The metabolic series approach has successfully linked internal dosimetries of metabolically related compounds reducing cost and time for chemical risk assessments. Here, we developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the propyl metabolic series including propyl acetate, 1-propanol, propionaldehyde, and propionic acid. Manufacturers use these compounds as organic solvents and intermediates during chemical synthesis. Public exposures can occur through using consumer products containing propyl compounds like cosmetics, aerosol sprays, or foods, and occupational exposures can occur at manufacturing facilities. To develop the PBPK model, we measured in vitro metabolism of propyl acetate in blood and liver S9 fractions. We measured concentrations of propyl compounds in blood following intravenous (iv) infusion of 13C-propanol or 13C-propionic acid and closed chamber inhalation exposures to propyl acetate or propanol in rats. Using these studies and other published data, we modified an existing PBPK model for the butyl metabolic series to simulate time course concentrations of propyl compounds in rats and humans. Consistent with measured in vitro and in vivo data, the optimized propyl series model predicts rapid clearance of propyl acetate, higher concentrations of propanol in blood from propyl acetate inhalation compared to propanol inhalation in rats but not in humans, and low concentrations of propionic acid in blood from exposures to propyl acetate or propanol. Regulators can use this model as a tool for propyl compound risk assessment by linking internal dosimetries under various exposure scenarios.

中文翻译：

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使用基于生理的药代动力学（PBPK）模型，将大鼠和人类中丙基代谢系列的内部剂量联系起来。

代谢系列方法已成功链接了与代谢相关的化合物的内部剂量，从而降低了化学风险评估的成本和时间。在这里，我们针对包括乙酸丙酯，1-丙醇，丙醛和丙酸在内的丙基代谢系列，在大鼠和人类中建立了基于生理的药代动力学（PBPK）模型。制造商在化学合成过程中将这些化合物用作有机溶剂和中间体。通过使用含有丙基化合物的消费品（例如化妆品，气雾剂或食品），可以发生公共接触，而在生产设施中也可以发生职业接触。要开发PBPK模型，我们测量了血液和肝脏S9部分中乙酸丙酯的体外代谢。我们在静脉内（iv）输注13C-丙醇或13C-丙酸并在大鼠中于乙酸丙酯或丙醇的密闭室内吸入暴露后，测量了血液中丙基化合物的浓度。使用这些研究和其他已公开的数据，我们修改了丁基代谢系列的现有PBPK模型，以模拟大鼠和人类中丙基化合物的时程浓度。与测量的体内和体外数据一致，优化的丙基系列模型预测了乙酸丙酯的快速清除，吸入乙酸丙酯的血液中丙醇的浓度高于大鼠而非人的丙醇吸入，以及丙二醇在大鼠中的浓度较低。暴露于乙酸丙酯或丙醇引起的血液。