Combined exposure to dissimilarly acting anti-androgens causes markedly increased frequency of hypospadias in the rat

The incidence of hypospadias is increasing, but it is unclear whether human exposure to endocrine disrupting chemicals is related to this. Risk assessment based on no observed adverse effect levels (NOAELs) for single compounds indicates that human tissue levels are too low levels to cause concern for adverse reproductive effects.

However, many anti-androgenic chemicals have been found as mixtures in humans. Here, we present some results from our mixture study on four dissimilarly acting anti-androgens, i.e. vinclozolin (androgen receptor antagonist), DEHP (testosterone synthesis inhibitor), finasteride (inhibitor of steroid type II 5-reductase) and prochloraz (multiple mechanisms).

Groups of rats were gavaged during gestation and lactation with the chemicals alone or a mixture of the chemicals at their individual NOAELs or 5 and 10 times higher. External malformations of the male reproductive organs were scored on PND 47/48 using a score from 0 to 3 (normal-marked) for the endpoints hypospadia and vaginal opening.

Animals with scores 2 or 3 were only found in the two highest mixture groups and the highest dose of vinclozolin, and score 3 was only observed in the highest mixture group. Also, a combination of doses of each chemical that on its own did not produce clear sign of hypospadias (DEHP, finasteride and prochloraz) or a frequency around 14% (vinclozolin) induced a 100% frequency of hypospadias.

In conclusion, doses of anti-androgens, which appear to induce only low frequencies of hypospadias when judged on their own, may induce a very high frequency when they interact in concert with other anti-androgens.