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OCR for page 239
Biological Disposition
of Airborne Particles:
Basic Principles en cl
Application to Vehicular
~ · -
~mlsslons
RICHARD B. SCHLESINGER
New York University Medical Center
Structure of the Respiratory Tract / 240
Upper Respiratory Tract / 240 Tracheobronchial
Tree / 241 Pulmonary Region / 244 Research
Recommendations / 246
Ventilation / 246
Ventilatory Parameters / 246 Comparative Aspects of
Ventilation / 248 Airflow Patterns / 248 Research
Recommendations / 249
Deposition of Inhaled Particles in the Respiratory Tract / 250
Deposition Mechanisms and Controlling Factors / 250 Measurement
of Deposition / 253 Factors Modifying Deposition / 258
Localized Patterns of Deposition / 259 Mathematical
Modeling / 260 Research Recommendations / 262
Retention of Deposited Particles / 263
Clearance Mechanisms: Basic Structure and Function / 263 Clearance
Kinetics / 266 Factors Modifying Clearance / 272 Research
Recommendations / 273
Disposition of Vehicular Particulate Emissions / 275
Diesel Exhaust Particles / 275 Metals / 276
Sulfates / 280 Research Recommendations / 281
Summary 1 283
Summary of Research Recommendations: Discussion / 284
Summary of Research Recommendations: Priorities / 285
Air Pollution, the Automobile, and Public Health. @) 1988 by the Health Effects
Institute. National Academy Press, Washington, D.C.
239
OCR for page 240
240
Biological Disposition of Airborne Particles
The primary route of exposure to motor
vehicle emissions is inhalation. The respi-
ratory tract has a large internal surface area
that is directly and continually exposed to
10,000 to 20,000 liters of ambient air in-
haled daily, making it a potential target site
for exhaust products. In addition, because
the barrier between inhaled air and the
pulmonary bloodstream is very thin, the
respiratory tract is also an efficient portal of
entry into the general circulation.
A large fraction of emissions is either
directly released in particulate form or be-
comes adsorbed onto the surface of other
ambient particles. The disposition of in-
haled particles, and any adsorbed constitu-
ents, determines the dose delivered to tar-
get tissues. However, their ultimate fate and
any potential hazard depend upon various
interacting parameters: the physicochemical
characteristics of the particles, the amount
that actually deposits in the respiratory tract,
and the rates and routes by which deposited
material is cleared from the respiratory tract
or translocated to other organs.
Particles derived from motor vehicles do
not have unique properties that influence
their deposition or clearance. Thus, their dis-
position can be assessed in general terms.
This chapter is a review of the biological dis-
position of inhaled particulate matter in
terms of the factors that influence and control
its deposition, clearance, translocation, and
ultimate retention. The fate of specific non-
organic particles found in automobile ex-
haust will be assessed as examples of the dis-
position of toxicologically relevant material.
Some of the information presented is
based on studies with humans, but much is
derived from experiments with laboratory
animals. Since human experimentation is
precluded in many instances and often
yields only limited data, surrogate animal
models are needed. However, extrapola-
tion from animal studies requires informa-
tion on similarities and differences between
species that may influence the disposition of
inhaled materials. Thus, an attempt has
been made to interrelate and integrate hu-
man data with that obtained with experi-
mental animals and, in some cases, even
. . .
Wlt 1 in vitro systems.
The chapter is divided into five major
sections. The first describes the anatomy of
. . .
t :le respiratory tract, since airway structure
is a major determinant of particle disposi-
tion. The second section discusses the as-
pects of ventilation important in exposure
assessment, including scaling for different
· ~1 . ~ - ~ . - ~ ·1 ~
species.
l he third section describes the
physical mechanisms by which inhaled par-
tlcles deposit in the respiratory tract, their
controlling influences and modifying fac-
tors. It critically reviews the available data
for total and regional deposition in humans
and experimental animals and provides a
comparative analysis of interspecies depo-
sition patterns. The fourth section discusses
the structure, physiology, kinetics, and
modifiers of the mechanisms by which
deposited particles are cleared from, or
translocated and retained within, the respi-
ratory tract. The fifth section discusses the
fate of specific nonorganic particles of rel-
evance to automobile exhaust toxicology,
that is, diesel particles, metals, and sulfates.
