Comparative computational modeling of airflows and vapor dosimetry in the respiratory tracts of rat, monkey, and human

Abstract

Computational fluid dynamics (CFD) models are useful for predicting site-specific dosimetry of airborne materials in the respiratory tract and elucidating the importance of species differences in anatomy, physiology, and breathing patterns. We improved the imaging and model development methods to the point where CFD models for the rat, monkey, and human now encompass airways from the nose or mouth to the lung. A total of 1272, 2172, and 135 pulmonary airways representing 17±7, 19±9, or 9±2 airway generations were included in the rat, monkey and human models, respectively. A CFD/physiologically based pharmacokinetic model previously developed for acrolein was adapted for these anatomically correct extended airway models. Model parameters were obtained from the literature or measured directly. Airflow and acrolein uptake patterns were determined under steady-state inhalation conditions to provide direct comparisons with prior data and nasal-only simulations. Results confirmed that regional uptake was sensitive to airway geometry, airflow rates, acrolein concentrations, air:tissue partition coefficients, tissue thickness, and the maximum rate of metabolism. Nasal extraction efficiencies were predicted to be greatest in the rat, followed by the monkey, and then the human. For both nasal and oral breathing modes in humans, higher uptake rates were predicted for lower tracheobronchial tissues than either the rat or monkey. These extended airway models provide a unique foundation for comparing material transport and site-specific tissue uptake across a significantly greater range of conducting airways in the rat, monkey, and human than prior CFD models.

FIG. 1.

Surface maps of hybrid CFD/PBPK models for (a) the male Sprague Dawley rat, (b) male Rhesus monkey, and (c) female human showing specific regions of the respiratory airways categorized by epithelial cell type (nose) or anatomic region as indicated by the different surface colors. The cylinders in each model include the external facial features (nose or mouth) and are used to initialize inhalation atmospheric concentrations of acrolein. Shading is used to show the surface boundaries for each airway compartment (color coding for all figures can be viewed in the online version).

FIG. 1.

Surface maps of hybrid CFD/PBPK models for (a) the male Sprague Dawley rat, (b) male Rhesus monkey, and (c) female human showing specific regions of the respiratory airways categorized by epithelial cell type (nose) or anatomic region as indicated by the different surface colors. The cylinders in each model include the external facial features (nose or mouth) and are used to initialize inhalation atmospheric concentrations of acrolein. Shading is used to show the surface boundaries for each airway compartment (color coding for all figures can be viewed in the online version).

FIG. 2.

Regional airflow velocities (m/s) in the nose, larynx, and lung and corresponding acrolein flux rates (pg/cm²/s) of the rat CFD/PBPK model. Steady-state CFD simulations were conducted at twice the resting minute volume (434ml/min) and a constant inhalation concentration of 0.6 ppm acrolein in the cylinder. Solid black lines in the CFD airflow simulations indicate cross sections of the nose, mouth, larynx, and lung regions used to calculate the Reynolds numbers in Table 5.

FIG. 3.

Regional airflow velocities (m/s) in the nose, larynx, and lung and corresponding acrolein flux rates (pg/cm²/s) of the monkey CFD/PBPK model. Steady-state CFD simulations were conducted at twice the resting minute volume (907ml/min) and a constant inhalation concentration of 0.6 ppm acrolein in the cylinder. Solid black lines in the CFD simulations indicate cross sections of the nose, mouth, larynx, and lung regions used to calculate the Reynolds numbers in Table 5.

FIG. 4.

Regional airflow velocities (m/s) in the nose, mouth, larynx, and lung and corresponding acrolein flux rates (pg/cm²/s) of the (a) human nasal and (b) human oral breathing CFD/PBPK models. Steady-state CFD simulations were conducted at twice the resting minute volume (13.8 l/min) and a constant inhalation concentration of 0.6 ppm acrolein in the cylinder. Solid black lines in the CFD simulations indicate cross sections of the nose, mouth, larynx, and lung regions used to calculate the Reynolds numbers in Table 5.

FIG. 4.

Regional airflow velocities (m/s) in the nose, mouth, larynx, and lung and corresponding acrolein flux rates (pg/cm²/s) of the (a) human nasal and (b) human oral breathing CFD/PBPK models. Steady-state CFD simulations were conducted at twice the resting minute volume (13.8 l/min) and a constant inhalation concentration of 0.6 ppm acrolein in the cylinder. Solid black lines in the CFD simulations indicate cross sections of the nose, mouth, larynx, and lung regions used to calculate the Reynolds numbers in Table 5.

FIG. 5.

Ventral views of airflow streamlines (shaded by absolute velocities, m/s) showing different upper respiratory tract origins for lobar ventilation in the rat under steady-state inhalation conditions at twice the resting minute volume (434 ml/min). Airflows were visualized by seeding streamlines across the bronchi ventilating the right upper, right caudal, accessory, and left lobes (left to right).

FIG. 6.

Ventral views of airflow streamlines (shaded by absolute velocities, m/s) showing different upper respiratory tract origins for lobar ventilation in the human (oral breathing) under steady-state inhalation conditions at twice the resting minute volume (13.8 l/min). Airflows were visualized by seeding streamlines across the bronchi ventilating each of the lobes.

FIG. 7.

Comparison of nasal extraction predictions from the CFD/PBPK model with time-averaged experimental data in rats from Struve et al. (2008) and Morris (1996). Simulations and experiments were conducted at 300ml/min steady-state inhalation.

FIG. 8.

Impact of changes to VmaxC in nonnasal tissues in the human oral breathing model. Case 1 represents the original model where VmaxC is constant in nasal through laryngeal tissues but reduced to 25 or 50% in the trachea and main bronchi or bronchiolar region, respectively. Case 2 represents a reduction of VmaxC to 25% of the nasal values in the oral, oropharyngeal, and laryngeal tissues. Case 3 extends case 2 by increasing VmaxC in the trachea and main bronchi by 50%, whereas case 4 increases VmaxC in the bronchioles by 50%. Regional uptake efficiencies are shown in the upper graph, whereas surface flux rates are shown for each case study (bottom). Note that the scale used for surface flux rates was compressed to highlight site-specific differences in uptake. Peak fluxes and locations were 712 pg/cm²/s in case 1 (oral larynx), 506 pg/cm²/s in case 2 and 3 (lung bifurcations), and 610 pg/cm²/s in case 4 (lung bifurcations).