Many pesticides can antagonize the androgen receptor (AR) or inhibit androgen synthesis
but their potential to cause reproductive toxicity related to disruption of androgen action during fetal life is difficult to predict. Currently no approaches for using
data to anticipate such
effects exist. Prioritization schemes that limit unnecessary
testing are urgently needed.
The aim was to develop a quantitative
to
extrapolation (QIVIVE) approach for predicting
anti-androgenicity arising from gestational exposures and manifesting as a shortened anogenital distance (AGD) in male rats.
We built a physiologically based pharmacokinetic (PBK) model to simulate concentrations of chemicals in the fetus resulting from maternal dosing. The predicted fetal levels were compared with analytically determined concentrations, and these were judged against
active concentrations for AR antagonism and androgen synthesis suppression.
We first evaluated our model by using
and
anti-androgenic data for procymidone, vinclozolin, and linuron. Our PBK model described the measured fetal concentrations of parent compounds and metabolites quite accurately (within a factor of five). We applied the model to nine current-use pesticides, all with
evidence for anti-androgenicity but missing
data. Seven pesticides (fludioxonil, cyprodinil, dimethomorph, imazalil, quinoxyfen, fenhexamid,
-phenylphenol) were predicted to produce a shortened AGD in male pups, whereas two (
, pyrimethanil) were anticipated to be inactive. We tested these expectations for fludioxonil, cyprodinil, and dimethomorph and observed shortened AGD in male pups after gestational exposure. The measured fetal concentrations agreed well with PBK-modeled predictions.
Our QIVIVE model newly identified fludioxonil, cyprodinil, and dimethomorph as
anti-androgens. With the examples investigated, our approach shows great promise for predicting
anti-androgenicity (i.e., AGD shortening) for chemicals with
activity and for minimizing unnecessary
testing. https://doi.org/10.1289/EHP6774....

Quantitative in Vitro to in Vivo Extrapolation (QIVIVE) for Predicting Reduced Anogenital Distance Produced by Anti-Androgenic Pesticides in a Rodent Model for Male Reproductive Disorders

10.1289/EHP6774