title: Use of novel inhalation kinetic studies to refine physiologically-based pharmacokinetic models for ethanol in non-pregnant and pregnant rats.
abstract: Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrations (BEC) in the range associated with these effects. Previous laboratory reports often lacked sufficient detail to adequately simulate reported exposure scenarios associated with BECs in this range, or lacked data on the time-course of EtOH in target tissues (e.g. brain, liver, eye, fetus). To address these data gaps, inhalation studies were performed at 5000, 10 000, and 21 000 ppm (6 h/d) in non-pregnant female Long-Evans (LE) rats and at 21 000 ppm (6.33 h/d) for 12 d of gestation in pregnant LE rats to evaluate our previously published PBPK models at toxicologically-relevant blood and tissue concentrations. Additionally, nose-only and whole-body plethysmography studies were conducted to refine model descriptions of respiration and uptake within the respiratory tract. The resulting time-course and plethysmography data from these in vivo studies were compared to simulations from our previously published models, after which the models were recalibrated to improve descriptions of tissue dosimetry by accounting for dose-dependencies in pharmacokinetic behavior. Simulations using the recalibrated models reproduced these data from non-pregnant, pregnant, and fetal rats to within a factor of 2 or better across datasets, resulting in a suite of model structures suitable for simulation of a broad range of EtOH exposure scenarios.
authors.affiliation: Neurotoxicology Branch/Toxicity Assessment Division, Office of Research and Development (ORD), US Environmental Protection Agency , Research Triangle Park, NC , USA .
authors.forename: Sheppard A
authors.initials: SA
authors.lastname: Martin
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Oshiro
authors.forename: Paul A
authors.initials: PA
authors.lastname: Evansky
authors.forename: Laura L
authors.initials: LL
authors.lastname: Degn
authors.forename: Allen D
authors.initials: AD
authors.lastname: Ledbetter
authors.forename: Jermaine
authors.initials: J
authors.lastname: Ford
authors.forename: Q
authors.initials: Q
authors.lastname: Todd Krantz
authors.forename: William R
authors.initials: WR
authors.lastname: LeFew
authors.forename: Tracey E
authors.initials: TE
authors.lastname: Beasley
authors.forename: Hisham
authors.initials: H
authors.lastname: El-Masri
authors.forename: Eva D
authors.initials: ED
authors.lastname: McLanahan
authors.forename: William K
authors.initials: WK
authors.lastname: Boyes
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bushnell
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D001944:Breath Tests; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D005123:Eye / Q000196:embryology / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005865:Gestational Age; D019570:Inhalation Exposure / Q000009:adverse effects / Q000032:analysis; D007700:Kinetics; D008099:Liver / Q000196:embryology / Q000378:metabolism; D018811:Maternal Exposure / Q000009:adverse effects; D008431:Maternal-Fetal Exchange / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D010991:Plethysmography; D011247:Pregnancy; D020318:Rats, Long-Evans
chemical_list: D000431:Ethanol
keywords: Ethanol; physiologically-based pharmacokinetic (PBPK) models; pregnancy; rats