Radiation Protection Dosimetry (2014), Vol. 160, No. 1–3, pp. 104 –107 Advance Access publication 9 April 2014
doi:10.1093/rpd/ncu060
STOCHASTIC DOSIMETRY MODEL FOR RADON PROGENY IN THE RAT LUNG R. Winkler-HeiI1, W. Hofmann1,* and M. Hussain2 1 Division of Physics and Biophysics, Department of Materials Research and Physics, University of Salzburg, Hellbrunner Str. 34, 5020 Salzburg, Austria 2 Higher Education Commission of Pakistan, 44000 Islamabad, Pakistan *Corresponding author: [email protected]
INTRODUCTION Experimental data on lung cancer risk in rats following inhalation of radon progeny indicate that mean lifetime risk coefficients per unit exposure are consistent with the epidemiological findings for uranium miners(1). This suggests that the rat lung is a suitable surrogate for the human lung for radon-induced lung cancer risk assessment. This notion was further supported by the dosimetric models of Harley(2) and Hofmann et al.(3), which predicted comparable bronchial doses in humans and laboratory rats. Both lung dosimetry models were based on the symmetric typical path model for the whole lung of Yeh et al.(4). However, this lung model cannot account for the experimentally observed variability of airway dimensions within a given airway generation and the distinct asymmetric (or monopodial) branching pattern of the rat lung(5). As a consequence of the monopodial branching structure, airways in the rat lung characterised by the same airway generation number may have significantly different geometric dimensions and therefore physiological functions. For instance, the transition from bronchial to alveolated airways may vary from generations 4 to 31. This suggests that airway diameters are a more appropriate morphometric parameter to classify local particle deposition patterns and, consequently, bronchial doses than the commonly used airway generations(6). Thus, the primary objectives of the present study are (i) to develop a stochastic dosimetry model for the rat lung, (ii) to predict dose distributions in rat bronchial airways for exposure conditions used in rat inhalation studies and (iii) to compare these dose
distributions with those for the human lung, which are also based on a stochastic dosimetry model(7).
MATERIALS AND METHODS The linear dimensions of the rat lung model are derived from morphometric measurements of the tracheobronchial tree of the Long –Evans rat (5) and the Sprague –Dawley rat (8), while the acinar structure is based entirely on the Sprague –Dawley rat (9,10). In the present calculations, a scaled-down version of the bronchial airway system is used, normalised to a functional residual capacity (FRC) of 3.49 ml, assuming a total lung capacity (TLC) of 11.48 ml for an average weight of male rats of 300 g, based on allometric equations(11). The airway diameters and lengths of the alveolated airways, however, are assumed to represent already airway dimensions at FRC(9) and thus no scaling procedure was applied. For particle transport and deposition calculations with the stochastic deposition code IDEAL(12,13), individual paths of inhaled particles through the asymmetric stochastic airway system are randomly selected by Monte Carlo methods from the probability distributions of the airway parameters and their correlations(10). Within a given selected airway, deposition is randomly selected from the commonly used analytical deposition equations for the various physical deposition mechanisms(13). For pre-filtration in nasal passages, the semi-empirical deposition equations of Cheng et al.(14) for ultrafine particles and those of Kelly et al.(15) for larger particles were applied. Calculated deposition fractions in bronchial and acinar
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://rpd.oxfordjournals.org/ at University of Ulster on June 28, 2015
The stochastic dosimetry model presented here considers the distinctly asymmetric, stochastic branching pattern reported in morphometric measurements. This monopodial structure suggests that an airway diameter is a more appropriate morphometric parameter to classify bronchial dose distributions for inhaled radon progeny than the commonly assigned airway generation numbers. Bronchial doses were calculated for the typical exposure conditions reported for the Pacific Northwest National Laboratory rat inhalation studies, yielding an average bronchial dose of 7.75 mGy WLM21. If plotted as functions of airway generations, the resulting dose distributions are highest in the central bronchial airways, while significantly decreasing towards peripheral generations. However, if plotted as functions of airway diameters, doses are much more uniformly distributed among bronchial airways. The comparison between rat and human lungs indicates that dose conversion coefficients for the rat lung are higher than the corresponding values for the human lung by a factor of 1.34 for the experimental PNNL exposure conditions, and of 1.25 for typical human indoor conditions.
