CFD-PBPK hybrid model for simulating gas and vapor uptake in the rat nose
CFD-PBPK hybrid model for simulating gas and vapor uptake in the rat nose
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DOI：
10.1006/taap.1998.8407
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发表时间：
1998-05-01
影响因子：
3.8
通讯作者：
Ultman, JS
中科院分区：
文献类型：
--
作者：
Bush, ML;Frederick, CB;Ultman, JS
在啮齿动物的实验室研究中，吸入有机蒸气通常会优先损害嗅觉上皮。这种局灶性损伤的形成可能完全或部分归因于鼻腔内蒸气吸收的空间分布的相应不均匀性。作为确定这种剂量分布的工具，我们开发了一种基于计算流体动力学 (CFD) 和基于生理学的药代动力学 (PBPK) 模型相结合的数学模型，用于模拟大鼠鼻子中有毒气体的吸收。鼻气道被细分为四个不同的鼻道，每个鼻道都包含一个主要的气流。每个鼻道进一步分为四个连续区域，连接到包含粘液、上皮和上皮下隔室的单独组织堆上。 16 个气道区域的气相传质系数和气流的值通过使用市售 CFD 软件求解纳维-斯托克斯和对流扩散方程来确定。然后将这些值输入到 16 个组织堆中毒物运输的 PBPK 模拟中。该模型通过使用啮齿动物吸入研究中对三种“非反应性”蒸气的总体吸收数据进行了验证，这些蒸气要么完全惰性（即丙酮），在水介质中可逆电离（即丙烯酸），要么被酶抑制剂（即异戊醇）阻止代谢。敏感性分析表明，精确的传质系数值对于模拟大鼠鼻子中非反应性蒸气的区域浓度和吸收是不必要的，但组织中扩散系数的可靠估计对于准确模拟至关重要。 (C) 1998 年学术出版社。
In laboratory studies of rodents, the inhalation of organic vapors often results in preferential damage to olfactory epithelium. Such focal lesion formation may be due either wholly or in part to a corresponding nonuniformity in the spatial distribution of vapor uptake within the nasal cavities. As a tool for determining this dose distribution, a mathematical model based on a combination of computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) modeling was developed for simulating toxicant vapor uptake in the rat nose. The nasal airways were subdivided into four distinct meatuses selected such that each contained a major air flow stream. Each meatus was further divided into four serial regions attached to separate tissue stacks containing mucus, epithelial, and subepithelial compartments. Values for the gas-phase mass transfer coefficients and gas flows in the 16 airway regions were determined by a solution of the Navier-Stokes and convection-diffusion equations using commercially available CFD software. These values were then input to a PBPK simulation of toxicant transport through the 16 tissue stacks. The model was validated by using overall uptake data from rodent inhalation studies for three "unreactive" vapors that were either completely inert (i.e., acetone), reversibly ionized in aqueous media (i.e., acrylic acid), or prevented from being metabolized by an enzyme inhibitor (i.e., isoamyl alcohol). A sensitivity analysis revealed that accurate values of the mass transfer coefficient were not necessary to simulate regional concentrations and uptake of unreactive vapors in the rat nose, but reliable estimates of diffusion coefficients in tissue were crucial for accurate simulations. (C) 1998 Academic Press.