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1 Radiation and Environmental Physics Department, KFKI Atomic Energy Research Institute, H-1525 Budapest 114, Hungary; 2 Institute of Physics and Biophysics, University of Salzburg; and 3 Department of Informatics and Telematics, Polytechnical University of Salzburg, A-5020 Salzburg, Austria
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The apparent discrepancy between the reported preferential occurrence of bronchial carcinomas in central bronchial airways and current dose estimates for inhaled particles suggests that experimentally observed local accumulations of particles within bronchial airway bifurcations may play a crucial role in lung cancer induction. Here, we computed three-dimensional particle deposition patterns in lobar-segmental airway bifurcations and quantified the resulting inhomogeneous deposition patterns in terms of deposition enhancement factors, which are defined as the ratio of local to average deposition densities. Our results revealed that a small fraction of epithelial cells located at carinal ridges can receive massive doses that may be even a few hundred times higher than the average dose for the whole airway. This lends further credence to the hypothesis that the apparent site selectivity of neoplastic lesions may indeed be caused by the enhanced deposition of toxic particulate matter at bronchial airway bifurcations.
inhaled particles; health effects; deposition distributions
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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AMBIENT PARTICLES IN THE DIAMETER range of 1 nm to 20 µm may be deposited in human lungs on inspiration ("respirable particles") and are therefore available for interactions with pulmonary surfaces (16). As a result, many diseases of the human respiratory tract can directly be linked to inhaled material, such as cigarette smoke and toxic occupational or environmental aerosols (32). There is a general agreement that the occurrence of lung diseases depends on the amount of mass deposited in the whole or specific regions of the lungs.
The regional pattern of deposition of inhaled particles is often a determinant of pathogenic potential and is clearly related to the topographical distribution of certain occupational lung diseases, such as silicosis and coal workers' pneumoconiosis among coal miners or lung cancer among uranium miners (25). Bronchogenic carcinoma in the general population, which occurs primarily among cigarette smokers, has a seeming predilection for certain bronchi. In experimental studies with hollow casts of the human upper tracheobronchial tree, the deposition patterns of particles were compared with published reports of the frequency of primary sites of carcinoma origin, and the result was strong correlation (34, 36).
There is also pathological evidence that bronchogenic carcinomas may originate at bifurcation sites. Early histological studies (1, 5, 13-15, 19, 24, 27, 28) already indicate that neoplastic and preneoplastic lesions predominate at bifurcation regions of the central airways. Veeze (37) has suggested the following order of cancer incidence among the bronchi: main, 10%; lobar, 30%; segmental, 30%; and subsegmental, 30%. Recently, it has been suggested that accumulation of carcinogenic radioactive particles and particles with adsorbed carcinogens from cigarette smoke at airway carinas is a potentially important mechanism of human pulmonary carcinogenesis (6). In addition, animal studies suggest that clearance of particles from carinas is much slower than from tubular airway segments (6). These observations were recently extended when human autopsy lungs were analyzed by microdissection of the mucosa of carinas and tubular segments in the large airways (7). When analyzing generations 1-4, it was found that the median ratio of the concentration of particles in the mucosal tissues of the carinas to the mucosal tissues of the immediately preceding tubular segment was ~9:1 in a series of 10 never-smoker lungs. Of particular note was the marked person-to-person variation, with some individuals having numerous carinal-tubular pairs with ratios higher than 100 (7). Whether these differences reflect individual-to-individual variations in deposition or clearance patterns or abnormally high levels of epithelial particle uptake and translocation is unknown, but at least in theory such individuals may be particularly susceptible to the toxic effects of inhaled particles.
It is of worth to mention that the knowledge of the distribution of deposition in the airways may have important practical applications in the case of the therapeutic aerosols as well.
Current lung radiation dosimetry models do not take into consideration the inhomogeneity of deposition and clearance patterns, and the reported locations of cancer manifestation are at variance with the calculated dose patterns among human bronchial airways (17, 20). The enhanced deposition at carinal ridges may be a more relevant deposition quantity for risk-assessment purposes than average deposition patterns. The reason for increased deposition in the vicinity of the carina is that impaction and interception dominate here because the streamline curvature is the largest and diffusional deposition dominates because the boundary layer thickness is minimal at this location.
