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Human Studies Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park 27711; and Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill, North Carolina 27599
ABSTRACT
INTRODUCTION
METHOD
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Kim, Chong S., S. C. Hu, P. DeWitt, and T. R. Gerrity.
Assessment of regional deposition of inhaled particles in human lungs by serial bolus delivery method. J. Appl.
Physiol. 81(5): 2203-2213, 1996.
Detailed
regional deposition of inhaled particles was investigated in young
adults (n = 11) by use of a
serial bolus aerosol delivery technique. A small bolus (45 ml
half-width) of monodisperse aerosols [1-, 3-, and
5-µm particle diameter
(Dp)] was
delivered sequentially to a specific volumetric depth of the lung
(100-500 ml in 50-ml increments), while the subject inhaled clean
air via a laser aerosol photometer (25-ml dead volume) with a constant
flow rate (
= 150, 250, and 500 ml/s) and
exhaled with the same without a pause to the
residual volume. Deposition efficiency (LDE) and deposition fraction in
10 local volumetric regions and total deposition fraction of the lung
were obtained. LDE increased monotonically with increasing lung depth
for all three Dp.
LDE was greater with smaller values in all lung
regions. Deposition was distributed fairly evenly throughout the lung
regions with a tendency for an enhancement in the distal lung regions for Dp = 1 µm.
Deposition distribution was highly uneven for
Dp = 3 and 5 µm, and the region of the peak deposition shifted toward the proximal
regions with increasing
Dp. Surface dose
was 1-5 times greater in the small airway regions and 2-17
times greater in the large airway regions than in the alveolar regions.
The results suggest that local or regional enhancement of deposition occurs in healthy subjects and that the local enhancement can be an
important factor in health risk assessment of inhaled particles.
aerosols; respiratory airways; inhalation
INTRODUCTION DEPOSITION DOSE AND SITE of inhaled particles within
the lung are key determinants in health risk assessment of particulate pollutants. Previous lung deposition studies have dealt largely with
total lung deposition measurement, and a body of data has been reported
for normal subjects with respect to particle size and the mode of
inhalation (4, 12, 15, 30). Those studies have shown that total lung
deposition varies widely, depending on particle size and breathing
pattern, namely, the larger the particle size for particles >0.5 µm
diameter or the smaller the particle size for particles <0.5 µm
diameter, the greater the lung deposition. However, because particle
deposition does not take place uniformly throughout the lung, there
exist local regions of the lung at which deposition dose exceeds the
average lung dose (20, 22). It is also anticipated that local
deposition varies to a much greater extent than total lung deposition,
which may result in incidents of extreme dose enhancement at local
regions. This may have significant implications in health risk
assessment, because a high local dose may cause tissue injuries or
initiate a disease process (27), whereas the average lung dose is still in the acceptable range. Information on detailed regional lung deposition is lacking. Traditionally, regional lung deposition has been
assessed by inhalation of aerosols labeled with a We have developed a novel method to measure regional lung deposition in
situ. By delivering a series of inert aerosol boluses to specific
target lung regions, deposition values were obtained for 10 different
regions with varying volumetric depth. The method is noninvasive, is
easy to use, and does not require radioactive labeling of aerosol. The
purpose of this study was to obtain the detailed regional deposition
data in humans that can be used to develop improved deposition models
and to reduce the uncertainty in health risk assessment of inhaled
particles.
METHOD Theoretical Analysis
If particle deposition efficiency in the
ith compartment is defined by
xi and
deposition efficiencies are the same on inspiration and expiration, the
deposition amount in each volumetric region as a fraction of inhaled
bolus can be calculated as illustrated in Fig. 1, where
xi is defined by
the amount of aerosol depositing in a volumetric compartment
i divided by the amount entering the compartment. In Fig. 1, expressions for inspiratory and expiratory deposition are shown on the top and bottom of each volumetric compartment, respectively. The fraction of aerosol that is available for exhalation at end inspiration is shown on the right-hand
side of each bolus inhalation diagram. Recovery of bolus aerosol from the ith compartment is then expressed
by
-emitting radionuclide and subsequent lung scanning with a gamma camera over a
24-h period (23, 28). This method is based on the premise that
particles deposited in the ciliated airways are cleared out of the lung
within 24 h so that the lung deposition can be obtained for two
regions, the tracheobronchial (ciliated) and alveolar (nonciliated)
regions, by time-series measurements of particle activity in the lung.
