Comparative Risks of Aldehyde Constituents in Cigarette Smoke Using Transient Computational Fluid Dynamics/Physiologically Based Pharmacokinetic Models of the Rat and Human Respiratory Tracts

被引:52
作者
Corley, Richard A. [1 ]
Kabilan, Senthil [1 ]
Kuprat, Andrew P. [1 ]
Carson, James P. [2 ]
Jacob, Richard E. [1 ]
Minard, Kevin R. [1 ]
Teeguarden, Justin G. [1 ]
Timchalk, Charles [1 ]
Pipavath, Sudhakar [3 ]
Glenny, Robb [4 ]
Einstein, Daniel R. [1 ]
机构
[1] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA
[2] Univ Texas Austin, Texas Adv Comp Ctr, Austin, TX 78758 USA
[3] Univ Washington, Radiol, Seattle, WA 98195 USA
[4] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA
基金
美国国家卫生研究院;
关键词
CFD; PBPK; acetaldehyde; acrolein; formaldehyde; cigarette smoke; respiratory tract; risk assessment; IONIZATION MASS-SPECTROMETRY; INHALATION TOXICITY; INHALED ACROLEIN; NASAL PASSAGES; HUMAN LUNG; HISTOCHEMICAL-LOCALIZATION; INSPIRED ACETALDEHYDE; TISSUE DISPOSITION; AEROSOL DEPOSITION; HYDROGEN-SULFIDE;
D O I
10.1093/toxsci/kfv071
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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.
引用
收藏
页码:65 / 88
页数:24
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