Lower Respiratory Tract Structure of Laboratory Animals and Humans: Dosimetry Implications

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1 Aerosol Science and Technology ISSN: (Print) (Online) Journal homepage: Lower Respiratory Tract Structure of Laboratory Animals and Humans: Dosimetry Implications F. J. Miller, R. R. Mercer & J. D. Crapo To cite this article: F. J. Miller, R. R. Mercer & J. D. Crapo (1993) Lower Respiratory Tract Structure of Laboratory Animals and Humans: Dosimetry Implications, Aerosol Science and Technology, 18:3, , DOI: / To link to this article: Published online: 11 Jun Submit your article to this journal Article views: 976 View related articles Citing articles: 15 View citing articles Full Terms & Conditions of access and use can be found at

2 Lower Respiratory Tract Structure of Laboratory Animals and Humans: Dosimetry Implications F. J. Miller* Chemical Industry Institute of Toxicalogy, P.O. Box 12137, Research Triangle Park, NC R. R. Mercer and J. D. Crapo Center for Extrapolation Modeling, Duke University Medical Center, Durham, NC Significant differences in lower respiratory tract structure exist both within species and among species at each level of anatomy. Irregular dichotomous and trichotomous branching patterns of airways are present in human and nonhuman primate lungs. In contrast, the dog and common laboratory rodents exhibit a predominantly monopodial branching system. The effects of these various branching patterns on airfiow distribution, gas uptake, and the deposition of particles have not been sufficiently studied to determine the extent to which branching patterns impart regional inhomogeneities or local variations in the deposition of inhaled material. To date, detailed morphometric data have not been used to examine aerosol particle deposition. We have been using three-dimensional reconstruction techniques to examine various aspects of lung structure. Studies vary from the reconstruction of individual cells to reconstructing conducting ainray and alveolar duct branching systems. When using physical models for dosimetric calculations, realistic geometry is critical to be certain that the model appropriately captures the complexity of the branching system studied. There are various 'length pathways to reach the alveolar (gas exchange) region in all types of mammalian lungs. The average path length involves about 16 branches from the trachea to the terminal bronchioles (Weibel, 1963; Raabe et al., 1976; Yeh et al., 19791, but short path lengths may have as few as 8 or 10 branches. Analyses in mouse, rat, and baboon lungs demonstrate that the greater lung size in larger species is the result of an increase in both the number and size of ventilatory units, with the major contribution associated with the change in number of ventilatory units. Here, a ventilatory unit is defined to be the collection of alveoli and alveolar ducts distal to the bronchiolaralveolar duct junction. The ratio of ventilatory unit diameter to alveolar diameter is constant over a range of lung sizes from those of mice to men. A ventilatory unit is typically about 17.5 alveolar diameters in size. This new knowledge about lung structure and geometry applies to a number of areas. Among these are (a) examining lobar and path-specific deposition patterns for pharmaceutical aerosol distributions, (b) selecting critical sites for potential lung injury, and (c) establishing respiratory tract structure based criteria for the optimum design of pharmaceutical aerosols. INTRODUCTION Lower respiratory tract structure varies both within a species and among species. Irregular dichotomous and trichotomous airway branching patterns are present in human and nonhuman primate lungs. In contrast, the dog and common laboratory rodents exhibit a predominantly monopodial branching system. The effects on airflow distribution, gas uptake, and the *To whom correspondence should be addressed deposition of particles of these various branching patterns have not been sufficiently studied to determine the extent to which branching patterns impart regional inhomogeneities or local variations in the deposition of inhaled material. Whereas the primary interest for pharmaceutical aerosols relates to their therapeutic use in humans, drug development involves extensive use of laboratory animals. Understanding interspecies differences in respiratory tract structure and the influence of structure on delivered Aerosol Scicnce and Technology 18: (1993) Q 1993 Elscvier Science Publishing Co., Inc.

