Ann. occup. Hyg., Vol. 41, Supplement 1, pp. 503-508, 1997
© 1997 British Occupational Hygiene Society
Published by Elsevier Science Ltd. All rights reserved
Printed in Great Britain
0003-4878/97 $17.00 + 0.00
Inhaled Particles VIII
PII: S0003^t878(96)00171-8
DEPOSITION AND CLEARANCE OF FINE PARTICLES
IN THE HUMAN RESPIRATORY TRACT
C. Roth, W. G. Kreyling, G. Scheuch, B. Busch and W. Stahlhofen
National Research Centre for Environment and Health, Institute for Inhalation Biology,
Ingolstadter Landstr. 1, 85764 Neuherberg, Germany
INTRODUCTION
Total deposition of respirable particles in the human respiratory tract is well
determined by experimental data and model calculations whereas regional deposition is still under discussion, particularly in the size range from 0.1-1.0 urn particle
diameter. Experimental data on regional deposition of radiolabelled aerosol
particles can be derived from gamma camera images on the basis of the particle
clearance kinetics during the first few days after inhalation, since the limited
resolution of the planar image allows no separation between the peripheral and the
bronchial airways.
When particles are deposited in the human respiratory tract, two distinct phases
of clearance from the thorax are usually observed: a fast cleared fraction during the
first hours after inhalation followed by much slower clearance. It is generally
assumed that the fast phase, completed within about 24 h, represents predominantly mucociliary clearance of particles deposited in the tracheobronchial tree,
whereas the slow phase represents predominantly clearance from the alveolar
region (Lippmann, 1977; Stahlhofen etal., 1980). Nevertheless, during recent years
the assumption that there also exists a slow cleared component from the tracheobronchial region has been confirmed by a large number of experiments (Scheuch,
1991; Stahlhofen et al, 1994).
Recently, a new radio-aerosol "Technegas" (TcG; Tetley Manufacturing Ltd,
Lucas Heights, Australia) was developed for lung ventilation scans in nuclear
medicine. "Technegas" (TcG) is a condensation type aerosol consisting of hydrophobic inert graphite particles. For the production of TcG 20-100 \i\ of Na" m TcO 4
in saline is put into the cavity of a graphite crucible which is dried at 50-70°C.
Thereafter the cavity of the crucible is heated to 2500°C in an atmosphere of pure
argon for 5 s such that carbon as well as the salt and 99mTc evaporates, followed by
condensation during cooling. This procedure is similar to the production of the
C-60 molecules, named buckminster-fullerenes (Kroto et al., 1985). Therefore, it
was assumed that TcG consists of ultrafine spherical particles which are formed via
homogenous condensation from fullerene vapor at temperatures > 500°C. More
recent investigations have shown that these ultrafine particles agglomerate rapidly
to fine particles (Lemb et al., 1993). The latter is in agreement with the fact that the
distribution of deposited TcG applied to the lungs of normal subjects was found in
the entire ventilated lungs, that is, it is transported in the lungs like a gas.
503
504
C. Roth et al.
The aim of this study was the application of the new radio-aerosol TcG in order
to determine its lung deposition and clearance kinetics from the lungs. Since the
median diameter of this aerosol was reported to be 0.1 um or even less it would
provide regional deposition data in a size range lacking information (Roth et al.,
1994). A unique feature of this aerosol is its high specific 99mTc radioactivity of
> 100 MBq/L aerosol reported to be tightly bound to the particle matrix (Burch et
al., 1986) allowing gamma camera analysis after single breath inhalation.
MATERIALS AND METHODS
The particle size distribution of the TcG-aerosol was determined with a
Differential Mobility Analyser (DMA; Hauke GmbH, A-4810 Gmunden, Austria). To balance the production efficiency of the generator using 50 ul Na" m TcO 4
saline, the whole aerosol of 6 L volume produced during one run was collected on a
filter. The 99mTc activity of the initial 50 ^il sample was compared to that of the filter
and the crucible. To investigate the salt content of the aerosol particles, the filter
was washed with distilled water and the Na+-ion concentration was determined
using a Na+-ion sensitive electrode (PHM 95, Radiometer, Copenhagen) to
calculate the sodium chloride mass.
To test the hygroscopic behaviour of the TcG-particles a Tandem Differential
Mobility Analyser was used, consisting of two DMAs and controlled humidifiers
for the sheath air and aerosol flow of the second DMA. With the first DMA, a
monodisperse fraction of the polydisperse TcG-aerosol was separated and subsequently moistened to a relative humidity RH > 90%. The altered size distribution
due to the growth of the particles related to their hygroscopic content was
determined by the second DMA (Busch et al., 1994).