In all five sections, knowledge gaps are
highlighted and recommendations for re-
search to fill these gaps are presented.
Structure of the
Respiratory Tract
The respiratory tract is divided into two
. . . .
sections accorc lug to tunctlon: one IS con-
cerned with transporting air from the ex-
ternal environment to the sites of gas
exchange and consists of the upper respira-
tory tract and the tracheobronchial tree; the
other, the pulmonary region, is involved in
gas exchange.
Upper Respiratory Tract
This region originates at the nostrils and
mouth and extends through the larynx; a
diagram of the human upper respiratory
tract is shown in figure 1. Air entering the
nostrils passes first through the vestibule,
the narrowest cross-section in the entire
nasal region, before entering the main nasal
passages. These consist of two airways
separated almost symmetrically by the na-
sal septum. They are convoluted (due to
OCR for page 241
Richard B. Schlesinger
Vestibule
.....
t\ \\ \ ~ \_Trachea
Figure 1. Diagram of the human upper respiratory
tract.
the folds of the nasal turbinates), down-
ward-curving shelf-like structures, result-
ing in a large surface area and a relatively
narrow distance between opposing airway
walls. Here, exchange of heat and moisture
modify the temperature and humidity of
the inhaled air. The nasopharynx begins at
the posterior end of the turbinates, where
the septum ends and the nasal passage
narrows and turns downward. Although
the basic structure of the nasal airways is
similar in humans and most other mam-
mals, there are considerable interspecies
differences in the relative position, shape,
and size of individual components, as
shown in figure 2. For example, the naso-
pharynx in the rat encompasses a greater
percentage of the total length of the nasal
passages than in the human, whereas that
in rabbits and dogs is intermediate between
rats and humans.
The oral passages begin at the mouth and
are characterized by much greater inter-
and intraindividual variation in shape and
cross-section than the nasal passages. At the
posterior of the mouth, inhaled air enters
the oropharynx. The oro- and nasopharynx
join to form the hypopharynx, an airway
that extends to the entrance of the larynx.
The latter extends to the trachea and has a
variable cross-section depending upon the
rate of airflow through it.
241
r _Hypopharynx Figure 2. Silicone rubber replica casts of the naso
) pharyngeal region of different species: (A) human; (B)
_~:arunx rabbit; (C) rat; (D) guinea pig; (E) hamster; (F) ba
boon; scale in cm. (Adapted with permission from Patra
1986, and from Hemisphere Publishing Corporation.)
Tracheabronchial Tree
The tracheobronchial tree consists of air-
ways from the trachea through the terminal
bronchioles. The trachea divides into two
main bronchi which then enter the lungs at
the hilar region. These main bronchi fur-
ther subdivide into smaller airways. Sup-
port for the trachea and bronchi are derived
from cartilagenous rings or plates. As the
bronchial tree proceeds distally, the carti-
lage eventually disappears, and these air-
ways the bronchioles are supported by
smooth muscle. In humans, the transition
from bronchi to bronchioles occurs in air-
ways of~1-mm diameter.
Simplistically, the tracheobronchial tree
can be considered to be a system of tubes
connected at specific division points. In
most cases, division is by dichotomy,
whereby a single branch (the parent) gives
.% j ,,,
A B
BEAN\ ;7
Ok
(,/
Figure 3. Schematic diagram of tracheobronchial
tree branching patterns: (A) human lung; (B) mono-
podial system common in experimental animals.
OCR for page 242
242
Biological Disposition of Airborne Particles
rise to two branches (the daughters). To
describe this structure, the position of an
individual airway is usually assigned a code
number. There are two basic coding sys-
tems: the numbering of divisions up from
distal end branches or, alternatively, down
from the trachea. For example, in the of-
ten-used Weibel ordering system (Weibel
1963), each branching division is known as
a generation; the trachea is generation 0,
and each distal division increases by one
number.
