Mixture effects of endocrine disrupting compounds in vitro.
Four different equi-molar mixtures were investigated for additive endocrine disrupting effects in vitro using the concentration addition model. It was found that additive effects on the same molecular target (the androgen receptor; AR) can be predicted for both mixtures of compounds with effect on the AR (flutamide, procymidone and vinclozolin) and of compounds with and without effects on the AR [finasteride, mono-(2-ethylhexyl) phthalate, prochloraz and vinclozolin]. For a paraben mixture (methyl paraben, ethyl paraben, propyl paraben, butyl paraben and iso-butyl paraben) antagonistic effect on AR could not be predicted under assumption of additivity in our model system. For a mixture containing three azole fungicides (epoxiconazole, propiconazole and tebuconazole), the observed AR antagonistic effects were close to the predicted effect assuming additivity. Azole fungicides are known inhibitors of androgen biosynthesis and in the steroid synthesis assay using H295R cells, the inhibition of testosterone production was close to additive, whereas the inhibition of oestradiol production was over-estimated for the mixture of azole fungicides, when compared with the effect predicted when assuming additivity. Overall these and other studies show that weak endocrine disrupting compounds, like parabens and azole fungicides, give rise to combination effects when they occur in mixtures. These combination effects should be taken into account in regulatory risk assessment not to under-estimate the risks for adverse effects associated with exposure to disrupting chemicals.
Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense C, Denmark.
M B
MB
Kjaerstad
C
C
Taxvig
H R
HR
Andersen
C
C
Nellemann
D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000633:toxicity; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004338:Drug Combinations; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000633:toxicity*; D004958:Estradiol / Q000096:biosynthesis; D005485:Flutamide / Q000008:administration & dosage / Q000633:toxicity; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D010080:Oxazoles / Q000008:administration & dosage / Q000633:toxicity; D010226:Parabens / Q000008:administration & dosage / Q000633:toxicity; D011944:Receptors, Androgen / Q000187:drug effects*; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014230:Triazoles / Q000008:administration & dosage
D000726:Androgen Antagonists; D001643:Bridged Bicyclo Compounds; D004338:Drug Combinations; D052244:Endocrine Disruptors; D005659:Fungicides, Industrial; D010080:Oxazoles; D010226:Parabens; D011944:Receptors, Androgen; D014230:Triazoles; C045950:propiconazole; D013739:Testosterone; C087114:tebuconazole; D004958:Estradiol; D005485:Flutamide; C035988:procymidone; C025643:vinclozolin