Quantitative in vitro to in vivo extrapolation (QIVIVE) of atrazine's effects on phosphodiesterase and aromatase mRNA expression in vitro to the rat in vivo based on pharmacokinetic

This study investigated the effects of atrazine (ATZ) and its metabolites on phosphodiesterase (PDE) activity ex vivo and aromatase mRNA expression in two steroidogenic cell lines (H295R and JEG-3). The pharmacokinetics of ATZ and its chlorometabolites were characterized for intact female Sprague-Dawley (SD) rats. A “Quantitative In Vitro to In Vivo Extrapolation” (QIVIVE) method was developed and used to calculate the margins of exposure to chlorotriazines in humans. Atrazine, and to a much lesser extent, its metabolites, resulted in PDE inhibition ex vivo . The IC 50 for atrazine was 39.52 μM. Neither H295R nor JEG-3 cells metabolize atrazine in vitro . 10 μM atrazine induced a 2- to 3-fold increase in aromatase mRNA expression in H295R cells. JEG3 cells gave similar results. Pharmacokinetic parameters for the chlorotriazines in female SD rats indicated that atrazine is rapidly absorbed and cleared from plasma after a bolus dose. QIVIVE analyses revealed the AUC at the No Observed Effect Concentration (NOEC) for atrazine inhibition of PDE ex vivo following 1 h of exposure was 350- to 1013-fold greater than the AUC plasma concentration following gavage or dietary dosing in vivo at the lowest NOEL currently used as a point of departure (POD) in human risk assessment. These results indicate that atrazine-induced PDE inhibition in vitro would not have a functional effect in vivo at the POD from animal studies or in humans exposed to atrazine via diet, drinking water or occupationally.