a dose-additive combined effect to agents in the mixture having a single common mechanism of toxic action. This initial study of a three-part series begins to examine this issue in greater detail by testing three α-halogenated acetonitriles: (1) in sham combinations, (2) in true combinations, and (3) with a nonreactive nonpolar narcotic. Iodo-, bromo-, and chloro-derivatives of acetonitrile were selected for testing based on their electro(nucleo)philic reactivity, via the S(N)2 mechanism, and their time-dependent toxicity individually. Reactivity of each agent was assessed in tests with the model nucleophile glutathione (GSH). Each acetonitrile was reactive with GSH, but the nonpolar narcotic 3-methyl-2-butanone was not. In addition, toxicity of the agents alone and in mixtures was assessed using the Microtox(®) acute toxicity test at three time points: 15, 30, and 45 min of exposure. Each of the three agents alone had time-dependent toxicity values of about 100%, making it likely that most of the toxicity of these agents, at these times, was due to reactivity. In contrast, the nonpolar narcotic agent lacked time-dependent toxicity. In mixture testing, sham combinations of each acetonitrile showed a combined effect consistent with predicted effects for dose-addition at each time point, as did the sham combination of the nonpolar narcotic. Mixture toxicity results for true acetonitrile combinations were also consistent with dose-addition, but the acetonitrile-nonpolar narcotic combinations were generally not consistent with either the dose-addition or independence models of combined effect. Based on current understanding of mixture toxicity, these results were expected and provide a foundation for the second and third studies in the series.
多种毒性作用模式的概念表示，一种化学物质可以在同一浓度系列内引起两种或更多种毒性作用，例如反应性毒性和麻醉性。似乎这种毒性作用会干扰对混合物毒性的精确预测能力，并使得更难以将剂量相加的组合效应与混合物中具有单一共同毒性作用机制的药剂明确联系起来。本系列的初步研究更详细地开始检验这个问题，方法是测试三种α-卤代乙腈：（1）在假混合物中，（2）在真混合物中，以及（3）与非反应性非极性麻醉剂。基于其通过 S(N)2 机制的亲电性（亲核性）反应性以及它们各自的时间依赖性毒性，选择碘代、溴代和氯代乙腈衍生物进行测试。每种试剂的反应性都通过与模型亲核试剂谷胱甘肽（GSH）的测试进行评估。每种乙腈都与 GSH 反应，但非极性麻醉剂 3-甲基-2-丁酮则不然。此外，还使用 Microtox（®）急性毒性测试在三个时间点：暴露 15、30 和 45 分钟，评估单独和混合物中试剂的毒性。三种试剂中的每一种单独都具有约 100%的时间依赖性毒性值，这表明在这些时间点，这些试剂的大部分毒性可能归因于反应性。相比之下，非极性麻醉剂缺乏时间依赖性毒性。在混合物测试中，每种乙腈的假混合物都显示出与每个时间点剂量相加预测效果一致的组合效应，非极性麻醉剂的假混合物也是如此。真正的乙腈混合物的毒性结果也与剂量相加一致，但乙腈-非极性麻醉剂混合物通常不符合剂量相加或独立组合效应模型。根据对混合物毒性的当前理解，这些结果是预期的，并为该系列的第二和第三项研究奠定了基础。
