-------
the sky and the layer is above the absorption region. The process responsible for this is single
scattering which changes the direction of the incident radiation such that there is a shorter path
through the absorbing layer and more is transmitted to the ground. However, when the sun is
high in the sky or the scattering layer is below the absorbers this effect does not occur.
For tropospheric aerosols, the net effect is a reduction in global irradiance at all
wavelengths similar to the total energy shown in Figure 8-19. Frederick et al. (1989) have
calculated the expected change in Robertson-Berger meter readings from 1969 to 1986 for
34.5°N based on changes in column ozone as reported by Watson et al. (1988). They compared
ratios with and without an aerosol layer of optical depth 0.1 independent of wavelength in the
lowest 2 km for 1986 only. For clear atmospheres, the ratio changed from 1.02 without the
aerosol to 0.92 with the aerosol indicating that the effect on UV-B transmission of the depletion
in column ozone from 1969 to 1986 could be compensated by a concomitant increase in
particulate matter. Measurements made at Barcelona, Spain, by Lorente et al. (1994) show that
the UV-B at the surface is reduced by 37% during the most polluted days and UV-A is reduced
by 30% compared to the clearest days. By reflecting some UV back to space, tropospheric
aerosols actually decrease the irradiance of this flux to the surface.
8.8.3.1 Modeling Aerosol Direct Solar Radiative Forcing
Some basic aspects of scattering and absorption by small particles typically present in
aerosol layers govern the sign and magnitude of the direct radiative forcing by aerosols. These
properties are discussed in Section 8.2 of this chapter. The reflectance of an aerosol layer is
chiefly determined by the optical depth, single scattering albedo, co^, and some measure of the
scattering phase function. The single scattering albedo, the ratio of the light-scattering
coefficient and the light-extinction coefficient, is a measure of the absorptance of the aerosol
layer. Related quantities are the specific extinction and specific scattering coefficients, tyext and
tyscap which are defined as the coefficients per unit mass in units of m2g"1. The phase function
determines the probability that incident radiation will scatter into a particular direction given by
the scattering angle measured from the forward direction of the incident radiation.
8-97
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100
90
80
t? 70
_3
2 60
o>
u
50
E
= 40
30
20
10
Direct
6:00 8:00 10:00 12:00 2:00 4:00 6:00
AM NOON PM
Local Time
Figure 8-19. Surface measurements of direct, diffuse, and global solar radiation expressed
as illuminance, at Albany, NY, on August 23,1992, and August 26,1993.
Source: Harrison and Michalsky (1994).
At visible wavelengths, the optical depth of tropospheric aerosols ranges from less than
0.05 in remote, pristine environments to about 1.0 near the source of copious emissions (Weller
and Leiterer, 1988). The optical depth decreases quite rapidly with increasing wavelength if the
layer is composed of fine particles as can be seen from Equation 8-37. Aerosol layers, therefore,
tend to be fairly transparent at thermal wavelengths and their radiative forcing is confined to
solar wavelengths. Because there are strong water vapor absorption bands in the solar near-
infrared (see Figure 8-20), the dominant effect of tropospheric aerosols is in the visible
wavelengths. Harshvardhan (1993) has shown that, to the first order, the change in the albedo
with the addition of a thin aerosol layer over a surface of reflectance, Rx, is
8-98
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m = 1.53-0.0011
m = 1.53-0.011
m = 2.0-0.641
0.01 0.1 1.0 10
Radius (|jm)
Figure 8-20. Single scattering albedo of monodispersed spherical aerosols of varying
radius and three different refractive indices at a wavelength of 0.63 /j,m.
Source: Harshvardhan (1993).
AR « R a(l - R J2 - 2A R
a b a b
(8-38)
where Ra and Aa are the reflectance and absorptance, respectively, of the aerosol layer. The
perturbation, AR, will be positive when
(1 - con)/co R < (1 - RJ2/2Re
(8-39)
where P is the average backscatter fraction and can be computed from the scattering phase
function. A positive value for the change in albedo implies a negative solar radiative forcing
because the planetary albedo increases and less solar energy is absorbed by the earth-atmosphere
system.
8-99
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From Equation 8-39, it is obvious that the sign of the forcing will be determined to a large
extent by the single scattering albedo. At visible wavelengths, most constituents of tropospheric
aerosols, with the exception of elemental carbon, are nonabsorbing and co^ =1.0 (Bohren and
Huffman, 1983) so that the change in albedo will be positive. Aerosols with absorbing
components can be modeled as equivalent scatterers of refractive index, m = n - ik, with the
imaginary index being a measure of particle absorption. Figure 8-20, shows the computed
values of single scattering albedo at a wavelength of 0.63 //m for single particles of varying
radius. The three separate curves are for aerosols composed of carbon (m = 2.0 - 0.64/') and two
models of sulfate aerosols containing absorptive components. Given the properties of an aerosol
layer, the change in albedo can be computed from Equation 8-38. To calculate the radiative
forcing, one must also include the effects of other atmospheric constituents such as molecular
scattering, stratospheric O3, water vapor absorption, and, most importantly, cloud cover.
8.8.3.2 Global Annual Mean Radiative Forcing
Charlson et al. (1991) calculated the global mean radiative forcing due to anthropogenic
aerosols by making the following assumptions. They assumed that the perturbation would be
exceedingly small over cloudy areas because cloud optical depths are one to two orders of
magnitude greater than aerosol optical depths (Rossow and Schiffer, 1991). For nonabsorbing
aerosols, they found that the change in planetary albedo could be expressed as
c) (1 - Rs2)
(8-40)
where T is the transmittance of the atmosphere above the aerosol layer and Nc is the global mean
cloud fraction. The planetary mean radiative forcing is then
AFR = ARpS0/4
(8-41)
8-100
-------
where SJ4 is the annual global mean insolation of the earth-atmosphere system (Hartmann,
1994) with S0 being the solar constant, which equals to 1,370 W m"2. For the generally accepted
values of T = 0.71, Nc = 0.6, Rx = 0.15 and P = 0.3, Charlson et al. (1991)
AFR = 30.OT
(8-42)
obtained such that for u, the optical depth at visible wavelengths ranging from 0.05 to 0.10, the
direct solar radiative forcing is 1.5 to 3.0 W m"2, a value comparable to the long-wave radiative
forcing of all the anthropogenic greenhouse gases (Section 8.8.2).
The above estimate was refined by Charlson et al. (1992) in which the anthropogenic
sulfate aerosol burden was actually related to the source strength of anthropogenic SO2, the
fractional yield of emitted SO2 that reacts to produce sulfate aerosol and the sulfate lifetime in
the atmosphere. The scattering properties of the sulfate aerosol were also modeled in terms of a
relative humidity factor that accounts for the increase in particle size associated with
deliquescent or hygroscopic accretion of water with increasing RH. The relationship between
optical depth and the areal mean column burden of anthropogenic sulfate aerosol, Bsulfate, is
T = Xsulfate f(RH) Bsdfate (8-43)
where Xsulfate is the molar scattering cross section of sulfate at a reference low RH (30%) and
f(RH) is the relative humidity factor. The sulfate burden, is related to SO2 emissions and sulfate
lifetime. For an emission rate of 90 x 1012 g of sulfur per year, a yield fraction of 0.4, a sulfate
lifetime of 0.02 years (7 days) and the molar scattering cross section of sulfate of 500 n^mol"1
(corresponding to specific extinction coefficient of 5 m^"1), Charlson et al. (1992) estimated that
AF^ = 1.0 W m"2, with an uncertainty factor of 2, which perhaps should be more considering that
the uncertainty in the specific extinction coefficient alone is higher (Hegg et al., 1993, 1994;
Anderson et al., 1994).
The above is an estimate for the forcing due to industrial emissions. Another
anthropogenic source of aerosols is biomass burning. Penner et al. (1992) have estimated
8-101
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that the radiative forcing due to this activity could be as much as 0.9 W m"2, which is comparable
to the sulfate forcing. One difference is that the smoke produced is somewhat absorbing and the
atmosphere would experience a positive forcing of 0.5 W m"2. Estimates of the global forcing
due to biomass burning are even more uncertain than those for sulfate because of the sparsity of
data on the relevant radiative properties of biomass aerosols.
8.8.4 Climate Response
8.8.4.1 Early Studies
Global Background Aerosols
The role of aerosols in modifying the Earth's climate through solar radiative forcing has
been a topic of discussion for many decades. Modeling studies assumed a climatological
background distribution of aerosols such as that of Toon and Pollack (1976). Two simple types
of climate models were used to calculate the effects of aerosols on climate: (1) the radiative-
convective model, which resolves radiative perturbations in an atmospheric column, and (2) the
energy balance model, which allows for latitudinal dependence, but parameterizes all processes
in terms of the surface temperature. A typical study was that of Charlock and Sellers (1980)
who used an enhanced one-dimensional radiative-convective model that included the effects of
meridional heat transport and heat storage. The model was run with and without a prescribed
aerosol layer of visible optical depth equal to 0.125 for conditions representative of 40° and 50°
N latitude. The annual mean surface temperature with aerosols was 1.6 °C lower than that for
the aerosol-free run.
Coakley et al. (1983) were the first to use an energy balance model to compute the
latitudinally dependent radiative forcing for the Toon and Pollack (1976) aerosol distribution,
including the effects of absorbing components. Even for moderately absorbing aerosols (m= 1.5
- 0.01/'), the solar radiative forcing was negative, except in the 80° to 90° N latitude belt, which
has a very high surface albedo. Here the criterion given by Equation 8-31 is not satisfied and the
change in albedo is negative (i.e., the solar radiative forcing is positive). The model results
showed global mean surface temperature decreases ranging from 3.3 °C for nonabsorbing
aerosols to 2.0 °C for the absorbing aerosols. The maximum temperature drop was at polar
latitudes even for the absorbing layer because advective processes responded to the aerosol-
8-102
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induced cooling at low- and middle-latitudes. Other two-dimensional model studies have
confirmed this basic picture (Jung and Bach, 1987).
Regional and Seasonal Effects
Apart from global studies, there have been several programs devoted to ascertaining the
effects of aerosols on regional and seasonal scales. An example is the radiative effect of aerosols
in the Arctic (Rosen et al., 1981). A field experiment, the Arctic Gas and Aerosol Sampling
Program, was conducted in 1983 (Schnell, 1984). It was determined that aerosols had a
substantial absorbing component. The study by MacCracken et al. (1986) used both one- and
two-dimensional climate models to evaluate the climatic effects. They found that the initial
forcing of the surface-atmosphere system is positive for surface albedos greater than 0.17, and
the equilibrium response of the one-dimensional radiative-convective model showed surface
temperature increases of 8 °C. Infrared emission from the warmer atmosphere was found to be
an important forcing agent of the surface. The two-dimensional model was run through the
seasonal cycle and had an interactive cryosphere. Peak warming occurred in May, a month later
than the peak radiative forcing, as a result of earlier snow melt.
Massive Aerosol Loads
In the 1980s, there were several studies related to what became known as the "nuclear
winter" phenomenon (Turco et al., 1983) (i.e., the climatic consequences of widespread nuclear
war). Modeling efforts ranged from radiative-convective models (Cess et al., 1985) to three-
dimensional general circulation models (GCM) (Thompson et al., 1987; Ghan et al., 1988), and
mesoscale models (Giorgi and Visconti, 1989) with interactive smoke generation and removal
processes and fairly detailed smoke optics. A review of modeling efforts has been made by
Schneider and Thompson (1988) and Turco et al. (1990). The latter study summarized the best
estimates of possible reduction in surface temperature from the smoke lofted into the atmosphere
during the initial acute phase.
General Circulation Model studies (Thompson et al., 1987; Ghan et al., 1988) indicate that
for a July smoke injection, the average land temperatures over the latitude zone from 30° to 70°
N, over a 5-day period, would decrease by 5 °C for smoke of optical depth equal to 0.3, but
could decrease by 22 °C for large loadings of optical depth equal to
8-103
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3.0. However, the temperature in the interior of land masses could drop by as much as 30 °C.
The temperature perturbations for smoke injections in other seasons are smaller. At lower
latitudes, the cooling is moderated by the delay in smoke transport (assuming initial injection in
high northern latitudes), and the more humid climate. Model studies also indicate a dramatic
decrease in rainfall over land and a failure of the Asian monsoon (Ghan et al., 1988).
8.8.4.2 Recent Regional Studies
There have been more recent studies of possible climatic effects resulting from severe
aerosol loading on regional scales. The Arctic haze problem has been investigated extensively.
Blanchet (1989, 1991), using a GCM, studied the effects of increasing aerosol loads north of
60° N. Although the solar heating rate in the troposphere increased quite dramatically, the
temperature did not rise substantially. The positive forcing of 0.1 to 0.3 Kday"1 resulted in a
decrease in the meridional heat flux. Quite importantly, the simulated cloud cover in the
experiment was altered sufficiently to produce changes in net radiative fluxes at the top were
locally an order of magnitude greater than the initial forcing. This implies that it may be very
difficult to identify climate change effects due to aerosols alone. Another effect of aerosols at
high latitudes that has the potential for affecting climate is the change in surface albedo due to
deposition of soot. This was studied by Vogelmann et al. (1988) with respect to the nuclear
winter problem. They found that the cooling due to smoke aerosol could be moderated
somewhat by the "dirty" snow at very high latitudes.
Several studies have examined the effect of smoke from forest fires on climate. Since
these are natural phenomena, it is important to understand their effects in order to place
anthropogenic effects in context. Evidence of substantial climatic effects is present only when
the smoke loading is substantial. For example, Robock (1988) examined the situation in
northern California where a subsidence inversion trapped smoke in mountain valleys for several
days in September 1987. One station recorded an anomaly in the maximum temperature of
-20 °C. Veltischev et al. (1988) analyzed data covering the period of major historical fires in
Siberia, Europe, and Canada. They estimated that the optical depth of
8-104
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smoke following fires in Siberia in 1915 was about 3.0 and surface temperature dropped by
5 °C.
Other studies have also shown a relationship between smoke and surface temperature.
Robock (1991) studied the smoke from Canadian fires in July 1982. He compared forecasted
temperatures with observations and found that regions of negative anomaly were well correlated
with the smoke layer. Westphal and Toon (1991) used a mesoscale model with interactive
smoke physics and optics to simulate the smoke plume and its meteorological effects. They
calculated the albedo of the smoke-covered area to be 35%, and the resulting surface cooling
was 5 °C.
Perhaps the most extensive recent investigation of the possible climatic effects of heavy
aerosol burdens was the study of the Kuwait oil fires in 1991. Several modeling studies were
undertaken. Browning et al. (1991) simulated the smoke plume with a long-range dispersion
model and concluded that the smoke would remain in the troposphere and not be lofted into the
stratosphere where the residence time would be much longer. They estimated a maximum
temperature drop of 10 °C beneath the plume, within about 200 km (i.e., only a regional, not
global climatic effect). Bakan et al. (1991) used a GCM with an interactive tracer model to
simulate the plume dispersion and climatic effects. The maximum temperature drop was
estimated to be about 4 °C near the source. The local and regional nature of the effect was
confirmed during a field experiment undertaken in May/June, 1991. The smoke from the oil
fires had insignificant global effects because (1) particle emissions were less than expected, (2)
the smoke was not as black as expected, (3) the smoke was not carried high in the atmosphere,
and (4) the smoke had a short atmospheric residence time (Hobbs and Radke, 1992).
The study of severe events such as those described above is useful for investigating model
response since such strong forcings usually provide unambiguous climate response signals. The
simulated climate response to the more modest radiative forcing due to the distribution of natural
and usual anthropogenic sulfate or smoke aerosols is well within the internal model variability.
However, an estimate of the magnitude of possible effects can be obtained by model simulations
that integrate the chemistry, optics, and meteorology of anthropogenic aerosols.
8-105
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8.8.4.3 Integrated Global Studies
Ideally, one should study the problem in an integrated manner, in which the emissions of
sulfate precursors are tracked globally and the radiative forcing of the resulting aerosols
computed locally in space and time. A further step would be to let the radiative response impact
climate interactively. This latter step could be carried out by a GCM coupled to an oceanic
model. Recent studies have accomplished various elements in this scenario.
Global three-dimensional models of the tropospheric sulfur cycle consider emission,
transport, chemistry, and removal processes for both natural and anthropogenic sources. The
primary natural source is dimethylsulfide (DMS), which is released by oceanic phytoplankton
(Nguyen et al., 1983; Shaw, 1983; Charlson et al., 1987). The DMS reacts in air to form sulfate
aerosols. Anthropogenic emissions are over land, especially in the heavily industrialized areas
of the Northern Hemisphere. Examples of such sulfur cycle models are the Lagrangian model of
Walton et al. (1988) and Erickson et al. (1991), known as the GRANTOUR model, and the
Eulerian transport model of Langner and Rodhe (1991) and Langner et al. (1992), known as the
MOGUNTIA model. Both models use prescribed mean winds, typically obtained from GCM
simulations, to provide monthly mean concentrations of sulfate aerosols.
With such detailed input, it is possible to construct global maps of the radiative forcing due
to sulfate and compare the magnitude with that due to greenhouse gases. Kiehl and Briegleb
(1993) carried out such a study using the monthly mean sulfate abundances from the
MOGUNTIA model. For meteorological parameters, they used 1989 monthly mean temperature
and moisture fields data from the European Center for Medium Range Weather Forecasting.
Vertical distributions of clouds were taken from a GCM simulation using the National Center for
Atmospheric Research Community Climate Model (CCM2) since such detailed observations are
lacking. However, attempts were made to adjust the total cloud cover to correspond to
observations.
The radiative forcing was calculated by Kiehl and Briegleb using an 18-band 5-Eddington
model in the shortwave and a 100 cm"1 resolution band model in the longwave, which includes
the contributions due to trace gases such as CH4, NO2, and chlorofluorocarbons. The optical
properties of sulfate aerosol were calculated spectrally using the refractive indices for 75%
sulfuric acid (H2SO4) and 25% water (H2O) and an
8-106
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assumed log-normal size distribution that has a geometric mean diameter by volume of 0.42 //m.
The specific extinction coefficient of the dry particles was found to be a very strong function of
wavelength, decreasing from 10 m2g"1 at 0.3 //m to less than 2.0 n^g"1 at 1.0 //m. This is
significant in interpreting the computed forcing when comparisons are made with earlier studies
that used a constant value for the specific extinction coefficient.
The value of the specific extinction coefficient depends on the size distribution of the
aerosols but that also affects the phase function such that changes in the coarse particle or fine
particle mode do not greatly affect the total radiative forcing (Kiehl and Briegleb, 1993). This is
because the extinction cross section has a sharp maximum for particles that are of the same
dimension as the wavelength and falls off rapidly for smaller and larger particles (Covert et al.,
1980).