In a dichotomous branching system, the
pattern can vary in terms of the degree of
symmetry (figure 3~. If both daughters
have the same diameter and length, and
branch from the parent at the same angle,
the mode of division is known as regular or
symmetrical. If the two daughters differ
from each other in one or more dimen-
sions, the mode of branching is termed
irregular or asymmetrical, the extreme case
of which is monopody. In a monopodial
branching system, the larger-diameter
daughter (major daughter) may not be eas-
ily distinguishable from the parent since the
change in diameter and direction from the
parent may be negligible.
A major difference in respiratory tract
anatomy between humans and most other
mammals commonly used in inhalation
studies is in the pattern of bronchial airway
branching. Figure 4 shows casts of the
upper bronchial tree in humans and in a
number of other species, and figure 5 pre-
sents a quantitative analysis that allows
characterization of branching patterns. In a
regular dichotomous branching system, the
ratio of daughter diameters is 1, whereas in
a perfect monopodial branching system,
the ratio of major daughter diameter to
Figure 4. Silicone rubber replica casts of the tra-
cheobronchial tree of different species. (A) human; (B)
baboon; (C) dog; (D) rhesus monkey; (E) rabbit; (F)
guinea pig; (G) rat; (H) hamster; (I) mouse. Both
photos are reproduced here at the same scale, given in
inches at the bottom. (Adapted with permission from
Patra 1986, and from Hemisphere Publishing Corpo-
ration. )
parent diameter is 1. The human bronchial
tree, at least for the first six generations,
exhibits the most symmetrical branching of
all of the species shown, whereas the dog's
bronchial tree is almost ideally monopodal.
The other species exhibit various degrees of
irregularity. Recent qualitative observa-
tions on the tracheobronchial trees of two
nonhuman primates-the rhesus monkey
and the baboon suggest a branching pat-
tern that is more irregular than that of
humans, but not to the extent of the exper-
imental animal species shown in figure 5
(Patra 1986~. But although there may be
striking interspecies differences in the upper
bronchial tree, the branching patterns in
most mammals tend to approach more
regular symmetry in distal conducting air-
ways.
An important difference between regu
OCR for page 243
Richard B. Schlesinger
A ~ Major/minor
· Major/parent
· Minor/parent
c', 3.0
o
Go 2.c
LU
LU
~ 1.0
-
c`' 3.0
o
~ 2.0
I; 1.0
6
n
90:
u,
at, 60
Al
~ 30
an
At:
90
Hamster
B · Major
~ Minor
Human
Hamster
~ 60 _ /
L9U ~
, 30 ~ l:
0
1 2 3 4 5 6
Herman
AIRWAY GENERATION
Human
_:
Rabbit
Dog
Rat
l l l l l l
1 2 3 4 5 6
Dog
- iV:
I'
Rat
1~ ~
1 2 3 4 5 6 1 2 3 4 5 6
AIRWAY GENERATION
Figure 5. Morphometric relationships for the bronchial trees of different species.
Each panel is derived from measurements of a single silicone rubber cast. (A) Ratios
of airway diameters as a function of branching generation; (B) ratios of branching
angles as a function of generation. (Adapted with permission from Schlesinger and
McFadden 1981 .)
lar and irregular dichotomous branching
modes concerns the number of airways
between the trachea and the terminal bron-
chioles. In a regular dichotomous branch-
ing system, the number of divisions and,
243
therefore, the path length, between the
trachea and the most distal conducting air-
ways is the same along any pathway. In
addition, all airways at any branch level
have exactly the same dimensions. In an
OCR for page 244
244
Biological Disposition of Airborne Particles
Table 1. Airway Path Lengths
Number of Airway Divisions (Generations)a
Mean Range of Means
Species (for entire lung) (for individual lobes) Reference
Human 17 Weibel (1963)
Human 15 1017 Schum et al. (1976)
Rat 15 11-19 Raabe et al. (1977)
Hamster 14 10-18 Raabe et al. (1977)
Dog (beagle) 18 15-21 Schum et al. (1976)
a From trachea through terminal bronchioles.