STOCHASTIC DOSIMETRY OF RADON IN RAT LUNG
RESULTS The exposure parameters used in the present study refer to the exposure conditions reported for the rat inhalation experiments at the Pacific Northwest National Laboratory (PNNL), USA(18): attached fraction: AMD ¼ 0.3 mm (equivalent to AMAD ¼ 0.5 mm) with GSD ¼ 2.0, unattached fraction ( fp ¼ 3 %): AMD of 5 nm with GSD of 1.1 and an
equilibrium factor of 0.37(3). Since differences of tidal volumes, VT, and breathing frequencies, f, reported for different rat strains may be attributed primarily to differences in weight rather than to strain(19), an average breathing pattern for whole-body inhalation of VT ¼ 2.0 ml and f ¼ 117 min21 was used, based on a weight of 300 g(3). To facilitate visual comparison between the human and rat lungs, the smaller airway diameters of the rat lung were scaled up to the larger diameters of the human lung by applying a linear scaling factor defined as the ratio of the tracheal diameters(6). These modified rat airway diameters are denoted as human equivalent diameters. Deposition fractions of inhaled attached and unattached radon progeny are plotted in Figure 1 as functions of airway generation numbers (panel A) and human equivalent airway diameter classes (panel B) for both the human and rat lungs. In general, rat and human deposition fractions exhibit the same pattern in both generation and airway diameter plots, with deposition peaks in large bronchial and bronchiolar airways. The decrease of the deposition curves in the peripheral airways in the generation plot is caused primarily by the decreasing fraction of bronchial airways in small distal airway generations of the asymmetric lung models. In the diameter plot, these deposition fractions are assigned to the smallest diameter classes, thereby enhancing deposition in this diameter range. Bronchial doses produced by the inhalation of attached and unattached radon progeny are plotted in Figure 2 as functions of airway generation numbers ( panel A) and human equivalent airway diameter classes ( panel B) for both the human and rat lungs. In addition to the application of the rat inhalation exposure conditions, human doses were also computed for typical indoor exposures, with AMD (attached) ¼ 0.15 mm (GSD ¼ 2.0), AMD (unattached) ¼ 1.2 nm (GSD ¼ 1.1), unattached fraction fp ¼ 8 %,
Figure 1. Deposition fractions of inhaled radon progeny in bronchial airways plotted as functions of airway generation (A) and human equivalent diameter class (B) for both rat and human lungs.
105
Downloaded from http://rpd.oxfordjournals.org/ at University of Ulster on June 28, 2015
airway generations are typically based on 10 000 to 100 000 simulations. Average mucociliary clearance velocities in rat bronchial airways were calculated by solving the mass transport equations based on the assumption of conservation of mucus volume and normalised to a measured tracheal mucus velocity of 1.9 mm min21(16). Since mucus velocities in the rat lung exhibit a statistically significant relationship with an airway diameter, a stochastic element is introduced into the clearance calculations by correlating the mucus velocity in a randomly selected airway with the diameter of that airway. The correlation of the thickness of the bronchial epithelium with the corresponding airway diameters is approximated by a polynomial function(3,17). Thus, the distribution of airway diameters within a given airway generation leads to a distribution of sensitive basal and secretory cell depths, and hence distributions of cellular doses. Measurements of the distribution of cells across the epithelium indicated that basal and secretory cell nuclei of 7 mm in diameter are located 1–2 mm above the basal membrane, forming a cellular monolayer. Doses received by these nuclei are computed for uniform 218Po and 214Po activities on cylindrical bronchial airway surfaces. Corresponding calculations of bronchial doses in the human lung are based on the stochastic dosimetry model IDEAL-DOSE(7).
R. WINKLER-HEII ET AL.
Table 1. Mean bronchial and acinar doses for the human and rat lung. Mean cellular dose (mGy WLM21)
Rat (PNNL) Rat (PNNL), cross-fire Human (PNNL) Human (indoor)
Bronchial region
Acinar region
6.87 7.75 5.80 6.20
0.85 0.85 0.09 0.17
in Table 1. The cross-fire from the alveolar region slightly increases doses in rat bronchiolar airways, while this effect is negligible in the human lung(22). Doses to alveolar cells were computed by assuming uniform nuclide and cell distributions throughout the acinar region, assuming an average weight of 1.5 g for a 300 g rat (11). The ratio of alveolar-to-bronchial doses in the rat lung is 10 %, while it is 2–4 % in the human lung for the PNNL and indoor exposure conditions.