The direct radiative forcing is calculated by adding the sulfate burden to the model and
computing the change in absorbed solar radiation. Figures 8-2la and 8-2Ib, from Kiehl and
Briegleb (1993) show the annual mean direct solar radiative forcing resulting from
anthropogenic sulfate aerosols (global mean = -0.28 W m"2) and anthropogenic plus natural
sulfate (global mean = -0.54 W m"2). The patterns are similar to those obtained earlier by
Charlson et al. (1991), but the magnitude is roughly half. Most of the difference is due to the
assumption of a constant value of 5.0 m2g"1 for the specific extinction coefficient in the earlier
study, but there was also a difference in the phase function used. Therefore, assumptions
regarding radiative properties were able to account for all the differences. Points to note in the
figure are the local concentrations of anthropogenic forcing and particularly the hemispheric
asymmetry in the forcing, even when natural sulfate is included. Although the southern
hemisphere is largely ocean, the direct forcing due to natural sulfate is substantial only in the
clear oceanic areas since, in the presence of clouds, the additional sulfate effect is minimal.
To place the role of anthropogenic sulfate in perspective, Kiehl and Briegleb (1993)
compared the direct radiative forcing with that of increasing greenhouse gases from preindustrial
times to the present. The greenhouse gas forcing is calculated by computing the spatial
distribution of the change in the net longwave flux at the tropopause for the trace gas increases
from the preindustrial period to the present. The annual averaged results for
8-107
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,-2\
Annual Mean Forcing (W rrr)
anthropogenic sulfate aerosols
-2.5 -2.0 -1.5 -1.0 -0.5 0
Figure 8-21a. Annual mean direct radiative forcing (W m"2) resulting from anthropogenic
sulfate aerosols.
Source: Kiehl and Briegleb (1993).
Annual Mean Forcing (W m"2)
anthropogenic plus natural sulfate aerosols
-3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0
Figure 8-21b. Annual mean direct radiative forcing (W m"2) resulting from anthropogenic
and natural sulfate aerosols.
Source: Kiehl and Bnegleb (1993).
8-108
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greenhouse gases alone and in combination with anthropogenic sulfate are shown in
Figure 8-22a and 8-22b, respectively. The greenhouse gas forcing is, of course, positive and is
the greatest in the clear regions over the land and oceanic deserts. The global annual mean is 2.1
W m"2. When the negative forcing of aerosols is added, the global annual mean direct radiative
forcing due to anthropogenic activities is 1.8 W m"2. However, locally, there are regions where
the anthropogenic sulfate forcing cancels the greenhouse forcing.
The forcing is simply an initial perturbation. Because the sulfate forcing is in the
shortwave and felt primarily at the surface (for nonabsorbing aerosols), a coupled atmospheric-
oceanic climate model is required to determine the effect on climate. Taylor and Penner (1994)
have used the GRANTOUR model to provide the sulfate input to a GCM (CCM1), which was
coupled to a 50 m mixed-layer ocean model with sea ice and a specified meridional oceanic heat
flux.
To assess the anticipated patterns of climate response to anthropogenic emissions of both
SO2 and CO2, Taylor and Penner performed four 20-simulated-year integrations in which the
atmospheric CO2 concentration was fixed at either the preindustrial level (275 ppm) or the
present day concentration (345 ppm). Anthropogenic sulfur emissions, corresponding to 1980,
were either included or excluded. Table 8-7 summarizes their annual average results. The
global average anthropogenic sulfate forcing was found to be -0.95 W m"2; more than three
times larger than calculated by Kiehl and Briegleb (1993). The differences in the annual
anthropogenic sulfate forcing value in the two studies is due partially to the sulfate chemistry in
the model used by Taylor and Penner, (1994). For example, there is a stronger seasonal cycle
with enhanced northern hemisphere concentrations in summer. The remainder may be
contributed to the use of a constant specific scattering coefficient (8.5 n^g"1 at 0.55 //m) instead
of the RH-dependent model used by Kiehl and Briegleb (1993). As noted earlier, the value of
the specific scattering coefficient chosen could be a gross overestimate and, therefore the values
of the sulfate forcing shown in Table 8-7 are probably much too high.
Some noteworthy features of Table 8-7 are that the combined CO2 and sulfate forcing is
not linearly additive and there is a pronounced asymmetry in the climate response in the two
hemispheres. What is clear is that the anthropogenic sulfate is expected to reduce somewhat the
anticipated warming resulting from the increased emission of greenhouse gases, especially
8-109
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,-2\
Annual Mean Forcing (W m )
greenhouse
0.50 1.0 1.5 2.0 2.5 3.0
Figure 8-22a. Annual averaged greenhouse gas radiative forcing (W m"2) from increases
in CO2, CH4, N2O, CFC-11, and CFC-12 from preindustrial time to the
present.
Source: Kiehl and Briegleb (1993).
Annual Mean Forcing (W m"2)
greenhouse plus anthropogenic sulfate
•<:-:--:-::--:::f::-:--:-:::-^
'
m
-0.50 0 0.50 1.0 1.5 2.0 2.5 3.0
Figure 8-22b. Annual averaged greenhouse gas forcing plus anthropogenic sulfate aerosol
forcing (W m"2).
Source: Kiehl and Bnegleb (1993).
8-110
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TABLE 8-7. RADIATIVE FORCING AND CLIMATE STATISTICS
oo
Case
Northern Hemisphere
Preindustrial
Present-day CO2
Present-day sulfate
Combined CO2 and sulfate
Observed climate statistics
Southern Hemisphere
Preindustrial
Present-day CO2
Present-day sulfate
Combined CO2 and sulfate
Observed climate statistics
Global average
Preindustrial
Present-day CO2
Present-day sulfate
Combined CO2 and sulfate
Observed climate statistics
AF
(W m'2)
1.26
-1.60
-0.34
1.25
-0.30
0.95
1.26
-0.95
0.31
(°C)
12.5
14.5
11.3
13.0
14.9
12.5
14.8
11.7
13.6
13.5
12.5
14.6
11.5
13.3
14.2
(Ac)
1.9
-1.2
0.5
2.3
-0.8
1.1
2.1
-1.0
0.8
P
(mm d'1)
3.40
3.48
3.36
3.43
2.6
3.54
3.61
3.48
3.56
2.7
3.47
3.55
3.42
3.49
2.7
AP
(mm d'1)
0.09
-0.04
0.03
0.08
-0.06
0.02
0.08
-0.05
0.02
C
56.6
55.0
56.9
55.8
58.9
62.4
61.1
63.1
62.1
65.6
59.5
58.0
60.0
58.9
62.2
AC
-1.7
0.3
-0.9
-1.3
0.7
-0.3
-1.5
0.5
-0.6
SI
4.87
4.13
5.54
4.85
4.4
6.64
4.39
7.24
5.40
4.5
5.76
4.26
6.39
5.13
4.5
ASI
-0.74
0.67
-0.02
-2.26
0.59
-1.24
-1.50
0.63
-0.63
AF = radiative forcing; Ts = surface temperature; P = precipitation; C = cloud cover; SI = sea ice coverage.
Source: Taylor and Penner (1994).
-------
in the Northern Hemisphere. On a regional scale, Taylor and Penner (1994) found that the
strongest response was in the polar regions associated with an increase in sea ice. Note that the
change in sea ice coverage, (AST), in the northern hemisphere is essentially zero as the sulfate
completely cancels the CO2 effect. Also, the greatest cooling is found over broad regions of the
Northern Hemisphere continents where all the sulfur emission is occurring. However, the
maximum cooling is not over Europe where the maximum radiative forcing occurs, but further
north, and associated with changes in sea ice.
Comparative Lifetimes of the Forcing
One extremely important aspect in comparing the effects of CO2 and sulfur
emissions is the disparate lifetimes of the forcing mechanisms. The residence times of trace
gases that result in a positive longwave forcing of the climate system is from decades to a
century or more (Houghton et al., 1990). On the other hand, the cycling time for sulfate in the
troposphere is only about a week (Langner and Rodhe, 1991), which is dependent on the
frequency of precipitation removal (Charlson et al., 1992). Therefore, any changes in industrial
emission patterns will be reflected immediately in the sulfate forcing, but the concentration of
CO2 and the accompanying forcing will continue to rise for more than a century even if
emissions were kept constant at present levels. See Figure 8-23.
One could infer from the above discussion that sulfate emissions are providing
some amelioration of greenhouse warming, and that a curtailment of such emissions might result
in enhanced global warming. However, given the uncertainties in present estimates of the
effects of aerosols, especially the fact that many feedbacks are not fully included, it would be
premature to base any decisions on these current discussions of the possible effects of aerosols
on climate.
8.8.5 Aerosol Effects on Clouds and Precipitation
8.8.5.1 Indirect Solar Radiative Forcing
Cloud Microphysical Properties
A substantial portion of the solar energy reflected back to space by the earth
system is due to clouds. The albedo (i.e., reflectivity) of clouds, in turn, depends to a large
extent on the optical thickness, which is the column integrated light-extinction coefficient (see
8-112
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o
10
3
.Q
E
o
o
in
a
o
Growth phase
Levelling-off
phase
Reduction phase
Time
Figure 8-23.
Time
Schematic illustration of the difference between response times of climate forcing due to CO2
(heating) and sulfate (cooling) during different patterns of global fossil fuel consumption.
Source: Charlson et al. (1991)
Section 8.8.3). The light-extinction coefficient is related to the size distribution and number
concentration of cloud droplets. Because these cloud droplets nucleate on aerosols, it is to be
expected that changes in aerosol loading could affect cloud albedo, particularly that marine
stratiform clouds. Because of their effect on the Earth's radiative energy budget, marine status
and stratocumulus cloud systems are likely to influence climate and climate change. Their high
albedo compared with ocean background provide a large negative shortwave forcing which is
not compensated in thermal wavelengths because of their low altitude (Randall et al., 1984).
Recent studies by Ramanathan et al. (1995) and Cess et al. (1995) indicate that more solar
radiation is being absorbed by clouds in cloudy atmospheres than originally believed. This
finding has, however, not been confirmed.
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Stephens (1994) gave the volume light-extinction coefficient of a cloud of spherical
polydispersed drops ranging in size as:
Jext
= n n(r)Qext (r)r2dr (8-44)
where n(r) represents the size distribution and is the number concentration per unit volume per
unit radius increment and Qext is the extinction efficiency factor (see Section 8.3.1) which
approaches the value of 2.0 for drops that are large relative to the wavelength. At visible
wavelengths, this limit for the extinction efficiency factor is satisfied by cloud drops that are
typically 10 //m in radius. Therefore,
a
ext
n(r)r2dr. (8-45)
The mass concentration of water in clouds, called the liquid water content, M (in kg"3), is
proportional to the total volume of liquid water in a unit volume of air. This may be written as
r
max
M- f n(r)r3dr (8-46)
because the volume of each cloud drop is (4/3) TT r3. Comparing Equations 8-45 and 8-46, one
can see that
oext <* M/re (8-47)
where r is the effective radius, defined as the ratio
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r
max
/ n(r)r3dr
re = 7^ • (8-48)
max
/ n(r)r 2dr
r •
mi n
For identical meteorological conditions, the liquid water content will be the same in two cloud
layers that are composed of droplets of different effective radius. If other paramaters remain the
same, the light-extinction coefficient will increase as the effective radius decreases (Equation 8-
47). Therefore, if the geometric depth of two cloud layers is the same and the column amount of
liquid water is the same, the cloud with more numerous, but smaller drops, will have a larger
optical depth and a higher albedo. This sets the stage for a potentially important indirect effect
of anthropogenic aerosols on the Earth's radiation balance. As suggested by Twomey (1974),
the addition of cloud nuclei by pollution can lead to an increase in the solar radiation reflected
by clouds, a negative radiative forcing that is in addition to the direct radiative forcing discussed
in Section 8.8.3.
Another radiative consequence of pollution is the emission of elemental carbon, which can
be incorporated into clouds and increase the absorptance at visible wavelengths at which pure
water is nonabsorbing. This mechanism decreases the single scattering albedo of the cloud
material (see Figure 8-20), causing a decrease in the reflectance of the layer. There are,
therefore, two competing mechanisms, but Twomey et al. (1984) assessed the relative
magnitudes of the two effects based on observations of clean and polluted air in Arizona, and
concluded that increases in albedo from increases in cloud droplet concentration would dominate
over the absorption effect.
Cloud Lifetimes
Another possible indirect effect of aerosols on clouds and precipitation is that of increased
cloud condensation nuclei (CCN), the inhibition of precipitation (Albrecht, 1989; Twomey,
1991). Cloud condensation nuclei can be either hygroscopic or deliquescent, having large light
scattering efficiency due to hygroscopic growth. With more droplets, coagulative growth, which
is the mechanism of water removal in liquid water clouds, will be hindered. This will result in
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longer residence times for clouds and a higher mean albedo time, which, again, is indirect
negative solar radiative forcing.
There is some observational evidence that cloud amounts have increased during the recent
decades. Henderson-Sellers (1986, 1989) has analyzed surface based meterological observations
from several stations in the United States and Canada. There is coherent increase in cloud
amount in all seasons between 1900 and 1982 with most of the increase occuring between 1930
and 1950. Attribution of this increase to anthropogenic causes is very difficult. The possibility
of jet contrails playing a role has been mentioned by Changnon (1981) but this would not
explain the increase in the 1930-1950 time frame. Warren et al. (1988) have also noted a
positive trend in the total cloud amount and also for all classes of clouds globally over the
oceans. An increase in aerosol concentration is compatible with an increase in cloud lifetimes
for low level clouds so there is a plausible link between these observations and anthropogenic
activities but nothing definitive can be said at the moment.
Cloud Chemistry
Novakov and Penner (1993) pointed out that anthropogenic activity could modify the
nucleating properties of anthropogenic sulfate. It has already been mentioned that carbon black
influences the direct radiative forcing. The presence of carbon black and other organics can also
alter the hygroscopic properties of sulfate aerosols. For instance, the condensation of
hydrophobic organics onto preexisting sulfate particles may render these inactive as CCN. On
the other hand, the condensation of sulfuric acid vapor on a hydrophobic organic aerosol may
convert it to a hydrophilic particle. Because the indirect radiative forcing depends on the ability
of sulfate to nucleate, organics may enhance or diminish the potential indirect radiative forcing.
8.8.5.2 Observational Evidence
The relationship between the availability of CCN and cloud droplet size distribution has
been a subject of research in cloud physics for decades. It has been known, for instance, that
continental clouds are composed of far more numerous, but smaller drops than maritime clouds
(Wallace and Hobbs, 1977). The more difficult question is whether the additional
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contribution to CCN by anthropogenic activities has increased the reflectance of clouds over
large areas of the Earth. If so, this would be an additional indirect radiative forcing attributable
to sulfate emissions.
The most dramatic evidence of such an indirect effect (albeit on a small scale) is the
observation of "ship tracks" in marine stratocumulus (Conover, 1966; Coakley et al., 1987).
These are visible in satellite images as white lines against a gray background and follow the path
of ships that have been emitting effluents. King et al. (1993) reported the first radiation and
microphysics measurements on ship tracks obtained from a research aircraft as it flew within
marine stratocumulus clouds off California. Comparing the flight track with satellite images,
they were able to locate two distinct ship tracks in which they measured enhanced droplet
concentration, and liquid water contents, greater than in the surrounding clouds. They also
derived the effective radius of the cloud drops and found that there was a significant decrease
within the ship tracks. The radiation measurements were consistent with increased optical
depths in the ship tracks. The increased liquid water content is compatible with the suppression
of drizzle as a result of slower coagulative growth (Albrecht, 1989), an indirect aerosol effect.
Twomey (1991) estimated that the visible reflectance of clouds, R, is affected by cloud
droplet concentration, N, according to the following relationship for a fixed liquid water content,
M
dR) R(l-R)
~- (8-42)
The parameter, dR/dN, the susceptibility, is a measure of the sensitivity of cloud reflectance to
changes in microphysics (Platnick and Twomey, 1994). It has a maximum value atR = 0.5 and
is inversely proportional to the cloud droplet concentration such that when the cloud droplet
concentration is low as in marine clouds, the susceptibility is high. It is, therefore, not surprising
that emissions from ships can influence cloud albedo.
To determine whether the indirect effect of aerosols on clouds is detectable on a global
scale, Schwartz (1988) compared cloud albedos in the two hemispheres and also historic changes
in surface temperature from preindustrial times. The sulfate signal is expected in
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both: cloud albedos in the Northern Hemisphere should be higher, and the rate of greenhouse
warming should be slower. The results of his study were inconclusive in that no inter-
hemispheric differences were found. However, more recent studies suggest some influence of
sulfate emissions.
Falkowski et al. (1992) showed that cloud albedos in the central North Atlantic Ocean, far
from continental emission sources, were well correlated with chlorophyll in surface waters.
These correspond to higher ocean productivity and DMS emissions, indicating that natural
sources of sulfate emission can influence cloud albedo. More substantial evidence of the effect
of sulfate aerosol has been presented by Han et al. (1994) who made a near-global survey of the
effective droplet radii in liquid water clouds by inverting satellite visible radiances obtained
from advanced very-high-resolution radiometer (AVHRR) measurements. Han et al. (1994)
found systematic differences between the effective radius of continental clouds (global mean
effective radius = 8.5 //m) and maritime clouds (global mean effective radius =11.8 //m), which
is the expected result based on differences in CCN concentrations. In addition, they found
inter-hemispheric differences in the effective radius over both land and ocean. Northern
Hemisphere clouds had smaller effective radii, the difference being 0.4 //m for ocean and
0.8 //m for land. However, Southern Hemisphere clouds tended to be optically thicker, which
explains why Schwartz (1988) was unable to detect inter-hemispheric albedo differences.
8.8.5.3 Modeling Indirect Aerosol Forcing
If the appropriate radiative properties of aerosols are known, it is fairly straightforward to
model the direct solar radiative forcing of aerosols (Section 8.8.3) and estimate possible climatic
responses (Section 8.8.4). Calculations of the indirect forcing of aerosols, on the other hand, is
much more difficult since several steps are involved and the uncertainty at each level is high.
Charlson et al. (1992) proposed that enhancements in albedo would occur only for marine
stratocumulus clouds and for a uniform global increase of droplet concentration of 15% in only
these clouds, the global mean solar radiative forcing would be -1.0 W m"2, which is comparable
to the direct forcing (Section 8.8.4) and of the same sign. The greatest uncertainty in this
estimate is the degree that cloud droplet number concentration is enhanced by increasing
emissions. The uncertainty has been estimated by Kaufman et al.
