Additive and synergistic antiandrogenic activities of mixtures of azol fungicides and vinclozolin.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSION
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.


PRACTICE
Mixtures should also be considered for additive antiandrogenic activity in hazard and risk assessment.


IMPLICATIONS
Our evaluation provides an appropriate "proof of concept", but whether it equally translates to in vivo effects should further be investigated.
['Christen|Verena|V|', 'Crettaz|Pierre|P|', 'Fent|Karl|K|']
D000465:Algorithms D000726:Androgen Antagonists D000818:Animals D001393:Azoles D045744:Cell Line, Tumor D002470:Cell Survival D004305:Dose-Response Relationship, Drug D004338:Drug Combinations D004347:Drug Interactions D004357:Drug Synergism D005659:Fungicides, Industrial D007306:Insecticides D051379:Mice D010080:Oxazoles D011722:Pyrethrins D011944:Receptors, Androgen D018570:Risk Assessment
Antiandrogenicity Azol fungicides Pyrethroids Concentration addition Synergism Mixture activity