DISCUSSION equilibrium factor F ¼ 0.55(20) and average breathing rate ¼ 0.78 m3h21 in homes, consisting of 55 % sleeping, 15 % sitting and 30 % light exercise(21). If plotted as functions of bronchial airway generations, resulting dose distributions in the rat lung exhibit a significant peak in upper bronchial airways, while decreasing significantly towards peripheral bronchiolar generations. However, if plotted as functions of airway diameters, doses are much more uniformly distributed throughout the bronchial tree. In both the generation and diameter plots, doses in the larger bronchial airways of the rat lung are higher than those in the human lung, but lower in the peripheral bronchiolar airways. However, there are significant differences between the rat and the human lungs in both classification schemes. In the rat lung, bronchial doses decrease significantly with rising airway generation number, but remain relatively constant in the diameter plot. In contrast, bronchial doses in the human lung exhibit a relatively uniform distribution among bronchial generations, while rising sharply at the smallest diameters in the diameter plot. Mean bronchial doses, averaged with equal weight over all bronchial airway generations, and acinar doses for both rat and human lungs are summarised
In the present study, bronchial doses were calculated for the exposure conditions reported for the PNNL rat inhalation experiments, yielding a bronchial dose of 7.75 mGy WLM21. This value, based on an asymmetric, stochastic lung morphology, is very similar to authors’ earlier calculations with a symmetric, deterministic lung model(4) resulting in a bronchial dose of 7.13 mGy WLM21 for the same exposure conditions. For comparison, bronchial doses reported in other studies were 5.6(2) and 8.1(22) mGy WLM21. In lung dosimetry models, doses are commonly plotted as functions of airway generations. As shown in Figure 2A, dose distributions exhibit a significant maximum in upper bronchial airways, while decreasing significantly towards peripheral bronchiolar generations. This suggests that the large bronchial airways are the preferential target site for bronchial tumour induction. However, the corresponding distributions plotted as functions of airway diameters indicate that bronchial doses are much more uniformly distributed throughout the bronchial tree. This apparent discrepancy is caused by the monopodial structure of the rat lung, where the main stem bronchus extends to distal airway generations, while small airways can already be found in the proximal airway generations.
106
Downloaded from http://rpd.oxfordjournals.org/ at University of Ulster on June 28, 2015
Figure 2. Radon progeny doses to bronchial target cells plotted as functions of airway generation (A) and human equivalent airway diameter class (B) for both rat and human lungs.
STOCHASTIC DOSIMETRY OF RADON IN RAT LUNG
7. 8. 9. 10.
11.
12.
13.
14.
15. 16. 17.
REFERENCES 1. National Council on Radiation Protection and Measurement (NCRP). Evaluation of occupational and environmental exposures to radon and radon daughters in the United States. NCRP Report No. 78. NCRP (1984). 2. Harley, N. H. Radon daughter dosimetry in the rat tracheobronchial tree. Radiat. Prot. Dosim. 24, 457– 461 (1988). 3. Hofmann, W., Me´nache, M. G. and Graham, R. C. Radon progeny dosimetry in the rat lung. Health Phys. 64, 279–290 (1993). 4. Yeh, H. C., Schum, G. M. and Duggan, M. T. Anatomic models of the tracheobronchial and pulmonary regions of the rat. Anat. Rec. 195, 483– 492 (1979). 5. Raabe, O. G., Yeh, H. C., Schum, G. M. and Phalen, R. F. Tracheobronchial geometry: human, dog, rat, hamster. Report LF-53. Lovelace Foundation (1976). 6. Hofmann, W., Bergmann, R. and Koblinger, L. Characterization of local particle deposition patterns in
18. 19.
20. 21.
22.