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(1991) to be at least a factor of 2. Leaitch and Isaac (1994) have addressed this issue based on
their observations of the relationship between cloud droplet concentrations and cloud water
sulfate concentrations. They find that the assumptions in Kaufman et al. (1991) are within
reasonable bounds. The Scientific Steering Committee for the International Global Aerosol
Program concluded that the uncertainties involved in determining the indirect effects of aerosols
on the Earth's radiation balance are so great that no formal value can be given at this time
(Hobbs, 1994).
The indirect forcing has been included in climate model simulations by Kaufman and Chou
(1993) who used a zonally averaged multilayer energy balance model and by Jones et al. (1994)
who used a GCM. Kaufman and Chou (1993) modeled the competing effects of enhanced
anthropogenic emissions of CO2 and SO2 since preindustrial times. They concluded that SO2 has
the potential of offsetting CO2-induced warming by 60% for present conditions and 25% by the
year 2060 given the Intergovernmental Panel on Climate Change BAU (business as usual)
scenario of industrial growth (Intergovernmental Panel on Climate Change, 1994). They also
found a small inter-hemispheric difference in climate response, with the Northern Hemisphere
cooler than Southern Hemisphere by about -0.2 °C.
Jones et al. (1994) used a GCM with a prognostic cloud scheme and a parameterization of
the effective radius of cloud water droplets that links effective radius to cloud type, aerosol
concentration and liquid water content. The parameterization is based on extensive aircraft
measurements. The distribution of column sulfate mass loading was obtained from the model of
Langner and Rodhe (1991) separately for natural and anthropogenic sources. Simulated
effective radius distributions of low-level clouds showed land-ocean contrasts and also inter-
hemispheric differences as observed by Han et al. (1994). The indirect forcing due to
anthropogenic sulfate was estimated by performing a series of single-timestep calculations with
the GCM. For present conditions, the mean northern hemisphere forcing was calculated to be
-1.54 W m"2 and the southern hemisphere forcing was -0.97 W m"2. This is comparable to the
estimates of Charlson et al. (1992) and Kaufman and Chou (1993) and substantially larger than
the direct forcing estimates of Kiehl and Briegleb (1993). The combined direct and indirect
forcing is more than half the total positive forcing of greenhouse gas emissions. It should be
noted that the indirect effect is greatest when the atmosphere is very clean and so, in principle,
could saturate with time. The direct effect is
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linear with emissions and may dominate in the future. In any case, the negative forcing of
sulfate aerosols must be considered in any overall estimate of the total anthropogenic effect on
climate.
8.9 SUMMARY
8.9.1 Visibility Effects
This chapter presents (1) an overview of the effects of particulate matter on visibility, and
combines information from this chapter and other recent reviews by the National Research
Council (NRC), the National Acid Precipitation Assessment Program (NAPAP), and
Environmental Protection Agency (U.S. EPA) and (2) a discussion on the effects of particulate
matter on climate.
Several definitions of visibility have been noted in this chapter, and they are generally
consistent with each other. Section 169A of the 1977 Clean air Act Amendments (42 U.S.C.
7491) and the U.S. EPA 1979 Report to Congress defined visibility impairment as a reduction in
visual range and atmospheric discoloration. The National Research Council's Committee on
Haze in National and Wilderness Areas said, "Visibility is the degree to which the atmosphere is
transparent to visible light." These definitions indicate that visibility is determined by the clarity
(or transparency) and color fidelity of the atmosphere. Visibility can be numerically quantified
by equating it with the contrast transmittance of the atmosphere. This quantification is
consistent with both (1) the use of visual range to quantify visibility, and (2) the definition
recommended by the NRC.
All evaluations of visibility have focused on daytime visibility as perceived by a human
observer looking through one or more sight paths in the Earth's atmosphere. Weber's Law
indicates that if an object is just perceptible, the brightness of the object differs from the
brightness of its surroundings by a constant fraction, i.e., a constant percentage of the
surrounding brightness. A perception threshold of 2% brightness change is most commonly
used, but 5% is sometimes used in visibility analyses. Either contrast or modulation can be used
to quantify changes in brightness. Weber's law is not exact, so perception thresholds depend on
the viewing conditions. The eye is the most sensitive to objects that subtend an angle of
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approximately 1/3 degree, is somewhat less sensitive to objects that subtend larger angles, and
becomes rapidly less sensitive as the size of the object is decreased below a subtended angle of
0.1 degree. Many factors, such as the brightness level and the pattern of brightness surrounding
the object being viewed can affect the perception threshold. The contrast threshold of 2%
generally applies to objects that subtend an angle between 0.1 and 1.0 degree and are viewed
against uniform backgrounds.
The atmosphere is a very thin layer on the Earth and has strong vertical gradients. Because
of these gradients and the curvature of the Earth, the properties of the atmosphere exhibit
substantial variations in sight paths longer than roughly 100 km. The visual range is the greatest
distance at which a dark target can be perceived against the horizonal sky. Because of the non-
uniformities in the atmosphere, the visual range provides a meaningful characterization of the
Earth's atmosphere only for haze levels that cause the visual range to be much less than 100 km.
A sight path through the atmosphere is illuminated by direct sunlight, diffused skylight,
and light reflected by the Earth's surface. An observer looking through the atmosphere sees
light from two sources: (1) the light reflected from the object or terrain feature being viewed that
is transmitted through the sight path to the observer, and (2) the light scattered by the
atmosphere into the line of sight and then transmitted to the observer. These are known as the
transmitted radiance and the path radiance (air light), respectively.
Visibility is determined by the competition between the transmitted radiance and the path
radiance. The transmitted radiance carries all of the information about the nature of the object
being viewed. When this radiance is dominant, the features of the object can be easily perceived
and the visibility is good. The path radiance contains information only about the uniformity of
the intervening atmosphere, and no information about the object being viewed. When the path
radiance is dominant, it tends to obscure the object. These effects are easily seen by viewing
objects at various distances in a dense fog, but can also be seen on a clear day if sight paths of
sufficient length are available.
The transmitted radiance is attenuated by light extinction. The strength of that attenuation
is quantified by the light-extinction coefficient, which describes the rate of energy loss with
distance from a beam of light. The light-extinction coefficient for green light in particle-free air
(Raleigh scattering) is 1% per km, or 0.01 km"1. Extinction coefficients are
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most often measured in units of inverse megameters (Mn"1), and in these units the extinction
coefficient for clean air is 10 Mn"1.
Light extinction is caused by light scattering and light absorption by particles and gases.
In visibility analyses it is useful to consider each of these separate contributions to the light-
extinction coefficient; the coefficients for light absorption by gases (oag), light scattering by
gases (osg), light absorption by particles (oap), and light scattering by particles (osp). Because of
their different origins and composition, atmospheric particles are frequently divided into coarse
and fine particles. The corresponding division of coefficients for light scattering and absorption
then becomes, the coefficient for light-scattering and light-absorption by fine particles (osfpand
o^p) and the coefficient for light scattering and light-absorption by coarse particles (oscp and oacp).
The components of the light-extinction coefficient are related as follows:
°~ext = °abS + °~Scat
°ab=
°~Scat =
°Sp = °Sfp + ascp
°ap = °~afp + aacp
Light scattering by gases (Raleigh Scattering) is nearly constant, but decreases with increasing
altitude. Light absorption by gases is almost entirely due to NO2, and is typically significant
only near NO2 sources, e.g., in or downwind of urban areas or in plumes. Light absorption by
particles is principally caused by elemental carbon. Light scattering by particles is typically the
most important component of light extinction in causing visibility degradation. Further
discussion of this component of light extinction appears below.
If the average light-extinction coefficient and path length are known, the light
transmittance of a sight path can be calculated. Thus, the effect of light extinction on the
transmitted radiance is easily quantified.
The calculation of the path radiance is much more difficult. It requires a knowledge if (1)
the illumination of the sight path at each point along its length, (2) the light scattering properties
of the atmosphere at each point, and (3) the transmittance of the atmosphere
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between each point and the observer. The illumination is affected by the clouds in the sky, the
haze that contributes to diffuse skylight, and the variations of the reflectance of the Earth's
surface under the sight path. Light scattering and light absorption contribute differently, because
light absorption does not contribute to the scattering of light into the sight path. Thus, a given
amount of light extinction due to light absorption causes less visibility impairment than the same
amount of light extinction due to light scattering. Because of the differing effects of scattering
and absorption and the highly variable effects of the illumination, the path radiance is not closely
linked to light extinction. As a result, the visibility for a specific sight path under specific
illumination conditions is not closely linked to the light-extinction coefficient.
All of these effects can be mathematically simulated, and a simple theory for these
simulations is present in the text. The theoretical development includes the equations used to
generated photographs showing the visual effects with various amounts of haze. For simple
situations, e.g., a cloud-free sky and uniform haze, photographic simulation are quite realistic.
Examples appear in the National Acid Precipitation Assessment Program study. These
photographs, and other comparisons, indicated that the relationship between air pollution and
visibility is well understood.
As previously stated, the most important component of light extinction in causing visibility
degradation is typically light scattering by particles. Except in dust storms or during fog, snow,
or rain, most light scattering by particles is caused by fine particles, i.e. the accumulation mode,
-0.3 to 1.0 //m diameter. Coarse particles typically have a light-scattering efficiency 5 to 10
times less that the efficiency of fine particles. Coarse particles can have important visibility
effects in dusty or desert areas, but fine particles dominate the visibility effects in most of the
eastern United States.
The light-scattering efficiency of particles is a maximum for particles with a diameter
approximately equal to the wavelength of visible light. For a single particle, the maximum in
light-scattering efficiency occurs at a diameter approximately equal to
D = 0.28/(n-l)//m
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where n is the index of refraction of the particulate matter. This formula gives a diameter of
0.85 /u,m for an index of refraction of 1.33 (e.g. water) and a diameter of 0.56 //m for an index of
refraction of 1.5, which is larger than typical for ambient aerosol mixtures. Most fine particles
have smaller diameters. Therefore, processes that increase the particle size of fine particles tend
to increase the light-scattering efficiency of the particles.
Coagulation of nuclei particles, which can be smaller that 0.1 //m in diameter, in the
atmosphere will increase their light-scattering efficiency. Particles in the 0.2 to 0.3 //m in
diameter range are small enough that their light-scattering efficiency is roughly half that of
particles with the optimum size. Particles in this range coagulate very slowly, so they tend to
maintain their size in the atmosphere as long as they are not processed by clouds or fog.
Heterogenous processes in clouds and fogs can form particles in any size range, but these
processes are the dominant source of particles with a diameter near 0.7 //m, which is near the
optimum size for light scattering. Particles in this size range are frequently observed in air
samples processed by clouds or fog.
The dominant chemical components of fine parti culate matter are sulfates, organic species,
nitrates, crustal species, and elemental carbon. Sulfates and organic species dominate visibility
impairment in the eastern United States, and nitrates and organic species are dominant in many
western urban areas as well as the California Central Valley during winter months. Crustal
species are important contributors in dry areas, especially when these areas are farmed.
Elemental carbon is most important in urban areas, and in Phoenix, AZ can contribute about
one-third of the light extinction during some episodes.
Water uptake, which occurs when hygroscopic aerosol is exposed to elevated humidities,
increase light scattering by two mechanisms: (1) the mass concentration of parti culate matter is
increased, and (2) the increase particle size causes the light scattering efficiency to increase.
Thus, the materials present before the water uptake makes a larger contribution to light
scattering because they are now a component of larger particles. The overall effect on increasing
humidity on light scattering by particles was quantified nearly 20 years ago, but current research
is greatly increasing the detailed understanding of the response of aerosol particles to changing
humidities and the relationship of this response to the chemical composition of the particles.
Humidity effects generally become important at relative humidities between 60 and 70%, and
increase the light scattering by a factor of 2 at
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approximately 85% relative humidity. The light scattering increase rapidly with relative
humidity when the humidity exceeds 90%.
Potential indicators for a visibility and air quality include: (a) fine particle mass and
composition, or only fine particle mass; (b) light scattering by dried ambient particles; (c) light
scattering by particles under ambient conditions; (d) light extinction calculated from separate
measurements of dry scattering and absorption or ambient scattering and absorption; (e) light
extinction measured directly; and (f) contrast transmittance of a sight path.
The selection of an indicator should consider such factors as (1) the linkage between the
indicator and visibility, (2) the cost and feasibility of monitoring the indicator to determine both
compliance with the standard and progress toward achieving the standard, (3) the nature and
severity of the interferences inherent in the available monitoring methods, (4) the relationship
between the visibility indicator and indicators for other air quality standards, and (5) the
usefulness of monitoring data in analyses which have the purpose of determining the optimum
control measures to achieve the standard.
In general there is an inverse relationship between an indicator's ability to characterize air
quality and its ability to characterize visibility.
There is general agreement in the technical community that contrast transmittance would
not be a suitable indicator for regulatory purposes. It is affected by too many factors other than
air quality, such as cloud shadows, precipitation, fog, etc. Therefore, only the other indicators
merit consideration.
Visibility has value to individual economic agents primarily through its impact upon the
activities of consumers. Most economic studies of the effects of air pollution on visibility have
focused on the aesthetic effects to the individual, which are, at this time, believed to be the most
significant economic impacts of visibility degradation caused by air pollution in the United
States. It is well established that people notice those changes in visibility conditions that are
significant enough to be perceptible to the human observer, and that visibility conditions affect
the well-being of individuals.
One way of defining the impact of visibility degradation on the consumer is to determine
the maximum amount the individual would be willing to pay to obtain improvements in
visibility or prevent visibility degradation. Two economic valuation techniques have been used
to estimate willingness to pay for changes in visibility: (1) the
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contingent valuation method, and (2) the hedonic property value method. Both methods have
important limitations, and uncertainties exist in the available results. Recognizing these
uncertainties is important, but the body of evidence as a whole suggests that economic values for
changes in visibility conditions are probably substantial in some cases, and that a sense of the
likely magnitude of these values can be derived from available results in some instances.
Economic studies have estimated values for two types of visibility effects potentially related to
particulate air pollution: (1) use and non-use values for preventing the types of plumes caused
by power plant emissions, visible from recreation areas in the southwestern United States; and
(2) use values of local residents for reducing or preventing increases in urban hazes in several
different locations.
8.9.2 Climate Change
Aerosols of submicron size in the Earth's atmosphere perturb the radiation field. There is
no doubt that anthropogenic aerosol emissions, primarily sulfur oxides, have the potential to
affect climate; the question is by how much. There are two chief avenues through which
aerosols impact the radiation budget of the Earth. The direct effect is that of enhanced solar
reflection by the cloud-free atmosphere. Since aerosols, even those containing some absorptive
component, are primarily reflective, their impact is felt as a negative radiative forcing (i.e., a
cooling) on the climate system. Although there is some uncertainty in the global distribution of
such aerosols and in the chemical and radiative properties of the aerosols, the radiative effects
can still be modeled within certain bounds. Estimates of this forcing range from -0.3 W m"2 to
about twice that value for current conditions over pre-industrial times.
The indirect forcing results from the way in which aerosols affect cloud microphysical
properties. The most important is the effective radius of cloud droplets, which decrease in the
presence of higher concentrations of Cloud Condensation Nuclei (CNN) since more nucleating
sites are available for droplets to form. This effect is most pronounced when the concentration,
N, is very low, and clouds are moderately reflective. Other effects are the enhancement of cloud
lifetimes and also changes in the nucleating ability of CCN through chemical changes. Although
estimates of the indirect effect are uncertain by at least a factor of 2, but perhaps much more, it
appears to be potentially more important than the direct
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effect. Taken together, on a global mean basis, anthropogenic emissions of aerosols could have
offset substantially the positive radiative forcing due to greenhouse gas emissions. High priority
should be given to acquiring the measurements needed to quantifying these effects with greater
accuracy.
The one crucial difference between aerosol forcing and greenhouse (gas) forcing is the
atmospheric lifetime of aerosols and gases and hence, forcing. The aerosol forcing is fairly
localized, whereas the greenhouse forcing is global. One should, therefore, expect
inter-hemispheric differences in the forcing and perhaps climate response. However, climate
models are not currently at the level of sophistication needed to determine climate response
unambiguously. With few exceptions, global observations of surface temperature can not
separate natural and anthropogenic causal mechanisms.
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9. EFFECTS ON MATERIALS
The deposition of airborne particles on the surface of building materials and culturally
important articles (e.g., statuary) can cause damage and soiling, thus reducing the life usefulness
and aesthetic appeal of such structures (National Research Council, 1979; Baedecker et al.,
1991). Furthermore, the presence of particles on surfaces may also exacerbate the physical and
chemical degradation of materials that normally occur when these materials are exposed to
environmental factors such as wind, sun, temperature fluctuations, and moisture. Beyond these
effects, particles, whether suspended in the atmosphere, or already deposited on a surface, also
adsorb or absorb acidic gases from other pollutants like sulfur dioxide (SO2) and nitrogen
dioxide (NO2), thus serving as nucleation sites for these gases. The deposition of "acidified"
particles on a susceptible material surface is capable of accelerating chemical degradation of the
material. Therefore, concerns about effects of particles on materials are relate both to impacts
on aesthetic appeal and physical damage to material surfaces, both of which may have serious
economic consequences. Insufficient data are available regarding perception thresholds with
respect to pollutant concentration, particle size, and chemical composition to determine the
relative roles these factors play in contributing to materials damage.
This chapter briefly discusses the effects of particle exposure on the aesthetic appeal and
physical damage to different types of building materials. This chapter also discusses the effects
of dry deposition of acid forming gases on economically important materials. For more detailed
discussion of the effects of acid gases on materials, see the 1991 National Acid Precipitation
Assessment Program report (Baedecker et al., 1991).
9.1 CORROSION AND EROSION
9.1.1 Factors Affecting Metal Corrosion
The mechanisms controlling atmospheric corrosion of metals have been thoroughly
discussed in the National Acid Precipitation Assessment Program (Baedecker et al., 1991). In
summary, metals undergo corrosion in the absence of pollutant exposure through a series of
physical, chemical, and biological interactions involving moisture, temperature, oxygen, and
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various types of biological agents. In addition to these environmental factors, atmospheric
pollutant exposure may accelerate the corrosion process. Pollutant-induced corrosion arises
from complex interactions of the pollutant with the metal surface and the metal corrosion film.
In the absence of moisture, there would be limited pollutant-induced or nonpollutant-induced
corrosion.
