Christen Verena, Crettaz Pierre, Fent Karl
University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz, Switzerland.
Federal Office of Public Health, Division Chemical Products, 3003 Bern, Switzerland.
Toxicol Appl Pharmacol. 2014 Sep 15;279(3):455-466. doi: 10.1016/j.taap.2014.06.025. Epub 2014 Jul 11.
Many pesticides including pyrethroids and azole fungicides are suspected to have an endocrine disrupting property. At present, the joint activity of compound mixtures is only marginally known. Here we tested the hypothesis that the antiandrogenic activity of mixtures of azole fungicides can be predicted by the concentration addition (CA) model.
The antiandrogenic activity was assessed in MDA-kb2 cells. Following assessing single compounds activities mixtures of azole fungicides and vinclozolin were investigated. Interactions were analyzed by direct comparison between experimental and estimated dose-response curves assuming CA, followed by an analysis by the isobole method and the toxic unit approach.
The antiandrogenic activity of pyrethroids deltamethrin, cypermethrin, fenvalerate and permethrin was weak, while the azole fungicides tebuconazole, propiconazole, epoxiconazole, econazole and vinclozolin exhibited strong antiandrogenic activity. Ten binary and one ternary mixture combinations of five antiandrogenic fungicides were assessed at equi-effective concentrations of EC25 and EC50. Isoboles indicated that about 50% of the binary mixtures were additive and 50% synergistic. Synergism was even more frequently indicated by the toxic unit approach.
Our data lead to the conclusion that interactions in mixtures follow the CA model. However, a surprisingly high percentage of synergistic interactions occurred. Therefore, the mixture activity of antiandrogenic azole fungicides is at least additive.
Mixtures should also be considered for additive antiandrogenic activity in hazard and risk assessment.
Our evaluation provides an appropriate "proof of concept", but whether it equally translates to in vivo effects should further be investigated.
包括拟除虫菊酯和唑类杀菌剂在内的许多农药被怀疑具有内分泌干扰特性。目前，复合混合物的联合活性仅为人所知甚少。在此，我们检验了一个假设，即唑类杀菌剂混合物的抗雄激素活性可以通过浓度相加（CA）模型来预测。
在MDA-kb2细胞中评估抗雄激素活性。在评估单一化合物活性后，研究了唑类杀菌剂与乙烯菌核利的混合物。通过假设CA的实验剂量-反应曲线与估计剂量-反应曲线的直接比较来分析相互作用，随后通过等效线法和毒性单位法进行分析。
拟除虫菊酯溴氰菊酯、氯氰菊酯、氰戊菊酯和氯菊酯的抗雄激素活性较弱，而唑类杀菌剂戊唑醇、丙环唑、环氧唑、烯唑醇和乙烯菌核利表现出较强的抗雄激素活性。在EC25和EC50的等效浓度下评估了五种抗雄激素杀菌剂的十种二元和一种三元混合物组合。等效线表明，约50%的二元混合物是相加的，50%是协同的。毒性单位法更频繁地表明存在协同作用。
我们的数据得出结论，混合物中的相互作用遵循CA模型。然而，协同相互作用的比例高得出奇。因此，抗雄激素唑类杀菌剂的混合物活性至少是相加的。
在危害和风险评估中，也应考虑混合物的相加抗雄激素活性。
我们的评估提供了一个适当的“概念验证”，但其是否同样适用于体内效应仍有待进一步研究。
