ABSTRACT
The current risk assessment of environmental contaminants is generally based on an assessment of single substance toxicity, in contrast to real-world environmental contamination, which is often composed of chemical mixtures. The evaluation and prediction of the toxicity of a mixture of substances from its constituents therefore deserves special attention in ecotoxicology. While the toxicity of mixtures with well- defined modes of action can be accurately described by the two concepts of concentration addition and response addition, it is more difficult to evaluate the combination effects of substances when less information on the mechanisms of their toxic effects is available. This study tests an application of combination toxicity concepts with a different goal: It evaluates whether mixture toxicity studies can also be applied to gain more insight into the modes of action of the constituents of a given mixture.
To this end, an analysis of the mixture toxicity of different nitrobenzenes on the reproduction of the green alga Scenedesmus vacuolatus was undertaken. Using lipophilicity-based quantitative structure-activity-relationship modelling for nitrobenzenes, the assumption is held that mononitrobenzenes may exert narcotic effects as a common type of action, while dinitrobenzenes show a somewhat greater toxicity. From the literature, QSAR models based on quantum chemical parameters suggest that some mononitrobenzenes may be effective by additional other modes of action. The toxicity of a mixture of 14 nitrobenzenes clearly exceeds the predicted combined effects as expected for the sum of toxic units from a uniform narcotic mode of action. Moreover, the observed combined effect is smaller than that predicted from simply similar acting compounds calculated on the basis of the parametrised dose-response functions using concentration addition. Further modelling of the combined effect, joining the model of concentration addition for components with anticipated similar modes of action and of response additio n for those with independent action, let us to propose that not all of the nitrobenzenes follow the same mode of action. This is in line with a hypothesis derived from quantum chemical QSAR considerations. Overall, it appears that combined effect analysis can be applied as a pharmacological probe to test for the similarity of the mode of action of mixture components.