The atmospheric corrosion of most metals is a diffusion-controlled electrochemical
process. For an electrochemical reaction to take place, there must exist an electromotive force
between points on the metal surface; a mechanism for charge transfer between the electronic
conductors; and a conduction path between the cathode and anode reaction centers (Haynie,
1980). The rate of corrosion is still, however, dependent upon the deposition rate and nature of
the pollutant (discussed in Chapter 3 of this document); the variability in the electrochemical
reactions; the influence of the metal protective corrosion film; the effects of the pollutant
coupled with the amount of moisture present (time-of-wetness; relative humidity) (Zhang et al.,
1993; Pitchford and McMurry, 1994; Li et al., 1993); the presence and concentration of other
surface electrolytes; and the orientation of the metal surface.
The principal form of atmospheric metal corrosion is the uniform corrosion of the metal
surface. Other forms of corrosion include pitting, grain-boundary corrosion, and stress-
corrosion cracking.
9.1.1.1 Moisture
The formation of a moisture layer (condensation) on the metal surface is dependent upon
precipitation in the form of rain, fog, mist, thawing snow and sleet, and dew. The moisture layer
provides a medium for conductive paths for electrochemical reactions and a medium for water
soluble air pollutants.
A moisture layer may also form as the result of the reaction of adsorbed water with the
metal surface or protective corrosion film, deposited particles and salts from the reaction of the
metal surface, and deposited particles with reactive gases. Of particular importance is the
production of hydrated corrosion products that increase the absorption rate of moisture. The
presence of these hygroscopic salts can drastically decrease the critical relative humidity,
resulting in large amounts of moisture on the metal surface.
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When the temperature of a metal is below the ambient dew point, water condenses on the
metal surface. Whether or not the metal reaches the temperature at which condensation occurs
varies with heat transfer between ground and metal and between air and metal. Condensation
occurs when the relative humidity adjacent to the surface exceeds a value in equilibrium with the
vapor pressure of a saturated solution of whatever salts are on the surface. The solution may
contain corrosion products, other hygroscopic contaminants, or both. Temperature, wind,
sunshine, and night sky cover then become factors in establishing corrosion rates, since they
determine whether there will be sufficient dew condensation.
The first evidence of ambient relative humidity-dependent atmospheric corrosion was
demonstrated by Vernon (1931, 1935). Vernon showed a dramatic increase in weight gain in
magnesium and iron samples when the relative humidity exceeded certain values (critical
relative humidities) in the presence of SO2. More recently, researchers have shown particle size
related effects based on relative humidity (Pitchford and McMurry, 1994). A more detailed
discussion on the water content of atmospheric aerosols and its dependence on relative humidity
appears in Chapter 3 of this document.
According to Schwartz (1972), the corrosion rate of a metal could increase by 20% for
each increase of 1% in the relative humidity above the critical relative humidity value. It is
evident that relative humidity has a considerable influence on the corrosion rate, as established in
laboratory trials by Haynie and Upham (1974) and Sydberger and Ericsson (1977). Although
these experimental results do not support the exact rate predicted by Schwartz (1972), they do
indicate that the corrosion rate of steel increases with increasing relative humidity.
Since average relative humidity is calculated from the relative humidity distribution, an
empirical relationship exists between average relative humidity and the fraction of time some
"critical humidity value " (minimum concentration of water vapor required for corrosion to
proceed) is exceeded, assuming a relatively constant standard deviation of relative humidity
(Mansfeld and Kenkel, 1976; Sereda, 1974). The fraction of time that the surface is wet must be
zero when the average relative humidity is zero and unity when the average relative humidity is
100%. According to Haynie (1980), the following equation is the simplest single-constant first-
order curve that can be fitted to observed data:
-------
f = (1 - k)/(100 - k)RH
(9-1)
where
f = fraction of time relative humidity exceeds the critical value,
RH = average relative humidity, and
k = an empirical constant less than unity.
Haynie (1980) analyzed and fitted, by the least-squares method, ten quarter-year periods of
relative humidity data from St. Louis International Airport to this equation. The fraction of time
the relative humidity exceeded 90% gave a value of 0.86 for k. This fraction and the data points
are plotted in Figure 9-1.
1.0
0.9
0.8
| 0-7
£
3 0.6
o>
E
K 0.5
i^
o
o 0.4
o
£ 0.3
0.2
0.1
10 20 30 40 50 60 70 80 90 100
Average Relative Humidity, percent
Figure 9-1. Empirical relationship between average relative humidity and fraction of time
when a zinc sheet specimen is wet.
Source: Haynie (1980).
Time-of-Wetness Sensors
Time-of-wetness sensors, sensors that detect moisture using an electrochemical cell, have
been developed to better determine critical relative humidities. The first of these
9-4
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sensors, developed by Sereda (1958) and Tomashov (1966), measured voltage and current
changes across galvanic cells. More recently, Mansfeld and Vijaykumar (1988) reported a
technique that uses single metal electrodes for detection of moisture and measurement of the
corrosion rate.
Haynie and Stiles (1992) evaluated the Mansfeld type Atmospheric Corrosion Rate
Monitor (ACRM) with 19 mo of exposure in an hourly monitored field environment. Duplicate
sensors were exposed each at 30° and 90° C. The distribution of measured currents were
bimodal for all sensors with definite minimums at around a cell resistance of 1065 ohms between
wet and dry modes. Thus, the sensors can be used to measure time-of-wetness with good
reproducibility between sensors exposed at the same time in the same manner. An analysis of
variance of the results revealed statistically significant differences between exposure months and
angles but not between sensors. Also, there was a significant interaction between month and
exposure angle. From these results it was concluded that the sensors are sensitive enough to
detect changes with time that are not associated with the primary effects of surface temperature
or air moisture content. The magnitude of the dew point/surface temperature difference when a
surface becomes wet changes with time, possibly as corrosion products and pollutant
concentrations change on the surface. Exposure angle affects time-of-wetness by changing the
surface temperature. The surface temperature is related to the relative sun angle and the angle
with respect to the night sky. The angle affects radiant heat transfer. This effect was observed
as an interaction between seasonal change and exposure angle. Further analysis of the
magnitude of the sensor responses when they were wet and comparing the results with weight
loss data and model predictions indicated that they were measuring cell resistance rather than
polarization resistance (Haynie and Stiles, 1992).
9.1.1.2 Temperature
Few recent studies were found on the effects of temperature on the corrosion process, and
earlier studies (Guttman and Sereda, 1968; Barton, 1976; Haynie et al., 1976; Guttman, 1968;
Haynie and Upham, 1974; Harker et al., 1980) disagree on the role temperature plays in the rate
of corrosion. How temperature affects the corrosion rate of metal was probably best explained
by Haynie (1980). He reported that the rate of metal corrosion is diffusion-
9-5
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controlled, and that under normal temperature conditions, effects on the rate of corrosion would
likely not be observed. A decrease in temperature would raise the relative humidity but decrease
diffusivity. When the temperature reaches freezing, a decrease in the overall corrosion rate
occurs because diffusion has to take place through a solid (Haynie, 1980; Biefer, 1981; Sereda,
1974). Available recent studies on the effects of temperature on metal corrosion are discussed
below in various subsections on pollutant-induced corrosion of various specific metals.
9.1.1.3 Formation of a Protective Film
The rust layer on steel is somewhat protective against further corrosion, though far less so
than the corrosion layer on zinc and copper. The content of soluble compounds in rust limits its
protection of steel. Rust samples analyzed by Chandler and Kilcullen (1968) and Stanners
(1970) contained 2 to 2.5% soluble SO;;" and 3 to 6% total SO;;". The outer rust layer contained a
small amount (0.04 to 0.2%) of soluble SO;;", compared with 2% in the inner rust layer. The
concentration of insoluble SO;;" was fairly uniform throughout the rust layers.
The composition of the rust layer has led to studies of the corrosion protective properties of
rust as a function of exposure pattern (Nriagu, 1978; Sydberger, 1976). Steel samples initially
exposed to low concentrations of sulfur oxides (SOX) and then moved to sites of higher SOX
concentrations corroded at a slower rate than did samples continuously exposed to the higher
concentrations. Exposure tests started in summer showed slower corrosion rates during the first
years of exposure than those started in winter.
The long-term corrosion rate of steel appears to depend on changes in the composition and
structure of the rust layer. During the initiation period, which varies with the SO2 concentration
and other accelerating factors, the rate of corrosion increases with time (Barton, 1976). Because
it is porous and non-adherent, the rust initially formed offers no protection and may accelerate
corrosion by retaining hygroscopic sulfates and chlorides, producing a micro-environment with a
high moisture content. This is consistent with the concept of sulfate nests discussed by Kucera
and Mattsson (1987). After the initiation stage, the corrosion rate decreases as the protective
properties of the rust layer improve. Satake and Moroishi (1974) relate this slowing down to a
decrease in the porosity of the rust layer.
9-6
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During a third and final stage, corrosion attains a constant rate and the amount of SO^" in rust is
proportional to atmospheric SO2 concentrations. The quantitative determination and subsequent
interpretation of corrosion rates becomes difficult if it is not known how long the metal has had
a surface layer of electrolyte. Variations in the "wet states" occur with relative humidity,
temperature, rain, dew, fog, evaporation, wind, and surface orientation. Capillary condensation
in rust can be related to the minimum atmospheric moisture content that allows corrosion to
occur (i.e., critical relative humidity). Centers of capillary condensation of moisture on metals
can occur in cracks, on dust particles on the metal surface, and in the pores of the rust
(Tomashov, 1966).
9.1.2 Development of a Generic Dose-Response Function
There are several factors that are important in the corrosion process. First, the rate of
corrosion is decreased in the absence of moisture (moisture layer). Secondly, the deposition rate
of a pollutant is more important in determining the rate of corrosion than the pollutant
concentration. Lastly, the protective corrosion layer may be affected by either dry or wet
deposition. A generic semi-theoretical model has been developed that takes into account these
factors (Edney et al., 1986; Haynie, 1988; Haynie et al., 1990; and Spence et al., 1992). The
model is based on the relative rates of the competing processes of buildup and dissolution of
protective corrosion product films. It is a mathematical function that expresses the relationship
between corrosion and environmental factors. The general form of the equation is:
C = btw+a/(Dc/dtw) (9-2)
or a transcendental form:
C = btw + a(l - exp[-Bc/a])/b (9.3)
where C is the amount of corrosion, tw is time-of-wetness, a is a film diffusivity term, and b is a
film dissolution rate. The last two terms are associated with the conditions of the environment
and the corrosion product film. For long-term exposures, the exponential term approaches zero
and the film reaches a steady state thickness. The equation simplifies to the linear form:
9-7
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C = btw + a/b. (9.4)
It is in determining the magnitude of the term b that the effects of pollution on corrosion can be
analyzed. More detailed discussion of a generic dose-response function comparing metal
corrosion in the absence of pollution and acidic dry deposition of acidic aerosols appears in
Baedecker et al. (1991).
9.1.3 Studies on Metals
9.1.3.1 Acid-Forming Aerosols
Ferrous Metals
Ferrous metals include iron, steel, and steel alloys. Stainless steels, incorporating
chromium, molybdenum, and nickel, are highly corrosion resistant because of the protective
properties of the oxide corrosion film; however, in more polluted areas, the oxide corrosion film
becomes less protective. Based on early studies, reported in the National Acid Precipitation
Assessment Program report (Baedecker et al., 1991), most steels are susceptible to corrosion
from pollutant exposure unless covered by an organic or metallic covering. The rate of
corrosion was related to the amount of SO2 in the atmosphere, showing increasing rates of
corrosion with increasing concentrations of SO2. The rate of corrosion was also found to depend
on the deposition rate of SO2.
A recent report by Butlin et al. (1992a) also demonstrated that the corrosion of mild steel
and galvanized steel was SO2-dependent. These researchers monitored the corrosion of steel
samples by SO2 and ozone (O3) under artificially fumigated environmental conditions, and NO2
under natural conditions. The natural meteorological conditions of the areas were unaltered.
Annual average SO2 concentrations ranged from 2.1 //g/m 3 in a rural area to 60 //g/m3 in one of
the SO2-fumigated locations. Annual average NO2 concentrations ranged from 1.5 //g/m3 in the
most rural area to 61.8 //g/m3 in the most polluted area. They found that corrosion of the steel
samples was more dependent on the long-term SO2 concentration and was only minimumly
affected by nitrogen oxides (NOX).
9-8
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Aluminum and Aluminum Alloys
Aluminum is generally considered corrosion resistant, but when exposed to very high SO2
concentrations and relative humidities above 50%, aluminum will corrode rapidly, forming a
hydrated aluminum sulfate. When aluminum is exposed to low concentrations of acid sulfate
particles, a protective aluminum oxide film is formed.
Early evaluations of the effects of SO2 exposure on aluminum indicated that corrosion of
aluminum by SO2 was exposure-dependent and insignificant, based on loss of metal thickness
(Haynie, 1976; Fink et al., 1971). However, Haynie (1976) reported SO2 exposure-related loss
in bending strength in the aluminum samples.
In a more recent study, Butlin et al. (1992a) reported that aluminum corrosion was
insignificant in SO2-spiked environments. The aluminum samples were exposed under natural
environmental conditions (29 sites) for up to 2 years. The corrosion was greater and often more
patchy on the underside of some of the metal samples. The authors attributed the increased
corrosion on the underside of some samples to the lack of pollutant washoff by rain and an
increased concentration of particulate matter (dust) in those test areas.
Aluminum alloy 3003-H14 was exposed to various acid forming aerosols and particles as
part of the National Acid Precipitation Assessment Program (Baedecker et al., 1991).
Aluminum samples were exposed at 5 sites (Newcomb, NY, Chester, NJ, Washington, DC,
Steubenville, OH, and Research Triangle Park, NC). Corrosion after 60 mo of exposure, as
measured by weight loss, was more than three times greater at the industrial site (NJ) than at
rural sites. Parti culate matter concentrations ranged from 14 //g/m3 in NY to 60 //g/m3 in OH
and DC. The concentration ranges for other pollutants at the 5 sites appears in Table 9-1. Even
at the industrial site the corrosion rate was very low at a factor of about 10 less than for
Galvalume (aluminum-zinc). The exposure time and the average corrosion rate by site is listed
in Table 9-2.
Copper and Copper Alloys
Graedel et al. (1987) studied the chemical composition of patinas exposed in the greater
New York area for from 1 to 100 years and compared the results with estimated dry and wet
deposition of pollutants between 1886 and 1983. They concluded that the long-term corrosion
of copper was not controlled by deposition of pollutants, but rather, it was more
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TABLE 9-1. ANNUAL AVERAGE AND MAXIMUM VALUES OF THE HOURLY
AVERAGES FOR SULFUR DIOXIDE (SO2), NITROGEN OXIDE (NOX),
AND OZONE (O3) AND ANNUAL AVERAGES OF THE MONTHLY AVERAGES
OF RAIN pH AT THE FIVE MATERIAL EXPOSURE SITES, BASED
ON DATA ACQUIRED DURING 1986a
Particulate
SO7 (ppb) NO7 (ppb) O, (ppb) Matter (//g/tn3)
Site
NC
DC
NJ
NY
OH
Avg.
2±4
12±9
6±7
2±3
15±17
Max.
45
91
87
29
450
Avg.
14±9
28±12
14±10
2±2
19±11
Max.
65
91
98
21
98
Avg.
25±21
17±16
30±20
30±14
19±17
Max.
99
99
114
99
94
Avg.
35
60
30
14
60
Avg.
4.33
4.10
4.16
4.28
3.90
aThe ± errors are estimates of one standard deviation on a single hourly average based on the dispersion of the
data.
Source: Baedecker et al. (1991).
TABLE 9-2. AVERAGE CORROSION RATES FOR 3003-H14 ALUMINUM
OBTAINED DURING THE NATIONAL ACID PRECIPITATION ASSESSMENT
PROGRAM BETWEEN 1982 AND 1987
Site
NC
DC
NJ
NY
OH
Exposure Time (y)
5
5
5
5
1
Average Corrosion Rate (//m/y)
0.036
0.069
0.106
0.036
0.056
Source: Baedecker et al. (1991).
likely controlled by the availability of copper to react with deposited pollutants. The patina, that
is mostly basic sulfate, is not readily dissolved by acids and thus provides significant protection
for the substrate metal. However, according to Simpson and Horrobin (1970), the formation of
these basic copper salts can take as long as 5 or more years and will vary with the concentration
of SO2 or chloride particles, the humidity, and the temperature.
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Butlin et al. (1992a) reported an average rate for copper corrosion of 1 ± 0.2 //m/y in 19 of
29 sites evaluated. In areas where there was above average SO2, mass loss ranged from 1.5 to
1.75 //m/y. The lowest recorded mass loss was 0.66 //m/y in an area with low precipitation and
low SO2. The maximum pit depth over a 2-year period was 63 //m.
Meakin et al. (1992) reported on the atmospheric degradation of monumental bronzes.
They measured ion concentrations in rain run off from brigade markers at the Gettysburg
National Military Park as well as rain samples. There was a very strong correlation between
copper and sulfate ions with a regression coefficient not significantly different from the
stoichiometric value for cupric sulfate. There appeared to be little correlation between the
acidity of the run off and the acidity of the rain fall on the markers. Dry deposition between rain
events was concluded to dominate the soluble corrosion of the bronze.
Because of the complexity of the patina formation, few damage functions have been
reported and most of those that have been reported were based on short-term data when the
patina had not developed. Corrosion rates of 0.5 to 1 //m/y have been predicted by these
equations. However, the values greatly over estimate long-term damage and would be
misleading in an economic assessment.
Although limited to 5 years of exposure, the National Acid Precipitation Assessment
Program study (Baedecker et al., 1991; Cramer et al., 1989) may be useful in evaluating the
affects of SO2 on copper because it analyzed 110 Cu soluble corrosion data with components of
the previously discussed generic damage function. The average total corrosion rate between
3 and 5 years was about 1 //m/y but the soluble portion was less than a third of that which could
be statistically attributed to SO2. The resulting coefficient for the product of SO2 times the time-
of-wetness was 0.18 cm/s which has the units of a deposition velocity. This term may be
multiplied by a stoichiometric conversion factor to get a corrosion rate. With SO2 expressed in
mg/m3 and time-of-wetness in years, the conversion factor for//m/y of Cu to cupric sulfate is
0.035. The coefficient is 0.0063 and for an average concentration of 20 mg/m3 of SO2 the
resulting corrosion rate is 0.126 //m/y of wetness. If the surface is wet only a quarter of the
time, the corrosion rate attributable to SO2 is around 0.03 //m/y. If the patina color has aesthetic
value, and SO2 accelerates the formation, then, in the case of Cu, the presence of SO2 may be
beneficial.
