Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
Toxicol Appl Pharmacol. 2011 Feb 15;251(1):16-31. doi: 10.1016/j.taap.2010.11.009. Epub 2010 Nov 20.
Atrazine (ATR) is a chlorotriazine herbicide that is widely used and relatively persistent in the environment. In laboratory rodents, excessive exposure to ATR is detrimental to the reproductive, immune, and nervous systems. To better understand the toxicokinetics of ATR and to fill the need for a mouse model, a physiologically based pharmacokinetic (PBPK) model for ATR and its main chlorotriazine metabolites (Cl-TRIs) desethyl atrazine (DE), desisopropyl atrazine (DIP), and didealkyl atrazine (DACT) was developed for the adult male C57BL/6 mouse. Taking advantage of all relevant and recently made available mouse-specific data, a flow-limited PBPK model was constructed. The ATR and DACT sub-models included blood, brain, liver, kidney, richly and slowly perfused tissue compartments, as well as plasma protein binding and red blood cell binding, whereas the DE and DIP sub-models were constructed as simple five-compartment models. The model adequately simulated plasma levels of ATR and Cl-TRIs and urinary dosimetry of Cl-TRIs at four single oral dose levels (250, 125, 25, and 5mg/kg). Additionally, the model adequately described the dose dependency of brain and liver ATR and DACT concentrations. Cumulative urinary DACT amounts were accurately predicted across a wide dose range, suggesting the model's potential use for extrapolation to human exposures by performing reverse dosimetry. The model was validated using previously reported data for plasma ATR and DACT in mice and rats. Overall, besides being the first mouse PBPK model for ATR and its Cl-TRIs, this model, by analogy, provides insights into tissue dosimetry for rats. The model could be used in tissue dosimetry prediction and as an aid in the exposure assessment to this widely used herbicide.
莠去津（ATR）是一种广泛使用且在环境中相对持久的氯三嗪类除草剂。在实验啮齿动物中，过量暴露于 ATR 会对生殖、免疫和神经系统造成损害。为了更好地了解 ATR 的毒代动力学，并满足对小鼠模型的需求，我们为成年雄性 C57BL/6 小鼠建立了一个基于生理学的药代动力学（PBPK）模型，用于模拟 ATR 及其主要的氯三嗪代谢物（Cl-TRIs）去乙基莠去津（DE）、去异丙基莠去津（DIP）和二去烷基莠去津（DACT）。该模型充分利用了所有相关的、最近可用的小鼠特异性数据，构建了一个流量受限的 PBPK 模型。ATR 和 DACT 子模型包括血液、大脑、肝脏、肾脏、丰富且缓慢灌注的组织隔室，以及血浆蛋白结合和红细胞结合，而 DE 和 DIP 子模型则构建为简单的五隔室模型。该模型能够很好地模拟 ATR 和 Cl-TRIs 的血浆水平以及四种单次口服剂量水平（250、125、25 和 5mg/kg）下的 Cl-TRIs 的尿剂量。此外，该模型还能够很好地描述大脑和肝脏中 ATR 和 DACT 浓度的剂量依赖性。在广泛的剂量范围内，准确预测了累积的尿 DACT 量，这表明该模型有可能通过进行反向剂量学来推断人类暴露情况。该模型使用先前报道的小鼠和大鼠血浆 ATR 和 DACT 数据进行了验证。总的来说，除了是第一个用于 ATR 及其 Cl-TRIs 的小鼠 PBPK 模型外，该模型还通过类推，为大鼠的组织剂量学提供了见解。该模型可用于组织剂量预测，并作为评估这种广泛使用的除草剂暴露的辅助工具。