With head deposition data obtained from the initial scan, deposition
values in the three respiratory compartments are determined. However,
the method is laborious and cumbersome, involving radiolabeled aerosols
and a long study time. Furthermore, recent studies of Gehr et al. (8)
suggested that particle clearance from the ciliated airways may take
much longer than 24 h, complicating the premise of the clearance
method. The scintigraphic lung scan image by a gamma camera provides a
direct visual record of deposition distribution within the lung and a
means of quantitative analysis for regional deposition to a certain
extent (6, 7, 21). However, it is difficult to link the lung scan image
to specific anatomic sites of the lung, and the method remains largely
qualitative. Because of versatility, mathematical and computer models
have been frequently used to estimate regional lung deposition (16, 24,
33). However, these models are based on many assumptions of airway
geometry and flow conditions. Model predictions may not be warranted
until they have been validated by experimental data.
Here,
the aerosol fills the entire volume of
VT, and deposition takes place
throughout the lung regions where
VT communicates. DF in this case
is also defined as total lung deposition fraction (TDF). This
traditional aerosol inhalation mode may be divided into a series of
aerosol bolus inhalations: the volume
VT is divided into a number of
smaller compartments with equal volume, and a series of inhalations is
performed with the same VT in
which the aerosol fills only one volumetric compartment in each
inhalation, as shown in Fig. 1. TDF will
then be obtained by
(1)
where
n is the total number of volumetric
compartments and RCi (=
Nex/Nin)
is the recovery of bolus aerosol from the
ith compartment.
(2)
Fig. 1.
Calculation procedures for deposition efficiency
(xi) and
deposition fraction in local lung regions in a serial-compartment lung
model. Top: 3-compartment model
(i = 1-3). Aerosol recovery (RCi) and bolus deposition
fraction in each compartment (BDFij) are shown for each
sequential bolus inhalation (j = 1-3). Values of
xi were assumed
to be the same on inspiration and expiration. Expressions for
inspiratory and expiratory BDF are shown on
top and
bottom of each compartment,
respectively. Aerosol fractions remaining at end inspiration are shown
on right of each diagram.
Right: expressions for RC. Expressions
for RC and BDF are shown as a fraction of inhaled aerosol.
Nin and
Nex, number of
inhaled and exhaled particles.
[View Larger Version of this Image (29K GIF file)]
Values
of xi can then
be obtained from the ratio of RC values from two adjacent compartments
as
(3)
(4)
Once
xi values have
been obtained, the deposition fraction of a bolus aerosol in each
volumetric compartment (BDFij) can be obtained by combining the inspiratory and expiratory deposition in each compartment shown in Fig. 1. The subscript
j represents the number of sequential
bolus inhalations. The local deposition fraction (LDF) in the
ith compartment
(LDFi) and TDF of nonbolus
VT aerosol can then be obtained
by
(5)
and
(6)
where
n is the total number of volumetric
compartments of VT or the number
of sequential bolus inhalations. Therefore, total as well as regional
lung deposition can be determined by measuring the recovery of aerosols
from a series of bolus inhalations.
(7)
Experimental
Subjects. Healthy nonsmoking men (n = 11) were recruited locally (age 19-38 yr). The subjects had no history of smoking within 1 yr and no history of hay fever or asthma. All subjects underwent a screening procedure that included a complete medical history, physical examination, SMA-20 blood chemistry screen, and complete blood count with differential. For those who passed the initial screening, their basic lung functions were measured by spirometry and body plethysmography. All subjects were asked to read and sign a consent form approved by the Institutional Review Board of the University of North Carolina School of Medicine. Subject characteristics and lung function test results are given in Table 1.