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Zinc and Galvanized Steel
In the presence of moisture and oxygen, zinc will form an initial corrosion product of zinc
hydroxide. Carbon dioxide (CO2) in the atmosphere further reacts with this film to form basic
zinc carbonates. This corrosion product is insoluble in neutral environments but dissolves in
both strong acids and strong bases. Zinc is electrochemically more active than iron. Coating
steel with zinc provides a protection to the steel substrate against atmospheric corrosion.
Many studies conducted on the corrosive properties of zinc and zinc products are
extensively evaluated in the National Acid Precipitation Assessment Program report (Baedecker
et al., 1991). Two of the studies, conducted over a 20-year period, showed zinc corrosion rates
of 0.22 to 7.85 //m/y from 1931 to 1951 and 0.6 to 3.6 //m/y from 1957 to 1977 (Anderson,
1956; Showak and Dunbar, 1982). State College, PA was the only site common to both studies.
The corrosion rates were 1.13 and 1.2 //m/y.
Harker et al. (1980) examined the variables controlling the corrosion of zinc by SO2 and
sulfuric acid (H2SO4). Experimental conditions were selected from the following ranges:
Temperature 12to20°C
Relative humidity 65 to 100%
Mean flow velocity 0.5 to 8 m/s
Sulfur dioxide concentration 46 to 216 ppb
Sulfate aerosol mass concentration 1.2 mg/m3
Aerosol size distribution 0.1 to 1.0 //m
The factors controlling the rate of corrosion were found to be relative humidity, pollutant
flux, and the chemical form of the pollutant. Corrosion occurred only when the relative
humidity was greater than 60%. The deposition velocities were 0.07 cm/s for 0.1 to 1.0 ppm
H2SO4 aerosols and 0.93 cm/s for SO2 at a friction velocity of 35 cm/s. The results indicate that
SO2-induced corrosion of zinc proceeds at a rate approximately a factor of two greater than that
for the equivalent amount of deposited H2SO4 aerosol. Temperature did not appear to be a
controlling factor within the range 12 to 20 °C.
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Edney et al. (1986) conducted controlled environmental chamber experiments on
unexposed galvanized steel panels to determine the rate at which SO2 deposits to fresh test
panels and the fate of the deposited compound. During exposure, dew was periodically
produced on some of the panels. After exposure, samples were washed with sprays of different
pH levels to simulate acidic wet deposition. The runoff samples were analyzed for corrosion
product ions.
In the absence of dew, deposited SO2 was absorbed. With dew present, the absorption rate
increased substantially. At a chamber flow rate of 3 m/s, the flux of SO2 to the panel surfaces
was directly proportional to the air concentration and the regression slope represents a deposition
velocity of 0.9 cm/s. A linear regression slope between zinc and sulfate in the runoff was 1.06,
which is consistent with a stoichiometric reaction.
The National Acid Precipitation Assessment Program (Baedecker et al., 1991; Cramer et
al., 1989) included zinc and galvanized steel panels in its field exposure experiments in
Newcomb, NY, Newark, NJ, Washington, DC, Research Triangle Park, NC, and Steubenville,
OH. The NC and OH sites were the only two of the 5 sites that had covers and spray devices set
up to separate the effects of wet and dry deposition of pollutants. Air quality, meteorological
parameters, and rain chemistry were determined at all sites. Runoff samples were collected and
analyzed for both ambient rain and the deionized water spray.
In general, the rolled zinc corrosion rates were larger than those found for the galvanized
steel panels, most likely because of a protective chromate treatment that had been factory applied
to the galvanized steel. The deposition of SO2 was one of several corrosion contributing factors.
The concentrations of SO2 at the different sites varied by as much as a factor of 10, but the
corrosion rates were within a factor of 2 (see Table 9-3). Pollutant concentrations at the 5
exposure sites appear in Table 9-1.
At the NC and OH sites, exposed samples of both zinc and galvanized steel corroded more
than similar samples exposed to the clean simulated rain. Although SO2 levels were higher at
the OH site, the deionized water spray samples corroded about the same at both sites. This
result, together with high levels of particles at the industrial OH site, may indicate that much of
the deposited SO2 was neutralized by dry deposited alkaline particles.
Cramer et al. (1989) did a preliminary analysis of the soluble fraction of the total zinc
corrosion with respect to the model of the generic damage function. The multiple regression
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TABLE 9-3. AVERAGE CORROSION RATES FOR ROLLED ZINC AND
GALVANIZED STEEL OBTAINED DURING THE NATIONAL
ACID PRECIPITATION ASSESSMENT PROGRAM FIELD EXPERIMENTS
Average Corrosion Rate (//m/y)
Site
NC
DC
NJ
NY
OH
Exposure Time (y)
5
5
5
5
1
Rolled Zinc
0.81
1.27
1.32
0.63
1.33
Galvanized Steel
0.73
0.71
0.99
0.63
0.99
Source: Baedecker et al. (1991)
analysis gave significant coefficients for SO2, hydrogen ions (If), and CO2 in precipitation. The
coefficient for SO2 was not significantly different from stoichiometric for both the rolled zinc
and the chromated galvanized steel. Most of the zinc corrosion product was soluble. Haynie
et al. (1990) have calculated the solubility of basic zinc carbonate in equilibrium with water
containing CO2. Zinc solubility is very temperature dependent due to the strong inverse
dependence of CO2 solubility in water, leading to increased dissolution of the corrosion products
as the ambient temperature decreases.
In the study reported by Butlin et al. (1992a), galvanzied steel was found to corrode at a
rate of 1.45 //m/y (high precipitation, low SO2) to 4.25 //m/y (high SO2). Galvanized steel
samples from the area of low rainfall and low SO2 had a corrosion rate of 1.53 //m/y.
Metallographical evaluation of the galvanized steel samples showed only superficial corrosion
with no penetration of the zinc coating.
The various factors that contribute to the corrosion of zinc and galvanized steel are
discussed in more detail in terms of the model of the generic damage function in Spence and
Haynie (1990), Haynie et al. (1990), and Spence et al. (1992). The combined terms of the long-
term form of the model are:
C=F+Cd+CRA+CRC (9-5)
where C is total corrosion in //m, F is the equivalent thickness of zinc remaining in the insoluble
corrosion product film and, at steady state, is equal to a/b, Cd is the corrosion
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associated with deposition of SO2 both in wet and dry periods, and CRC is the corrosion due to
rain acidity (H+ and dissolved CO2). The SO2 contribution, Cj, is expressed as follows:
Cd = 0.045 Vd(S02)tw + 1.29 x 10 4ArN (9-6)
where,
Cd = zinc corrosion, //m
Vd = deposition velocity (wind speed, shape, and size dependent), cm/s
SO2 = ambient SO2 concentration, mg/m3.
A,. = ratio of actual to apparent surface area
N = number of times surface is dry during the exposure period.
The first additive term represents corrosion from the dry deposition of SO2 during periods
of wetness caused by condensation (dew), and the second term is the corrosion associated with
the adsorption of a monolayer of SO2 during periods of dryness.
In the absence of sufficient data to accurately determine each of the terms, Haynie et al.
(1990), and Spence et al. (1992) have applied assumed values for flat galvanized specimens
(different sizes), large sheets, and wire with reasonable success. More recently, Cramer and
Baker (1993) have applied the generic damage function to predict the expected life of the
restored tin plated roof of Monticello. Thus, the model can be used to assess the economic
effects of atmospheric corrosion on several metals, especially zinc.
9.1.3.2 Particles
Only limited information is available on the effects of particles alone on metals. Goodwin
et al. (1969) reported damage to steel, protected with a nylon screen, exposed to quartz particles.
The damage did not, however, become substantial until the particle size exceeded 5 //m. Barton
(1958) found that dust contributed to the early stages of metal corrosion. The effect of dust was
lessened as the rust layer formed. Other early studies also indicated that suspended particles can
play a significant role in metal corrosion. Sanyal and Singhania (1956) wrote that particles,
along with other cofactors and SO2, promoted the corrosion of metals in India. Yocom and
Grappone (1976) and Johnson et al. (1977) reported that moist air containing both particles and
SO2 resulted in a more rapid corrosion rate than air polluted with SO2 alone. Russell (1976)
stated that particles serve as points for
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the concentration of active ionic species on electrical contact surfaces, thereby increasing the
corrosion rate of SOX. However, other studies have not established a conclusive statistical
correlation between total suspended particulates (TSP) and corrosion, possibly due to data
limitations (Mansfeld, 1980; Haynie andUpham, 1974; andUpham, 1967; Yocom andUpham,
1977).
Edney et al. (1989) reported on the effects of particles, SO2, NOX, and O3 on galvanized
steel panels exposed under actual field conditions in Research Triangle Park, NC, and
Steubenville, OH, between April 25 and December 28, 1987. The panels were exposed under
the following conditions: (1) dry deposition only; (2) dry plus ambient wet deposition; and (3)
dry deposition plus deionized water. The average concentrations for SO2 (in ppb) and
particulate matter (in //g/m3) was 22 ppb and 70 //g/m3 and <1 ppb and 32 //g/m3 for
Steubenville and Research Triangle Park, respectively. By analyzing the runoff from the steel
panel the authors concluded that the dissolution of the steel corrosion products for both sites was
likely the result of deposited gas phase SO2 on the metal surface and not parti culate sulfate.
Dean and Anthony (1988) investigated the atmospheric corrosion of unstressed wrought
aluminum alloys at three sites representing industrial, marine, and coastal-industrial
environments. After 10 years of exposure, degradation was measured by several means. They
reached the following conclusions: (1) a sooty industrial environment is far more damaging than
a warm, salt-laden seacoast atmosphere, (2) by far the most noticeable effect of prolonged
atmospheric exposure is loss of ductility in susceptible alloys, and (3) sacrificial cladding
completely eliminates ductility loss.
Walton et al. (1982) performed a laboratory study of the direct and synergistic effects of
different types of particles and SOX on the corrosion of aluminum, iron, and zinc. The four most
aggressive species were salt and salt/sand from marine or deiced locations, ash from iron
smelters, ash from municipal incinerators, and coal mine dusts. Fly ashes of various types were
less aggressive. Coal ash with SOX did promote corrosion but oil fly ash was relatively
noncorrosive. This suggests that catalytic species in the ash promote the oxidation of SOX and
the presence of SOX alone is not sufficient to accelerate corrosion. Other laboratory studies of
metal corrosion provide considerable evidence that the catalytic effect is not significant and that
atmospheric corrosion rates are dependent on the
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conductance of the thin-film surface electrolyte and that the first-order effect of contaminant
particles is to increase solution conductance, and, hence corrosion rates (Skerry et al., 1988a,b;
Askey etal., 1993).
9.1.4 Paints
Paints, opaque film coatings, are by far the dominant class of manmade materials exposed
to air pollutants in both indoor and outdoor environments. Paints are used as decorative
coverings and protective coatings against environmental elements on a variety of finishes
including woods, metals, cement, asphalt, etc.
Paints primarily consists of two components: the film forming component and the
pigments. Paints undergo natural weathering processes from exposure to environmental factors
such as sunlight (ultraviolet light), moisture, fungi, and varying temperatures. In addition to the
natural weathering from exposure to environmental factors, evidence exists that demonstrates
pollutants affect the durability of paint (National Research Council, 1979).
Paint failure may be manifested by two general degradation modes. The first involves the
paint surface and includes paint discoloration, chalking, loss of gloss, and erosion. Paint erosion
can be measured by loss of thickness of the paint layer. The second is degradation at the
paint/substrate interface, which can be manifested as loss of adhesion leading to blistering and
peeling.
In paint formulas, the ratio of pigments to film formers is important to the overall
properties of gloss, hardness, and permeability to water. If the amount of film former is too low,
soiling is increased and the paint may lose the film flexibility needed for durability and become
brittle.
9.1.4.1 Acid-Forming Aerosols
Paint films permeable to water are also susceptible to penetration by SO2 and SO^"
aerosols. Baedecker et al. (1991) reviewed about twenty papers (1958 to 1985) dealing with
solubility and permeability of SO2 in paints and polymer films. Permeation and adsorption rates
varied by as much as several orders of magnitude depending on formulation. They concluded
that unpigmented polymer films have a large range of permeabilities but that the polymers used
in paint formulations generally do not form barriers to SO2 either in the
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gaseous state or in solution as sulfurous acid. Although 20% of the absorbed SO2 was retained
in alkyd/melamine and epoxide films and probably reacted with the polymer, there appears to be
little degradation to the polymer itself from SO2 at low concentrations. Absorption is inhibited
by pigments; those pigments that can catalyze the oxidation of SO2 and scavenge the resulting
sulfate ions can limit the penetration even more than can typical pigments.
Concentrations of SO2 found in fog or near industrial sites can increase the drying and
hardening times of certain kinds of paints. Holbrow (1962) found that the drying time of
linseed, tung, and certain castor oil paint films increased by 50 to 100% on exposure to 2,620 to
5,240 //g/m3 (1 to 2 ppm) SO2. The touch-dry and hard-dry times of alkyl and oleoresinous
paints with titanium dioxide pigments were also reported to increase substantially; however, the
exposure time of the wet films was not reported. Analysis of the dried films indicated that SO2
chemically reacted with the drying oils, altering the oxidation-polymerization process. No
studies have been reported on the effects of SO2 on the drying of latex paints.
Spence et al. (1975) conducted a controlled exposure study to determine the effects of
gaseous pollutants on four classes of exterior paints: oil-base house paint, vinyl-acrylic latex
house paint, and vinyl and acrylic coil coatings for metals. The house paints were sprayed on
aluminum panels. The coil coating panels were cut from commercially painted stock. Recorded
paint thickness was oil-base paint film, 58 //m; acrylic latex, 45 //m; vinyl coil coating, 27 //m;
and acrylic coil coating, 20 //m. Temperature, humidity, and SO2, (78.6 and 1,310 //g/m3), NO2
(94 and 940 //g/m3), and O3 (156.8 and 980 //g/m3) exposures were controlled. Each exposure
chamber had a xenon arc lamp to provide ultraviolet radiation. A dew/light cycle was included;
light exposure time was followed by a dark period during which coolant circulated through racks
holding the specimens, thereby forming dew on the panels. Each dew/light cycle lasted 40 min
and consisted of 20 min of darkness with formation of dew, followed by 20 min under the xenon
arc. The total exposure time was 1,000 h. Damage was measured after 200 h, 500 h, and 1,000
h by loss of both weight and film thickness. In evaluating the data, loss of weight was converted
to equivalent loss of film thickness.
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Visual examination of the panels coated with oil-base house paint revealed that all
exposure conditions caused considerable damage. The erosion rate varied from 28.3 to 79.14
//m/y, with an average of 60 //m/y. The investigators concluded that SO2 and relative humidity
markedly affected the rate of erosion of oil-base house paint. The presence of NO2 increased the
weight of the paint film. A multiple linear regression on SO2 concentration and relative
humidity yielded the following relation:
E= 14.3 + 0.0151 SO2 +0.388 RH (9-7)
where
E = erosion rate in //m/y,
SO2 = concentration of SO2 in //g/m3, and
RH = relative humidity in percent.
The authors reported the 95% tolerance limits on 99% of the calculated rates to be ±44 //m/y.
Blisters formed on the acrylic latex house paint at the high SO2 levels. The blisters
resulted from severe pitting and buildup of aluminum corrosion products on the substrate. The
paint acted as a membrane retaining moisture under the surface and excluding oxygen that would
passivate the aluminum. The vinyl coating and the acrylic coating are resistant to SO2. The
visual appearance of the vinyl coil coating showed no damage. The average erosion rate was
low, 3.29 //m/y. The average erosion rate for a clean air exposure was 1.29 //m/y. The acrylic
coil coating showed an average erosion rate of 0.57 //m/y (Spence et al., 1975).
A study of the effects of air pollutants on paint, under laboratory controlled conditions,
was conducted by Campbell et al. (1974). The paints studied included oil and acrylic latex
house paints, a coil coating, automotive refmish, and an alkyd industrial maintenance coating.
These coatings were exposed to clean air, SO2 at 262 and 2,620 //g/m3, and O3 at 196 and 1,960
Mg/m3. Light, temperature, and relative humidity were controlled. In addition, one-half of the
coatings were shaded during the laboratory exposures. Similar panels (half facing north) were
exposed at field sites in Leeds, ND; Valparaiso, IN; Research Center, Chicago, IL; and Los
Angeles, CA.
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The laboratory exposure chamber operated on a 2-h light-dew cycle (i.e., 1 h of xenon
light at 70% relative humidity and a temperature of 66 °C followed by 1 h of darkness at 100%
relative humidity and a temperature of 49 °C). Coating erosion rates were calculated after
exposure periods of 400, 700, and 1,000 h. Erosion rates for samples exposed to the lowest
exposure concentrations were not significantly different from values for clean air exposures due
to the high variability of the data. The erosion rates on the shaded specimens were significantly
less than the unshaded panel results; panels facing north were also less eroded. At the highest
exposure concentrations, erosion rates were significantly greater than controls for both
pollutants, with oil-base house paint experiencing the largest erosion rate increases, latex and
coil coatings moderate increases, and the industrial maintenance coating and automotive refmish
the smallest increases (Yocom and Grappone, 1976; Yocom and Upham, 1977; and Campbell
et al., 1974). Coatings that contained extender pigments, particularly calcium carbonate
(CaCO3), showed the greatest erosion rates from the SO2 exposures. Results of field exposures
also support these conclusions (Campbell et al., 1974).
Haynie and Spence (1984) evaluated data on two house paints that were exposed for up to
30 mo at 9 environmental monitoring sites in the St. Louis, MO area. The paints were
formulated with and without CaCO3 and applied to stainless steel panels. Multiple regression
analysis of mass loss versus the environmental variables revealed no statistical differences
associated with SO2.
Hendricks and Balik (1990) evaluated the effects of SO2 on free films of paint and the latex
polymer for one of the paints and established diffusion coefficients for SO2 in the various
formulations. Pigments, as well as fillers such as CaCO3, were found to decrease the diffusion
coefficient. A latex polymer desorbed all SO2 when placed in a vacuum but an alkyd retained
approximately 15 to 20% SO2 even after several days. Xu and Balik (1989, 1990) concluded
that the gas had reacted with the polymer in the paint. They also determined quantitatively the
rate of CaCO3 removal from paints exposed to different pH levels of sulfurous acid or distilled
water (weak carbonic acid). The rates of dissolution were dependent on acid strength but
removal was complete for all acids. The mass loss was 27%. A similar paint without CaCO3
lost only 7%.