107
human and rat lungs by different morphometric parameters. J. Aerosol Sci. 30, 651– 667 (1999). Hofmann, W., Winkler-Heil, R. and Hussain, M. Modeling intersubject variability of bronchial doses for inhaled radon progeny. Health Phys. 99, 523– 531 (2010). Koblinger, L. and Hofmann, W. Stochastic morphological model of the rat lung. Anat. Rec. 221, 533–539 (1988). Mercer, R. R. and Crapo, J. D. Three-dimensional reconstruction of the rat acinus. J. Appl. Physiol. 63, 785– 794 (1987). Koblinger, L., Hofmann, W., Graham, R. C. and Mercer, R. R. Aerosol inhalation in the rat lung. Part I: Analysis of the rat acinus morphometry and construction of a stochastic lung model. J. Aerosol Med. 8, 7–19 (1995). Takezawa, J., Miller, F. J. and O’Neil, J. J. Single-breath diffusing capacity and lung volumes in small laboratory mammals. J. Appl. Physiol. Respirat. Environ. Exercise Physiol. 48, 1052–1059 (1980). Koblinger, L. and Hofmann, W. Monte Carlo modelling of aerosol deposition in human lungs. Part I: Simulation of particle transport in a stochastic lung structure. J. Aerosol Sci. 21, 661–674 (1990). Hofmann, W. and Koblinger, L. Monte Carlo modelling of aerosol deposition in human lungs. Part II: Deposition fractions and their parameter variations. J. Aerosol Sci. 21, 675–688 (1990). Cheng, Y. S., Hansen, G. K., Su, Y. F., Yeh, H. C. and Morgan, K. T. Deposition of ultrafine aerosols in rat nasal molds. Toxicol. Appl. Pharmacol. 106, 222– 233 (1990). Kelly, J. T., Kimball, J. S. and Asgharian, B. Deposition of fine and coarse aerosols in a rat nasal mold. Inhal. Toxicol. 13, 577–588 (2001). Hofmann, W. and Asgharian, B. The effect of lung structure on mucociliary clearance and particle retention in human and rat lung. Toxicol. Res. 73, 448– 456 (2003). Mercer, R. R., Russell, M. L. and Crapo, J. D. Radon dosimetry based on the depth distribution of nuclei in human and rat lungs. Health Phys. 61, 117– 130 (1991). Cross, F. T. Radon inhalation studies in animals. Radiat. Prot. Dosim. 24, 463– 466 (1988). Costa, D. L. and Tepper, J. Approaches to lung function assessment in small mammals. In: Gardner, D. E., Crapo, D. J. and Massaro, E. J., Eds. Toxicology of the Lung. Raven Press, pp. 147– 174 (1988). National Research Council (NRC). Comparative Dosimetry in Mines and Homes. National Academy Press (1991). International Commission on Radiological Protection (ICRP). Guide to the practical application of the ICRP Human Respiratory Tract Model: ICRP supporting guidance. Ann. ICRP 32(1–2). Pergamon Press (2002). Fakir, H., Hofmann, W. and Caswell, R. S. Radon progeny microdosimetry in human and rat bronchial airways: the effect of crossfire from the alveolar region. Radiat. Prot. Dosim. 130, 149– 161 (2008).
Downloaded from http://rpd.oxfordjournals.org/ at University of Ulster on June 28, 2015
In pathological examinations, the locations of bronchial tumours are commonly related to airway diameters. Thus, an airway diameter seems to be a more appropriate spatial parameter to relate bronchial doses to bronchial carcinomas. Since the linear dimensions of the rat bronchial airways were obtained in lung casts at TLC, they have to be scaled down to the FRC of a living rat for realistic dose calculations. In the present calculations, all airway diameters and lengths were scaled down by a linear scaling factor defined as the cube root of the ratio FRC/TLC. Without application of such a scaling factor, average bronchial doses are 1.67 mGy WLM21, when compared with 6.87 mGy WLM21 (without considering cross-fire from the alveolar region). Thus, application of a scaled-down lung morphology leads to higher bronchial doses than the use of the originally reported data(5) resulting from increased deposition and clearance velocities and reduced surface areas and target cell depths. The comparison between rat and human lungs indicate that bronchial doses for the rat lung are slightly higher than the corresponding values for the human lung by a factor of 1.34 for the experimental PNNL exposure conditions, and of 1.25 for typical human indoor conditions. This similarity in bronchial doses suggests that mean lifetime risk coefficients per unit exposure are comparable, provided that inter-species differences can be neglected. This supports the view that the rat lung is indeed an appropriate surrogate for the human lung for lung cancer risk assessment.
