Prediction of adverse male reproductive health effects by integrating in vitro data and physiologically-based kinetic modelling

Currently, ∼352 pesticides are approved within the EU, but knowledge concerning sensitive endocrine effects on male reproductive health is scarce. Thus, there is an urgent need to improve non-animal test strategies that can help in predicting pesticides for adverse effects on male reproductive health.

The development of the male reproductive system strongly depends on androgens produced by the fetal testes, and hence the fetus is a target for compounds capable of interfering with the synthesis of these hormones or by antagonizing the androgen receptor. Our strategy combines androgen-related activity of pesticides on human cells with physiologically-based kinetic modeling.

Here, in vitro data pinpoints to compounds with a potential in vivo activity by identifying their critical internal exposure, while the kinetic model simulates the maternal doses necessary to reach critical levels in the fetus. We have developed a proof of principle showing that adverse effects on anogenital distance in male offspring, which is a unique and non-invasive marker for male reproductive health effects in animals and humans, can be predicted for selected pesticides.

We investigated this strategy on 9 pesticides and selected 3 compounds – fludioxonil, cyprodinil and dimethomorph – for in vivo ‘validation’ of the alternative approach in rats. Predicted fetal levels were within a factor of 2 from measured concentrations, and all three compounds showed a shorthened AGD in vivo.

In conclusion, our approach can be used to avoid unnecessary animal testing and focus on compounds that most likely will produce in vivo activity.