Verena Christen1, Pierre Crettaz2, Karl Fent3. 1. University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz, Switzerland. 2. Federal Office of Public Health, Division Chemical Products, 3003 Bern, Switzerland. 3. 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.
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. 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.
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.
Authors: Cynthia G Goodyer; Shirley Poon; Katarina Aleksa; Laura Hou; Veronica Atehortua; Amanda Carnevale; Gideon Koren; Roman Jednak; Sherif Emil; Darius Bagli; Sumit Dave; Barbara F Hales; Jonathan Chevrier Journal: Environ Health Perspect Date: 2017-05-26 Impact factor: 9.031