SOURCE: Adapted with permission from Schlesinger and McFadden 1981.
irregular dichotomous system, the number
of branch divisions from the trachea to each
distal bronchiole is not the same along
every pathway, and not all airways at a
given branch level have the same dimen-
sions. Table 1 presents the average number
of branching generations from the trachea
through the terminal bronchioles for vari-
ous species. Humans have the narrowest
range of branching generations, a reflection
of the greater symmetry of their lungs.
Because of the complexity of airway
branching structure, the geometry of the
tracheobronchial tree has been represented
by models; these are idealizations derived
from experimental data, usually from mea-
surements performed on castings prepared
from actual lungs. One of the most widely
used human structural models is the sym-
metrically dichotomous Weibel Model A
(Weibel 1963~. This is a 23-generation sys-
tem, with generations (}16 representing
conducting airways. Although the assump-
tion of regular dichotomy simplifies the
treatment of morphometric data, the actual
bronchial tree is asymmetrical, and a num-
ber of models of human airways that ac-
count for asymmetry have been described
(Horsfield and Cumming 1968; Olson et al.
1970; Horsfield et al. 1971; Parker et al.
1971~. In addition, Phalen and coworkers
(1978) and Yeh and Schum (1980) devel-
oped structural models of the human lung
which consist of"typical pathways," based
on mean dimensions, for each lobe within
the lung. Although the models were devel-
oped with symmetrical branching within
each lobe, they do account for the asym-
metry, and resultant variable path length,
between different lobes. Most of the tra
cheobronchial models have been based
upon measurements made in only one
lung. The very limited data base suggests
that there is significant variability in airway
dimensions between individuals (Nikiforov
and Schlesinger 1985), but the only model
that accounts for this is a statistical descrip-
tion of the tracheobronchial tree based upon
the Weibel geometry (Soon" et al. 1979~.
Structural models of the bronchial tree
have also been developed for experimental
animals. These include symmetrical dichot-
omous models for the rabbit (Kliment
1974), the rat (Kliment 1973), and the
guinea pig (Kliment et al. 1972) and typical
pathway models for the dog, the rat, and
the hamster (Yeh 1980~.
Pulmonary Region
The pulmonary region extends from the
respiratory bronchioles through the alveoli
and contains airways involved in gas ex-
change between the air and blood (figure
6a). In the human lung, the final generation
of airways that merely conduct air the
terminal bronchioles branch into several
generations of respiratory bronchioles,
which are characterized by the presence of
alveoli. The degree of alveolarization in-
creases toward the lung periphery; when
the airway becomes totally alveolarized, it
is termed an alveolar duct. This may
branch into other ducts, or into blind-
ended alveolar sacs. The adult human lung
contains ~ 375 million alveoli, the number
varying with body size, and the average
alveolar diameter is 25(}300 ,um. This re-
sults in a total alveolar surface area on the
order of 150-180 m2 (Weibel 1980~.
OCR for page 245
Richard B. Schlesinger
A
\' ''''":
245
B
~Type I alveolar cell -~~
Surface-active layer
(surfactant) (~7
\~1
Terminal bronchioles
Respiratory bronchioles
Alveoli
Alveolus pair space) <~: ~
Type It alveolal$y :(
~ Intern 4~\
Figure 6. (A) Diagram of the human airways in the pulmonary region; (B) diagram of the cellular makeup and
surrounding structures of the alveolus.
There are large interspecies differences in
the gross structure of the pulmonary region
(Gehr et al. 1981; Tyler 1983~. The number
of branching generations of respiratory
bronchioles and alveolar ducts varies, and
some species appear to have no respiratory
bronchioles. The degree of alveolarization
of the respiratory bronchioles also differs,
as does alveolar size and total alveolar sur-
face area, the latter increasing in direct
proportion to body mass.