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Inhalation procedure. After a few practice breaths, the subject inhaled filtered air via a laser aerosol photometer (25-ml dead space volume) from functional residual capacity (FRC) following a prescribed breathing pattern displayed on the computer screen. The subject then activated the data acquisition mode by pressing a hand-held switch during expiration, inhaled a prescribed volume, and exhaled to residual volume (RV) at a constant flow rate (Fig. 3). During the data acquisition mode, a small aerosol bolus (~45 ml half-width) was introduced into the inspiratory stream by opening an aerosol valve for a predetermined duration of time. The duration of valve opening was adjusted between 50 and 250 ms, depending on flow rate, to maintain a consistent bolus volume: the faster the flow rate, the shorter the duration. The peak concentration of bolus was maintained at 6-9 V; 1 V was equivalent to ~5,000 particles/cm3 for 1-µm-diameter particles. The bolus was delivered to a lung depth (Vp) of 100-500 ml in 50-ml increments. Typical bolus signals are shown in Fig. 4. This procedure was repeated with monodisperse aerosols of three different particle sizes [1, 3, and 5 µm diameter (Dp)], and for each Dp three different flow rates (
= 150, 250, and 500 ml/s) were used. In all tests the same was used
for inspiration and expiration, and the inspiratory volume was
maintained at 500 ml from FRC. For a given bolus delivery condition, at
least five repeated measurements were made. For the purpose of
comparison and validation, nonbolus aerosols were also used in a few
subjects. The subject inhaled nonbolus aerosols from a 20-liter bag
with a single-breath maneuver (inhalation from FRC and exhalation to RV) that was the same maneuver used for bolus aerosols, and TDF values
were obtained for several breaths. The same aerosols were then inhaled
with a continuous-breathing maneuver (inhalation from FRC and
exhalation to FRC) for 1 min, and TDF was obtained breath by breath.
,
flow; Dp,
particle diameter.
Data analysis. For each breath the total number of particles inhaled (Nin) and exhaled (Nex) was calculated by integrating the product of aerosol number concentration, C(t), and volumetric
(t), over inspiratory and expiratory period, respectively. In the calculation the
baseline concentration was set at 3% of the peak value of the exhaled
bolus and was subtracted from the acquired signals. Recovery of bolus
aerosol (RCj) was plotted as a
function of Vp, where
Vp was defined as the inhaled air
volume from the mean concentration of the bolus to the end of
inspiration. RC data were then grouped for 10 Vp values from 50 to 500 ml with an interval of 50 ml. RC values (means ± SD) for each
Vp were obtained by averaging all
RC data falling within Vp ± 25 ml. Volumetric lung regions
(Vj,
j = 1-10) were defined by the
regions confined between two adjacent
Vp values. For example,
V1 is the region between
Vp = 0 and 50 ml,
V2 is the region between
Vp = 50 and 100 ml, and so on. The
mean RC vs. Vp data were used to calculate values of local deposition efficiency
(x or LDE) and LDF for each volumetric
region by Eqs. 5 and 6, respectively.
Surface dose in each volumetric region was calculated by dividing LDF
by surface area of the region. Weibel's symmetrical lung model (32)
adjusted for the lung volume of 3,500 ml (mean FRC of all subjects plus
one-half of VT) was used to
calculate the surface area. In Weibel's model the lung volume was
divided into 50-ml volumetric regions comparable to experimental
values, and the surface area of each region was calculated on the basis of the dimensions of individual airway branches.
For the purpose of comparison, deposition fractions in the conventional
three-compartment lung regions were determined. Each of the upper
airways (UA), tracheobronchial airways (TB), and alveolar regions (AL)
was defined by the volume region of 0-50, 50-150, and
150-500 ml, respectively. Deposition values in each of the regions
were obtained by summing LDF values of
Vi composing the corresponding
regions.
