Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat.
OBJECTIVE
The aim of this study was to assess whether the joint effects of three androgen receptor antagonists (vinclozolin, flutamide, procymidone) on male sexual differentiation after in utero and postnatal exposures can be predicted based on dose-response data of the individual chemicals.


METHODS
Test chemicals and mixtures were administered by gavage to time-mated nulliparous, young adult Wistar rats from gestational day 7 to the day before expected birth, and from postnatal days 1-16. Changes in anogenital distance (AGD) and nipple retention (NR) in male offspring rats were chosen as end points for extensive dose-response studies. Vinclozolin, flutamide, and procymidone were combined at a mixture ratio proportional to their individual potencies for causing retention of six nipples in male offspring.


RESULTS
With AGD as the end point, the joint effects of the three anti-androgens were essentially dose additive. The observed responses for NR were slightly higher than those expected on the basis of dose addition. A combination of doses of each chemical, which on its own did not produce statistically significant AGD alterations, induced half-maximal mixture effects. At individual doses associated with only modest effects on NR, the mixture induced NR approaching female values in the males.


CONCLUSIONS
Effects of a mixture of similarly acting anti-androgens can be predicted fairly accurately on the basis of the potency of the individual mixture components by using the dose addition concept. Exposure to anti-androgens, which individually appears to exert only small effects, may induce marked responses in concert with, possibly unrecognized, similarly acting chemicals.
Hass
Ulla
U
Danish Institute for Food and Veterinary Research, Department of Toxicology and Risk Assessment, Soborg, Denmark. ulh@dfvf.dk
Scholze
Martin
M
Christiansen
Sofie
S
Dalgaard
Majken
M
Vinggaard
Anne Marie
AM
Axelstad
Marta
M
Metzdorff
Stine Broeng
SB
Kortenkamp
Andreas
A
D000726:Androgen Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005485:Flutamide / Q000008:administration & dosage / Q000633:toxicity; D005544:Forecasting; D005837:Genitalia, Male / Q000002:abnormalities / Q000187:drug effects*; D008297:Male; D009558:Nipples / Q000002:abnormalities / Q000187:drug effects*; D010080:Oxazoles / Q000008:administration & dosage / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012733:Sex Differentiation / Q000187:drug effects*
D000726:Androgen Antagonists; D001643:Bridged Bicyclo Compounds; D010080:Oxazoles; D005485:Flutamide; C035988:procymidone; C025643:vinclozolin