Faust M, Altenburger R, Backhaus T, Blanck H, Boedeker W, Gramatica P, Hamer V, Scholze M, Vighi M, Grimme L H
Department of Biology and Chemistry, University of Bremen, D-28334 Bremen, Germany.
Aquat Toxicol. 2003 Mar 17;63(1):43-63. doi: 10.1016/s0166-445x(02)00133-9.
For a predictive assessment of the aquatic toxicity of chemical mixtures, two competing concepts are available: concentration addition and independent action. Concentration addition is generally regarded as a reasonable expectation for the joint toxicity of similarly acting substances. In the opposite case of dissimilarly acting toxicants the choice of the most appropriate concept is a controversial issue. In tests with freshwater algae we therefore studied the extreme situation of multiple exposure to chemicals with strictly different specific mechanisms of action. Concentration response analyses were performed for 16 different biocides, and for mixtures containing all 16 substances in two different concentration ratios. Observed mixture toxicity was compared with predictions, calculated from the concentration response functions of individual toxicants by alternatively applying both concepts. The assumption of independent action yielded accurate predictions, irrespective of the mixture ratio or the effect level under consideration. Moreover, results even demonstrate that dissimilarly acting chemicals can show significant joint effects, predictable by independent action, when combined in concentrations below individual NOEC values, statistically estimated to elicit insignificant individual effects of only 1%. The alternative hypothesis of concentration addition resulted in overestimation of mixture toxicity, but differences between observed and predicted effect concentrations did not exceed a factor of 3.2. This finding complies with previous studies, which indicated near concentration-additive action of mixtures of dissimilarly acting substances. Nevertheless, with the scientific objective to predict multi-component mixture toxicity with the highest possible accuracy, concentration addition obviously is no universal solution. Independent action proves to be superior where components are well known to interact specifically with different molecular target sites, and provided that reliable statistical estimates of low toxic effects of individual mixture constituents can be given. With a regulatory perspective, however, fulfilment of both conditions may be regarded as an extraordinary situation, and hence concentration addition may be defendable as a pragmatic and precautionary default assumption.
对于化学混合物水生毒性的预测评估，有两种相互竞争的概念：浓度相加和独立作用。浓度相加通常被认为是对作用方式相似的物质联合毒性的合理预期。在作用方式不同的有毒物质的相反情况下，选择最合适的概念是一个有争议的问题。因此，在淡水藻类试验中，我们研究了多种作用机制截然不同的化学物质多重暴露的极端情况。对16种不同的杀生物剂以及含有所有16种物质的两种不同浓度比例的混合物进行了浓度响应分析。将观察到的混合物毒性与预测值进行比较，预测值是通过交替应用这两种概念，根据各单一毒物的浓度响应函数计算得出的。独立作用的假设产生了准确的预测，无论混合物比例或所考虑的效应水平如何。此外，结果甚至表明，当以低于个体无观察效应浓度（NOEC）值的浓度组合时，作用方式不同的化学物质可能会表现出显著的联合效应，通过独立作用可以预测，据统计估计这些浓度仅会引发1%的无显著个体效应。浓度相加的另一种假设导致对混合物毒性的高估，但观察到的和预测的效应浓度之间的差异不超过3.2倍。这一发现与之前的研究一致，之前的研究表明作用方式不同的物质混合物具有近似浓度相加的作用。然而，出于以尽可能高的准确度预测多组分混合物毒性的科学目的，浓度相加显然不是通用的解决方案。当各组分已知与不同分子靶位点有特异性相互作用，并且能够给出各混合物成分低毒性效应的可靠统计估计时，独立作用被证明更具优势。然而，从监管角度来看，满足这两个条件可能被视为一种特殊情况，因此浓度相加作为一种务实和预防性的默认假设可能是合理的。