Patil et al. (1990) reported that certain combinations of SO2/H2O/UV light (high SO2
levels) had detrimental effects when they were evaluating various techniques for measuring
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film degradation. Mechanical properties were dominated by cross-linking. While SO2 had little
effect when dry, there was considerable chain scissioning when exposed wet. Sanker et al.
(1990) found that after exposing the polymer to SO/UV light that there was a decrease in
carbonyl signal associated with the acrylate group, whereas no decrease in carbonyl signal was
associated with samples exposed to UV light alone. They reported a synergistic effect on
polymer degradation between UV light and SO2 under both wet and dry conditions.
Edney (1989) and Edney et al. (1988, 1989) measured the chemical composition of runoff
from painted red cedar and zinc panels exposed at field sites in Raleigh, NC, and Steubenville,
OH, and in controlled chambers. Acidic gases such as SO2 and nitric acid dissolved alkaline
(CaCO3 or ZnO) components in the paint.
Williams et al. (1987) demonstrated that weathering of wood prior to painting decreases
the adhesion of paint. Significant decreases in paint adhesion were noted in panels weathered
for 4 weeks and those weathered for 16 weeks had about a 50% decrease in adhesive strength.
In similar studies, it was shown that acid treatment of specimens during weathering increased the
rate of surface deterioration; the rate of wood weathering increased by as much as 50% when it
was exposed to sulfurous, sulfuric, or nitric acids (Williams, 1987, 1988).
As part of the National Acid Precipitation Assessment Program, Davis et al. (1990) studied
the effects of SO2 on oil/alkyd systems on steel using a custom designed exposure chamber in
which a dew cycle could be simulated. Energy dispersive X-ray microscopy scans were made
across primer/paint cross-sections. Samples were exposed to 1 ppm SO2 at 90 to 95% relative
humidity, and thermally cycled (12-h dew cycle followed by 12-h drying period) or the chamber
was maintained at a constant temperature. Controls were exposed under similar conditions but
without SO2. All samples gained weight after 7 days of exposure. The greatest weight gain was
noted in the cyclic samples (30 to 40% more than those samples maintained under constant
temperatures). After 28 days to cyclic (dew/drying) conditions samples exposed to SO2 had
rusted scribe marks while the controls showed only light rust.
As the specimens were exposed in the chamber, the tensile strength decreased significantly
and the locus of failure shifted from within the coating system to the primer-metal interface.
The relationship of tensile strength to metal/primer failure was
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approximately linear, suggesting that the decrease in tensile strength was dominated by a loss or
weakening of adhesion between the substrate and the primer (Davis et al., 1990).
9.1.4.2 Particles
Several studies suggest that particles serve as carriers of other more corrosive pollutants,
allowing the pollutants to reach the underlying surface or serve as concentration sites for other
pollutants (Cowling and Roberts, 1954).
Reports have indicated that particles can damage automobile finishes. In an early study,
staining and pitting of automobile finishes was reported in industrial areas. The damage was
traced to iron particles emitted for nearby plants (Fochtman and Langer, 1957). General Motors
conducted a field test to determine the effect of various meteorological events, the chemical
composition of rain and dew, and the ambient air composition during the event, on automotive
paint finishes. The study was conducted in Jacksonville, FL. Painted (basecoat/clearcoat
technology) steel panels were exposed for varying time periods, under protected and unprotected
conditions. Damage to paint finishes appeared as circular, elliptical, or irregular spots, that
remained after washing. Using scanning electron microscopy (high magnification) the spots
appeared as crater-like deformities in the paint finish. Chemical analyses of the deposit
determined calcium sulfate to be the predominant species. It was concluded that calcium sulfate
was formed on the paints surface by the reaction of calcium from dust and sulfuric acid
contained in rain or dew. The damage to the paint finish increased with increasing days of
exposure (Wolff et al., 1990). Table 9-4 contains the atmospheric pollutants and their
concentrations during the study.
The formulation of the paint will affect the paint's durability under exposure to varying
environmental factors and pollution; however, failure of the paint system results in the need for
more frequent repainting and additional cost.
9.1.5 Stone and Concrete
Air pollutants are known to damage various building stones. Some of the more susceptible
stones are the calcareous stones, such as limestone, marble and carbonated cemented stone. The
deterioration of inorganic building materials occurs initially through surface weathering.
Moisture and salts are considered the most important factors in building
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TABLE 9-4. SUMMARY OF MEASURED PARAMETERS
JACKSONVILLE, FLORIDA
(Statistics based on 8-h samples)
IN
Variable
Fine particulatesd (//g/m3)
Particulate matter6 (//g/m3)
Total suspended particulates (//g/m3)
Fine sulfatesf (//g/m3)
Sulfates6 (Mg/m3)
Sulfur dioxide (//g/m3)
Fine ammonium (//g/m3)
Fine organic carbon (//g/m3)
Organic carbon6 (//g/m3)
Fine elemental carbon (//g/m3)
Elemental carbon6 (//g/m3)
Fine calcium (ng/m3)
Calcium (ng/m3)
Fine silica (ng/m3)
Silica6 (ng/m3)
Potassium6 (ng/m3)
Titanium6 (ng/m3)
Iron6 (ng/m3)
Total nitrates (//g/m3)
Nitric acid (//g/m3)
Fine nitrates (//g/m3)
Nitrogen oxide (ppb)
Nitrogen dioxide (ppb)
Oxone (maximum) (ppb)
Meanb
22.2
38.7
55.8
6.9
7.7
6.7
2.5
2.0
4.4
1.3
1.8
284.0
3,572.0
132.0
995.0
348.0
42.0
421.0
1.3
0.7
0.6
3.1
8.8
48.0
Overall3
Standard
Deviation
11.0
15.9
22.2
4.6
4.9
9.8
1.5
1.3
2.8
1.1
1.8
224.0
3,850.0
214.0
909.0
140.0
38.0
388.0
1.3
1.2
0.3
4.0
5.9
20.2
Maximum6
58.2
89.8
129.2
18.1
18.9
56.6
7.8
6.4
12.9
5.4
8.5
1,145.0
21,073.0
1,797.0
6,572.0
920.0
237.0
3,090.0
8.4
7.8
1.5
19.2
32.3
93.0
aOverall = combination of three daily 8-h samples.
bMean daily ozone maximum.
°Maximum ozone concentration over the study period.
d<2.5 ^m.
ePM10 variables.
f<2.5 ^m.
Source: Wolff et al. (1990).
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material damage. Many researchers believe that the mechanism of damage from air pollution
involves the formation of salts from reactions in the stone; subsequently, these surface salts
dissolve in moist air and are washed away by rainfall. Luckat (1977) reported good correlation
with stone damage and SO2 uptake. Riederer (1974) and Niesel (1979) reported that stone
damage is predominantly associated with relative humidity >65% and freeze/thaw weathering.
Still other researchers suggest that microorganisms must also be considered in order to quantify
damage to building materials due to ambient pollutant exposure (Winkler, 1966; Riederer, 1974;
Krumbein and Lange, 1978; Eckhardt, 1978; Hansen, 1980). Sulfur chemoautotrophs are well
known for the damage they can cause to inorganic materials. These microorganisms (e.g.,
Thiobacillus) convert reduced forms of sulfur to H2SO4 (Anderson, 1978) and the presence of
sulfur oxidizing bacteria on exposed monuments has been confirmed (Vero and Sila, 1976). The
relative importance of biological, chemical, and physical mechanisms, however, have not been
systematically investigated. Thus, damage functions definitely quantifying the relationship of
pollutant concentrations to stone and concrete deterioration are not available in the literature.
Baedecker et al. (1991) reviewed the published literature on calcareous stones and
concluded that the most significant damage to these stones resulted from the exposure to natural
constituents of nonpolluted rain water; carbonic acid from the reaction of CO2 with rain reacts
with the calcium in the stone. Based on the work conducted by the National Acid Precipitation
Assessment Program, 10% of chemical weathering of marble and limestone was caused by wet
deposition of hydrogen ions from all acid species. Dry deposition of SO2 between rain events
caused 5 to 20% of the chemical erosion of stone and the dry deposition of nitric acid was
responsible for 2 to 6% of the erosion (Baedecker et al., 1991).
Niesel (1979) completed a literature review on the weathering of building stone in
atmospheres containing SOX, which includes references from 1700 to 1979. In summary,
he reported that weathering of porous building stone containing lime is generally characterized
by accumulation of calcium sulfate dihydrate in the near-surface region. The effect of
atmospheric pollutants on the rate of weathering is believed to be predominantly controlled by
the stone's permeability and moisture content. Migrating moisture serves primarily as a transport
medium. Sulfur dioxide is sorbed and thus can be translocated internally while being oxidized
to sulfates. Reacting components of the building stone are
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thus leached, the more soluble compounds inward and the less soluble toward the surface, often
forming a surface crust.
Sengupta and de Gast (1972) reported that SO2 sorption causes physical changes in stone
involving changes in porosity and water retention. Removal of CaCO3 changes the physical
nature of the stone surface. The hard, nonporous layer that forms as a result of alternate freezing
and thawing may blister, exfoliate, and separate from the surface. If the stone contains some
substances that are unaffected by SO2, the surface can deteriorate unevenly. The conversion of
CaCO3 to calcium sulfate results in a type of efflorescence called "crystallization spalling."
Baedecker et al. (1992) reported the results of a study on carbonate stone conducted as a
part of National Acid Precipitation Assessment Program. Physical measurements of the
recession of test stones exposed to ambient conditions at an angle of 30° to horizontal at 5 sites
ranged from 15 to 30 //m/y for marble and from 25 to 45 //m/y for limestone and were
approximately double the recession estimates based on the observed calcium content of run-off
solutions from test slabs. The difference between the physical and chemical recession
measurements was attributed to the loss of mineral grains from the stone surfaces that were not
measured in the run-off experiments. The erosion due to grain loss did not appear to be
influenced by rainfall acidity, however, preliminary evidence suggested that grain loss may be
influenced by dry deposition of SO2 between rain events. Chemical analysis of the run-off
solutions and associated rainfall blanks suggested 30% of erosion by dissolution could be
attributed to the wet deposition of hydrogen ion and the dry deposition of SO2 and nitric acid
between rain events. The remaining 70% of erosion by dissolution is accounted for by the
solubility of carbonate stone in rain that is in equilibrium with atmospheric CO2 (clean rain).
These results are for slabs exposed at 30° angles. The relative contribution of SO2 to chemical
erosion was significantly enhanced for slab having an inclination of 60° to 85°. The dry
deposition of alkaline particles at the two urban sites competed with the stone surface for
reaction with acidic species.
Sweevers and Van Grieken (1992) studied the deterioration of sandstone, marble and
granite under ambient atmospheric conditions. Specially constructed sampling devices, called
"micro catchment units", were installed to sample the run-off water (i.e. the rain that flows over
the stones). Several analysis techniques were invoked for the analysis of the bulk
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runoff water, as well as electron probe X-ray microanalysis for individual particles in the runoff.
There was a strong calcium to sulfate correlation on sandstone but not on granite after extended
exposures.
Webb et al. (1992) studied the effects of air pollution on limestone degradation in Great
Britain. There was a significant trend to increased weight loss with increased average SO2
concentration, but a negative trend with total NOX and with NO2. Rainfall did not significantly
affect limestone degradation. Based on a mass and ion balance model, the natural solubility of
limestone in water was the dominant term in describing the stone loss. The average overall
recession rate was 24 //m/y. The increase in stone loss due to SO2 was less than 1 //m/year/ppb.
Butlin et al. (1992b) correlated damage to stone samples exposed at 29 monitoring sites in
Great Britain. Portland limestone, White Mansfield dolomitic sandstone, and Monks Park
limestone tablets (50 x 50 x g //m) were exposed both under sheltered and unsheltered
conditions. Weight change and ionic composition of surface powders were determined after one
and two years of exposure.
The results showed the expected increases in acidic species and soluble calcium in the
sheltered tablets. The stone deterioration data were statistically analyzed with respect to the
environmental variables at the sites. Significant correlations existed between the mean annual
SO2 concentration, rainfall volume, and hydrogen ion loading and the weight changes. These
three correlations contain the three components that appear to be responsible for the degradation
of calcareous stone, (1) dry deposition of acid gases and aerosols, (2) dissolution by acid species
in rain water, and (3) the dissolution of stone by unpolluted rain water.
By analyzing storm runoff from a Vermont marble sample and comparing the results with
the pollution exposure history, Schuster et al. (1994) have determined the relative contributions
of wet and dry deposition to accelerated damage. Data were compared with runoff from glass
for the same seven selected summer storms. Even though the exposure site had low
concentrations of SO2, it was estimated that between 10 and 50% of calcium washed from the
marble surface during a storm was from the dissolution of gypsum formed by the reaction of
SO2 during dry periods.
Yerrapragada et al. (1994) exposed samples of Carrara and Georgia marble for 6, 12, or 20
mo under normal atmospheric conditions. The samples were exposed outside, but
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protected from the rain, at sites in Jefferson County, KY. These authors also analyzed samples
of Georgia marble of varying ages from cemeteries in the Los Angeles basin. The researchers
reported that SO2 is more reactive with the calcium in marble under higher NO2 conditions. The
effects were noted even under relatively low SO2 and NO2 concentrations (10 to 20 and 22 to 32
ppb, respectively). Carrara marble was found to be more reactive with SO2 than Georgia
marble, possibly due to the more compactness of the Georgia marble.
The effect of dry deposition of SO2, NO2, and NO both with and without O3 on limestones
and dolomitic sandstone was reported by Haneef et al. (1993). Samples of Portland limestone,
Massamgis Jaune Roche limestone, and White Mansfield dolomitic sandstone were exposed to
10 ppm of each of the pollutants at a controlled relative humidity of 84% and a temperature of
292 °K. The stone samples were exposed to the controlled environment for 30 days. There was
a small increase in sample weights after the 30 day exposure for all samples. Those samples
exposed to O3 in addition to one of the other pollutants (SO2, NO2, or NO) showed a significant
increase in weight gain. All stone samples also showed retained sulfates or nitrates, particularly
in the presence of O3. When viewed by electron/optical techniques, a crust was noted on the
surface and lining the pores of the stones exposed to SO2 but not those exposed to NO2 or NO.
Wittenburg and Dannecker (1992) measured dry deposition and deposition velocities of
airborne acidic species on different sandstones. During different air-monitoring campaigns
carried out in urban sites in East and West Germany, the dry deposition of particles and gaseous
sulfur and nitrogen containing species on three different sandstones and on an inert substrate
were measured. The measured depositions were related to the ambient air concentrations of the
most important gaseous and paniculate species. Dry deposition velocities were calculated and
the proportions of particle and gas input depositions on the sandstones were estimated.
Salt accumulation in building stones was mainly caused by the gaseous components,
especially SO2. The deposition velocities were strongly dependent upon stone type. The
contribution of sulfate particle deposition on sandstones was around 5 to 10% for vertical
surfaces depending on the atmospheric conditions (Wittenburg and Dannecker, 1992).
Cobourn et al. (1993) used a continuing monitoring technique to measure the deposition
velocity of SO2 on marble and dolomite stone surfaces in a humid atmosphere over a
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2,000 ppm-h exposure period at approximately 10 ppm SO2 and 100% relative humidity. The
measured average deposition velocities of SO2 over the two stones were comparable in
magnitude. For dolomite, the measured deposition velocity varied between 0.02 and 0.10 cm/s,
whereas for the marble, the deposition velocity varied between 0.03 and 0.23 cm/s. The
measured deposition velocity for both types of stone changed as a function of time. The
deposition velocity over dolomite increased gradually with time. The increase was attributed to
a gradual increase of liquid water on the surface, brought about by the formation of the
deliquescent mineral epsomite. The wide variation appeared to be associated with the absence or
presence of condensed moisture on the marble sample surfaces. For most of the marble runs, the
deposition velocity generally decreased slightly with time, after an initial period. The decrease
could have been due to the build-up of reactions products on the stone surface.
Under high wind conditions, particles have been reported to result in slow erosion of
marble surfaces, similar to sandblasting (Yocom and Upham, 1977). Mansfeld (1980), after
performing statistical analysis of damage to marble samples exposed for 30 mo at 9 air quality
monitoring sites in St. Louis, MO, concluded that exposure to TSP and nitrates were correlated
with stone degradation. However, there is some concern over the statistical techniques used.
Generally, black and white areas can be observed on the exposed surfaces of any building.
The black areas, found in zones protected from direct rainfall and from surface runs, are covered
by an irregular, dendrite-like, hard crust composed of crystals of gypsum mixed with dust,
aerosols, and particles of atmospheric origin. Among these the most abundant are black
carbonaceous particles originating from oil and coal combustion. On the other hand, surfaces
directly exposed to rainfall show a white color, since the deterioration products formed on the
stone surface are continuously washed out.
The accumulation of gypsum on carbonate stone has been investigated by McGee and
Mossotti (1992) through exposure of fresh samples of limestone and marble at monitored sites,
examination of alteration crusts from old buildings, and laboratory experiments. McGee and
Mossotti (1992) concluded that several factors contribute to gypsum accumulation on carbonate
stone. Marble or limestone that is sheltered from direct washing by rain in an urban
environment with elevated pollution levels is likely to accumulate a gypsum crust.
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Crust development may be enhanced if the stone is porous or has an irregular surface area.
Gypsum crusts are a superficial alteration feature; gypsum crystals form at the pore opening/air
interface, where evaporation is greatest. Particles of dirt and pollutants are readily trapped by
the bladed network of gypsum crystals that cover the stone surface, but the particles do not
appear to cause the formation of gypsum crusts. Sabbioni and Zappia (1992) analyzed samples
of damaged layers on marble and limestone monuments and historical buildings from 8 urban
sites in Northern and Central Italy. Samples of black crust were taken from various locations at
each site to be representative of the entire site. The predominant species in the black crust
matrix was calcium sulphate dihydrate (gypsum). The evaluation of enrichment factors with
respect to the stone and to the soil dust showed the main components of the atmospheric
deposition to be from the combustion of fuels and incineration. Saiz-Jimenez (1993) also found,
after analyzing the organic compounds extracted for black crusts removed for building surfaces
in polluted areas, that the main components were composed of molecular markers characteristic
of petroleum derivatives. The composition of each crust, however, is governed by the
composition of the particular airborne pollutants in the area.