3 Miller et al. dose has important clinical implications. Increasing our ability to target specific regions of the respiratory tract for the delivery of pharmaceutical aerosols requires an interdisciplinary approach involving physical and biomedical scientists. Experts in the generation and delivery of aerosols need to be aware of the structure and function of the various regions of the respiratoq tract in order to target the delivery of aerosols to the desired region. This targeting must take into account the various mechanisms of deposition that govern the delivery of aerosols to the upper respiratory tract, tracheobronchial, and pulmonary regions. A large body of information on the structure of the conducting airways, alveolar ducts, and alveoli of the lung is available for a number of laboratory animal species (Kliment, 1972, 1973; Raabe et al., 1976; Yeh et al., 1979; Schreider and Hutchens, 1980) and for humans (Landahl, 1950; Weibel, 1963; Horsfield and Cumming, 1968; Raabe et al., 1976; Yeh and Schum, 1980). Data on the structure of the pulmonary acinus of the rat are available from Mercer and Crapo (1987), from Mercer and co-workers (1991a,b) and from Rodriguez et al. (1987). Acinar structural data for humans are available from a number of sources (Hansen and Ampaya, 1975; Hansen et al., 1975; Schreider and Raabe, 1981; Haefeli- Bleuer and Weibel, 1988); Rodriguez et al. (1987) have studied the geometry and morphometry of the peripheral airway system of rabbits. Collectively, these data establish that there are significant variations in airway and alveolar duct structure both within a given lung and among species. Various mathematical models for particle deposition have been developed using information on lung structure together with equations describing the physical processes (mechanisms) involved in particle deposition-dating as far back as the mid-1930s (Findeisen, 1935). The Task Group on Lung Dynamics (1966) provided a model for predicting regional respiratory tract deposition in humans, as a function of particle size and level of physical exertion. Various improvements in modeling the deposition of relatively insoluble spherical particles have been made: particle transport described by a convective diffusion equation (Taulbee and Yu, 1975), an analytic solution of the particle transport equation (Yu, 1978), deposition efficiencies for various mechanisms in bifurcating airways with parabolic velocity profiles (Pich, 1972; Ingham, 1975; Cai and Yu, 1988), and simultaneous action of inertial impaction and gravitation deposition mechanisms in curved tubes and airway bifurcations (Baliish6zy et al., 1990). Additional complexities must be addressed in developing mathematical deposition models for pharmaceutical aerosols owing to the hygroscopicity of the drugs and/or the drug delivery medium. Relative to their initial diameter, hygroscopic particles absorb water as they are transported in inspired air, changing shape, size, and density, as a function of location within the respiratory tract (Martonen et al., 1985). Hygroscopic particle deposition was first modeled by the Task Group on Lung Dynamics (1966) in a computational model that assumed for calculation purposes that the particle had achieved an equilibrium diameter for 99.5% relative humidity at inhalation. Austin et al. (1979) developed an empirical model for lung deposition of stable and unstable aerosols in the human respiratory tract, treating particle growth via an approximate equation for the size change of dilute solution or pure water droplets. An analytical model of hygroscopic particle behavior in human airways was developed by Martonen (1982) that accounted for anatomical features, such as the larynx and cartilaginous rings in large airways, and that included original deposition efficiency

4 Factors for Modeling Dose to the Lung 259 formulae for laminar and turbulent airstreams. Martonen and colleagues (1982, 1985) and Martonen and Clark (1983) made various improvements in treating model assumptions and routes of breathing. Recently, Hiller (1991) reviewed the health implications of hygroscopic particle growth in the human respiratory tract, discussing particle growth, growth rate, respiratory tract temperature and humidity, deposition of hygroscopic particles and the hygroscopic behavior of therapeutic aerosols among other topics. Knowledge about lung structure and geometry contributes to understanding lobar and path-specific deposition patterns, which may have considerable toxicologic and therapeutic significance. As the speed and storage capacity of computers continues to increase along with improvements in the resolution of imaging equipment, three-dimensional reconstruction techniques are proving useful for examining various aspects of lung structure. Studies vary from the reconstruction of individual cells to those of conducting airways and alveolar duct branching systems. Here, we highlight recent contributions of computer-aided morphometry to the understanding of lung structure of laboratory animals and man and discuss implications of the resultant data to dosimetry modeling. LOWER RESPIRATORY TRACT STRUCTURE Anatomical Models of the Airways and Ventilatory Units When employing anatomical models of lung structure to make dosimetry calculations, the use of a realistic geometry is critically important so that the model appropriately captures the complexity of the system studied. The nature of short and long pathways to the alveolar (gasexchange) region in various mammalian lungs is illustrated schematically in Figure 1. The average path involves about 16 branches from the trachea to the terminal bronchioles (Weibel, 1963; Raabe et al., 1976; Yeh et al., 1979), but short path lengths may have as few as 8 or 10 branches. Thus, gas-exchange units at the end of short paths will be exposed to higher concentrations of inhaled material Physical Models for Extrapolation Rodent Primate Monopodial ~ipddial - Tripodial FIGURE 1. Short and long pathways are depicted for reaching the alveolar region in either a monopodial or a bipodial/tripodial (dichotomous/trichotomous) airway branching system. Reprinted with permission from Crapo et al. (1990).