Six healthy non-smokers (age 46 ± 9 years, 1 female, 5 males) with normal lung
function volunteered for the measurements of lung deposition and retention with
an inhalation apparatus described before (Scheuch et al., 1989). After several
breaths of clean air the subject started the inhalation of the aerosol from the
"Technegas" generator for one single breath. The subject inhaled with a constant
flow rate of 250 cm 3 s -1 and with a tidal volume of 1000 cm3. Three subjects
performed a breath-hold of 10 s at the end of inhalation, the other three exhaled
immediately after inhalation without any breath-hold.
A system of four shielded and collimated Nal(Tl) detectors (lung counter) has
been used for the determination of the 99mTc activity of the particles present in the
head, chest and stomach (Stahlhofen et al., 1980). The activity was measured
immediately after inhalation and at subsequent intervals up to 30 h. Total
deposition was calculated from the lung deposit, the exhaled " m Tc activity
collected on an exhalation filter and the 99mTc activity of a 250 cm3 sample drawn
from the TcG-generator onto a filter. To determine particle dissolution including
TcG-particle disintegration and leakage of 99mTc from TcG, urine was measured
after quantitative sampling for 24 h using the lung counter.
RESULTS
The size distribution of the TcG-aerosol is plotted in Fig. 1. Characterizing this
Fine particles in the human respiratory tract
505
600
-•-TcG particles
500
iAAA
-*-grown fraction (0.13 /L/m)
-•-grown fraction (0.25 fjrr\)
^graphite
J
400>
O
c
0
or
300
0
200
100-
JL
/^r^T^r^-^
^^^^^A
200
400
600
j
800
i • i
i
|
'
1000
'
'
1200
particle diameter d, nm
Fig. 1. Size distribution of TcG and the graphite aerosol (without Na" m TcO 4 saline). Additionally, two
distributions of 0.13 and 0.25 urn monodisperse fractions grown in the humid atmosphere (count mode
diameters of the fractions selected by the first DMA are indicated by arrows).
polydisperse distribution by a log-normal distribution yielded a count median
diameter (CMD) of 0.13 [Am, a mass median diameter (MMD) of 0.55 ^m and a
geometric standard deviation (GSD) of og = 2.0. For comparison the size
distribution of the graphite aerosol without Na"mTcO4-saline in Fig. 1 presents the
same distribution for particles < 200 nm, but does not show the shoulder at 300 nm.
The size distribution showed the same count median diameter but a much smaller
geometric standard deviation of og = 1.4. Figure 1 gives also the size distributions
of initially monodisperse TcG-particle fractions after hygroscopic growth in humid
atmosphere (RH > 90%). Both fractions of 0.13 and 0.25 urn particles selected by
the first DMA showed considerable particle growth of about a factor of 2 in
diameter.
Table 1 gives the balance of radioactivity and the partition of NaCl with respect
to the entire aerosol of 6 1. volume produced during one run. Sodium chloride is
Table 1. Balance of radioactivity and NaCl during TcG-aerosol production
50 ul/sample of Na TcO4-saline
TcG-particles on filter
Crucible
Wall losses
Relative "mTc-activity, %
Mass of sodium chloride, ug
100
30
12
58
425
214
211
C. Roth et al.
506
g
c
a>
*->
CD
^D)
C
CD
0.8 H
2
with breath-hold
0.7 A
without breath-hold
i
T
10
15
i
20
25
30
time after inhalation, h
Fig. 2. Intrapulmonary retention of TcG-particles obtained from all six volunteers, data of each subject
are fitted with a function of 2 exponential terms (note: the vertical axis is intersected).
completely evaporated and condensed partially on the aerosol particles. It can be
washed off in distilled water. The number concentration of the TcG-aerosol of 6 1.
volume was measured to be 2 x 107 cm" 3 and, therefore, the calculated mass of
carbon of the TcG particles produced during one run is about the same as the mass
of NaCl given in Table 1.
Monitoring the aerosol concentration photometrically in front of the mouth of
the volunteer showed an at least two-fold increase of the photometer signal of the
exhaled air compared to that of the inhaled air consistent with the hygroscopic
growth of the exhaled TcG aerosol due to its NaCl-content as described above.