doi:10.1093/rpd/ncu060
STOCHASTIC DOSIMETRY MODEL FOR RADON PROGENY IN THE RAT LUNG R. Winkler-HeiI1, W. Hofmann1,* and M. Hussain2 1 Division of Physics and Biophysics, Department of Materials Research and Physics, University of Salzburg, Hellbrunner Str. 34, 5020 Salzburg, Austria 2 Higher Education Commission of Pakistan, 44000 Islamabad, Pakistan *Corresponding author: [email protected]
INTRODUCTION Experimental data on lung cancer risk in rats following inhalation of radon progeny indicate that mean lifetime risk coefficients per unit exposure are consistent with the epidemiological findings for uranium miners(1). This suggests that the rat lung is a suitable surrogate for the human lung for radon-induced lung cancer risk assessment. This notion was further supported by the dosimetric models of Harley(2) and Hofmann et al.(3), which predicted comparable bronchial doses in humans and laboratory rats. Both lung dosimetry models were based on the symmetric typical path model for the whole lung of Yeh et al.(4). However, this lung model cannot account for the experimentally observed variability of airway dimensions within a given airway generation and the distinct asymmetric (or monopodial) branching pattern of the rat lung(5). As a consequence of the monopodial branching structure, airways in the rat lung characterised by the same airway generation number may have significantly different geometric dimensions and therefore physiological functions. For instance, the transition from bronchial to alveolated airways may vary from generations 4 to 31. This suggests that airway diameters are a more appropriate morphometric parameter to classify local particle deposition patterns and, consequently, bronchial doses than the commonly used airway generations(6). Thus, the primary objectives of the present study are (i) to develop a stochastic dosimetry model for the rat lung, (ii) to predict dose distributions in rat bronchial airways for exposure conditions used in rat inhalation studies and (iii) to compare these dose
distributions with those for the human lung, which are also based on a stochastic dosimetry model(7).
MATERIALS AND METHODS The linear dimensions of the rat lung model are derived from morphometric measurements of the tracheobronchial tree of the Long –Evans rat (5) and the Sprague –Dawley rat (8), while the acinar structure is based entirely on the Sprague –Dawley rat (9,10). In the present calculations, a scaled-down version of the bronchial airway system is used, normalised to a functional residual capacity (FRC) of 3.49 ml, assuming a total lung capacity (TLC) of 11.48 ml for an average weight of male rats of 300 g, based on allometric equations(11). The airway diameters and lengths of the alveolated airways, however, are assumed to represent already airway dimensions at FRC(9) and thus no scaling procedure was applied. For particle transport and deposition calculations with the stochastic deposition code IDEAL(12,13), individual paths of inhaled particles through the asymmetric stochastic airway system are randomly selected by Monte Carlo methods from the probability distributions of the airway parameters and their correlations(10). Within a given selected airway, deposition is randomly selected from the commonly used analytical deposition equations for the various physical deposition mechanisms(13). For pre-filtration in nasal passages, the semi-empirical deposition equations of Cheng et al.(14) for ultrafine particles and those of Kelly et al.(15) for larger particles were applied. Calculated deposition fractions in bronchial and acinar
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://rpd.oxfordjournals.org/ at University of Ulster on June 28, 2015
The stochastic dosimetry model presented here considers the distinctly asymmetric, stochastic branching pattern reported in morphometric measurements. This monopodial structure suggests that an airway diameter is a more appropriate morphometric parameter to classify bronchial dose distributions for inhaled radon progeny than the commonly assigned airway generation numbers. Bronchial doses were calculated for the typical exposure conditions reported for the Pacific Northwest National Laboratory rat inhalation studies, yielding an average bronchial dose of 7.75 mGy WLM21. If plotted as functions of airway generations, the resulting dose distributions are highest in the central bronchial airways, while significantly decreasing towards peripheral generations. However, if plotted as functions of airway diameters, doses are much more uniformly distributed among bronchial airways. The comparison between rat and human lungs indicates that dose conversion coefficients for the rat lung are higher than the corresponding values for the human lung by a factor of 1.34 for the experimental PNNL exposure conditions, and of 1.25 for typical human indoor conditions.
STOCHASTIC DOSIMETRY OF RADON IN RAT LUNG
RESULTS The exposure parameters used in the present study refer to the exposure conditions reported for the rat inhalation experiments at the Pacific Northwest National Laboratory (PNNL), USA(18): attached fraction: AMD ¼ 0.3 mm (equivalent to AMAD ¼ 0.5 mm) with GSD ¼ 2.0, unattached fraction ( fp ¼ 3 %): AMD of 5 nm with GSD of 1.1 and an
equilibrium factor of 0.37(3). Since differences of tidal volumes, VT, and breathing frequencies, f, reported for different rat strains may be attributed primarily to differences in weight rather than to strain(19), an average breathing pattern for whole-body inhalation of VT ¼ 2.0 ml and f ¼ 117 min21 was used, based on a weight of 300 g(3). To facilitate visual comparison between the human and rat lungs, the smaller airway diameters of the rat lung were scaled up to the larger diameters of the human lung by applying a linear scaling factor defined as the ratio of the tracheal diameters(6). These modified rat airway diameters are denoted as human equivalent diameters. Deposition fractions of inhaled attached and unattached radon progeny are plotted in Figure 1 as functions of airway generation numbers (panel A) and human equivalent airway diameter classes (panel B) for both the human and rat lungs. In general, rat and human deposition fractions exhibit the same pattern in both generation and airway diameter plots, with deposition peaks in large bronchial and bronchiolar airways. The decrease of the deposition curves in the peripheral airways in the generation plot is caused primarily by the decreasing fraction of bronchial airways in small distal airway generations of the asymmetric lung models. In the diameter plot, these deposition fractions are assigned to the smallest diameter classes, thereby enhancing deposition in this diameter range. Bronchial doses produced by the inhalation of attached and unattached radon progeny are plotted in Figure 2 as functions of airway generation numbers ( panel A) and human equivalent airway diameter classes ( panel B) for both the human and rat lungs. In addition to the application of the rat inhalation exposure conditions, human doses were also computed for typical indoor exposures, with AMD (attached) ¼ 0.15 mm (GSD ¼ 2.0), AMD (unattached) ¼ 1.2 nm (GSD ¼ 1.1), unattached fraction fp ¼ 8 %,
Figure 1. Deposition fractions of inhaled radon progeny in bronchial airways plotted as functions of airway generation (A) and human equivalent diameter class (B) for both rat and human lungs.
105
Downloaded from http://rpd.oxfordjournals.org/ at University of Ulster on June 28, 2015
airway generations are typically based on 10 000 to 100 000 simulations. Average mucociliary clearance velocities in rat bronchial airways were calculated by solving the mass transport equations based on the assumption of conservation of mucus volume and normalised to a measured tracheal mucus velocity of 1.9 mm min21(16). Since mucus velocities in the rat lung exhibit a statistically significant relationship with an airway diameter, a stochastic element is introduced into the clearance calculations by correlating the mucus velocity in a randomly selected airway with the diameter of that airway. The correlation of the thickness of the bronchial epithelium with the corresponding airway diameters is approximated by a polynomial function(3,17). Thus, the distribution of airway diameters within a given airway generation leads to a distribution of sensitive basal and secretory cell depths, and hence distributions of cellular doses. Measurements of the distribution of cells across the epithelium indicated that basal and secretory cell nuclei of 7 mm in diameter are located 1–2 mm above the basal membrane, forming a cellular monolayer. Doses received by these nuclei are computed for uniform 218Po and 214Po activities on cylindrical bronchial airway surfaces. Corresponding calculations of bronchial doses in the human lung are based on the stochastic dosimetry model IDEAL-DOSE(7).
R. WINKLER-HEII ET AL.
Table 1. Mean bronchial and acinar doses for the human and rat lung. Mean cellular dose (mGy WLM21)
Rat (PNNL) Rat (PNNL), cross-fire Human (PNNL) Human (indoor)
Bronchial region
Acinar region
6.87 7.75 5.80 6.20
0.85 0.85 0.09 0.17
in Table 1. The cross-fire from the alveolar region slightly increases doses in rat bronchiolar airways, while this effect is negligible in the human lung(22). Doses to alveolar cells were computed by assuming uniform nuclide and cell distributions throughout the acinar region, assuming an average weight of 1.5 g for a 300 g rat (11). The ratio of alveolar-to-bronchial doses in the rat lung is 10 %, while it is 2–4 % in the human lung for the PNNL and indoor exposure conditions.