5 Miller et al. for longer periods during a breath. An alternative way of expressing this concept is to consider the variation in the depth to which an inhaled bolus of a given volume of air will penetrate along a short path compared to a long one. Figure 2 shows schematically that for a given bolus of air, penetration into a ventilatory unit will be in somepaths but not in others. in the patchy nature of by many inhaled toxiulty in delivering some harmaceutical aerosols uniformly to the hile there is heterogeneity in the airway branching pattern in various species, there is probably significantly more heterogeneity in the alveolar duct branching pattern within the alveolar region. The complexity in the alveol system is illustrated in rat; the shortest an longest path lengths are numbered. The schematic is base analyses of three-dimcnsional rcercer and Crapo, 1987). gure 3, thc bold lines at the end of a represent alveolar sacs (terminal alveolar ducts), and the length of each duct is proportional to the length of the line, but branch anglcs are not represenithin the alveolar duct system of the rat, the branching system is complex, with as few as 3 and up to 13 branches contained in a single ventilatory unit. A ventilatory unit is defined to be the collection of alveoli and alveolar ducts distal to a single bronchiolar-alveolar duct junction. The alveolar duct branching system of the rat is so complex in three dimensions that multiple branches may occur within the distance of a single alveoluswhich for the rat is only about 100 pm. igure 3 is the fact that the ventilatory unit is designed so as to minimize distance across the unit, presumably to lessen oxygen diffusion gradients. given the size distribution of most maceutical aerosols, there may still be significant variability in the dose distribution within the ventilatory unit. over, path length distance from the trachea to the start of the bronchoalveolar duct branching system probably has a major influence on the variation in dose among ventilatory units. Analyses in mouse, rat, and baboon lungs demonstrate that large lungs result from an increase in both the number and size of ventilatory units, with the majority of the changes rclatcd to number of ventilatory units. Evidence for this is as follows. The size of the average ventilatory unit increases only about 5- to 10-fold from mouse to baboon, although body weight increases by more than three orders of magnitude (Crapo et al., 1990). GURE 2. Schematic diagram showing that variations in conducting airway path length result in some ventilatory units receiving inhaled air for a greater portion ol inspiration than do other units.

6 Factors for Modeling Dose to the Lung 261 Bronchio- Alveolar Junction FIGURE 3. Branching pattern of the alveolar duct system in a rat lung based on three-dimensional reconstructions. Alveolar sacs (terminal alveolar ducts) are drawn in a bold line at the end of each path. The length of each duct is proportional to the length of the line, but branch angles are not representative. The scale marker (100 ~ m is ) about the diameter of an alveolus. The shortest and longest path lengths are numbered beginning at the bronchoalveolar duct junction. Reprinted with permission from Mercer and Crapo (1987). fusion fixed lungs. Although there is a similarity in average ventilatory unit structure across the range of species included in Figure 4, the importance of heterogeneity in the human lung has received limited attention (Boyden, 1971; Haefeli- Concomitantly, the number of ventilatory units increases by about two orders of magnitude. The ratio of ventilatory unit diameter to alveolar diameter is constant over a range of lung sizes from murine to human (Figure 4). A ventilatory unit is typically Bleuer and Weibel, 1988). about 17.5 alveolar diameters in size. However, there are significant differences in ventilatory unit volume within a given species. For example, among the 140 rat ventilatory units studied by Mercer et al. (1991a), luminal gas volume varied from 0.2 to 3.4 mm3. Those investigators indicate that this size variation is apparently due to differences in the number of alveoli in each ventilatory unit, as determined by morphometric analyses of vascular per- Composition of Airways and Ventilatory Units In addition to data on the overall physical structure of the lower respiratory tract, information on the types of cells comprising various lung regions and the nature of the fluid layer overlying the epithelium is useful for modeling the deposition and fate of pharmaceutical aerosols. Quantita-