The alveolar surface is lined with a con-
tinuous layer of two distinct cell types
(figure 6b). About 9~95 percent is covered
by type I cells, which are characterized by a
central nucleus surrounded by cytoplasm
stretching out in thin winglike processes to
form part of the alveolar wall. The remain-
ing surface is covered by cuboidal-shaped
type II cells, which are actually more numer-
ous than the type I cells. The relative num-
bers of these cell types, as well as the percent-
age of the alveolar surface covered by each,
are similar in humans and most other mam-
mals (Crapo et al. 1983; Gehr 1984~.
The alveoli are supported by a frame-
work of connective tissue termed the inter-
stitium. Capillary endothelial cells are
joined through the interstitium to alveolar
epithelial cells, to form the "alveolo-cap-
illary membrane." This membrane is about
2 ,um thick in humans, but appears to be
thinner in most experimental animals
(Meessen 1960; Crapo et al. 1983; Gehr
1984~. The interstitium and associated
structures form the part of the lung known
as the parenchyma. This region also in-
cludes the pulmonary lymphatic vessels.
The lungs contain two lymphatic net-
works. One set (superficial or pleural net-
work) is located within the connective tis-
sue layer of the visceral pleura, whereas the
other (deep or peribronchovascular net-
work) consists of interconnecting vessels
within the connective tissue surrounding
both the airways (to the level of the respi-
ratory bronchioles) and the pulmonary vas-
cular system. A plexus of vessels connects
the two sets. In both systems, the network
begins as blind-ended capillaries and fluid
flows toward the hilar region of the lung.
Many larger lymphatic vessels are inter-
spersed with nodes (encapsulated aggre-
gates of lymphoid tissue); the most prom-
inent of these are located along the trachea
and main bronchi, and at branching sites
between these airways. More diffuse lym-
phoid aggregates occur near the branching
regions of smaller bronchi and bronchioles.
Eventually, the entire pulmonary lym
OCR for page 246
246
Biological Disposition of Airborne Particles
phatic system drains into the general ve
. .
nous c~rcu anon.
Research Recommendations
Quantitative anatomy or morphome-
try of the respiratory tract is essential for
understanding the dosimetry of inhaled
particles. The structure of the various com-
ponents of the respiratory tract influences
the airflow and, thus, the resultant pattern
of particle deposition and the distribution
of sites of potential damage. Morphometry
must be assessed in humans as well as
experimental animals, the latter so as to
assist in the extrapolation of toxicologic
data to humans. Data are available for
normal adult humans and some other spe
. . . .
cles, rut cntlca gaps remain.
· Recommendation 1. Variability in
morphometry of the tracheobronchial and
pulmonary regions in normal humans as
well as experimental animals (including dif-
ferent strains) should be studied. Better
statistical descriptions of interindividual
variation at all levels of the respiratory tract
are needed to validate conclusions drawn
from current theoretical or empirical dep-
osition models, which are generally based
upon a single morphometric model.
· Recommendation 2. Lung morphom-
etry should be assessed in potentially "sus-
ceptible" subsegments of the human pop-
ulation: children, the elderly, and people
with respiratory disease. Although data are
becoming available on the morphometry
of children's lungs at different ages, these
are not yet sufficient to develop a compre-
hensive morphometric model describing
growth of the tracheobronchial tree. No
information exists at all for assessment of
morphometric changes due to aging or
disease.
Recommendation 3. Comparative
morphometry of human and animal upper
respiratory tracts should be assessed. Be-
cause of large interspecies differences in the
nasopharyngeal region, more quantitative
information is needed to allow better com-
parison with that in humans. For example,
rodents have essentially a straight pathway
from the nostrils to the trachea, a situation
radically different from that in humaps and
nonhuman primates. In humans, more de-
tailed information on dimensions of the
oral passages under different ventilatory
conditions is also needed to assess particle
removal by the upper respiratory tract.
~ Recommendation 4. Comparative
structure and physiology of human and
animal pulmonary lymphatic systems
should be studied. This knowledge is
needed for better comparisons of particle
clearance by this route in humans and ex-
perimental animals.