Total deposition DE with breath-hold (DE = 47 ± 4%) is about twice the value
of that without breath-hold (DE = 27 ± 4%). The new ICRP model (ICRP 66,
1994) provides DE = 29.3% for a log-normal size distribution with a MMD of 0.55
urn, a GSD of og = 2.0, at the same breathing conditions.
Figure 2 shows lung retention curves obtained from all six subjects to demonstrate the rather small intersubject variability and the fast v. slow phase of
clearance. All data are corrected for physical decay of 99mTc.
Fitting the data obtained from all six volunteers with 2 exponential terms, yielded
a mean lung retention (± SEM) of:
{(0.086 ± 0.024) exp((1.03 ± 0.79)t)} + {(0.91 ± 0.019) exp((0.003 ± 0.0011)t)}
Rates are given in h corresponding to half-lives of 1.6 h and 228 h (9 d).
The dissolution of " m Tc activity from the particles as determined from urine
samples proved to be relatively constant at 9 ± 2.1% of the inhaled 99mTc activity
Fine particles in the human respiratory tract
0
24-h-retention ^ ^
long-term retention m
507
dissolution
03
.*:
05
c
o
v»—>
<D
•—•
<D
E
I
c
JO
c
o
't—•
<D
O
T
C\J
Fig. 3. 24 h retention, long-term retention and dissolution for six subjects.
for all six subjects. Dissolution occurred predominantly during the first 6 h after
inhalation.
Figure 3 shows the retained fraction 24 h after inhalation and the dissolved
fraction for each subject. Estimation of the fast cleared particle fraction as the
difference between particle deposition v. particle dissolution and 24 h retention
yielded 5.5 ± 3.5%.
DISCUSSION
TcG-particles are not ultrafine but agglomerates with a polydisperse size
distribution of a count median diameter of the distribution of 0.13 (j,m and a mass
median diameter of 0.55 um. The TcG-particles contain NaCl. As a result, they
grow in the humid atmosphere of the respiratory tract at least an order of
magnitude in mass (more than a factor of 2 in diameter). This was indicated by
aerosol photometry of the in- and exhaled aerosol and shown by the Tandem-DMA
measurements. Due to this dynamic behaviour, the distribution of the deposited
TcG-particles in the lungs is difficult to predict. According to the ICRP model
(ICRP 66, 1994) total deposition does not vary very much for mass median
diameters between 0.5-1 um. Therefore, the measured total deposition agrees well
with the predicted values for both the dry mass median particle diameter and the
estimated diameter after particle growth. Particles in the diameter range between
0.2 and 1 um have very low intrinsic motion and are therefore considered as a
nondiffusive gas. Based on these measurements and taking the growth of TcG
508
C. Roth et al.
particles into account, it is likely that particles will be deposited in all regions
ventilated during the single breath maneuver. There is modest TcG particle
dissolution in the lungs which either might reflect leakage of the radio-tracer or
particle disintegration and dissolution.
In addition to the 24 h retention and TcG dissolution, the long-term retention is
given in Fig. 3 for each subject. The latter is the long-term retention fraction of a
function of 2 exponential terms fitting the data of each subject. Note that the
long-term retention value is not necessarily compatible with the long-term fraction
and the corresponding A-value reported earlier (Stahlhofen et al., 1980) since the
latter would require lung retention measurements of more than 3 days. Interestingly, the long-term retentions of those subjects performing a breath-hold were
significantly smaller than those of the subjects performing no breath-hold. Accordingly, fast particle clearance was detected after breath-hold while virtually no fast
particle transport was observed for the other subjects, see Fig. 3. During
breath-hold, deposition of these fine TcG particles increased throughout the lungs
as shown by the deposition data given above. This is true particularly in small
airways contributing to the fast particle clearance. Therefore, the fast cleared
fraction of 6.0 ± 2.6% is more distinct in those subjects which performed a
breath-hold when compared to the others.
The ICRP model (ICRP 66, 1994) predicts that the fast cleared fraction
represents only half of the bronchiolar deposition, the other half is long-term
retained. Based on our data of 5.5% of fast-cleared particles, 11% deposited
99m
TcG particles in the bronchiolar region, a bronchiolar dose as high as 330
uSv/MBq is obtained. With the recommended loading activity of 200-400 MBq and
an inhaled fraction of 10% of the produced aerosol, a dose of 7-14 mSv is delivered
to the airways (Bailey, 1996). This high dose needs careful consideration.
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