title: Use of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry comparisons of ester vapors.
abstract: Numerous inhalation studies have demonstrated that exposure to high concentrations of a wide range of volatile acids and esters results in cytotoxicity to the nasal olfactory epithelium. Previously, a hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of organic acids in the rodent and human nasal cavity. This study extends this methodology to a representative volatile organic ester, ethyl acrylate (EA). An in vitro exposure of explants of rat olfactory epithelium to EA with and without an esterase inhibitor demonstrated that the organic acid, acrylic acid, released by nasal esterases is primarily responsible for the olfactory cytotoxicity. Estimates of the steady-state concentration of acrylic acid in olfactory tissue were made for the rat nasal cavity by using data from a series of short-term in vivo studies and from the results of CFD-PBPK computer modeling. Appropriate parameterization of the CFD-PBPK model for the human nasal cavity and to accommodate human systemic anatomy, metabolism, and physiology allowed interspecies dose comparisons. The CFD-PBPK model simulations indicate that the olfactory epithelium of the human nasal cavity is exposed to at least 18-fold lower tissue concentrations of acid released from EA than the olfactory epithelium of the rat nasal cavity under the same exposure conditions. The magnitude of this difference varies with the specific exposure scenario that is simulated and with the specific dataset of human esterase activity used for the simulations. The increased olfactory tissue dose in rats relative to humans may be attributed to both the vulnerable location of the rodent olfactory tissue (comprising greater than 50% of the nasal cavity) and the high concentration of rat olfactory esterase activity (comparable to liver esterase activity) relative to human olfactory tissue. These studies suggest that the human olfactory epithelium is protected from vapors of organic esters significantly better than rat olfactory epithelium due to substantive differences in nasal anatomy, nasal and systemic metabolism, systemic physiology, and air flow. Although the accumulation of acrylic acid in the nasal tissues may be a primary concern for nasal irritation and human risk assessment, acute animal inhalation studies to evaluate lethality (LD50-type studies) conducted at very high vapor concentrations of ethyl acrylate indicated that a different mechanism is primarily responsible for mortality. The rodent studies demonstrated that systemic tissue nonprotein sulfhydryl depletion is a primary cause of death at exposure concentrations more than two orders of magnitude above the concentrations that induce nasal irritation. The CFD-PBPK model adequately simulated the severe depletion of glutathione in systemic tissues (e.g., liver and lung) associated with acute inhalation exposures in the 500-1000 ppm range. These results indicate that the CFD-PBPK model can simulate both the low-dose nasal tissue dosimetry associated with irritation and the high-dose systemic tissue dosimetry associated with mortality. In addition, the comparison of simulation results for ethyl acetate and acetone to nasal deposition data suggests that the CFD-PBPK model has general utility as a tool for dosimetry estimates for a wide range of other esters and slowly metabolized vapors.
authors.affiliation: Toxicology Department, Rohm and Haas Company, Spring House, Pennsylvania 19477, USA. clay_frederick@merck.com
authors.forename: Clay B
authors.initials: CB
authors.lastname: Frederick
authors.forename: Larry G
authors.initials: LG
authors.lastname: Lomax
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Black
authors.forename: Lavorgie
authors.initials: L
authors.lastname: Finch
authors.forename: Harvey E
authors.initials: HE
authors.lastname: Scribner
authors.forename: Julia S
authors.initials: JS
authors.lastname: Kimbell
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Morgan
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Subramaniam
authors.forename: John B
authors.initials: JB
authors.lastname: Morris
mesh_terms: D000179:Acrylates / Q000493:pharmacokinetics / Q000633:toxicity*; D000280:Administration, Inhalation; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D003198:Computer Simulation; D004950:Esterases / Q000378:metabolism; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D009831:Olfactory Mucosa / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
chemical_list: D000179:Acrylates; D002273:Carcinogens; C040833:ethyl acrylate; D004950:Esterases