Ventilation
Ventilatory Parameters
Ventilation is the movement of air in and
out of the respiratory tract and is a factor in
determining the amount of an exposure
atmosphere that is actually inhaled. Venti-
latory parameters also affect the deposition
of particles once inhaled.
The amount of air inspired (or expired)
during a normal breath is the tidal volume
~ VT); it averages 450-600 ml in resting
healthy males and slightly less for females.
The fraction of the VT that does not reach
the alveolated airways about 150-200
ml in resting males and 120-160 ml in
females is termed the anatomic dead
space volume ( VDanac)
Not all of the inspired air reaching the
pulmonary region is equally effective in
oxygenating the blood, since air may enter
alveoli that are ventilated but poorly per-
fused. The portion of VT that does not
equilibrate with gas pressure in the pulmo-
nary capillary blood is the alveolar dead
space volume (ED, ). The total volume of
inhaled air that does not participate in gas
exchange, VDanac + VDa,v, is termed the total
or ph,vs~olog~cal dead space ~ ED ~
During expiration, air within the tra-
cheobronchial tree largely from the pre-
vious inspiration is expelled along with
some alveolar air which is a mixture from a
number of inspirations. Particles inhaled
OCR for page 247
Richard B. Schlesinger
247
into the pulmonary region can therefore be
exhaled over a number of breaths. Thus,
the time available to deposit inhaled parti-
cles in the conducting airways is fairly short
(a few seconds), whereas the residence time
in pulmonary air may be longer (about a
minute).
Total ventilation ~ VE), or minute volume
(MV), is defined as the volume of air
expired each minute and is equal to VT
times the breathing frequency by. The av-
erage f during normal quiet breathing in
adults is 11-17 breaths/min, and the rest-
~ng VE averages ~10 liters/mint The VE
consists of anatomic dead space ventilation
(VD~nat) and total alveolar ventilation (VA),
the latter being the amount of air entering
the pulmonary region each minute. The
effective portion of VA that participates in
gas exchange is equal tOf(VT- VDIO').
Ventilation is affected by numerous ex-
ogenous factors such as altitude, ambient
temperature, and smoking, as well as
endogenous factors such as body size. Two
of the major modifiers in any particular
individual are physical activity and age.
Physical Activity. Healthy humans at
rest normally breath through the nose, but
when respiratory demand increases above a
certain level there is a shift to oronasal
(combined nose and mouth) breathing.
Maximum inspiratory nasal airflow occurs
at a VE of 30 40 liters/min (Swift and
Proctor 1977; Niinimaa et al. 1980), at
which point ~40 60 percent of total air-
flow occurs through the nose. As respi-
ratory demand increases further, the pro-
portion of air entering the mouth increases,
but even at high demand the oral path-
way accounts for no more than 60 per-
cent of the inhaled air (Swift and Proctor
1987~.
With mounting respiratory demand, VT
and f increase, and the maximum volume
of air that can be inhaled per minute, or
the maximum voluntary ventilation, may
rise to more than 10 times the resting
ventilatory level. As breathing frequency
increases, expiratory time diminishes, but
inspiratory time remains relatively con-
stant. Furthermore, respiratory pauses, the
gaps between expiration and inspiration
which can occupy 25 percent of the breath-
ing cycle in resting individuals, become
shorter with increasing level of activity.
Growth and Aging. The volume of air in
the lungs and the ventilatory capacity de-
pend on body and lung size and, thus,
increase with growth from childhood. In
addition, the contribution of VT and f to
total ventilation also changes; VT increases
while f decreases until maturity is reached
(Mauderly 1979~.
Ventilatory function reaches a peak be-
tween the ages of 20 and 35 and then begins
to decline. Although various models have
been proposed to describe these changes,
they differ in their assumptions about the
rate of functional decline (Buist 1982~. Fur-
thermore, most of the reported data for
age-related changes in lung function are
derived from cross-sectional population
studies and may not reflect the true aging
process, especially since these studies may
be measuring the heartiest survivors. The
best way to avoid possible bias is to exam-
ine true aging patterns in longitudinal stud-
ies in which the same people are tested over
a number of years. Such analyses are scarce,
and those that do exist have measured only
a few parameters (Fowler 1985~.
