title: Dosimetric adjustment factors for methyl methacrylate derived from a steady-state analysis of a physiologically based clearance-extraction model.
abstract: Cells within the epithelial lining of the nasal cavity metabolize a variety of low-molecular-weight, volatile xenobiotics. In common with terminology developed for other metabolizing organs, the nose extracts these chemicals from the airstream, thereby clearing some portion of the total nasal airflow. In this article, a physiologically based clearance-extraction (PBCE) model of nasal metabolism is used to predict extraction for steady-state conditions. This model, developed by simplification of existing physiologically based pharmacokinetic (PBPK) nasal models, has three tissue regions in two flow paths. A dorsal flow stream sequentially passes over a small area of respiratory epithelium and then over the entire olfactory epithelial surface within the nose. A ventral airstream, consisting of most of the total flow, passes over the larger portion (>80%) of the respiratory epithelium. Each underlying tissue stack has a mucus layer, an epithelial tissue compartment, and a blood exchange region. Metabolism may occur in any of the subcompartments within the tissue stacks. The model, solved directly for a steady-state condition, specifies the volumetric airflow over each stack. Computational fluid dynamic (CFD) solutions for the rat and human for the case with no liquid-phase resistance provided a maximum value for regional extraction, E(max)'. Equivalent air-to-liquid phase permeation coefficients (also referred to as the air-phase mass transfer coefficient) were calculated based on these E(max)' values. The PBCE model was applied to assess expected species differences in nasal extraction and in localized tissue metabolism of methyl methacrylate (MMA) in rats and in humans. Model estimates of tissue dose of MMA metabolites (in micromol metabolized/h/ml tissue) in both species were used to evaluate the dosimetric adjustment factor (DAF) that should be applied in reference concentration (RfC) calculations for MMA. For human ventilation rates equivalent to light exercise, the DAF was estimated to be 3.02 at 28.4 ppm, the benchmark concentration for nasal lesions. Depending on specific assumptions about distribution of esterase activities in human tissues, the range of DAF values was 1.56-8.00. The DAF for heavy exercise with a ventilation rate of 42 L/min was still 2.98. Estimated DAFs were concentration dependent, varying between 2.4 and 4.76 in the inhaled concentration range from 1 and 400 ppm. Present default methods utilize a DAF of 0.145. These steady-state calculations with this PBCE model should be useful in risk assessment calculations for a variety of vapors and gases that are converted to toxic metabolites in cells in the respiratory tract.
authors.affiliation: K. S. Crump Group, ICF Consulting, Research Triangle Park, North Carolina 27709, USA. manders@cvmbs.colostate.edu
authors.forename: M E
authors.initials: ME
authors.lastname: Andersen
authors.forename: R
authors.initials: R
authors.lastname: Sarangapani
authors.forename: C B
authors.initials: CB
authors.lastname: Frederick
authors.forename: J S
authors.initials: JS
authors.lastname: Kimbell
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics; D000465:Algorithms; D000818:Animals; D003198:Computer Simulation; D004848:Epithelium; D006801:Humans; D019570:Inhalation Exposure; D020366:Methylmethacrylate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008954:Models, Biological; D009079:Mucociliary Clearance / Q000502:physiology*; D009831:Olfactory Mucosa / Q000378:metabolism; D010539:Permeability; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000085:Acetates; D020366:Methylmethacrylate; C007650:ethyl acetate