Sabbioni et al. (1992) conducted a laboratory study on the interaction between
carbonaceous particles and carbonate building stones. Three types of building stones with the
common characteristic of a carbonate matrix were used: (1) Carrar marble, (2) Travertine, and
(3) Trani stone. Samples of the emissions from two oil-combustion sources, representative of a
centralized domestic heating system and an electric generating plant, were characterized by
means of chemical and physical analysis and spread manually on the stone samples. Any excess
was removed using compressed air. The distribution of the particles on the surface of the
samples was controlled by optical microscopy. The stone samples were weighed before and
after the particle deposition. Stones without particles were also exposed as reference samples.
The samples with particles containing the highest carbon content had the lowest reactivity in the
sulfation process. Particles with high sulphur content enhanced the reactivity of the stone
samples with SO2 (Sabbioni et al., 1992).
Del Monte et al. (1981) reported evidence of a major role for carbonaceous particles in
marble deterioration, using scanning electron microscopy. The majority of the carbonaceous
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particles were identified as products of oil fired boiler/combustion. Particle median diameter
was «10 //m.
Delopoulou and Sikiotis (1992) compared the corrosive action of nitrates and sulfates on
pentelic marble with that of NOX and SO2. This was achieved by passing the polluted ambient
air through a filter pack before it entered the reactor chamber holding the marble grains. As a
consequence, the air reaching the marble was free of nitrates and sulfates while it contained all
the NOX and SO2. The effects on the marble grains were quantified and compared with those
from a reactor through which unfiltered ambient air was passed simultaneously and under the
same conditions. They reported that the action of the acids was much greater than that of the
oxides, despite the fact that the concentrations of the latter were much greater.
9.1.6 Corrosive Effects of Acid-Forming Aerosols and Particles on Other
Materials
Exposure to ionic dust particles can contribute significantly to the corrosion rate of
electronic devices, ultimately leading to failure of such device. Anthropogenically and naturally
derived particles ranging in size from tens of angstroms to 1 //m cause corrosion of electronics
because many are sufficiently hygroscopic and corrosive at normal relative humidities to react
directly with non-noble metals and passive oxides, or to form sufficiently conductive moisture
films on insulating surfaces to cause electrical leakage. The effects of particles on electronic
components were first reported by telephone companies, when particles high in nitrates caused
stress corrosion cracking and ultimate failure of the wire spring relays (Hermance, 1966;
McKinney and Hermance, 1967). More recently, attention has been directed to the effects of
particles on electronic components, primarily in the indoor environment.
Sinclair (1992) discussed the relevance of particle contamination to corrosion of
electronics. Data collected during the 1980s show that the indoor mass concentrations of
anthropogenically derived airborne particles and their arrival rates at surfaces are comparable to
the concentrations and arrival rates of corrosive gases for many urban environments.
Frankenthal et al. (1993) examined the effects of ionic dust particles, ranging from 0.01 to
1 (j,m in size, on copper coupons under laboratory conditions. The copper coupons,
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after being polished with diamond paste, were inoculated with ammonium sulfate [(NH4)2SO4)]
particles and exposed to air at 100 °C and relative humidities ranging from 65 to 100% for up to
600 h. The particles were deposited on the metal surface by thermophoretic deposition and
cascade impaction.
Exposure of the copper coupons to (NH4)2SO4 at 65% relative humidity had little effect on
the corrosion rate. However, when the relative humidity was increased to 75%, the critical
relative humidity for (NH4)2SO4 at 100 °C, localized areas of corrosion were noted on the metal
surface. The corrosion product, determined to be brochantite, was only found in areas where the
(NH4)2SO4 was deposited on the metal surface. When relative humidity was increased to 100%,
the corrosion became widespread (Frankenthal et al., 1993).
9.2 SOILING AND DISCOLORATION
A significant detrimental effect of particle pollution is the soiling of manmade surfaces.
Soiling may be defined as a degradation mechanism that can be remedied by cleaning or
washing, and depending on the soiled material, repainting. Faith (1976) described soiling as the
deposition of particles of less than 10 //m on surfaces by impingement. Carey (1959) observed
when particles descended continuously onto paper in a room with dusty air, the paper appeared
to remain clean for a period of time and then suddenly appeared dirty. Increased frequency of
cleaning, washing, or repainting over soiled surfaces becomes an economic burden and can
reduce the life usefulness of the material soiled. In addition to the aesthetic effect, soiling
produces a change in reflectance from opaque materials and reduces light transmission through
transparent materials (Beloin and Haynie, 1975; National Research Council, 1979). For dark
surfaces, light colored particles can increase reflectance (Beloin and Haynie, 1975).
Determining at what accumulated level particle pollution leads to increased cleaning is
difficult. For instance, in the study by Carey (1959), it was found that the appearance of soiling
only occurred when the surface of the paper was covered with dust specks spaced 10 to 20
diameters apart. When the contrast was strong, e.g., black on white, it was possible to
distinguish a clean surface from a surrounding dirty surface when only 0.2% of the areas was
covered with specks, while 0.4% of the surface had to be covered with specks
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with a weaker color contrast. Still, the effect is subjective and not easy to judge between
coverages.
Support for the Carey (1959) work was reported by Hancock et al. (1976). These authors
also found that with maximum contrast, a 0.2% surface coverage (effective area coverage; EAC)
by dust can be perceived against a clean background. A dust deposition level of 0.7% EAC was
needed before the object was considered unfit for use. The minimum perceivable difference
between varying gradations of shading was a change of about 0.45% EAC. Using the
information on visually perceived dust accumulation and a telephone survey, Hancock et al.
(1976) concluded that a dustfall rate of less than 0.17% EAC/day would be tolerable to the
general public.
Some materials that are soiled are indoors. In general, particle pollution levels indoors
may be affected by outdoor ambient levels; however, other factors generally have greater effects
on concentration and composition (Yocom, 1982). For that reason, discussion of indoor soiling
will be limited primarily to works of art.
9.2.1 Building Materials
Dose-response relationships for particle soiling were developed by Beloin and Haynie
(1975) using a comparison of the rates of soiling and TSP concentrations on different building
materials (painted cedar siding, concrete block, brick, limestone, asphalt singles, and window
glass) at 5 different study sites over a 2-y period. Particle concentrations ranged from 60 to 250
mg/m3 for a rural residential location and an industrial residential location, respectively. The
results were expressed as regression functions of reflectance loss (soiling) directly proportional
to the square root of the dose. With TSP expressed in mg/m3 and time in months, the regression
coefficients ranged from -0.11 for yellow brick to +0.08 for a coated limestone depending on
the substrate color and original reflectance. For dark surfaces, light colored particles can
increase reflectance. Not all of the coefficients were significantly different from zero.
A theoretical model of soiling of surfaces by airborne particles has been developed and
reported by Haynie (1986). This model provides an explanation of how ambient concentrations
of particulate matter are related to the accumulation of particles on surfaces and ultimately the
effect of soiling by changing reflectance. Soiling is assumed to be the
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contrast in reflectance of the particles on the substrate to the reflectance of the bare substrate.
Thus, the average reflectance from the substrate (R) equals the reflectance from the substrate not
covered by particles [Ro(l-X)] plus the reflectance from the particles (RpX) where X is the
fraction of surface covered by particles.
Under constant conditions, the rate of change in fraction of surface covered is directly
proportional to the fraction of surface yet to be covered. Therefore, after integration: X = 1-
exp(-kt) where k is a function of particle size distribution and dynamics and t is time. Lanting
(1986) evaluated similar models with respect to soiling by paniculate elemental carbon (PEC) in
the Netherlands. He determined that the models were good predictors of soiling of building
materials by fine mode black smoke. Based on the existing levels of PEC, he concluded that the
cleaning frequency would be doubled.
An important particle dynamic is deposition velocity which is defined as flux divided by
concentration and is a function of particle diameter, surface orientation, and surface roughness,
as well as other factors such as wind speed, atmospheric stability, and particle density. Thus,
soiling is expected to vary with the size distribution of particles within an ambient concentration,
whether a surface is facing skyward (horizontal versus vertical), and whether a surface is rough
or smooth.
Van Aalst (1986) reviewed particle deposition models existing at that time and pointed out
both their benefits and their faults. The lack of significant experimental verification was a major
fault. Since then, Hamilton and Mansfield (1991, 1993) have applied the model reported by
Haynie (1986) and Haynie and Lemmons (1990) to soiling experiments with relatively good
predictive success.
Terrat and Joumard (1990) found that the simple plate method (a measurement of the
number of particles deposited on a flat inert plate of material), as well as the measurement of
reflectance and transmission of the light really showed the amount of soiling deposit in a town.
The simple plates are more suitable for high particle polluted areas and the optical methods are
more suitable for low pollution areas. This study also provided evidence that motor vehicles are
mainly responsible for soiling the facades along roads.
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9.2.1.1 Fabrics
No recent information on the effects of particles on fabrics was located in the published
literature. Earlier studies indicate particles are only damaging to fabrics when they are abrasive.
Yocom and Upham (1977) reported that curtains hanging in an open window often split in
parallel lines along the fold after being weakened by particle exposure. The appearance and life
usefulness also may be lessened from increased frequencies of washing as a result of particle
"soiling". Rees (1958) described the mechanisms (mechanical, thermal, and electrostatic) by
which cloth is soiled. Tightly woven cloth exposed to moving air containing fine carbon
particles was found to be the most resistant to soiling. Soiling by thermal precipitation was
related to the surface temperature of the cloth versus that of the air. When the surface
temperature of the cloth was greater than that of the air, the cloth resisted soiling. When cloth
samples were exposed to air at both positive and negative pressure, the samples exposed to
positive pressure showed greater soiling than those exposed to equivalent negative pressure.
9.2.1.2 Household and Industrial Paints
Research suggest that particles can serve as carriers of more corrosive pollutants, allowing
the pollutants to reach the underlying surface or serve as concentration sites for other pollutants
on painted surfaces (Cowling and Roberts, 1954). Paints may also be soiled by liquids and solid
particles composed of elemental carbon, tarry acids, and various other constituents.
Haynie and Lemmons (1990) conducted a soiling study at an air monitoring site in a
relatively rural environment in Research Triangle Park, NC. The study was designed to
determine how various environmental factors contribute to the rate of soiling of white painted
surfaces. White painted surfaces are highly sensitive to soiling by dark particles and represent a
large fraction of all manmade surfaces exposed to the environment. Hourly rainfall and wind
speed, and weekly data for dichotomous sampler measurements and TSP concentrations were
monitored. Gloss and flat white paints were applied to hardboard house siding surfaces and
exposed vertically and horizontally for 16 weeks, either shielded from or exposed to rainfall.
Particle mass concentration, percentage of surfaces covered by fine and coarse mode fractions,
average wind speed and rainfall amounts, and paint reflectance
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changes were measured at 2, 4, 8, and 16 weeks. The scanning electron microscopy stubs, that
had been flush-mounted on the hardboard house siding prior to painting, were also removed and
replaced with unpainted stubs at these intervals.
The unsheltered panels were initially more soiled by ambient pollutants than the sheltered
panels; however, washing by rain reduced the effect. The vertically exposed panels soiled at a
slower rate than the horizontally exposed panels. This was attributed to additional contribution
to particle flux from gravity. The reflectivity was found to decrease faster on glossy paint than
on the flat paint (Haynie and Lemmons, 1990).
Least squares fits through zero of the amounts on the surfaces with respect to exposure
doses provided the deposition velocities. There was no statistical difference between the
horizontal and vertical surfaces for the fine mode and the combined data given a deposition
velocity of 0.00074 + 0.000048 cm/s (which is lower than some reported values). The coarse
mode deposition velocity to the horizontal surfaces at 1.55 cm/s is around five times greater than
to vertical surfaces at 0.355 cm/s. By applying assumptions these deposition velocities can be
used to calculate rates of soiling for sheltered surfaces. The empirical prediction equation for
gloss paint to a vertical surface based on a theoretical model (Haynie, 1986) is:
R = R0 exp (-0.0003 [0.0363Cf + 0.29CJt) (9.8)
where R and R0 are reflectance and original reflectance, respectively, Cf and Cc are coarse and
fine mode particle concentrations in //g/m3, respectively, and t is time in weeks of exposure.
The fine mode (<2.5 //m) did not appear to be washed away by rain, but most of the coarse
mode (>2.5 //m to 10 //m) was either dissolved to form a stain or was washed away. Therefore,
for the surfaces exposed to rain, the 0.0363 coefficient for the fine mode should remain the same
as it is for sheltered surfaces but there should be a time-dependent difference in the coefficient
for the coarse mode.
Based on the results of this study, the authors concluded that: (1) coarse mode particles
initially contribute more to soiling of both horizontal and vertical surfaces than fine mode
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particles; (2) coarse mode particles, however, are more easily removed by rain than are fine
mode particles; (3) for sheltered surfaces reflectance changes is proportional to surface coverage
by particles, and particle accumulation is consistent with the deposition theory; (4) rain interacts
with particles to contribute to soiling by dissolving or desegregating particles and leaving stains;
and (5) very long-term remedial actions are probably taken because of the accumulation of fine
rather than coarse particles (Haynie and Lemmons, 1990).
Similar results were also reported by Creighton et al. (1990). They found that horizontal
surfaces, under the test conditions, soiled faster than did the vertical surfaces, and that large
particles were primarily responsible for the soiling of horizontal surfaces not exposed to rainfall.
Soiling was related to the accumulated mass of particles from both the fine and coarse fractions.
Exposed horizontal panels stain because of dissolved chemical constituents in the deposited
particles. The size distribution of deposited particles was bimodal, and the area of coverage by
deposited particles was also bimodal with a minimum at approximately 5 //m. The deposition
velocities for each of the size ranges onto the horizontal, sheltered panel was in general
agreement with both the theoretical settling velocity of density 2.54 g/cm3 spheres and the
reported results of laboratory tests. An exponential model (Haynie, 1986) was applied to the
data set and gave a good fit.
Spence and Haynie (1972) reported on the published data on the effects of particles on the
painted exterior surfaces of homes in Steubenville and Uniontown, OH, Suitland and Rockville,
MD, and Fairfax, VA. There was a direct correlation between the ambient concentration of
particulate matter in the city and the number of years between repainting. The average
repainting time for homes in Steubenville, where parti culate matter concentrations averaged 235
Mg/m3, was approximately one year. In the less polluted city, Fairfax, where the particulate
matter concentrations only reached 60 //g/m3 (arithmetic means), the time between repainting
was 4 years. Parker (1955) reported the occurrence of black specks on the freshly paint surface
of a building in an industrial area. The black specks were not only aesthetically unappealing, but
also physically damaged the painted surface. Depending on the particle concentration, the
building required repainting every 2 to 3 years.
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9.2.1.3 Soiling of Works of Art
Ligocki et al. (1993) studied potential soiling of works of art. The concentrations and
chemical composition of suspended particles were measured in both the fine and coarse size
modes inside and outside five Southern California museums during summer and winter months.
The seasonally averaged indoor/outdoor ratios for particle mass concentrations ranged from 0.16
to 0.96 for fine particles and from 0.06 to 0.53 for coarse particles, with lower values observed
for buildings with sophisticated ventilation systems that include filters for particle removal.
Museums with deliberate particle filtration systems showed indoor fine particle concentrations
generally averaging less than 10 //g/m3. One museum with no environmental control system
showed indoor fine particles concentrations averaging nearly 60 //g/m3. Analysis of indoor
versus outdoor concentrations of major chemical species indicated that indoor sources of
organics may exist at all sites, but that none of the other measured species appear to have major
indoor sources at the museums studied. The authors concluded that a significant fractions of the
dark-colored fine elemental carbon and soil dust particles present in the outdoor environment
had penetrated to the indoor atmosphere of the museums studied and may constitute a soiling
hazard to displayed works of art.
Methods for reducing the soiling rate in museums that included reducing the building
ventilation rate, increasing the effectiveness of particle filtration, reducing the particle deposition
velocity onto surfaces of concern, placing objects within display cases or glass frames, managing
a site to achieve lower outdoor aerosol concentrations, and eliminating indoor particle sources
were proposed by Nazaroff and Cass (1991). According to model results, the soiling rate can be
reduced by at least two orders of magnitude through practical application of these control
measures. Combining improved filtration with either a reduced ventilation rate for the entire
building or low-air-exchange display cases would likely reduce the soiling hazard in museums.
9.3 ECONOMIC ESTIMATES
Only limited new information was located in the published literature on the economic cost
of soiling and corrosion by particles. Many of these studies are flawed or represent monetary
cost for materials damage and soiling that are not representative of monetary losses
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today. A detailed discussion of earlier studies on economic loss from exposure to acid forming
aerosols and other particles can be found in the previous criteria document for paniculate matter
(U.S. Environmental Protection Agency, 1982). The following sections describe methods for
determining economic losses from materials damage and soiling from air pollution and includes
the limited body of new information available since publication of the 1982 particulate matter
criteria document.
9.3.1 Methods for Determining Economic Loss from Pollutant Exposure
Several types of economic losses result from materials damage and soiling. Financial or
out-of-pocket losses include the reduction in service life of a material, decreased utility,
substitution of a more expensive material, losses due to an inferior substitute, protection of
susceptible materials, and additional required maintenance, including cleaning. The major losses
of amenity, as defined by Maler and Wyzga (1976), are associated with enduring and suffering
soiled, damaged, or inferior products and materials because of particle pollution and any
corrosive pollutant that may be absorbed on or adsorbed to particles. In addition, amenity losses
are suffered when pollution damage repair or maintenance procedures result in inconvenience or
other delays in normal operations. Some of these losses, such as effects on monuments and
works of art, are especially difficult to specify (Maler and Wyzga, 1976).
The compilation and assessment of materials damage and soiling research reveals a variety
of techniques employed by different disciplines to estimate economic losses associated with
soiling and materials damage. Attempts have been made to address the following questions.
• At what concentration or deposition rate is materials damage and soiling perceived?
• What is the relationship between the color of the particle and perceived materials
damage and soiling?
• What is the physical or economic life of various materials, coatings, structures, etc.?
• What is the inventory of pollution sensitive materials, coatings, structures, etc.?
• What behaviors are undertaken to avert, mitigate, or repair pollution-related damages?
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• What is the economic cost of materials damage and soiling due to exposure to acid
forming aerosols and other particles?
The answers to these questions are certainly relevant to the structure of a modeling
framework, the collection of data, and the estimation of effects of materials damage and soiling
on economic values. The analytical approach selected depends on whether financial losses or
losses of amenity are emphasized, the type of damage being considered, and the availability of
cost information. Economic losses from pollutant exposure can be estimated using the damage
function approach or using direct economic methods.
