title: Additive and synergistic antiandrogenic activities of mixtures of azol fungicides and vinclozolin.
abstract: 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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  Mixtures should also be considered for additive antiandrogenic activity in hazard and risk assessment.
  
  
  CONCLUSIONS
  Our evaluation provides an appropriate "proof of concept", but whether it equally translates to in vivo effects should further be investigated.
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz, Switzerland.
authors.forename: Verena
authors.initials: V
authors.lastname: Christen
authors.affiliation: Federal Office of Public Health, Division Chemical Products, 3003 Bern, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Crettaz
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz, Switzerland; ETH Zürich, Department of Environmental System Sciences, Institute of Biogeochemistry and Pollution Dynamics, Universitätsstrasse 16, CH-8092 Zürich, Switzerland. Electronic address: karl.fent@fhnw.ch.
authors.forename: Karl
authors.initials: K
authors.lastname: Fent
mesh_terms: D000465:Algorithms; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D001393:Azoles / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004357:Drug Synergism; D005659:Fungicides, Industrial / Q000633:toxicity*; D007306:Insecticides / Q000633:toxicity; D051379:Mice; D010080:Oxazoles / Q000633:toxicity*; D011722:Pyrethrins / Q000633:toxicity; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics; D018570:Risk Assessment
chemical_list: D000726:Androgen Antagonists; D001393:Azoles; D004338:Drug Combinations; D005659:Fungicides, Industrial; D007306:Insecticides; D010080:Oxazoles; D011722:Pyrethrins; D011944:Receptors, Androgen; C025643:vinclozolin
keywords: Antiandrogenicity; Azol fungicides; Concentration addition; Mixture activity; Pyrethroids; Synergism