DISCUSSION equilibrium factor F ¼ 0.55(20) and average breathing rate ¼ 0.78 m3h21 in homes, consisting of 55 % sleeping, 15 % sitting and 30 % light exercise(21). If plotted as functions of bronchial airway generations, resulting dose distributions in the rat lung exhibit a significant peak in upper bronchial airways, while decreasing significantly towards peripheral bronchiolar generations. However, if plotted as functions of airway diameters, doses are much more uniformly distributed throughout the bronchial tree. In both the generation and diameter plots, doses in the larger bronchial airways of the rat lung are higher than those in the human lung, but lower in the peripheral bronchiolar airways. However, there are significant differences between the rat and the human lungs in both classification schemes. In the rat lung, bronchial doses decrease significantly with rising airway generation number, but remain relatively constant in the diameter plot. In contrast, bronchial doses in the human lung exhibit a relatively uniform distribution among bronchial generations, while rising sharply at the smallest diameters in the diameter plot. Mean bronchial doses, averaged with equal weight over all bronchial airway generations, and acinar doses for both rat and human lungs are summarised
In the present study, bronchial doses were calculated for the exposure conditions reported for the PNNL rat inhalation experiments, yielding a bronchial dose of 7.75 mGy WLM21. This value, based on an asymmetric, stochastic lung morphology, is very similar to authors’ earlier calculations with a symmetric, deterministic lung model(4) resulting in a bronchial dose of 7.13 mGy WLM21 for the same exposure conditions. For comparison, bronchial doses reported in other studies were 5.6(2) and 8.1(22) mGy WLM21. In lung dosimetry models, doses are commonly plotted as functions of airway generations. As shown in Figure 2A, dose distributions exhibit a significant maximum in upper bronchial airways, while decreasing significantly towards peripheral bronchiolar generations. This suggests that the large bronchial airways are the preferential target site for bronchial tumour induction. However, the corresponding distributions plotted as functions of airway diameters indicate that bronchial doses are much more uniformly distributed throughout the bronchial tree. This apparent discrepancy is caused by the monopodial structure of the rat lung, where the main stem bronchus extends to distal airway generations, while small airways can already be found in the proximal airway generations.
106
Downloaded from http://rpd.oxfordjournals.org/ at University of Ulster on June 28, 2015
Figure 2. Radon progeny doses to bronchial target cells plotted as functions of airway generation (A) and human equivalent airway diameter class (B) for both rat and human lungs.
STOCHASTIC DOSIMETRY OF RADON IN RAT LUNG
7. 8. 9. 10.
11.
12.
13.
14.
15. 16. 17.
REFERENCES 1. National Council on Radiation Protection and Measurement (NCRP). Evaluation of occupational and environmental exposures to radon and radon daughters in the United States. NCRP Report No. 78. NCRP (1984). 2. Harley, N. H. Radon daughter dosimetry in the rat tracheobronchial tree. Radiat. Prot. Dosim. 24, 457– 461 (1988). 3. Hofmann, W., Me´nache, M. G. and Graham, R. C. Radon progeny dosimetry in the rat lung. Health Phys. 64, 279–290 (1993). 4. Yeh, H. C., Schum, G. M. and Duggan, M. T. Anatomic models of the tracheobronchial and pulmonary regions of the rat. Anat. Rec. 195, 483– 492 (1979). 5. Raabe, O. G., Yeh, H. C., Schum, G. M. and Phalen, R. F. Tracheobronchial geometry: human, dog, rat, hamster. Report LF-53. Lovelace Foundation (1976). 6. Hofmann, W., Bergmann, R. and Koblinger, L. Characterization of local particle deposition patterns in
18. 19.
20. 21.
22.