In the present study, we compute local deposition patterns in central human airway bifurcations, quantify their inhomogeneities at the cellular level, and point to the possible consequences of the inhomogeneity regarding the health effects of inhaled aerosols by computational fluid dynamics models. It is our contention that only the inclusion of the specific contribution of the bifurcation zone or carinal ridge deposition into risk assessment protocols makes the dose distribution compatible with clinically observed sites of cancer incidences (30). The computational fluid dynamics models can predict local deposition, whereas the so-called lung deposition models describe average deposition.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, local deposition patterns in airway bifurcations are analyzed by a recently developed numerical particle deposition model (3). Here, the airflow fields are computed by the FIRE finite volume fluid dynamics program package in "physiologically realistic airway bifurcation" geometries (18). This three-dimensional geometry model is idealized, however, to ensure smooth transitions between the airways with realistic length, diameter, branching angles, daughter airway, and carina curvatures. At present, we apply only symmetric branching to characterize the most general relationships of the local deposition patterns.
In the model, aerosol particles are randomly selected at the inlet cross section with a Monte Carlo random-number generator in accordance with the assumed inlet air velocity profile, which is parabolic in the present study. Thus the inlet number and velocity distributions of particles follow parabolic distributions. Velocity of flow and particle in the same points are equal at the inlet.
Particle trajectories are calculated by our earlier numerical particle deposition model (2). In this model, the four dominant deposition mechanisms, i.e., inertial impaction, gravitational sedimentation, Brownian diffusion, and interception, are assumed to operate simultaneously. Local deposition patterns within the bifurcation geometry are then determined by the intersection of the simulated particle trajectories with the surrounding wall surfaces. Because deposition efficiencies, deposition densities, and number of particles are higher for inhalation than for exhalation, we have limited the present analysis to the inspiratory phase of the breathing cycle.
For the quantification of the inhomogeneity of predicted deposition patterns, the whole surface of the bifurcation is scanned by a prespecified surface element. Local deposition enhancement factors are then determined as the ratio of local to average deposition densities, where deposition densities are computed as the number of deposited particles in a surface area divided with the size of the surface area (3, 4). In case of a significant inhomogeneity of the analyzed deposition patterns, computed deposition-enhancement factors are very sensitive to the size of the scanning surface element. There is growing evidence that the presence of several neighboring cells is necessary for the development of a solid tumor (10). Hence, we have selected a 100 × 100 µm element size, which corresponds to ~10 × 10 epithelial cells.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Simulation of particle deposition patterns. In humans, the majority of bronchial carcinomas has been detected in lobar and segmental bronchi, that is, in the third and fourth airway generations (the trachea is counted here as generation 0) (29). In the present study, we computed deposition patterns of inhaled particulate matter at these locations of the tracheobronchial tree for different inspiratory flow rates (from resting to heavy-exercise breathing conditions) and for the whole range of respirable particle sizes (1 nm to 20 µm) in a physiologically realistic bifurcation geometry (18).
The structure of the deposition patterns strongly depends on the local airflow field, which, in turn, is highly influenced by the bifurcation geometry. Here, the realistic airway geometry is characterized by smooth transitions between the parent and daughter branches and a rounded carinal ridge. For example, the sharpness of the carina determines whether there is reverse flow or not at the flow divider where the inspiratory deposition hot spots are usually located. Figure 1 represents the main and secondary air flows in a physiologically realistic lobar-segmental airway bifurcation under 30 l/min respiratory minute volume breathing conditions, corresponding to light physical activity, during inspiration of a laminar, parabolic inlet flow. The 30 l/min refers to tracheal minute volume supposing equal inspiration and expiration times without breath hold. Thus the flow rate in the trachea is 60 l/min and in the parent airway of this bifurcation, in airway generations 3-4, it is 7.5 l/min. The secondary flow pattern in Fig. 1 clearly demonstrates the formation of reversed flows in the vicinity of the rounded carinal ridge.
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Computation of deposition enhancement factors.
