A Validated Hybrid Computational Fluid Dynamics-Physiologically Based Pharmacokinetic Model for Respiratory Tract Vapor Absorption in the Human and Rat and Its Application to Inhalation Dosimetry of Diacetyl

Abstract

Diacetyl vapor is associated with bronchiolar injury in man but primarily large airway injury in the rat. The goal of this study was to develop a physiologically based pharmacokinetic model for inspired vapor dosimetry and to apply the model to diacetyl. The respiratory tract was modeled as a series of airways: nose, trachea, main bronchi, large bronchi, small bronchi, bronchioles, and alveoli with tissue dimensions obtained from the literature. Airborne vapor was allowed to absorb (or desorb) from tissues based on mass transfer coefficients. Transfer of vapor within tissues was based on molecular diffusivity with direct reaction with tissue substrates and/or metabolism being allowed in each tissue compartment. In vitro studies were performed to provide measures of diacetyl metabolism kinetics and direct reaction rates allowing for the development of a model with no unassigned variables. Respiratory tract uptake of halothane, acetone, ethanol and diacetyl was measured in male F344 rat to obtain data for model validation. The human model was validated against published values for inspired vapor uptake. For both the human and rat models, a close concordance of model estimates with experimental measurements was observed, validating the model. The model estimates that limited amounts of inspired diacetyl penetrate to the bronchioles of the rat (<2%), whereas in the lightly exercising human, 24% penetration to the bronchioles is estimated. Bronchiolar tissue concentrations of diacetyl in the human are estimated to exceed those in the rat by 40-fold. These inhalation dosimetric differences may contribute to the human-rat differences in diacetyl-induced airway injury.

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

“…This is consistent with absorption of some of the diacetyl from the airstream along the course of the nasal passageways. 52,53 Sex had no effect on diacetyl-induced necrosis pathology scores (Supplemental Table 1). The pathology score for knockout mice was significantly greater than for wild-type mice (P Z 0.0224) at level T1 after the 300-ppm exposure ( Figure 2E).…”

Deposition of Inhaled Gases and Vapors

“…In the inhibited animals it would be anticipated that uptake efficiency would mimic that for nonmetabolized vapors and be simply reflective of solubility (partition coefficient) and nasal perfusion. This has been observed (Gloede et al, 2011;Morris et al, 1993). Finally, it should be noted that metabolism is saturable; thus, vapor uptake of metabolized vapors should Minute ventilation (min.…”

“…Absorption of gases and vapors in the proximal airways limits penetration to the distal airways and, thus, serves as an important respiratory defense mechanism (Brain, 1979). Indeed, the absence of deleterious effects from an inspired gas or vapor in the bronchiolar airways may simply be due to the fact that the chemical is completely absorbed in the large airways and does not penetrate to the distal bronchioli (Gloede et al, 2011). That the upper respiratory tract (URT, all airways proximal to the larynx) provides an essential defense mechanism has long been appreciated (Jordan and Carlson, 1913).…”

“…Although not physiologic, this provides definitive data on URT absorption efficiency at specific flow rates. Data so obtained can be used to validate a model that can then be used to estimate absorption under normal cyclic flow conditions (Gloede et al, 2011;Morris, 2012). Alternatively, air can be bled from the nasopharynx at low flow rates in animals (or humans) respiring normally.…”

“…This process cannot be mimicked by unidirectional (constant inspiration) flow regimes. However, data collected under unidirectional flow can be used to validate models that incorporate absorption/ desorption cycling (Gloede et al, 2011;Hinderliter et al, 2005;Plowchalk et al, 1997).…”