7 Miller et al. 3 - Ventilatory Unit Diameter 2. (mm) Alveolar Diameter (mm) FIGURE 4. Thc relationship between ventilatory unit diameter and alveolar diameter for various mammalian species. Reprinted with permission from Mercer and Crapo (1992). tive data are available for various laboratory animals on the types of cells in the lower respiratory tract, including information on cell number, volume, surface area, and diameter (Jeffery and Reid, 1975; Plopper et al., 1983, 1989; Crapo et al., 1982, 1983; Stone et al., 1992). Comparable quantitative data on a region-specific basis for humans are more limited (Mercer et al., 1991a). Figure 5 shows electron micrographs of human and rat airway epithelium. Such micrographs provide the basic input data for morphometric analyses on cell type. In addition to knowledge of physicochemical properties of pharmaceutical aerosols, data on cell type are vital for targeting drug delivery to various regions of the lung. Initial drug development and toxicity studies are often constructed using laboratory animals. Interpretation of the results of these studies relative to effects that can be expected with human use is critically linked to the availability of cell type data for people. Table 1 shows airway cell type as a function of location in the human lung. Ciliated cells are the predominant cell type in all airways. Goblet cells decrease in number dramatically from the large bronchi to the terminal bronchioles of humans, whereas secretory cells increase proceeding distally. A comparison between rats and humans for these three cell types is shown in Figure 6. Between the two species, ciliated cells are comparable for various airway locations (Figure 6a). Independent of location, the rat has a smaller percentage of goblet cells than does man (Figure 6b). Also, secretory cells are more frequent in rats compared to humans, except in the terminal bronchioles where they are comparable (Figure 6c). With respect to the cellular composition of the alveolar (ventilatory unit) region, Figure 7 shows the relative distribution of the major cells and tissues in various species. For each tissue compartment, the average volume is depicted as a percentage of all tissue contained in the alveolar septum, excluding blood in capillary lumens. The human lungs were from smokers and contained a large number of macrophages. Thus, to compare the hu-

8 Factors for Modeling Dose to the Lung 5. Elcctron micrographs showing rat and human airway epithelium. Lower left: Human bronchus micrograph has scveral ciliatcd cells (C) and basal cells (B), a goblet cell (G), and one cell of indeterminate type (I). Upper left: Higher magnification view shows cilia as they penetrate into the mucous lining laycr(s). Right slde: rat bronchus micrograph showing a ciliated cell (C) and a secretory cell (S). Reprinted with permission from Health Physics (Mercer et al., 1991b) with pcrmission from thc Health Physics Society. TABLE 1. Volume Proportion of Airway Cell Type in thc Human Bronchial Tree Cell type (5%) Ciliated Preciliated Basal Goblet Secretory Indeterminate Large bronchi (d = 3-5 mm, T = 57.8 pm)a Bronchi (d = 1-3 mm, T = 50 Frn) Terminal bronchiales (7 = 9.8 pm) "No significant basal cell population present at this level. Data derived from volume densities given in Tables 1-3 of Mercer ct al. (1991b). "d, diameter; r, epithelial thickness.