Changes in lung function with aging are
the result of deterioration of the lung tissue
itself, a decrease in the strength of the
respiratory muscles, and an increase in the
stiffness of the thoracic cage. The time
course varies from individual to individual
and may be aggravated by chronic pollut-
ant exposure. Some ventilatory indices are
affected by age, whereas others are not.
Figure 7 shows a diagram of the various
divisions into which the volume of air in
the lungs may be separated. With age,
functional residual capacity (FRC) and re-
sidual volume (RV) increase, whereas vital
capacity (VC), inspiratory capacity (IC),
and expiratory reserve volume (ERV) de-
crease. Anatomic dead space ~ VD ~ in-
creases w~th age because of a decrease ~n
lung elasticity and a resultant increase in
lung volume at the same pressure differen-
tials.
Aging is associated with regional in-
equalities in the distribution of ventilation
OCR for page 248
248
Biological Disposition of Airborne Particles
~I
AN I
Figure 7. Diagram of subdivisions of lung volumes
as measured with a spirometer. A typical spirometer
tracing is shown on the right. TLC = total lung
capacity, VC = vital capacity, RV = residual volume,
FRC = functional residual capacity, IRV = inspira-
tory reserve volume, ERV = expiratory reserve vol-
ume, VT = tidal volume, and IC = inspiratory
capacity.
and a decrease in the uniformity of perfu-
sion (Holland et al. 1968~. Nonuniform
mixing of inspired air may result when
sections of the lungs communicate poorly
with others and, because of this, some alve-
olar regions may not be continuously venti-
lated during normal tidal breathing. Non-
uniform perfusion results in an increase
in VD} which, together with the increase
In VD, results In an ag~ng-related rise
in VD . Although this does not affect rest-
ing levels of BE, which show no major
change with aging, the ability of the lungs
to respond to increased activity is altered,
and maximum voluntary ventilation de-
clines by about 30 percent between ages 30
and 70.
Comparative Aspects of Ventilation
Since much of the toxicologic work with
inhaled particles involves experimental an-
imals, it is essential that their respiratory
mechanics be quantitated. Various animal
data exist (see, for example, Guyton 1947;
Spell 1969), but the methods used to obtain
them were not standardized, so there is
much variability, even for similarly sized
animals of the same species. "Repre-
sentative" ventilatory values for a particu-
lar species are therefore difficult to snecifv.
so generalized values based on scaling pro
cedures are used. Scaling is based on the
principle that respiratory mechanical prop-
erties may be related to body size or mass in
some consistent fashion, even though there
may be interspecies differences in the mech-
anisms that determine these properties.
This allows quantitative comparisons of
function between animals of different sizes,
within or between species. Scaling makes
use of dimensional or dimensionless pa-
rameters that either remain constant with
body size or can be related to body size by
some proportionality factor (Leith 1983~.
For example, VE is proportional to body
mass (M) raised to the 3/4 power, whereas
lung volumes, such as VT, tend to vary
with M to the first power. Similarly,
breathing frequency is proportional to
M-~/4, whereas the ratio of VD to VT is
Independent of body size.
Stahl (1967), after an extensive literature
search, developed predictive equations re-
lating respiratory variables in mammals to
body weight. These equations can be used
to scale values between animals of different
species as well as between individuals of
different body weights within one species,
as long as the animals are in comparable
physiological states. Scaling is not a precise
technique, however, and is only as good as
the values upon which the exponents and
proportionality factors are based. For ex-
ample, many of these values have been
obtained in anesthetized animals, in which
actual lung volumes and ventilation may be
less than normal (Sweeney et al. 1983~.
Airflow Patterns
Patterns of airflow in the conducting air-
ways are a major determinant of particle
deposition sites. Basic principles of airflow
are presented by Ultman (this volume).
Aspects of airflow critical to particle depo-
sition are addressed below.