TDF was obtained by summing LDFs of all
Vi compartments. TDF was also
obtained by direct integration of RC vs.
Vp curves, inasmuch as
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(8) |
RESULTS
Recovery vs. Penetration Depth With Respect to Particle Size and Flow
Typical recovery data from one subject and the summary of all subject data are shown in Figs. 5 and 6, respectively. RC decreased with increasing Vp for each Dp and, but the decrease of RC was greater with
particles of larger size. For example, for = 250 ml/s RC decreased from 1.0 to 0.78 for
Dp = 1.0 µm, from 0.99 to 0.05 for
Dp = 3.0 µm,
and from 0.94 to 0 for
Dp = 5.0 µm as
Vp increased from 50 to 500 ml.
Figures 5 and 6 also show that RC values were smaller with lower
values (longer respiratory time) for a given
Dp. For example,
RC (mean ± SD) was 0.93 ± 0.03, 0.96 ± 0.01, and 0.97 ± 0.01 for Dp = 1.0 µm; 0.54 ± 0.06, 0.68 ± 0.08, and 0.79 ± 0.04 for
Dp = 3 µm; and
0.25 ± 0.06, 0.35 ± 0.05, and 0.40 ± 0.08 for
Dp = 5 µm for
= 150, 250, and 500 ml/min, respectively, at
Vp = 200 ml. The
effect was consistent for other values of
Vp, as shown in Fig. 6, although
the effect was minimal for
Dp = 5 µm,
particularly with high values at small
Vp regions. RC values were very
repeatable and consistent in a given subject, as shown in Fig. 5, and
the intersubject variability was small, as indicated by small error
bars in Fig. 6.
), 250 (
), and 500 (
)
ml/s. For clarity, error bars (±SD) are shown only for 250 ml/s flow rate. Magnitude of error for other flow rates is similar to
that for 250 ml/s.
Local Deposition Efficiency
Figure 7 shows LDE values for each 50-ml volumetric region as a function of Vp for different Dp and. LDE increased with an increase of
Vp for all experimental
conditions. For each condition, LDE was greater with larger
Dp or lower
in all volumetric regions of the lung. For example,
for = 250 ml/s, LDE increased from 0.0005 to 0.022 for Dp = 1.0 µm, from 0.0045 to 0.29 for
Dp = 3.0 µm,
and from 0.03 to 0.38 for
Dp = 5.0 µm as
Vp increased from 50 to 500 ml.
With a decrease of from 250 to 150 ml/s, LDE
increased by 65-184, 9-76, and 6-68% for
Dp = 1, 3, and 5 µm, respectively, depending on
Vp. The increase was more
pronounced with
Dp = 1 µm than
Dp = 3 or 5 µm
in all regions of the lung, but the difference was particularly
noticeable for Vp > 250 ml. A
smaller but consistent increase was found in most of the lung regions
with Dp = 3 and 5 µm. When was increased from 250 to 500 ml/s, LDE
decreased, averaging across lung regions, by 54 ± 17, 45 ± 4, and 17 ± 15% for
Dp = 1, 3, and 5 µm, respectively. The percent decrease was consistent in the deep
regions of the lung (Vp > 250 ml) for each Dp,
but considerable variation was found in the small
Vp regions. Overall, LDE varied
more with small-size particles and with low values.
= 150 (), 250 (), and 500 () ml/s. Error bars (±SE) are shown for = 250 ml/s.
Local Deposition Fraction
Deposition values in each 50-ml volumetric region are shown in Fig. 8. LDF varied widely with Vp, ranging from ~0 to 0.028 for Dp = 1 µm, from 0.004 to 0.11 for Dp = 3 µm, and from 0.04 to 0.16 for Dp = 5 µm for values used. LDF increased with increasing Vp initially, reached a peak
value, and then decreased with a further increase of
Vp. The peak value was found at
Vp = 300-350 ml for
Dp = 1 µm, but
the peak region was shifted proximally to Vp = 200-250 ml for
Dp = 3 µm and
to Vp = 100-150 ml for
Dp = 5 µm (Fig.
