Corley Richard A, Kabilan Senthil, Kuprat Andrew P, Carson James P, Jacob Richard E, Minard Kevin R, Teeguarden Justin G, Timchalk Charles, Pipavath Sudhakar, Glenny Robb, Einstein Daniel R
*Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352; Texas Advanced Computing Center, University of Texas, Austin, Texas 78758; Radiology, University of Washington, Seattle, Washington 98195; and Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington 98195
*Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352; Texas Advanced Computing Center, University of Texas, Austin, Texas 78758; Radiology, University of Washington, Seattle, Washington 98195; and Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington 98195.
Toxicol Sci. 2015 Jul;146(1):65-88. doi: 10.1093/toxsci/kfv071. Epub 2015 Apr 8.
Computational fluid dynamics (CFD) modeling is well suited for addressing species-specific anatomy and physiology in calculating respiratory tissue exposures to inhaled materials. In this study, we overcame prior CFD model limitations to demonstrate the importance of realistic, transient breathing patterns for predicting site-specific tissue dose. Specifically, extended airway CFD models of the rat and human were coupled with airway region-specific physiologically based pharmacokinetic (PBPK) tissue models to describe the kinetics of 3 reactive constituents of cigarette smoke: acrolein, acetaldehyde and formaldehyde. Simulations of aldehyde no-observed-adverse-effect levels for nasal toxicity in the rat were conducted until breath-by-breath tissue concentration profiles reached steady state. Human oral breathing simulations were conducted using representative aldehyde yields from cigarette smoke, measured puff ventilation profiles and numbers of cigarettes smoked per day. As with prior steady-state CFD/PBPK simulations, the anterior respiratory nasal epithelial tissues received the greatest initial uptake rates for each aldehyde in the rat. However, integrated time- and tissue depth-dependent area under the curve (AUC) concentrations were typically greater in the anterior dorsal olfactory epithelium using the more realistic transient breathing profiles. For human simulations, oral and laryngeal tissues received the highest local tissue dose with greater penetration to pulmonary tissues than predicted in the rat. Based upon lifetime average daily dose comparisons of tissue hot-spot AUCs (top 2.5% of surface area-normalized AUCs in each region) and numbers of cigarettes smoked/day, the order of concern for human exposures was acrolein > formaldehyde > acetaldehyde even though acetaldehyde yields were 10-fold greater than formaldehyde and acrolein.
计算流体动力学（CFD）建模非常适合在计算呼吸组织对吸入物质的暴露时考虑物种特异性的解剖结构和生理特征。在本研究中，我们克服了先前CFD模型的局限性，以证明逼真的瞬态呼吸模式对于预测特定部位组织剂量的重要性。具体而言，大鼠和人类的扩展气道CFD模型与气道区域特异性的基于生理的药代动力学（PBPK）组织模型相结合，以描述香烟烟雾中3种反应性成分的动力学：丙烯醛、乙醛和甲醛。对大鼠鼻腔毒性的醛类未观察到不良反应水平进行模拟，直至逐次呼吸的组织浓度分布达到稳态。使用香烟烟雾中代表性的醛类产量、测量的抽吸通气曲线和每天吸烟支数进行人类口腔呼吸模拟。与先前的稳态CFD/PBPK模拟一样大鼠前呼吸鼻上皮组织对每种醛类的初始摄取率最高。然而，使用更逼真的瞬态呼吸曲线时前背侧嗅上皮中随时间和组织深度变化的曲线下面积（AUC）浓度通常更高。对于人类模拟，口腔和喉部组织接受的局部组织剂量最高，且对肺部组织的穿透性比在大鼠中预测的更高。基于组织热点AUC（每个区域中表面积标准化AUC的前2.5%）的终生平均每日剂量比较和每天吸烟支数，尽管乙醛产量比甲醛和丙烯醛高10倍，但人类暴露的关注顺序为丙烯醛>甲醛>乙醛。