In the damage function approach, physical damage (any undesirable change in the function
of specific materials, including appearance, leading to failure of specific components) is
determined before economic cost is estimated. Physical damage is estimated from ambient
pollutant concentrations over a specified period of time. Depending on the material damaged,
both short-term and long-term exposure data may be necessary to determine a more accurate
estimate of damage related to pollution exposure. The damage function is expressed in terms
appropriate to the interaction of the pollutant and material. For example, the corrosion of metal
may be expressed in units of thickness lost, while the deterioration of paint from soiling may be
expressed in units of reflectance lost. A willingness-to-pay value, mitigation, or replacement
cost is then applied to estimate a monetary value of damages caused by changes in pollutant
concentrations. It is, however, difficult to estimate fully the financial losses because reliable
information is not available on the physical damage of all economically important materials, and
on the spatial and temporal distribution of these materials. Further, current techniques do not
reflect the use of more resistant and reduced-maintenance materials, and loss estimates may
assume that substitute materials cost more than the original materials, and that the cost
differential is attributable solely to pollution.
Another major problem in developing reliable damage functions is the inability to separate
pollutant effects from natural weathering processes due to various meteorological parameters
(temperature, relative humidity, wind speed, and surface wetness). Since weathering is a natural
phenomenon, proceeding at a finite rate irrespective of anthropogenic pollution, materials
damage estimates must represent only that damage directly produced by
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anthropogenic pollutant exposure. Also, this approach cannot account for irreplaceable items
such as works of art or national monuments.
In the studies that do not use the physical damage approach to derive monetized economic
damages reflecting the estimates of damages associated with pollution, the loss of amenity or
direct financial losses are estimated econometrically. These approaches have been used to relate
changes in air pollution directly with the economic value of avoidance or mitigation of damages.
A major source of error using these approaches is the requirement that all factors that affect cost
other than air quality have to be accounted for. In general all approaches to estimating costs of
air pollution effects on materials are limited by the difficulty in quantifying the human response
to damage based upon the ability and the incentive to pay additional costs (Yocom and
Grappone, 1976).
9.3.2 Economic Loss Associated with Materials Damage and Soiling
Information on the geographic distribution of various types of exposed materials may
provide an indication of the extent of potential economic costs of damge to materials from air
pollution. Lipfert and Daum (1992) analyzed the efforts made to determine the geographic
distribution of various types of materials. They focused on the identification, evaluation and
interpretation of data describing the distribution of exterior construction materials, primarily in
the United States. Materials distribution surveys for 16 cities in the United States and Canada
and five related data bases from government agencies and trade organizations were examined.
Data on residential buildings were more available than non-residential buildings; little
geographically resolved information on distributions on materials in infrastructure was found.
Lipfert and Daum (1992) observed several important factors relating pollution to
distribution of materials. In the United States, buildings constitute the largest category of
surface areas potentially at risk to pollution damage. Within this category, residential buildings
are the most important. On average, commercial and industrial buildings tend to be larger than
residential buildings and to use more durable materials. However, because they are more
numerous (and use less durable materials) more surface area for residential buildings is exposed
to potentially damaging pollutants. For residential buildings in general, painted surfaces are
preferred over masonry in the Northeastern United States (with the
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exception of large inner cities), brick is popular in the South and Midwest) and stucco in the
West. The use of brick appears to be declining, painted wood increasing, and the use of vinyl
siding is gaining over aluminum. One of the factors underlying the present regional distribution
of materials is their durability under the environmental conditions which exist when they were
installed. Thus, changing pollution levels have possibly affected materials selection, and is
expected to do so.
Haynie (1990) examined the potential effects of PM10 nonattainment on the costs of
repainting exterior residential walls due to soiling in 123 counties. The analysis was based on a
damage function methodology developed for a risk assessment of soiling of painted exterior
residential walls (Haynie, 1989). The data base was updated with 1988 and 1989 AIRS data.
An extreme value statistical model was used to adjust every sixth day monitoring to 365 days for
counting violation days (one violation in 60 does not translate to 6 violations in 360). The
resulting paint cost due to soiling was subjected to a sensitivity analysis using various assumed
values. When the model is restricted to only a national average of 10% of households repainting
because of soiling, the effects of other assumptions become inversely related and tend to cancel
out each other (possibly associated with individual cost minimization choices).
The top twenty counties were ranked by estimated soiling costs. Fourteen of the counties
with actual violation days in 1989 were in this group. All but three were west of the Mississippi.
A total of 29 counties with measured violations are in the set of 123 counties for which PM10
nonattainment soiling costs were calculated. When the given set of behavior assumptions was
used, there were no costs calculated for 19 counties that actually measured violations in 1989.
The distribution of a national estimated $1 billion in painted exterior residential wall soiling
costs is shown in Figure 9-2.
An experimentally determined soiling function for unsheltered, vertically exposed house
paint was used to determine painting frequency (Haynie and Lemmons, 1990) . An equation
was set up to express paint life in integer years because the painting of exterior surfaces is
usually controlled by season (weather). Different values for normal paint life without soiling
and levels of unacceptable soiling could be used in the equation. If four was taken as the most
likely average paint life for other than soiling reasons, then painting because of soiling would
likely be done at 1, 2, or 3 year intervals.
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>100 10-100 1-10 0.1-1 0.01-0.1
County Paint Soiling Costs - Million Dollars
Figure 9-2. Geographic distribution of paint soiling costs.
Source: Haynie (1990).
Soiling costs by county were calculated and ranked by decreasing amounts and the
logarithm of costs plotted by rank. The plot consisted of three distinct straight lines with
intersections at ranks 4 and 45. The calculated cost values provide a reasonable ranking of the
soiling problem by county, but do not necessarily reflect actual painting cost associated with
extreme concentrations of particles. Households exposed to extremes are not expected to
respond with average behavior. The authors concluded that repainting costs could be lowered if:
(1) individuals can learn to live with higher particle pollution, accepting greater reductions in
reflectance before painting; (2) painted surfaces were washed rather than repainted; and (3) if
materials or paint colors that do not tend to show dirt were used.
Extrapolating the middle distribution of costs to the top four ranked counties reduces their
estimated costs considerably. For example Maricopa County, AR, was calculated to rank first at
$70.2 million if all households painted each year as predicted, but was calculated to be only
$29.7 million based on the distribution extrapolation.
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Based on these calculations and error analysis, the national soiling costs associated with
repainting the exterior walls of houses probably were within the range of $400 to $800 million a
year in 1990. This sector represents about 70% of the exterior paint market, so that
extrapolating to all exterior paint surfaces gives a range of from $570 to $1,140 million (Haynie
andLemmons, 1990).
A number of other studies have attempted to model the economic losses of soiling due to
particulate air pollution. Based on the hypothesis that air pollution affects the budget allocation
decisions of individuals, MathTech (1983) used a household sector model to establish a
statistical relationship between TSP and the demand for laundry and cleaning products and
services using 1972-1973 Bureau of Labor Statistics Consumer Expenditure data. Given
knowledge of the pattern of demand for these goods, standard methods of welfare economics
were used to estimate the benefits (or compensating variation) of changes in TSP concentrations.
The results of this study indicated that the annual benefits of attaining the primary PM10 standard
were approximately $88.3 million to $1.2 billion in 1980 dollars for the period 1989 to 1995.
The applicability of the underlying relationship to current air quality and economic conditions is
uncertain given that potential changes in consumer tastes and the opportunity set of goods
influencing budget allocation decisions could have changed over the intervening 20 years.
MathTech (1990) also assessed the effects of acidic deposition on painted wood surfaces
using individual maintenance behavior data. The effects were a function of the repainting
frequency of the houses as well as pollution levels.
Gilbert (1985) used a household production function framework to design and estimate the
short-run costs of soiling. The results were comparable to those reported by MathTech (1983).
Smith and Gilbert (1985) also used a hedonic property value model to analyze the effects of
particles in the long term, examining the possibility of households moving in response to air
pollution.
McClelland et al. (1991) conducted a field study valuing eastern visibility using the
contingent valuation method. Given the problem of embedding between closely associated
attributes, the survey instrument provided for separation of the visibility, soiling, and health
components of the willingness-to-pay estimates. Households were found to be willing to pay
$2.70 per //g/m3 change in particle pollution to avoid soiling effects.
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The findings of the aforementioned studies are consistent with the hypotheses that there are
economic costs associated with elevated pollution levels across multiple sectors and that
households are willing to pay positive amounts to reduce particle concentrations to reduce the
risk of materials damage and soiling. However, these studies have done little to advance our
knowledge of perception thresholds in relationship to concentration, particle size, and chemical
composition. Without such information it is very difficult and highly uncertain to quantify the
relationship between ambient particle concentrations and soiling and associated economic cost.
9.4 SUMMARY
Available information supports the fact that exposure to acid forming aerosols promotes
the corrosion of metals beyond the corrosion rates expected from exposure to natural
environmental elements (wind, rain, sun, temperature fluctuations, etc.). Many metals form a
protective film that protects against corrosion; however, high concentrations of anthropogenic
pollutants, lessen the effectiveness of the protective film. Acid forming aerosols have also been
found to limit the life expectancy of paints by causing discoloration, loss of gloss, and loss of
thickness of the paint film layer.
Various building stones and cement products are damaged from exposure to acid-forming
aerosols. However, the extent of the damage to building stones and cement products produced
by the pollutant species, beyond that expected as part of the natural weathering process is
uncertain. Several investigators have suggested that the damage attributed to acid forming
pollutants is overestimated and that stone damage is predominantly associated with relative
humidity, temperature, and, to a lesser degree, air pollution.
A significant detrimental effect of particle pollution is the soiling of painted surfaces and
other building materials. Soiling is defined as a degradation mechanism that can be remedied by
cleaning or washing, and depending on the soiled surface, repainting. Available data on
pollution exposure indicates that particles can result in increased cleaning frequency of the
exposed surface, and may reduce the life usefulness of the material soiled. Data on the effects of
particulate matter on other surfaces are not as well understood. Some evidence does, however,
suggest that exposure to particles may damage fabrics, electronics, and works
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of art composed of one or more materials, but this evidence is largely qualitative and sketchy.
The damaging and soiling of materials by acid forming aerosols and other particles have an
economic impact, but this impact is difficult to measure. One problem is the lack of sufficient
data to separate costs between various pollutants and to separate cost of pollutant exposure from
that of normal maintenance. Attempts have been made to quantify the pollutants exposure levels
at which materials damage and soiling have been perceived. However, to date, insufficient data
are available to advance our knowledge regarding perception thresholds with respect to pollutant
concentration, particle size, and chemical composition.
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10. DOSIMETRY OF INHALED PARTICLES IN THE
RESPIRATORY TRACT
10.1 INTRODUCTION
Development of an efficient air-breathing respiratory tract was a critical requirement for
mammalian evolution. The combination of airways and airspaces in an internalized and
arborized arrangement that expands with incoming tidal air and contracts with its ebb led to the
vertebrate lung. This very design that led to the close proximity of the alveolar air spaces to the
outside environment for efficient air exchange also makes the lung vulnerable to insult by
inorganic and organic dusts, and by microorganisms. The intense perfusion of these spaces by
essentially the entire cardiac output also makes the lung vulnerable to many blood-borne,
chemical, microbial, and immunologic agents.
It is a basic tenet of toxicology that the dose delivered to the target site, not the external
exposure, is the proximal cause of a response. Therefore, there is increased emphasis on
understanding the exposure-dose-response relationship. In the case of PM, exposure is what gets
measured (or estimated) in the typical study and what gets regulated; inhaled dose is the
causative factor. Even if inhaled dose could be easily defined, it fits within a complex
continuum. For example, as illustrated in Figure 10-1, it is ultimately desirable to have a
comprehensive biologically-based dose-response model that incorporates the mechanistic
determinants of chemical disposition, toxicant-target interactions, and tissue response integrated
into an overall model of pathogenesis. Mathematical dosimetry models that incorporate
mechanistic determinants of disposition (deposition, absorption, distribution, metabolism, and
elimination) of chemicals have been useful in describing relationships along this continuum
(e.g., between exposure concentration and target tissue dose), particularly as applied to
describing these relationships for the exposure-dose-response component of risk assessment.
With each progressive level, incorporation and integration of mechanistic determinants allow
further elucidation of the exposure-dose-response continuum and, depending on the knowledge
of model parameters and fidelity to the biological system, a more accurate characterization of the
pathogenetic process. Thus, once the site and
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Protective
Predictive
Chemical
Exposure
Concentration
"Dose"
Exposure
Default
Exposure
Mechanisms v
Disposition Models
Exposure
Toxicological
Response
Response
Qualitative
Response
Response
Disposition Models Toxicant-Target Models
Disposition Models Toxicant-Target ModelsTissue Response Models
Quantitative
Figure 10-1. Schematic characterization of comprehensive exposure-dose-response
continuum and the evolution of protective to predictive dose-response
estimates.
Source: Adapted from Conolly (1990) and Andersen et al. (1992).
mechanisms are known, dosimetry may prove useful in linking exposure to internal dose and
effects, and to the extrapolation of variability both within and across species. For example, a
healthy individual and a person with emphysema will not get identical doses to specific lung
regions even if their external exposure is identical. Knowledge of how and to what extent
disease factors affect dose can assist in characterizing susceptible subpopulations. If a rat and a
human are identically exposed, they will receive different doses to regions of the respiratory
tract. Insofar as this is quantitatively understood, laboratory animal data can be made more
useful in assessing human health risks.
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Characterization of the exposure-dose-response continuum for PM requires the elucidation
and understanding of the mechanistic determinants of inhaled particle dose, toxicant-target
interactions, and tissue responses. Only the first level of characterization, i.e., description of the
factors that influence inhaled dose has been accomplished to any degree for PM. Inhaled
particles are deposited in the respiratory tract by mechanisms of interception, impaction,
sedimentation, diffusion, and electrostatic precipitation. The relative contribution of each
deposition mechanism to the fraction of inhaled particles deposited varies for each region of the
respiratory tract (extrathoracic, ET; tracheobronchial, TB; and alveolar, A). Subsequent
clearance of deposited particles depends on the initial deposition site, physicochemical properties
of the particles (e.g., solubility), translocation mechanisms such as mucociliary transport and
endocytosis by macrophages or epithelial cells, and on the time since initial deposition.
Retained particle burdens and ultimate particle disposition are determined by the dynamic
relationship between deposition and clearance mechanisms.
The biologically effective dose resulting from inhalation of airborne particles can be
defined as the time integral of total inhaled particle mass, particle number, or particle surface
area per unit of surface area (e.g., surface area of a given region such as the TB) or per unit mass
of the respiratory tract. Choice of the metric to characterize the biologically effective inhaled
dose should be motivated by insight on the mechanisms of action of the compound (or particles)
in question. Conceptually, as illustrated in Figure 10-2, the exposure-dose-response continuum
can be represented as events in the progression from exposure to disease. The components
depicted in Figure 10-2 are not necessarily discrete, nor the only events in the continuum, and
represent a conceptual temporal sequence. The left-most component of the continuum generally
precedes any component to the right, but some impacts may be detectable in parallel. As our
understanding of the continuum is supplemented by identification of the important intervening
relationships and the components are characterized more precisely or with greater detail, the
health events of concern can be viewed as a series of changes from homeostatic adaption,
through dysfunction, to disease and death. The critical effect could become that biologic marker
deemed most pathognomonic or of prognostic significance, based on validated hypotheses of the
role of the marker in the development of disease. The appropriate dose metric would then be
defined by a measure
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Exposure
Effect
Susceptibility
Figure 10-2. Biological marker components in sequential progression between exposure
and disease.
Source: Schulte (1989).
that characterizes the biologically effective dose for the mechanism of action causing that critical
effect.
Elucidation of the toxic moiety as well as the mechanism of action for PM have remained
elusive, however. The link to the epidemiological findings discussed in Chapter 12 lies in
understanding the sites of injury and the types of injury. The appropriate dose metric for PM
might accurately be described by particle deposition alone of the particles exert their primary
action on the surface contacted (Dahl et al., 1991). For longer-term effects, the deposited dose
may not be a decisive metric, since particles clear at varying rates from the different respiratory
tract regions. At this point, when considering the epidemiologic data, dose metrics can only be
separated into two major categories: (1) the pattern and quantity of deposited particle burdens,
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and (2) the pattern and quantity of retained particle burdens. The deposited dose or initial acute
deposition (e.g., particle mass burden per 24-hours) may be relevant to "acute" effects observed
in the epidemiologic studies such as "acute" mortality, hospital admissions, work loss days, etc.
On the other hand, retained dose may be more appropriate for chronic responses such as
induction of chronic disease, shortening of life-span ("premature mortality"), morbidity, or
diminished quality of life.
Another aspect of the definition of the dose metric that would benefit from mechanism of
action information include whether mass is the appropriate measure of particle burden and how
to normalize the inhaled particle burdens. To date, most of the epidemiologic studies have relied
upon the particle mass concentration (//g/m3) to characterize particle exposures. Alternative
expressions that may be more relevant to certain mechanisms of injury include numbers of
particles or aggregate particle surface area. For example, the fine fraction contains by far the
largest number of particles and those particles have a large aggregate surface area. Oberdorster
et al. (1992) have shown ultrafme particles are less effectively phagocytosed by macrophages
than larger particles. Anderson et al. (1990) have shown that the deposition of ultrafme particles
in patients with COPD is greater than in healthy subjects. The need to consider particle number
is accentuated when the high deposition efficiency of small particle numbers in the lower
respiratory tract, the putative target for both the mortality and morbidity effects of PM
exposures, is taken into account.
Insight on how PM causes injury would also inform what normalizing factor to use to
define the dose metric. Particle mass or number burdens could be normalized to respiratory tract
surface area, to lung mass, or to other anatomical or functional units critical to determining the
toxicity such as ventilatory units, alveoli, or macrophages. Clearly, inhaled dose is important,
but the most appropriate dose metric or metrics to quantitatively link with the observed acute or
chronic health outcomes await elucidation of the pertinent mechanisms of injury and tissue
response.
For the present document, average daily deposited particle mass burden in each region of
the respiratory tract has been selected as the dose metric to characterize "acute" effects. Average
retained particle mass burden in each region for humans and in the lower respiratory tract for
laboratory animals has been selected as the dose metric for "chronic" effects. As discussed in
Section 10.7.3., these choices were dictated by the selection of the dosimetry models and the
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availability of anatomical and morphometric information. Both deposited particle mass and
number burdens in each respiratory tract region are estimated for human exposures. Retained
particle burdens are normalized per gram of lung tissue.
The chapter first describes important particle characteristics and the basic mechanisms of
particle deposition and clearance in the respiratory tract. The available mathematical dosimetry
models for humans and laboratory animals are reviewed as a background to the application
presented in Section 10.7. