Aerosol Science and Technology

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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, 257-271, DOI: 10.1080/02786829308959603

To link to this article: https://doi.org/10.1080/02786829308959603

Published online: 11 Jun 2007.

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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 27709
R. R. Mercer and J. D. Crapo
Center for Extrapolation Modeling, Duke University Medical Center, Durham, NC 27710
Significant differences in lower respiratory tract struc-
ture exist both within species and among species a t
each level of anatomy. Irregular dichotomous and tri-
chotomous branching patterns of airways are present
in human and nonhuman primate lungs. In contrast,
the dog and common laboratory rodents exhibit a pre-
dominantly monopodial branching system. The effects
of these various branching patterns on airfiow distri-
bution, gas uptake, and the deposition of particles have
not been sufficiently studied to determine the extent to
which branching patterns impart regional inhomo-
geneities or local variations in the deposition of in-
haled material. To date, detailed morphometric data
have not been used to examine aerosol particle deposi-
tion. We have been using three-dimensional recon-
struction techniques to examine various aspects of lung
structure. Studies vary from the reconstruction of indi-
vidual 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 stud-
ied. There are various 'length pathways to reach the
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 monopo-
dial branching system. The effects on air-
flow distribution, gas uptake, and the
*To whom correspondence should be addressed
Aerosol Scicnce and Technology 18:257-271 (1993)
Q 1993 Elscvier Science Publishing Co., Inc.
alveolar (gas exchange) region in all types of mam-
malian lungs. The average path length involves about
16 branches from the trachea to the terminal bronchi-
oles (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 associ-
ated 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 bronchiolar-
alveolar 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) estab-
lishing respiratory tract structure based criteria for the
optimum design of pharmaceutical aerosols.
deposition of particles of these various
branching patterns have not been suffi-
ciently 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 phar-
maceutical aerosols relates to their thera-
peutic use in humans, drug development
involves extensive use of laboratory ani-
mals. Understanding interspecies differ-
ences in respiratory tract structure and
the influence of structure on delivered

dose has important clinical implications.
Increasing our ability to target specific
regions of the respiratory tract for the
delivery of pharmaceutical aerosols re-
quires an interdisciplinary approach in-
volving 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 up-
per respiratory tract, tracheobronchial,
and pulmonary regions.
A large body of information on the
structure of the conducting airways, alveo-
lar ducts, and alveoli of the lung is avail-
able 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 Cum-
ming, 1968; Raabe et al., 1976; Yeh and
Schum, 1980). Data on the structure of
the pulmonary acinus of the rat are avail-
able 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 varia-
tions in airway and alveolar duct structure
both within a given lung and among
species.
Various mathematical models for parti-
cle deposition have been developed using
information on lung structure together
with equations describing the physical
processes (mechanisms) involved in parti-
cle deposition-dating as far back as the
Miller et al.
mid-1930s (Findeisen, 1935). The Task
Group on Lung Dynamics (1966) provided
a model for predicting regional respira-
tory tract deposition in humans, as a func-
tion of particle size and level of physical
exertion. Various improvements in model-
ing the deposition of relatively insoluble
spherical particles have been made: parti-
cle 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 bi-
furcating airways with parabolic velocity
profiles (Pich, 1972; Ingham, 1975; Cai
and Yu, 1988), and simultaneous action of
inertial impaction and gravitation deposi-
tion mechanisms in curved tubes and air-
way bifurcations (Baliish6zy et al., 1990).
Additional complexities must be ad-
dressed in developing mathematical depo-
sition models for pharmaceutical aerosols
owing to the hygroscopicity of the drugs
and/or the drug delivery medium. Rela-
tive to their initial diameter, hygroscopic
particles absorb water as they are trans-
ported 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 pur-
poses 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 equa-
tion for the size change of dilute solution
or pure water droplets. An analytical
model of hygroscopic particle behavior in
human airways was developed by Marto-
nen (1982) that accounted for anatomical
features, such as the larynx and cartilagi-
nous rings in large airways, and that
included original deposition efficiency
Factors for Modeling Dose to the Lung 259