9 Miller et al. Large Bronchlrrrachea Bronchl Termlnai Bronchioles Large Bronchlmachea Bronchl Terminal Bronchioles man data to the other species, the total tissue excluding macrophages was set to 97% of the alveolar septum. Note the consistency of cellular composition across the range of mammalian species depicted in Figure 7. Allometric studies of alveolar size have been conducted by ercer et al. (1992) for the mouse, rat, rabbit, and human lung. A scaling factor of 0.53 was found to relate increases in the number of alveoli per lung with increasing body weight. Stone and co-workers (1992) determined the number of cells per alveolus for each of the five major cell types (alveolar macrophage, type I epithelial, type I1 epithelial, interstitial, and endothelial) (see Figure 8). Based upon their studies, the average number of cells per alveolus for rats versus humans is: endothelial (21 vs. 1481, interstitial (13 vs. 106), type I1 (6 vs. 67), type I (4 vs. 40), and alveolar macrophage (1.4 vs. 12). The data for the human lung were obtained from a nonsmoker. Note that, in this instance, macrophages comprise about 3% of the cells. This supports the normalization used by Crapo et al. (1990) for the human data of Figure 7 and indicates that nonsmoking human lungs are similar in cellular composition to those of laboratory animals. The data of Stone et al. (1992) support the assertion that both an increase in the number and size of alveoli contribute to an increased lung volume as body size increases. Large Bronchlnrachea Bronchi Termmal Bronchioles FI HUMAN. Comparison of human and rat airways for various cell types as a function of location in the tracheobronchial tree. (a) Ciliated cells; (b) secretory cclls; (c) goblet cells. Data derived from Tables 1-6 of Mercer el al. (1991b). The type of morphometric data available on lower respiratory tract structure in large part determines the nature of anatomical models of lung structure that can be used for mathematically predicting the deposition of inhaled materials in the tracheobronchial and pulmonary airways. Three models of lower respiratory tract structure in the rat lung - are illustrated in lotting the cumulative cross-

10 Factors for Modeling Dose to the Lung L Cat Rabbit Guinea Pig Mouse Hamster Baboon Human FIGURE 7. Cellular and tissue distribution in the alveolar region of various mammalian lungs. For each tissue compartment, the average volume is shown as a percentage of all tissue comprising the septum (excluding blood in capillary lumens). The human lungs were from smokers and contained a large number of macrophages so the total tissue excluding macrophages was set at 97% of the alveolar septum in order to normalize the human data to the other spccics in the figure. Figure reprinted with permission from Gehr and Crapo (1988).. Number of cells per alvcolus and their composition as a function of body weight. Species include the mouse, rat, rabbit, and human (nonsmokers). Reprinted with permission from Stone ct al. (1992).

11 Miller et al. Alveolar,ducts c Alveoli 4 I I I I I Distance ( cm ) (a) Unequal Airway Path Lengths + Unequal Alveolar Duct Path Lengths F I I I I I I I Distance ( cm ) FIGURE 9. Representations of the lower respiratory tract of the rat used for dosimetry modeling. (a) Trumpet model based upon regular dichotomous branching. (b) Model obtained using information on unequal airway and alveolar duct path lengths. (b)

12 Factors for Modeling Dose to the Lung BRONCHUS AIRWAVF VENTIWY UNITS 1.Omm FIGURE 9. (c) Physical modcl utilizing individual branch path data coupled with specific ventilatory units arising at the ends of the paths. Panels reprinted with permission from figures contained in Crapo et a1.(1990) and Mercer et al. (1991a). sectional surface area of the lower respiratory tract, as a function of distance from the trachea, and assuming regular dichotomous branching for the airways in the alveolar ducts, yields a representation of lung structure typically referred to as a "trumpet" model (Figure 9a). Morphometric data for such a model were developed by Yeh et al. (1979). The lung is divided into conducting airway, alveolar duct, and alveolar regions, as the trumpet goes from the trachea to alveolar sacs. Importantly, the assumption of regular dichotomous branching requires that all of the gasexchange area be located within a narrow zone at the end of the trumpet. Figure 9b illustrates a trumpet-like model representation using data on unequal airway path lengths and unequal alveolar duct path lengths based on actual measurements of the branching pattern in the rat lung. This panel more accurately reflects correct lung anatomy because it allows for alveolar ducts and alveoli arising from short paths (about 3.5 cm from trachea to the first alveolar ducts). An important difference between Figure 9a, and b, is that the majority of the gasexchange area is more proximal from the end of the trumpet in panel b compared to panel a. Thus, the distribution of dose of a pharmaceutical aerosol would be predicted to be more variable to the gasexchange regions of the lung when using the more accurate anatomical model represented in panel b. A further refinement in accuracy of representation of lung anatomy for the rat is depicted in Figure 9c. Employing serial sections of the rat lung with three-

