title: Comparative Risks of Aldehyde Constituents in Cigarette Smoke Using Transient Computational Fluid Dynamics/Physiologically Based Pharmacokinetic Models of the Rat and Human Respiratory Tracts.
abstract: 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.
authors: *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 rick.corley@pnnl.gov.
authors: Richard A
authors: RA
authors: Corley
authors: *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.
authors: Senthil
authors: S
authors: Kabilan
authors: *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.
authors: Andrew P
authors: AP
authors: Kuprat
authors: *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.
authors: James P
authors: JP
authors: Carson
authors: *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.
authors: Richard E
authors: RE
authors: Jacob
authors: *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.
authors: Kevin R
authors: KR
authors: Minard
authors: *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.
authors: Justin G
authors: JG
authors: Teeguarden
authors: *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.
authors: Charles
authors: C
authors: Timchalk
authors: *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.
authors: Sudhakar
authors: S
authors: Pipavath
authors: *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.
authors: Robb
authors: R
authors: Glenny
authors: *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.
authors: Daniel R
authors: DR
authors: Einstein
mesh_terms: D000447:Aldehydes / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D006801:Humans; D008954:Models, Biological; D051381:Rats; D012906:Smoke; D014026:Nicotiana
chemical_list: D000447:Aldehydes; D012906:Smoke
keywords: CFD; PBPK; acetaldehyde; acrolein; cigarette smoke; formaldehyde; respiratory tract; risk assessment