formulae for laminar and turbulent highlight recent contributions of com-

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) re-
viewed the health implications of hy-
groscopic particle growth in the human
respiratory tract, discussing particle
growth, growth rate, respiratory tract tem-
perature and humidity, deposition of hy-
groscopic particles and the hygroscopic
behavior of therapeutic aerosols among
other topics.
Knowledge about lung structure and
geometry contributes to understanding lo-
bar and path-specific deposition patterns,
which may have considerable toxicologic
and therapeutic significance. As the speed
and storage capacity of computers contin-
ues to increase along with improvements
in the resolution of imaging equipment,
three-dimensional reconstruction tech-
niques 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
puter-aided morphometry to the under-
standing of lung structure of laboratory
animals and man and discuss implications
of the resultant data to dosimetry model-
ing.
LOWER RESPIRATORY TRACT STRUCTURE
Anatomical Models of the Airways and
Ventilatory Units
When employing anatomical models of
lung structure to make dosimetry calcula-
tions, the use of a realistic geometry is
critically important so that the model ap-
propriately captures the complexity of the
system studied. The nature of short and
long pathways to the alveolar (gas-
exchange) 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 ~ i p d d i a -l Tripodial

FIGURE 1. Short and long pathways are depicted for reaching

the alveolar region in either a monopodial or a bipodial/tripo-
dial (dichotomous/trichotomous) airway branching system.
Reprinted with permission from Crapo et al. (1990).

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 toxi-
ulty in delivering some
harmaceutical aerosols uniformly to the
hile there is heterogeneity in the air-
way branching pattern in various species,
there is probably significantly more het-
erogeneity 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 rc-
ercer 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 represen-
ithin the alveolar duct system of
the rat, the branching system is complex,
with as few as 3 and up to 13 branches
GURE 2. Schematic diagram showing that variations in con-
ducting airway path length result in some ventilatory units
receiving inhaled air for a greater portion o l inspiration than do
other units.
Miller et al.
contained in a single ventilatory unit. A
ventilatory unit is defined to be the collec-
tion of alveoli and alveolar ducts distal to
a single bronchiolar-alveolar duct junc-
tion. The alveolar duct branching system
of the rat is so complex in three dimen-
sions that multiple branches may occur
within the distance of a single alveolus-
which for the rat is only about 100 pm.
igure 3 is the fact that the
ventilatory unit is designed so as to mini-
mize 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 distri-
bution within the ventilatory unit.
over, path length distance from the tra-
chea to the start of the bronchoalveolar
duct branching system probably has a ma-
jor 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 venti-
latory units. Evidence for this is as fol-
lows. 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 or-
ders of magnitude (Crapo et al., 1990).
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).

Concomitantly, the number of ventilatory fusion fixed lungs. Although there is a

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
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 indi-
cate that this size variation is apparently
due to differences in the number of alve-
oli in each ventilatory unit, as determined
by morphometric analyses of vascular per-
similarity in average ventilatory unit struc-
ture across the range of species included
in Figure 4, the importance of hetero-
geneity in the human lung has received
limited attention (Boyden, 1971; Haefeli-
Bleuer and Weibel, 1988).
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 compris-
ing 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-

-
3
Ventilatory Unit
Diameter 2 .
(mm)
Alveolar Diameter
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 labora-
tory animals on the types of cells in the
lower respiratory tract, including informa-
tion 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). Compara-
ble 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 toxic-
ity studies are often constructed using lab-
oratory 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 air-
way cell type as a function of location in
the human lung. Ciliated cells are the
Miller et al.
(mm)
predominant cell type in all airways. Gob-
let cells decrease in number dramatically
from the large bronchi to the terminal
bronchioles of humans, whereas secretory
cells increase proceeding distally. A com-
parison 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 termi-
nal bronchioles where they are compara-
ble (Figure 6c).
With respect to the cellular composi-
tion of the alveolar (ventilatory unit)
region, Figure 7 shows the relative distri-
bution of the major cells and tissues in
various species. For each tissue compart-
ment, the average volume is depicted as a
percentage of all tissue contained in the
alveolar septum, excluding blood in capil-
lary lumens. The human lungs were from
smokers and contained a large number of
macrophages. Thus, to compare the hu-
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 42.4 4.5 18.5 22.0 4.1 8.5
Bronchi ( d = 1-3 mm, T = 50 Frn) 46.0 8.4 16.8 20.4 3.6 4.5
Terminal bronchiales (7 = 9.8 pm) 52.8 2.9 - 0.0 36.5 7.8
"No significant basal cell population present at this level.
Data derived from volume densities given in Tables 1-3 of Mercer c t al. (1991b).
"d, diameter; r , epithelial thickness.
 Miller et al.