Within straight tubes, two main types of
flow may occur: laminar and turbulent. In
laminar flow, gas molecules move in par-
allel as a smooth stream, with the highest
velocity occurring at the center of this
stream. The flow can be imagined as con-
centric layers of air sliding or telescoping
lengthwise along each other, with no trans
OCR for page 249
Richard B. Schlesinger
249
verse mixing between layers. In turbulent
flow, gas molecules are in an agitated state,
and there is erratic mixing of concentric
layers. Random secondary flows (eddies)
are superimposed on the average longitudi-
nal motion of flow velocity. Flow that is
partially laminar and partially turbulent is
termed transitional.
The type of flow that occurs depends
upon the strength of the inertial forces in
the moving air in relation to the frictional
and viscous forces acting on it. For exam-
ple, turbulence occurs when the former
exceed the latter. Airflow may thus be
described in terms of the ratio of inertial
forces to viscous and frictional forces,
which is expressed as the dimensionless
Reynolds number (Re). The Reynolds
number depends on the geometry of the
conduit through which the air passes and
the velocity of airflow, and flow character-
istics change as Re passes certain critical
values. Thus, for steady flow in a straight,
smooth-walled, circular tube, flow will be
laminar when Re is less than 2100, transi-
tional when Re is between 2100 and 4000,
and fully turbulent when it exceeds 4000
(Hinds 1982~.
Within the respiratory tract, bends, bi-
furcations, constrictions, surface roughness
and convolutions, and other features of
airway shape that add inertial forces may
lead to turbulent flow at a velocity lower
than that at which turbulence would be
initiated in a smooth, straight, obstacle-free
tube having the same cross-section. Thus,
flow instability and turbulence may occur
in the upper respiratory tract and upper
tracheobronchial tree at Reynolds numbers
well below 2100 (West and Hugh-Jones
1959; Dekker 1961; Sekihara et al. 1968;
Olson et al. 1973; Swift and Proctor 1977~.
Turbulence is also produced by the contin-
uous acceleration and deceleration of air
during the breathing cycle (Lakin and Fox
1974~. But although turbulent flow gener-
ated in the upper airways upon inspiration
may be propagated into a few generations
of downstream bronchi, air velocity de-
creases with depth into the lung, and in the
smaller conducting airways, flow is always
laminar.
Because of structural differences between
the tracheobronchial trees of humans and
most other mammals, one would expect
differences in resultant flow patterns. For
example, the trachea of most mammals is
much longer relative to its diameter than is
the human trachea. Thus, any turbulence
introduced by flow through the larynx is
much less likely to persist into the down-
stream bronchi of nonhuman mammals.
Unfortunately, there are few data on air-
flow patterns in the airways of most com-
monly used experimental animals (see, for
example, Snyder and Jaeger 1983~.
Research Recommendations
Ventilatory patterns and airflow dynamics
are critical determinants of dose to the
respiratory tract from inhaled particles.
The following important gaps In our
knowledge of ventilation in humans and in
experimental animals should be filled.
~ Recommendation 5. Patterns and dis-
tribution of airflow in the tracheobronchial
tree of healthy adult experimental animals
and humans should be determined. This
information is important for the develop-
ment of deposition models and for the
extrapolation of results of toxicologic stud-
ies to humans.
Recommendation 6. Effects of aging
on ventilation in humans and experimental
animals should be determined by use of
longitudinal studies of humans and experi-
mental animals involving numerous venti-
latory parameters. In animals, a cross-cor-
relation of age equivalencies between
species should be performed, so that pa-
rameters of toxicologic studies may be bet-
ter related to lung function in humans.
Recommendation 7. Ventilatory me-
chanics and airflow in children should be
analyzed. Although data are available for
some stages of growth, there is a gap
between birth and ~9 years of age.
~ Recommendation 8. Flow patterns in
the upper respiratory tracts of experimental
animals and humans should be studied.
Most experimental animals are obligate na
OCR for page 288
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Representative terms from entire chapter:
pulmonary region
