The majority of the 353 currently used pesticides within the EU have not been tested for sensitive endocrine endpoints such as anogenital distance (AGD). Since it is not feasible to test all of these pesticides by using in vivo methods within the foreseeable future, the development of alternative approaches for predicting endocrine disrupting effects is imperative. In this context, the morphometric measure AGD has proven to be a non-invasive, life-long biomarker for adverse effects on male reproductive health in animals and humans. The aim of this project was to develop and validate a novel approach for predicting effects on AGD based on in vitro profiling in combination with physiologically-based kinetic (PBK) modelling. PBK models were developed for nine pesticides and used to predict the in vivo doses necessary to obtain the expected critical concentrations in the rat fetus. The pesticides fludioxonil, cyprodinil, and dimethomorph, which all are androgen receptor antagonists and inhibitors of testosterone synthesis in vitro, were selected for validation in a rat developmental study. AGD was, as predicted, slightly reduced in male pups and the fetal concentrations of pesticides were shown to be within a factor of 2 from the PBK model prediction levels, demonstrating the feasibility of the approach.
In conclusion, we have identified three pesticides as being weak endocrine disruptors and have demonstrated the utility of the approach by a proof-of-principle study showing positive predictions for male reproductive health effects. This concept may be used in the future for prioritizing the 353 pesticides for further in vivo testing.