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
Large Bronchlrrrachea Bronchl Termlnai Bronchioles
the number of cells per alveolus for each
of the five major cell types (alveolar
macrophage, type I epithelial, type I1 ep-
ithelial, 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 non-
smoker. Note that, in this instance,
macrophages comprise about 3% of the
Large Bronchlmachea Bronchl Terminal Bronchioles
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 com-
position 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

The type of morphometric data available

FI HUMAN on lower respiratory tract structure in

. Comparison of human and rat air-
ways for various cell types as a function of loca-
tion in the tracheobronchial tree. (a) Ciliated
cells; (b) secretory cclls; (c) goblet cells. Data
derived from Tables 1-6 of Mercer el al. (1991b).
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-
Factors for Modeling Dose to the Lung

L
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 compart-
ment, 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).
 Miller et al.

Alveolar
,ducts

c Alveoli

I I I I I

0 1 2 3 4 5 6
Distance ( cm )
(a)
Unequal Airway Path Lengths
4 F + Unequal Alveolar
Duct Path Lengths

I I I I I I I

0 1 2 3 4 5 6
Distance ( cm )
(b)

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 infor-
mation on unequal airway and alveolar duct path lengths.
Factors for Modeling Dose to the Lung

BRONCHUS AIRWAVF

V E N T I W Y 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 con-
tained in Crapo et a1.(1990) and Mercer et al. (1991a).

sectional surface area of the lower respi-
ratory tract, as a function of distance from
the trachea, and assuming regular di-
chotomous branching for the airways in
the alveolar ducts, yields a representation
of lung structure typically referred to as a
"trumpet" model (Figure 9a). Morphome-
tric 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 gas-
exchange area be located within a narrow
zone at the end of the trumpet.
Figure 9b illustrates a trumpet-like
model representation using data on un-
equal 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 aris-
ing 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 gas-
exchange 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 pre-
dicted to be more variable to the gas-
exchange regions of the lung when using
the more accurate anatomical model rep-
resented 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-
 Miller et al.

dimensional reconstruction methods, The potential impact of path length

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 pat-
tern of the airway segments and distal
ventilatory units. The average anatomic
dead space along the path from the tra-
chea to a bronchiolar-alveolar duct junc-
tion 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 anatomi-
cal models of lung structure should en-
hance the accuracy of predictions of dose
to specific sites within the lower respira-
tory tract and enhance our ability to make
interspecies dosimetric extrapolations for
pharmaceutical aerosols.
and ventilatory volume differences on
dosimetry prediction is illustrated in Fig-
ure 10, which shows the relative dose
distribution among ventilatory units com-
prising the right middle lobe of the rat.
The airway branching pattern in the fig-
ure is based upon three-dimensional re-
constructions. 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 parti-
cle, 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 adja-
cent 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).
Factors for Modeling Dose to the Lung

pected variability in ventilatory unit depo-
sition 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 vari-
ous 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 per-
fusion using a sequence of fixatives de-
signed 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 mod-
els for the deposition of highly soluble
pharmaceutical aerosols will enable better
future estimation of deposition and mass
transfer of these aerosols at specific loca-
tions within the lower respiratory tract.
To date, recent knowledge about air-
way cell type, thickness of liquid layers
lining the respiratory tract, alveolar duct
branching patterns, etc. has not been in-
corporated into dosimetry models for
pharmaceutical aerosols. However, some
of this information has been used to ex-
amine inhomogeneity of ventilatory unit
volume and its effects on reactive gas
uptake (Mercer et al., 1991a) and to ex-
amine 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 > 40

