Many pesticides can antagonize the androgen receptor (AR) or inhibit androgen synthesis in vitro but their potential to cause reproductive toxicity related to disruption of androgen action during fetal life is difficult to predict. Currently no approaches for utilizing in vitro data to anticipate such in vivo effects exist and limitation of unnecessary in vivo testing is urgently needed.
The aim was to develop a quantitative in vitro to in vivo extrapolation (QIVIVE) approach for predicting in vivo anti-androgenicity arising from gestational exposures and manifesting as a shortened anogenital distance (AGD) in male rats.
We built physiologically-based pharmacokinetic (PBK) models to simulate fetal levels of chemicals resulting from maternal dosing. The predicted fetal levels were compared to measured concentrations, and these were judged against in vitro active concentrations for AR antagonism and androgen synthesis suppression.
We applied the approach to three model pesticides (procymidone, vinclozolin, linuron) and nine current-use pesticides.
Our PBK model predicted accurately the measured fetal concentrations of compounds. Seven pesticides (fludioxonil, cyprodinil, dimethomorph, imazalil, quinoxyfen, fenhexamid, o-phenylphenol) and the model pesticides were predicted to produce a shortened AGD in male pups, while two (λ-cyhalothrin, pyrimethanil) were anticipated inactive. We tested these expectations for the model pesticides, fludioxonil, cyprodinil and dimethomorph and observed shortened AGD in male pups after gestational exposure.
Our QIVIVE model newly identified fludioxonil, cyprodinil and dimethomorph as new in vivo anti-androgens. With the examples investigated, our approach shows great promise for predicting in vivo anti-androgenicity for chemicals and for minimizing unnecessary in vivo testing.Læs publikation