Clewell H J, Gentry P R, Gearhart J M, Covington T R, Banton M I, Andersen M E
The K. S. Crump Group, Inc., ICF Consulting, 602 East Georgia Avenue, Ruston, Louisiana 71270, USA.
Toxicol Sci. 2001 Oct;63(2):160-72. doi: 10.1093/toxsci/63.2.160.
A physiologically based pharmacokinetic (PBPK) model for isopropanol (IPA) and its major metabolite, acetone, is described. The structure of the parent chemical model, which can be used for either IPA or acetone by choosing the appropriate chemical-specific parameters, is similar to previously published models of volatile organic chemicals such as styrene. However, in order to properly simulate data on the exhalation of IPA and acetone during inhalation exposures, it was necessary to expand the description of the lung compartment to include a subcompartment for the upper respiratory tract mucus layer. This elaboration is consistent with published PBPK models of other water-soluble vapors in which the mucus layer serves to absorb the chemical during inhalation and then release it during exhalation. In the case of IPA exposure, a similar PBPK structure is used to describe the kinetics of the acetone produced from the metabolism of IPA. The resulting model is able to provide a coherent description of IPA and acetone kinetics in the rat and human for exposures to IPA by several routes: intravenous, intraperitoneal, oral, inhalation, and dermal. It is also able to consistently reproduce kinetic data for exposures of rats or humans to acetone. Thus, the model provides a validated framework for performing chemical-specific route-to-route extrapolation and cross-species dosimetry, which can be used in place of generic default calculations in support of risk assessments for IPA and acetone.
描述了一种基于生理的异丙醇（IPA）及其主要代谢产物丙酮的药代动力学（PBPK）模型。通过选择合适的化学物质特异性参数，该母体化学模型的结构可用于IPA或丙酮，其结构类似于先前发表的挥发性有机化合物（如苯乙烯）的模型。然而，为了正确模拟吸入暴露期间IPA和丙酮的呼出数据，有必要扩展肺区室的描述，以包括上呼吸道黏液层的一个子区室。这种细化与已发表的其他水溶性蒸气的PBPK模型一致，在这些模型中，黏液层在吸入过程中吸收化学物质，然后在呼出过程中释放它。在IPA暴露的情况下，使用类似的PBPK结构来描述由IPA代谢产生的丙酮的动力学。所得模型能够对大鼠和人类通过几种途径暴露于IPA时的IPA和丙酮动力学提供连贯的描述：静脉内、腹膜内、口服、吸入和经皮。它还能够一致地再现大鼠或人类暴露于丙酮时的动力学数据。因此，该模型为进行化学物质特异性的途径间外推和跨物种剂量测定提供了一个经过验证的框架，可用于代替一般的默认计算，以支持对IPA和丙酮的风险评估。