20

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).
270
the results of gas deposition modeling are
not warranted for expected deposition of
these aerosols for various target sites
within the lung. However, detailed mor-
phometric data are available for use in
models that estimate the dosimetry of
pharmaceutical aerosols. The ability to
better understand the respiratory tract de-
position of pharmaceuticals can have im-
portant clinical implications: by altering
the formulation of particles to change hy-
groscopic growth and dissolution, the
deposition site and duration of inhaled
medications can be altered; dosimetry
model predictions of patterns of deposi-
tion can help identify experimental stud-
ies 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 con-
tribute to more rational aerosol design by
identifying particle attributes that maxi-
mize 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 labora-
tory animal strains are highly inbred,
whereas the human population is het-
erogeneous. In the rat, M h a c h e and
co-workers (1991) have shown that the
intra-animal variability in airway dimen-
sions 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 termi-
nal bronchioles is likely to be more pre-
valent for humans than for laboratory
animals. Improved dosimetry models can
enhance our ability to examine factors
influencing labor and path specific deposi-
tion 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
Miller et al.
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 Protec-
tion Agency Cooperative Agreement CR813113. The
research described in this article has been reviewed by
the Health Effects Research Laboratory, U.S. Environ-
mental Protection Agency, and approved for publica-
tion. Approval does not signify that the contents neces-
sarily 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). A m . Ind.
Hyg. Assoc. J . 40:1055-1066.
BalLshrizy, I., Martonen, T. B., and Hofmann, W. (1990).
Aerosol Sci. Technol. 13:308-321.
Boyden, E. A. (1971). A m . J. Anat. 132:275-300.
Cai, F.-S., and Yu, C. P. (1988). J . Aerosol Sci.
19:679-688.
Crapo, J. D., Barry, B. E., Gehr, P., Bachofen, M., and
Weibel, E. R. (1982). A m . Reu. Respir. Dis.
126:740-745.
Crapo, J. D., Chang, L.-Y., Miller, F. J., and Mercer, R.
R. (1990). In Principles of Route-to-Route Extrapola-
tion for Risk Assessment (T. R. Gerrity and C. J.
Henry, eds.). Elsevicr, Amsterdam, pp. 15-32.
Crapo, J. D., Young, S. L., Fram, E. K., Pinkerton, K.
E., Barry, B. E., and Crapo, R. 0. (1983). A m . Rev.
Respir. Dis. 128:S42-S46.
Findcisen, W. (1935). Pfliigers Arch. Ges. Physiol.
236:367-379.
Gehr, P., and Crapo, J. D. (1988). In Toxicology of the
Lung (D. E. Gardner, J. D. Crapo, and E. J. Mas-
saro, eds.). Raven, New York, pp. 1-42.
Haefeli-Bleuer, B., and Weibcl, E. R. (1988). Anat.
Rec. 220:401-414.
Hansen, J . E., and Ampaya, E. P. (1975). J. Appl.
Physiol. 38:990-995.
Hansen, J . E., Ampaya, E. P., Bryant, G. H., and Navin,
J. J. (1975). J. Appl. Physiol. 38:983-989.
Hiller, F. C. (1991). J. Aerosol Med. 4:1-23.
Horsfield, K., and Cumming, G. (1968). J. Appl. Phys-
iol. 24:373-383.
Ingham, D. B. (1975). J. Aerosol Sci. 6:125-132.
Jeffery, P. K., and Reid, L. (1975). 1. Anat. 120:295-320.
Kliment, V . (1972). J. Hyg. Epidemiol. Microbiol. Im-
munol. 16:107-114.
Kliment, V. (1973). Folia Morphol. 21:59-64.
Landahl, H. D. (1950). Bull. Math. Biophys. 12:43-56.
Factors for Modeling Dose to the Lung
Martonen, T. B. (1982). Bull. Math. Biol. 44:425-442.
Martonen, T . B., Barnett, A. E., and Miller, F. J.
(1985). Enuiron. Health Perspect. 63:ll-24.
Martonen, T. B., Bell, K. A., Phalen, R. F., Wilson, A.
F., and Ho, A. (1982). Ann. Occup. Hyg. 26:93-107.
Martonen, T . B., and Clark, M. L. (1983). Fundam.
Appl. Toxicol. 3: 10-15.
Mtnache, M. G., Patra, A. L., and Miller, F. J. (1991).
Neurosci. Behau. Reu. 15:63-69.
Mercer, R. R., and Crapo, J. D. (1987). J. Appl. Phys-
iol. 63:785-794.
Mercer, R. R., and Crapo, J. D. (1989). In JZktrapolatioa
of Dosimetric Relationships for Inhaled Particles and
Gases (J. D. Crapo, E. D. Smolko, F. J. Miller, J. A.
Graham, and A. W. Hayes, eds.). Academic Press,
San Diego, pp. 69-78.
Mercer, R. R., and Crapo, J. D. (1992). In Comparatiue
Biology of the Normal Lung (R. A. Parent, ed.). CRC
Press, Boca Raton, pp. 109-119.
Mercer, R. R., Anjilvel, S., Miller, F. J., and Crapo, J.
D. (1991a). J. Appl. Physiol. 70:2193-2205.
Mercer, R. R., Russell, M. L., and Crapo, J. D. (1991b).
Health Phys. 61:117-130.
Mercer, R. R., Russell, M. L., and Crapo, J. D. (1982).
Am. Reu. Respir. Dls. 145:355.
Miller, F. J., Overton, J. H., Jaskot, R. H., and Menzel,
D. B. (1985). Toxicol. Appl. Pharmacol. 79:ll-27.
Miller, F. J., Overton, J. H., Myers, E. T., and Graham,
J. A. (1982). In Alr Pollution by Nitrogen Oxldes (T.
Schneider and L. Grant, eds.). Elsevier, Amster-
dam, pp. 377-386.
Overton, J. H., Graham, R. C., and Miller, F. J. (1987).
Toxicol. Appl. Pharmacol. 88:418-432.
271
Pich, J. (1972). J . Aerosol Sci. 3:351-361.
Plopper, C. G., Mariassy, A. T., and Lollini, L. 0.
(1983). Am. Rev. Respir. Dis. 128:S4-S7.
Plopper, C. G., Weir, A., St. George, J., Tyler, N.,
Mariassy, A., Wilson, D., Mishio, S., Cram, D.,
Heidsiek, J., and Hyde, D. (1989). In Extrapolation
of Dosimetric Relationships for Inhaled Particles and
Gases (J. D. Crapo, E. D. Smolko, F. J. Miller, J. A.
Graham, and A. W. Hayes, eds.). Academic Press,
San Diego, pp. 19-34.
Raabe, 0 . G., Yeh, H. C., Schum, G. M., and Phalen,
R. F. (1976). Publication No. LF-53. Lovelace Foun-
dation, Albuquerque, NM.
Rodriguez, M., Bur, S., Favre, A., and Weibel, E. R.
(1987). Am. J . Anat. 180:143-155.
Schreider, J. P., and Hutchens, J. 0. (1980). Anat. Rec.
196:313-321.
Schreider, J. P., and Raabe, 0. G. (1981). Am. J . Anat.
162221-232.
Stone, K. C., Mercer, R. R., Gehr, P., Stockstill, B., and
Crapo, J. D. (1992). Am. J. Respir. Cell. Mol. Biol.
6:235-243.
Task Group on Lung Dynamics of ICRP. (1966). Health
Phys. 12:173-207.
Taulbee, D. B., and Yu, C. P. (1975). J. Appl. Physiol.
38:77-85.
Weibel, E. R. (1963). Mophometry of the Human Lung.
Academic Press, New York, 151 pp.
Yeh, H., and Schum, G. M. (1980). Bull. Math. Biol.
42:461-480.
Yeh, H.-C., Schum, G. M., and Dugan, M. T. (1979).
Anat. Rec. 195:483-492.
Yu, C. P. (1978). Powder Technol. 21:55-62.