13 Miller et al. dimensional reconstruction methods, Mercer and colleagues (1991a) developed a model for the portion of the rat lung distal to the lobar bronchus of the left lung. Figure 9c depicts the branching pattern of the airway segments and distal ventilatory units. The average anatomic dead space along the path from the trachea to a bronchiolar-alveolar duct junction was found by Mercer et al. (1991a) to be about 18% less than that obtained by Yeh et al. (1979) for the trumpet model in Figure 9a. Use of more accurate anatomical models of lung structure should enhance the accuracy of predictions of dose to specific sites within the lower respiratory tract and enhance our ability to make interspecies dosimetric extrapolations for pharmaceutical aerosols. The potential impact of path length and ventilatory volume differences on dosimetry prediction is illustrated in Figure 10, which shows the relative dose distribution among ventilatory units comprising the right middle lobe of the rat. The airway branching pattern in the figure is based upon three-dimensional reconstructions. The numbers depict the predicted dose to the various ventilatory units compared to the average dose for the entire lobe. Path length and volume of the ventilatory unit at the end of a path combine to yield ventilatory unit doses that can be threefold greater or smaller than the average. While these dosimetry calculations were done for the diffusion of a highly reactive gas or an ultrafine particle, they are probably reflective of ex- FIGURE 10. Hidden line view of the airways for a region of the rat lung arising from the lobar bronchus. Drawing is based upon three-dimensional reconstruction methods. The numbers adjacent to each bronchoalveolar duct junction are the predicted delivered dose of fresh inspired gas (assuming the gas to be highly reactive) or of ultrafine particles (size range where diffusion is responsible for deposition) relative to the lobar average predicted dose. Reprinted with permission from Mercer and Crapo (1989).

14 Factors for Modeling Dose to the Lung pected variability in ventilatory unit deposition for pharmaceutical aerosols having aerodynamic diameters less than 2 pm. For larger particles in pharmaceutical aerosols, deposition can occur higher in the respiratory tract, and their deposition may be more dependent on the regional cumulative ventilatory size. The thickness of the liquid lining (mucous) layer has been shown to be an important determinant of the tissue dose in the conducting airways for reactive gases (Miller et al., 1982, 1985; Overton et al., 1987). However, measurements of the thickness of this protective layer in various regions of the conducting airways of laboratory animals and man have been quite limited. Measurements of mucus and epithelial thickness in the human lung are shown in Figure 11 and were determined from specimens prepared by vascular perfusion using a sequence of fixatives designed to preserve the normal liquid lining layers of the lung. The thickness values shown in the figure were derived using data previously reported by Mercer and colleagues (1991b, 1992). Thickness of the mucous layer in humans varies by a factor of about four between the main bronchi and terminal bronchioles. Incorporating data such as those in Figure 11 into models for the deposition of highly soluble pharmaceutical aerosols will enable better future estimation of deposition and mass transfer of these aerosols at specific locations within the lower respiratory tract. To date, recent knowledge about airway cell type, thickness of liquid layers lining the respiratory tract, alveolar duct branching patterns, etc. has not been incorporated into dosimetry models for pharmaceutical aerosols. However, some of this information has been used to examine inhomogeneity of ventilatory unit volume and its effects on reactive gas uptake (Mercer et al., 1991a) and to examine the effect of depth distribution of nuclei in human and rat lungs on radon dosimetry (Mercer et al. 1991b). Since sedimentation and impaction govern the deposition of most particles comprising pharmaceutical aerosols and the influence of theses processes varies widely in the respiratory tract, inferences based upon MUCOUS 60 a EPITHELIUM THICKNESS ( Pm > n BRONCHI BRONCHIOLES FIGURE 11. Thickness of the mucous and epithelial layers as a function of location in the conducting airways of humans. Figure is based upon data contained in Mercer et al. (1991b, 1992).

