Filser Johannes Georg, Klein Dominik
Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany.
Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany.
Toxicol Lett. 2018 Apr;286:54-79. doi: 10.1016/j.toxlet.2017.07.896. Epub 2017 Jul 31.
Ethylene (ET) is the largest volume organic chemical. Mammals metabolize the olefin to ethylene oxide (EO), another important industrial chemical. The epoxide alkylates macromolecules and has mutagenic and carcinogenic properties. In order to estimate the EO burden in mice, rats, and humans resulting from inhalation exposure to gaseous ET or EO, a physiological toxicokinetic model was developed. It consists of the compartments lung, richly perfused tissues, kidneys, muscle, fat, arterial blood, venous blood, and liver containing the sub-compartment endoplasmic reticulum. Modeled ET metabolism is mediated by hepatic cytochrome P450 2E1, EO metabolism by hepatic microsomal epoxide hydrolase or cytosolic glutathione S-transferase in various tissues. EO is also spontaneously hydrolyzed or conjugated with glutathione. The model was validated on experimental data collected in mice, rats, and humans. Modeled were uptake by inhalation, wash-in-wash-out effect in the upper respiratory airways, distribution into tissues and organs, elimination via exhalation and metabolism, and formation of 2-hydroxyethyl adducts with hemoglobin and DNA. Simulated concentration-time courses of ET or EO in inhaled (gas uptake studies) or exhaled air, and of EO in blood during exposures to ET or EO agreed excellently with measured data. Predicted levels of adducts with DNA and hemoglobin, induced by ET or EO, agreed with reported levels. Exposures to 10000 ppm ET were predicted to induce the same adduct levels as EO exposures to 3.95 (mice), 5.67 (rats), or 0.313 ppm (humans). The model is concluded to be applicable for assessing health risks from inhalation exposure to ET or EO.
乙烯（ET）是产量最大的有机化学品。哺乳动物将这种烯烃代谢为环氧乙烷（EO），另一种重要的工业化学品。该环氧化物会使大分子烷基化，具有致突变和致癌特性。为了估算小鼠、大鼠和人类因吸入气态ET或EO而产生的EO负荷，开发了一种生理毒代动力学模型。它由肺、血液灌注丰富的组织、肾脏、肌肉、脂肪、动脉血、静脉血以及包含亚细胞内质网的肝脏等隔室组成。模拟的ET代谢由肝细胞色素P450 2E1介导，EO代谢由肝脏微粒体环氧化物水解酶或各种组织中的胞质谷胱甘肽S - 转移酶介导。EO也会自发水解或与谷胱甘肽结合。该模型根据在小鼠、大鼠和人类中收集的实验数据进行了验证。模拟的过程包括通过吸入摄取、上呼吸道的进出效应、在组织和器官中的分布、通过呼气和代谢消除以及与血红蛋白和DNA形成2 - 羟乙基加合物。在吸入（气体摄取研究）或呼出空气中ET或EO的模拟浓度 - 时间过程，以及在暴露于ET或EO期间血液中EO的模拟浓度 - 时间过程与实测数据高度吻合。由ET或EO诱导的与DNA和血红蛋白加合物的预测水平与报道水平一致。预计暴露于10000 ppm ET会诱导与暴露于3.95 ppm（小鼠）、5.67 ppm（大鼠）或0.313 ppm（人类）的EO相同的加合物水平。得出该模型适用于评估吸入ET或EO所致健康风险的结论。
