引言：ß-氯丁二烯（2-氯-1,3-丁二烯；CP）在大鼠和小鼠的吸入暴露后引发肺肿瘤。小鼠在较低的暴露下就会出现这些肿瘤，而大鼠需要更高的暴露。在大鼠中，CP的暴露会导致肺中谷胱甘肽（GSH）的耗尽。方法：PBPK模型的开发旨在将小鼠肺肿瘤的出现与CP代谢生成的活性代谢产物的代谢速率或在暴露期间代谢的总量关联起来，并且已被扩展以包括来自CP的活性代谢产物的生成。扩展的PBPK模型描述了不稳定的环氧代谢产物2-CEO，以及更稳定的环氧代谢产物1-CEO通过微粒体氧化生成活性代谢产物的代谢，并将这些代谢产物的生成与预测GSH随CP暴露增加而减少的药代动力学模型相关联。开发模型所需的关键信息可以从文献研究中获得，其中包括：1）CP的微粒体代谢产物，以及2）小鼠、大鼠、仓鼠和人中活性微粒体制备中清除CP和1-CEO的体外速率。结果：通过模型模拟，当暴露增加时，活性代谢产物浓度的不成比例增加和组织中GSH的减少与剂量依赖性肿瘤形成一致。在具有肺肿瘤发生率的中间生物测定浓度下，预测的组织GSH低于50％的背景水平。这些降低GSH的模拟结果与基因表达结果一致，显示出最敏感的途径是Nrf2调节氧化应激和GSH代谢。讨论：PBPK模型用于将预测的活性代谢产物的组织暴露与CP的毒性和致癌性相关联。版权所有©2023 Campbell, Clewell, Van Landingham, Gentry和Andersen。

Introduction: ß-chloroprene (2-chloro-1,3-butadiene; CP) causes lung tumors after inhalation exposures in rats and mice. Mice develop these tumors at lower exposures than rats. In rats CP exposures cause depletion of lung glutathione (GSH). Methods: PBPK models developed to relate the appearance of mouse lung tumors with rates of CP metabolism to reactive metabolites or total amounts metabolized during exposures have been expanded to include production of reactive metabolites from CP. The extended PBPK model describes both the unstable oxirane metabolite, 2-CEO, and metabolism of the more stable oxirane, 1-CEO, to reactive metabolites via microsomal oxidation to a diepoxide, and linked production of these metabolites to a PK model predicting GSH depletion with increasing CP exposure. Key information required to develop the model were available from literature studies identifying: 1) microsomal metabolites of CP, and 2) in vitro rates of clearance of CP and 1-CEO from active microsomal preparations from mice, rats, hamsters and humans. Results: Model simulation of concentration dependence of disproportionate increases in reactive metabolite concentrations as exposures increases and decreases in tissue GSH are consistent with the dose-dependence of tumor formation. At the middle bioassay concentrations with a lung tumor incidence, the predicted tissue GSH is less than 50% background. These simulations of reduction in GSH are also consistent with the gene expression results showing the most sensitive pathways are Nrf2-regulation of oxidative stress and GSH metabolism. Discussion: The PBPK model is used to correlate predicted tissue exposure to reactive metabolites with toxicity and carcinogenicity of CP.Copyright © 2023 Campbell, Clewell, Van Landingham, Gentry and Andersen.