15 270 Miller et al. the results of gas deposition modeling are not warranted for expected deposition of these aerosols for various target sites within the lung. However, detailed morphometric data are available for use in models that estimate the dosimetry of pharmaceutical aerosols. The ability to better understand the respiratory tract deposition of pharmaceuticals can have important clinical implications: by altering the formulation of particles to change hygroscopic growth and dissolution, the deposition site and duration of inhaled medications can be altered; dosimetry model predictions of patterns of deposition can help identify experimental studies needed to evaluate the usefulness and generalizability of the models; depending on the nature of the desired action of the drug, dosimetry models can help contribute to more rational aerosol design by identifying particle attributes that maximize or minimize drug delivery to various regions (Hiller, 1991). An important aspect to consider in the development of improved pharmaceutical aerosol formulations is that most laboratory animal strains are highly inbred, whereas the human population is heterogeneous. In the rat, Mhache and co-workers (1991) have shown that the intra-animal variability in airway dimensions and lengths exceeds the inter-animal variation in these parameters. Variability in deposition along specific paths from the trachea to terminal bronchioles and the ventilatory units attached to these terminal bronchioles is likely to be more prevalent for humans than for laboratory animals. Improved dosimetry models can enhance our ability to examine factors influencing labor and path specific deposition patterns of pharmaceutical aerosols in laboratory animals and humans. Efforts at Chemical Industry Institute of Technology were supported through resources provided by member companies. Efforts at Duke University were supported in part by National Institutes of Health grants R01 HL42609 and PO1 HL31992, Center for Indoor Air Research grant 90-22, U.S. Department of Energy grant DE-FG05-88ER60654, and U.S. Environmental Protection Agency Cooperative Agreement CR The research described in this article has been reviewed by the Health Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use. REFERENCES Austin, E. Brock, J., and Wissler, E. (1979). Am. Ind. Hyg. Assoc. J. 40: BalLshrizy, I., Martonen, T. B., and Hofmann, W. (1990). Aerosol Sci. Technol. 13: Boyden, E. A. (1971). Am. J. Anat. 132: Cai, F.-S., and Yu, C. P. (1988). J. Aerosol Sci. 19: Crapo, J. D., Barry, B. E., Gehr, P., Bachofen, M., and Weibel, E. R. (1982). Am. Reu. Respir. Dis. 126: Crapo, J. D., Chang, L.-Y., Miller, F. J., and Mercer, R. R. (1990). In Principles of Route-to-Route Extrapolation for Risk Assessment (T. R. Gerrity and C. J. Henry, eds.). Elsevicr, Amsterdam, pp Crapo, J. D., Young, S. L., Fram, E. K., Pinkerton, K. E., Barry, B. E., and Crapo, R. 0. (1983). Am. Rev. Respir. Dis. 128:S42-S46. Findcisen, W. (1935). Pfliigers Arch. Ges. Physiol. 236: Gehr, P., and Crapo, J. D. (1988). In Toxicology of the Lung (D. E. Gardner, J. D. Crapo, and E. J. Massaro, eds.). Raven, New York, pp Haefeli-Bleuer, B., and Weibcl, E. R. (1988). Anat. Rec. 220: Hansen, J. E., and Ampaya, E. P. (1975). J. Appl. Physiol. 38: Hansen, J. E., Ampaya, E. P., Bryant, G. H., and Navin, J. J. (1975). J. Appl. Physiol. 38: Hiller, F. C. (1991). J. Aerosol Med. 4:1-23. Horsfield, K., and Cumming, G. (1968). J. Appl. Physiol. 24: Ingham, D. B. (1975). J. Aerosol Sci. 6: Jeffery, P. K., and Reid, L. (1975). 1. Anat. 120: Kliment, V. (1972). J. Hyg. Epidemiol. Microbiol. Immunol. 16: Kliment, V. (1973). Folia Morphol. 21: Landahl, H. D. (1950). Bull. Math. Biophys. 12:43-56.

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