Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) at levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans.
Keywords: (14)C-ATR; (14)C-atrazine; ABC; ATP-binding cassette; ATR; AUC; Atrazine; BW; DACT; DE; DIP; Developmental toxicity; GD; LOAEL; Lactation; MCL; NOAEL; NSC; PAD; PBPK; PBPK modeling; PC; PND; Pesticides; Pregnancy; RBC; RfD; SRM; area under the curve; atrazine, 2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine; body weight; desethylatrazine, 2-chloro-4-amino-6-isopropylamino-s-triazine; desisopropylatrazine, 2-amino-4-chloro-6-ethylamino-s-triazine; didealkylatrazine, 2-chloro-4,6-diamino-1,3,5-triazine; gestational day; lowest observed adverse effect level; maximum contaminant level; no observed adverse effect level; normalized sensitivity coefficient; physiologically based pharmacokinetic; population adjusted dose; postnatal day; red blood cell; reference dose; selected reaction monitoring; tissue:blood partition/distribution coefficient.