9). LDF increased with a decrease in
in all regions of
Vp, but particularly in the
regions of large Vp for
Dp = 1 µm.
However, for Dp = 3 and 5 µm the effect of was minimal in the
regions of large Vp. The
effect was small in all regions of
Vp for
Dp = 5 µm. In
the shallow regions of the lung
(Vp < 250 ml) LDF increased with
an increase of Dp
regardless of . However, in the deeper regions
(Vp > 250 ml) the effect of
Dp was small and LDF was comparable between
Dp = 3 and 5 µm.
= 150 (), 250 (), and 500 () ml/s.
Error bars (±SE) are shown for = 250 ml/s.
Surface Dose in Local Lung Regions (LDF/Regional Surface Area)
The results of surface dose in local lung regions are summarized in Table 2 and illustrated in Fig. 9 for = 250 ml/s. Because of difficulties in estimating
the surface area of the upper airways
(Vp < 50 ml), the surface dose
was obtained for Vp > 50 ml.
Surface dose was much greater in the shallow airway region
(Vp < 200 ml) than in the deeper
alveolar region (Vp > 200 ml).
The difference was more pronounced with larger particles. Surface dose
was greater in the most proximal region of the lung (Vp = 50-100 ml) than at
Vp = 150-200 and 100-150
ml, regardless of
Dp
and . Surface dose was 2-17 times greater in the
shallow airway region of Vp = 50-100 ml and 1-5 times greater in the region of
Vp = 150-200 ml than in the
region of Vp = 250-350 ml,
which represents mainly the alveolar region, for all three
Dp and
values. The value was greater with larger
Dp but did not
vary much with .
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Upper Airway, Tracheobronchial, and Alveolar Deposition
Three-compartment regional lung deposition results are summarized in Fig. 10. With a standard breathing pattern of VT = 500 ml and frequency of 15 breaths/min ( = 250 ml/s), UA
deposition (oropharyngeal + laryngeal) was 0.7 ± 0.7 and 4.1 ± 3% for Dp = 3 and 5 µm, respectively. UA deposition was negligible for
Dp = 1 µm. TB
deposition was 1.7 ± 0.8, 10.7 ± 3.9, and 26.3 ± 4.3% and
AV deposition was 7.4 ± 1.5, 39.7 ± 1.7, and 39.0 ± 4.0%
for Dp = 1, 3, and 5 µm, respectively. Deposition was greater with = 150 ml/s and smaller with
= 500 ml/s than with = 250 ml/s in all three regions for
Dp = 1 and 3 µm. With
Dp = 5 µm, TB deposition increased with a decrease in
as with
Dp = 1 and 3 µm, but the effect of was not consistent in UA and
AV deposition.
Total Lung Deposition
The bolus data were analyzed by two methods to determine the TDF: 1) summation of LDF values in all local regions, as in Eq. 7, and 2) direct integration of RC vs. Vp curves, as in Eq. 8. TDF values were also obtained with nonbolus aerosols with the same single-breath maneuvers used for bolus aerosols. The results are summarized in Table 3. Also included in Table 3 are TDF values obtained with controlled continuous breathing. Mean TDF values obtained with the LDF method ranged from 4 to 18, 37 to 59, and 66 to 75% for Dp = 1, 3, and 5 µm, respectively, at = 150-500 ml/s. TDF was
greater with smaller values for three Dp values. These
values were consistent with those obtained with the integration method
for all Dp and
values tested, although values with the LDF method
tended to be greater than those with the integration method
(P = NS). Because the integration
method utilized raw data with no artificial divisions of lung volume, the good agreement between the two methods indicates that the calculation schemes used for determining LDE and LDF of local lung
regions are accurate. Table 3 also shows that TDF values obtained with
nonbolus aerosols are comparable to those of the LDF and integration
methods, indicating that a series of bolus inhalation is indeed
equivalent to inhalation of a single whole-breath aerosol.
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TDF values obtained with the single-breath LDE or integration method were comparable to those obtained with controlled continuous breathing for Dp = 3 and 5 µm but much smaller than with continuous breathing for Dp = 1 µm. The results indicate that deposition of particles with Dp = 3 and 5 µm was completed at a level of FRC during exhalation. Therefore, an extended exhalation from FRC to RV could not recover any more particles. However, because of a low deposition efficiency, particles with Dp = 1 µm could remain airborne in the airway space and can be exhaled with reserve air below FRC, resulting in a decrease in deposition with single-breath inhalation.
Comparison With Other Studies
TDF and three-compartment regional deposition results were compared with results from previous studies. Because the majority of the data reported previously was obtained with widely varying breathing patterns (12, 30), two studies were selected for comparison; these studies employed the same breathing pattern used in the present study: one experimental (15) and one theoretical (33). The results of Dp = 1 µm were excluded because of the discrepancy between single-breath and steady-state breathing, as shown above. The results are shown in Fig. 11. The present TDF values are in good agreement with those of two previous studies. However, the regional deposition values were variable among the studies. In the present study, AL deposition was greater but UA deposition was smaller than in the previous studies. The TB deposition values were greater than in previous experiments but smaller than the theoretical predictions.
DISCUSSION
We used a serial bolus aerosol delivery method to measure regional
deposition of inhaled particles in 10 volumetric regions of the lungs
of young adults during normal breathing. This was the first systematic
investigation for determining regional deposition in humans in situ
with inert aerosols. The results demonstrate that
1) deposition distribution within
the lung is highly uneven along the volumetric depth of the lung and
that the site of peak deposition shifts from the distal to the proximal
region of the lung with an increase of
Dp and
2) surface dose was many times greater in the conducting airways than in the alveolar region regardless of Dp
and . The bolus aerosol method has been used previously for a variety of lung studies: to investigate convective mixing of airway flow (14, 26), to detect small airway obstruction (1,
25), or to measure effective airway dimensions at local regions of the
lung (2, 11). However, the method has not been fully implemented for
measuring regional lung deposition during normal breathing. Heyder et
al. (13) first proposed the idea of using bolus aerosols to assess
regional deposition in the lung. Using a mathematical scheme that was
somewhat cumbersome, they calculated deposition efficiencies of
1-µm-diameter particles in 10 volumetric regions of the lung. The
bolus data used for the calculation were obtained in two subjects who
inhaled the bolus aerosol with a fixed breathing pattern of
VT = 1,000 ml and
= 250 ml/s. In the present study we developed a
simple unambiguous mathematical scheme to calculate regional deposition efficiencies; this scheme involved only two consecutive bolus recovery
values. The method was thoroughly examined with aerosols with
different-size particles
(Dp = 1-5
µm) and at different (150-500 ml/s) in
a large number of subjects.
Theoretical studies suggest that particles in the size range of
1-5 µm diameter deposit in the lung mainly by inertial impaction and sedimentation (9, 20). Theory predicts that inertial impaction
plays a significant role in the large airways where flow velocity is
high, whereas sedimentation plays a dominant role in the small
peripheral airways. Because the diameter of the airways decreases with
increasing depth into the lung, thus reducing the sedimentation
distance, deposition becomes more efficient in the distal regions of
the lung. Our results showing an increase of LDE with respect to
Vp are consistent with
theoretical expectations. Also LDE is greater with lower
in the
Dp range tested
in all regions of the lung. However, LDE was comparable between low and high with particles of larger
Dp, particularly
in the shallow lung regions. This indicates that particles in this size
range deposit in the lung mainly by sedimentation and that inertial impaction plays a significant role only in the regions of small Vp, both of which are consistent
with theoretical expectations.
Our results show that deposition sites vary with
Dp, shifting the
peak deposition site from the peripheral to proximal regions with an
increase of Dp
from 1 to 5 µm. This finding was expected, because small-size
particles, i.e.,
Dp = 1 µm, had
little chance of deposition in the proximal regions because of very low
LDE and subsequently could penetrate into deep regions of the lung where deposition efficiencies were high. However, because of enhanced losses in the proximal regions, large-size particles could not reach
deep lung regions in large quantity. As a result, low values of LDF
could be expected in the peripheral regions, despite high values of
LDE. Deposition values in the peripheral regions remained fairly
constant, despite the wide variation of ,
particularly for large-size particles. This result was due to the fact
that LDF was determined by the product of the amount of particles
available and the value of LDE in the peripheral regions. With low
, LDE was high but the number of particles available
was small, resulting in consistent values of LDF. This finding suggests
that, for Dp > 1 µm, regional deposition in the lung is dictated primarily by
particle size. , however, will likely become an
important factor for regional deposition for smaller-size particles
(i.e., Dp 
1 µm). Because the ratio of surface area to volume of the respiratory
airways is approximately proportional to the inverse of airway
diameter, surface area is smaller in the proximal than in the
peripheral volume regions. This will result in an increase in local
surface dose in the proximal volume regions. In the present study the
surface dose estimated by using airway dimensions of Weibel's lung
model was found to be highest in the 50- to 100-ml (large airway)
regions followed by the 150- to 200-ml (small airway) regions,
regardless of Dp
and . Previously, Hofmann et al. (16) showed in their
theoretical calculation that surface dose was highest in the large
airway regions and decreased monotonically with increasing lung depth
beyond the large airway regions. Our results are consistent with this
prediction, in that the large airway regions received the greatest
surface dose. However, the present results further indicate that the
small airway regions are also a major site of pronounced surface dose.
We showed previously that, within the bronchial airways, deposition
occurs preferentially near the bifurcation ridges, resulting in a
manyfold increase in surface dose near the bifurcation compared with
straight airway segments (22). The implication of these results is that
although the anatomic structure of the bronchial airways (as a
first-line host defense) might have been evolved to sustain the insult
of inhaled pollutants, the high magnitude of local surface dose could have potential to induce significant health hazard. The finding has
relevance to the clinical observations that many lung diseases often
originate from the small airways (17).
The present study employed a single-breath inhalation method that involved maximal expiration to RV. Because particles remaining in the airway space at the end of VT expiration would be washed out with continued maximal exhalation, the single-breath inhalation will result in lower deposition than expected with steady-state breathing, particularly for small-size particles with small deposition efficiency. Our results showing lower TDF values with single-breath than with steady-state breathing for Dp = 1 µm are consistent with the above reasoning. However, our results with Dp = 3 and 5 µm show comparable TDF values between single-breath and steady-state inhalation, indicating that deposition of these particles is essentially complete within each breath of steady-state breathing. Therefore, for the purpose of comparison with controlled continuous breathing, the present regional deposition data are valid only for these large-size particles.
Although our TDF values are comparable to those of previous studies (15, 32), the regional deposition values are in variance. One of the reasons for the inconsistency might be differences in the actual anatomic regions of the lung involved in the deposition measurements. In the present study the lung regions were determined on the basis of the volume of inhaled air: 50 ml for the UA and 50-150 ml for the TB regions. Previously, the volume of the oropharyngeal cavity has been reported variably, ranging from 35 to 50 ml (5, 11, 30). Hart et al. (10) measured the dead space volume (UA + TB) in a large number of adult subjects and found that the dead space volume was correlated linearly with height. For a man with a height of 180 cm, which was the average height of subjects in the current study, the dead space volume was ~160 ml. Therefore, our values used for the UA and TB regions are consistent with the above reported values. However, the actual delivery of aerosol boluses to these target regions may not be fully warranted for reasons discussed below.
The results of previous regional lung deposition studies were obtained by external scanning of the head (UA deposition) combined with mucociliary clearance measurements (TB deposition). Because of large variability of head deposition (30) and many factors other than just particle deposition affecting measurements of mucociliary clearance rate (31), one may not be certain whether mucociliary clearance measurement truly represents the TB deposition. These factors could have contributed to some of the differences in regional deposition among the present and previous experimental studies. Also the difference between the present results and those of previous theoretical studies is rather small, suggesting that experimental methods may indeed be the major factor for the observed difference.
The accuracy of the present results is limited by how the inhaled bolus flows in and out of intended lung regions. To ensure that inhaled boluses actually fill the intended anatomic sites in an orderly serial fashion, the following conditions may need to be satisfied: 1) an even distribution of inhaled air throughout the lung, 2) an equal time for filling and emptying of different lung regions, and 3) the reversibility of inspired air, i.e., the first-in last-out principle. Although these conditions may not be warranted in patients with lung disease, many ventilation distribution or imaging studies indicate that ventilation patterns of normal subjects are even and reversible (3, 19). However, there have been some suggestions that bolus aerosols may reach the lung regions deeper than anticipated via preferential flow passages (29). This implies that inhaled air may not be distributed evenly in the normal lungs, and the distribution patterns may vary during inspiration. If this really occurs, the actual anatomic regions may not be identified by serial compartmentalization of inhaled air. However, such an abnormal bolus distribution pattern is unlikely to be consistent among subjects or within a subject who inhales aerosols with different flow rates. This would result in wide inter- and intrasubject variation of bolus recovery or deposition data expressed by lung depth, particularly those in regions of shallow depth. However, our deposition results were very consistent with respect to lung depth for each subject and also among subjects, as shown in Figs. 5 and 6, respectively. In every set of measurements in all subjects, RC values decreased monotonically with an increase of Vp, indicating that a series of bolus aerosols was indeed delivered to regions of successively greater depth in an orderly fashion.
Previous studies suggested that bolus aerosols may penetrate the lung deeper than anticipated because of axial streaming (5, 29). This can take place because flow streams move faster in the central core than near the wall surface of a tube. However, because inhaled particles remain in the central core of the airways during axial streaming, there would be little chance of deposition of those particles in the overpenetrated regions if particles are exhaled immediately without breath holding. Furthermore, in our preliminary studies using a straight-tube model, we found that recovery of bolus aerosols delivered to the exit end of the tube was consistent with predictions based on the mean Vp. Because a particle filter was attached at the exit end of the tube, axial streaming could have resulted in greater particle collection in the filter and subsequently smaller recovery than expected. The results suggest that axial streaming of aerosol may not take place with cyclic flows to the same extent as predicted by the theory of fully developed laminar flow. Therefore, inhaled aerosol boluses would be expected to remain in the intended lung regions, and the present results may be a reasonable representation of regional deposition in normal human lungs. There are no known methods that can measure directly particle deposition sites in the human lung. Invasive animal studies may provide some clues of deposition sites but are unlikely to produce quantitative regional dosimetric data that can be extrapolated to human lungs. The present results may be useful, within their limitation, for assessing regional variation of lung deposition in humans.
In conclusion, we measured regional lung deposition of inhaled particles by means of the serial bolus aerosol delivery method. Deposition in lung regions as small as 50 ml was measured in healthy normal humans. We found remarkable variation in regional deposition dose showing the peak region dose, exceeding many times the average lung dose. These observations may have significant implications in health risk assessment of inhaled pollutant particles and serve as a basis for improved risk assessment models.
ACKNOWLEDGEMENTS
Disclaimer: Although the research described in this article has been supported by the US Environmental Protection Agency, it has not been subjected to Agency review and therefore does not necessarily reflect the views of the Agency, and no official endorsement should be inferred. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.
FOOTNOTES
Address for reprint requests: C. S. Kim, US Environmental Protection Agency, National Health and Environmental Effects Research Laboratory Human Studies Div., MD-58B, Research Triangle Park, NC 27711.
Received 3 November 1995; accepted in final form 18 June 1996.
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