Kim David, Andersen Melvin E, Pleil Joachim D, Nylander-French Leena A, Prah James D
Department of Environmental Science and Engineering, School of Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Toxicol Lett. 2007 Mar 30;169(3):222-35. doi: 10.1016/j.toxlet.2007.01.008. Epub 2007 Jan 30.
Aggregate (multiple pathway) exposures to methyl tertiary-butyl ether (MTBE) in air and water occur via dermal, inhalation, and oral routes. Previously, physiologically based pharmacokinetic (PBPK) models have been used to quantify the kinetic behavior of MTBE and its primary metabolite, tertiary-butyl alcohol (TBA), from inhalation exposures. However, the contribution of dermal and oral exposures to the internal dose of MTBE and TBA were not characterized well. The objective of this study was to develop a multi-route PBPK model of MTBE and TBA in humans. The model was based entirely on blood MTBE and TBA measurements from controlled human exposures. The PBPK model consists of nine primary compartments representing the lungs, skin, fat, kidney, stomach, intestine, liver, rapidly perfused tissue, and slowly perfused tissue. The MTBE and TBA models are linked by a single metabolic pathway. Although the general structure of the model is similar to previously published models of volatile organic compounds, we have now developed a detailed mathematical description of the lung, skin, and gastrointestinal tract. This PBPK model represents the most comprehensive and accurate description of MTBE and TBA pharmacokinetics in humans to date. The aggregate exposure model application for MTBE can be generalized to other environmental chemicals under this framework given appropriate empirical measurement data.
空气中和水中的甲基叔丁基醚（MTBE）通过皮肤、吸入和口服途径产生累积（多途径）暴露。此前，基于生理的药代动力学（PBPK）模型已被用于量化吸入暴露后MTBE及其主要代谢产物叔丁醇（TBA）的动力学行为。然而，皮肤和口服暴露对MTBE和TBA体内剂量的贡献尚未得到很好的描述。本研究的目的是建立人体中MTBE和TBA的多途径PBPK模型。该模型完全基于受控人体暴露后的血液MTBE和TBA测量值。PBPK模型由九个主要隔室组成，分别代表肺、皮肤、脂肪、肾脏、胃、肠道、肝脏、快速灌注组织和缓慢灌注组织。MTBE和TBA模型通过单一代谢途径相连。尽管该模型的总体结构与先前发表的挥发性有机化合物模型相似，但我们现在已经对肺、皮肤和胃肠道进行了详细的数学描述。这个PBPK模型是迄今为止对人体中MTBE和TBA药代动力学最全面、最准确的描述。在有适当经验测量数据的情况下，MTBE的累积暴露模型应用可以在此框架下推广到其他环境化学物质。
