title: A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites.
abstract: 1,3-Butadiene (BD), a volatile organic chemical (VOC), is used in synthetic rubber production and other industrial processes. It is detectable at low levels in ambient air as well as in tobacco smoke and gasoline vapors. Inhalation exposures to high concentrations of BD have been associated with lung cancer in both humans and experimental animals, although differences in species sensitivity have been observed. Metabolically active lung cells such as Pulmonary Type I and Type II epithelial cells and club cells (Clara cells)(1) are potential targets of BD metabolite-induced toxicity. Metabolic capacities of these cells, their regional densities, and distributions vary throughout the respiratory tract as well as between species and cell types. Here we present a physiologically based pharmacokinetic (PBPK) model for BD that includes a regional model of lung metabolism, based on a previous model for styrene, to provide species-dependent descriptions of BD metabolism in the mouse, rat, and human. Since there are no in vivo data on BD pharmacokinetics in the human, the rat and mouse models were parameterized to the extent possible on the basis of in vitro metabolic data. Where it was necessary to use in vivo data, extrapolation from rat to mouse was performed to evaluate the level of uncertainty in the human model. A kidney compartment and description of downstream metabolism were also included in the model to allow for eventual use of available urinary and blood biomarker data in animals and humans to calibrate the model for estimation of BD exposures and internal metabolite levels. Results from simulated inhalation exposures to BD indicate that incorporation of differential lung region metabolism is important in describing species differences in pulmonary response and that these differences may have implications for risk assessments of human exposures to BD.
authors.affiliation: The Hamner Institutes for Health Research, Research Triangle Park, NC, USA. Electronic address: jcampbell@thehamner.org.
authors.forename: Jerry
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Ramboll Environ, 1900 N. 18th St., Suite 804, Monroe, LA 71201, USA. Electronic address: cvanlandingham@environcorp.com.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Van Landingham
authors.affiliation: Pacific Northwest National Laboratory, 902 Battelle Boulevard, Richland, WA 99352, USA. Electronic address: susan.r.crowell@gmail.com.
authors.forename: Susan
authors.initials: S
authors.lastname: Crowell
authors.affiliation: Ramboll Environ, 1900 N. 18th St., Suite 804, Monroe, LA 71201, USA. Electronic address: rgentry@environcorp.com.
authors.forename: Robinan
authors.initials: R
authors.lastname: Gentry
authors.affiliation: Ramboll Environ, 20 Custom House Street, Suite 800, Boston, MA 02110, USA. Electronic address: dkaden@environcorp.com.
authors.forename: Debra
authors.initials: D
authors.lastname: Kaden
authors.affiliation: British American Tobacco (Investments) Ltd, Research and Development, Regents Park Road, Southampton SO15 8TL, UK. Electronic address: Stacy_Fiebelkorn@bat.com.
authors.forename: Stacy
authors.initials: S
authors.lastname: Fiebelkorn
authors.affiliation: R.J. Reynolds Tobacco Company, P.O. Box 1487, Winston-Salem, NC 27102, USA. Electronic address: loccisa@rjrt.com.
authors.forename: Anne
authors.initials: A
authors.lastname: Loccisano
authors.affiliation: The Hamner Institutes for Health Research, Research Triangle Park, NC, USA; Ramboll Environ, 1900 N. 18th St., Suite 804, Monroe, LA 71201, USA. Electronic address: hclewell@environcorp.com.
authors.forename: Harvey
authors.initials: H
authors.lastname: Clewell
mesh_terms: D000818:Animals; D002070:Butadienes / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002070:Butadienes; C031763:1,3-butadiene
keywords: 1,3-Butadiene; Lung metabolism; PBPK; Physiologically – based pharmacokinetic model