107
human and rat lungs by different morphometric parameters. J. Aerosol Sci. 30, 651– 667 (1999). Hofmann, W., Winkler-Heil, R. and Hussain, M. Modeling intersubject variability of bronchial doses for inhaled radon progeny. Health Phys. 99, 523– 531 (2010). Koblinger, L. and Hofmann, W. Stochastic morphological model of the rat lung. Anat. Rec. 221, 533–539 (1988). Mercer, R. R. and Crapo, J. D. Three-dimensional reconstruction of the rat acinus. J. Appl. Physiol. 63, 785– 794 (1987). Koblinger, L., Hofmann, W., Graham, R. C. and Mercer, R. R. Aerosol inhalation in the rat lung. Part I: Analysis of the rat acinus morphometry and construction of a stochastic lung model. J. Aerosol Med. 8, 7–19 (1995). Takezawa, J., Miller, F. J. and O’Neil, J. J. Single-breath diffusing capacity and lung volumes in small laboratory mammals. J. Appl. Physiol. Respirat. Environ. Exercise Physiol. 48, 1052–1059 (1980). Koblinger, L. and Hofmann, W. Monte Carlo modelling of aerosol deposition in human lungs. Part I: Simulation of particle transport in a stochastic lung structure. J. Aerosol Sci. 21, 661–674 (1990). Hofmann, W. and Koblinger, L. Monte Carlo modelling of aerosol deposition in human lungs. Part II: Deposition fractions and their parameter variations. J. Aerosol Sci. 21, 675–688 (1990). Cheng, Y. S., Hansen, G. K., Su, Y. F., Yeh, H. C. and Morgan, K. T. Deposition of ultrafine aerosols in rat nasal molds. Toxicol. Appl. Pharmacol. 106, 222– 233 (1990). Kelly, J. T., Kimball, J. S. and Asgharian, B. Deposition of fine and coarse aerosols in a rat nasal mold. Inhal. Toxicol. 13, 577–588 (2001). Hofmann, W. and Asgharian, B. The effect of lung structure on mucociliary clearance and particle retention in human and rat lung. Toxicol. Res. 73, 448– 456 (2003). Mercer, R. R., Russell, M. L. and Crapo, J. D. Radon dosimetry based on the depth distribution of nuclei in human and rat lungs. Health Phys. 61, 117– 130 (1991). Cross, F. T. Radon inhalation studies in animals. Radiat. Prot. Dosim. 24, 463– 466 (1988). Costa, D. L. and Tepper, J. Approaches to lung function assessment in small mammals. In: Gardner, D. E., Crapo, D. J. and Massaro, E. J., Eds. Toxicology of the Lung. Raven Press, pp. 147– 174 (1988). National Research Council (NRC). Comparative Dosimetry in Mines and Homes. National Academy Press (1991). International Commission on Radiological Protection (ICRP). Guide to the practical application of the ICRP Human Respiratory Tract Model: ICRP supporting guidance. Ann. ICRP 32(1–2). Pergamon Press (2002). Fakir, H., Hofmann, W. and Caswell, R. S. Radon progeny microdosimetry in human and rat bronchial airways: the effect of crossfire from the alveolar region. Radiat. Prot. Dosim. 130, 149– 161 (2008).
Downloaded from http://rpd.oxfordjournals.org/ at University of Ulster on June 28, 2015
In pathological examinations, the locations of bronchial tumours are commonly related to airway diameters. Thus, an airway diameter seems to be a more appropriate spatial parameter to relate bronchial doses to bronchial carcinomas. Since the linear dimensions of the rat bronchial airways were obtained in lung casts at TLC, they have to be scaled down to the FRC of a living rat for realistic dose calculations. In the present calculations, all airway diameters and lengths were scaled down by a linear scaling factor defined as the cube root of the ratio FRC/TLC. Without application of such a scaling factor, average bronchial doses are 1.67 mGy WLM21, when compared with 6.87 mGy WLM21 (without considering cross-fire from the alveolar region). Thus, application of a scaled-down lung morphology leads to higher bronchial doses than the use of the originally reported data(5) resulting from increased deposition and clearance velocities and reduced surface areas and target cell depths. The comparison between rat and human lungs indicate that bronchial doses for the rat lung are slightly higher than the corresponding values for the human lung by a factor of 1.34 for the experimental PNNL exposure conditions, and of 1.25 for typical human indoor conditions. This similarity in bronchial doses suggests that mean lifetime risk coefficients per unit exposure are comparable, provided that inter-species differences can be neglected. This supports the view that the rat lung is indeed an appropriate surrogate for the human lung for lung cancer risk assessment.
