Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo (USP), Avenida Professor Lineu Prestes, 580, São Paulo, SP, 05508-000, Brazil; Science and Technology Institute, Federal University of Alfenas (Unifal-MG), Rodovia José Aurélio Vilela, 11,999, Poços de Caldas, MG, 37715-400, Brazil.
Faculty of Technology, State University of Campinas (Unicamp), Rua Paschoal Marmo, 1888, Limeira, SP, 13484-332, Brazil.
Chemosphere. 2019 Nov;235:373-382. doi: 10.1016/j.chemosphere.2019.06.200. Epub 2019 Jun 26.
Pharmaceuticals are frequently detected in aquatic environments as mixtures and can cause toxic effects to non-target organisms. We aimed to evaluate the single and mixture effects of the pharmaceuticals metformin, bisoprolol, ranitidine and sotalol using Daphnia similis and Danio rerio. In addition, we aimed to test the predictive accuracy of the mathematical models concentration addition and independent action and to evaluate the nature of the possible toxicological interactions among these pharmaceuticals using the combination index-isobologram model. The acute toxicity of these four pharmaceuticals individually and of their binary mixtures were evaluated using the D. similis tests. Developmental and behavioral effects induced by the pharmaceuticals in quaternary mixtures were evaluated using D. rerio embryos. We observed that most of the binary mixture effects were in the zone between the effects predicted by the concentration addition and the independent action model. The combination index-isobologram model showed to be adequate to describe the nature of possible interactions occurring between the combined pharmaceuticals. Developmental and behavioral acute adverse effects seem not to be induced by the joint action of the quaternary mixture of the evaluated pharmaceuticals on D. rerio embryos, at the concentrations at which they are usually found in surface fresh waters. However, from the results obtained with D. similis, we can conclude that assessing the ecological risk based on the effects of individual pharmaceuticals can underestimate the risk level posed by these environmental contaminants.
药品经常作为混合物在水生环境中被检测到，并且可能对非靶标生物产生毒性作用。我们旨在使用大型蚤和斑马鱼评估药品二甲双胍、比索洛尔、雷尼替丁和索他洛尔的单一和混合物效应。此外，我们旨在测试浓度加和和独立作用的数学模型的预测准确性，并使用组合指数-等对这些药品之间可能的毒理学相互作用的性质进行评估。使用 D. similis 测试评估了这四种药品单独存在以及它们的二元混合物的急性毒性。使用斑马鱼胚胎评估了这些药品在四元混合物中引起的发育和行为效应。我们观察到，大多数二元混合物的效应处于浓度加和和独立作用模型预测的效应之间。组合指数-等对模型表明能够描述联合药品之间可能发生的相互作用的性质。在通常在地表淡水中发现的浓度下，四元混合物对斑马鱼胚胎联合作用似乎不会引起发育和行为的急性不良反应。然而，根据 D. similis 获得的结果，我们可以得出结论，仅基于单一药品的效应评估生态风险可能会低估这些环境污染物带来的风险水平。