Maximum values and associated distributions of enhancement factors are
computed here for the same physiologically realistic lobar-segmental
bifurcation model as used above. Figure 3
depicts computed deposition enhancement factor maximums at different
patch sizes of scanning in this geometry at 30 l/min minute volume
breathing condition during inspiration as a function of particle size
in the submicron size range (1 nm to 1 µm). The form of the scanning element is a square, and the patch size is characterized by its side
length. The strong dependency of enhancement factor on the patch size
illustrates the high degree of inhomogeneity of deposition within a
single airway bifurcation. At the smallest patch size (100 × 100 µm), which corresponds to ~10 × 10 epithelial cells, the
maximum enhancement factor increases with particle size from ~40 (at
1 nm) to ~80 (at 1 µm). The figure justifies the application of the
smallest patch size because at the second smallest patch size
(0.25 × 0.25 mm) the resulted enhancement factors are
significantly smaller. The reduction of the scanning element under
100 × 100 µm would increase further the computed enhancement
factors; however, we intend to analyze the inhomogeneity of deposition
in a dimension that is characteristic to a cluster of cells, ~10 × 10 epithelial cells.
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(1) |
is constant in the whole figure. Inspection of the figure
demonstrates that both Npatch,max and
Nbif increase monotonously with particle size
over 0.1 µm, but Npatch,max begins to increase at smaller particle sizes than Nbif, and both
increase very rapidly after a given particle diameter. Thus the ratio
of the two curves results in a sharp peak.
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(2) |
is the
deposition efficiency for the whole bifurcation, and EF is the
deposition enhancement factor on the patch. In case of polydisperse
aerosols, integration of Eq. 2 is necessary, e.g., by
introducing a histogram for the particle mass. The degree of
inhomogeneity of deposition in a patch compared to the average value
for the whole bifurcation, that is the deposition enhancement factor,
is indifferent whether we consider deposited particle number or
particle mass. This directly follows from the definition of the
enhancement factor.
Finally, we mention that our present estimates for the measure of
inhomogeneity of cellular burden of inhaled deposited particulate matter are most probably underestimated here because the present calculations refer only to primary deposition patterns. Particles deposit, in a healthy lung, in the mucus and not in the epithelia. The
mucus travels up on the airways propelled by the cilia. The carina are
also stagnation points in the mucus flow and are devoid of cilia; thus
the carina may be a preferential site also for accumulation, not only
for deposition, which further increases the inhomogeneity of cellular burden.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In current lung dosimetry models, the implicit assumption of a uniform deposition on bronchial airway surfaces is equivalent to the notion that all epithelial cells will receive the same average dose. In contrast, we propose to replace the average-dose concept by the distribution of local deposition or retention enhancement factors. This implies that a small fraction of the epithelium will receive massive doses, whereas the majority of the cells will receive correspondingly smaller doses or no dose at all. Computed maximum local deposition enhancement factors may provide a reasonable estimate of maximum local doses relative to average doses. Although our computations refer to the bronchial morphology of a healthy lung, deposition enhancement factors may even be higher in diseased lungs, where airways may be constricted or completely blocked (2).
The distribution of deposition enhancement factors reveals that the degree of inhomogeneity of particle deposition in bronchial airway bifurcations is rather high for all particle sizes, even for nanometer-sized ultrafine particles, and flow rates analyzed in the present study. In particular, cells located in the vicinity of the dividing spur may receive doses that may be a few hundred times higher than the average dose for the whole airway. In addition, mucociliary clearance, which is the major defense mechanism in the bronchial tree, is impaired at carinal ridges relative to tubular airway segments. Thus the site selectivity of neoplastic lesions at airway bifurcations in the upper bronchial tree may be the result of both selective deposition and reduced clearance of toxic particulate matter (6). Because all particle sizes display a similar pattern of preferential deposition at carinal ridges, other ambient particles, which are nontoxic per se, may further enhance the carcinogenic response at airway branching sites in a synergistic fashion.
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ACKNOWLEDGEMENTS |
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This research was supported by the Hungarian Országos Tudományos Kutatási: Alapprogramok (OTKA) T030571, OTKA T034564, and Nemzeti Kutatási Fejlesztési Program-3/005/2001 Projects, and by the Commission of the European Communities Contract no. MCFI-2000-01310, FIGD-CT-2000-00053 and FIS5-2002-00016 Projects.
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FOOTNOTES |
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Address for reprint requests and other correspondence: I. Balásházy, Radiation and Environmental Physics Dept., KFKI Atomic Energy Research Institute, PO Box 49, H-1525 Budapest 114, Hungary (E-mail: ibalas{at}sunserv.kfki.hu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published January 17, 2003;10.1152/japplphysiol.00527.2002
Received 18 June 2002; accepted in final form 8 January 2003.
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REFERENCES |
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DISCUSSION
REFERENCES
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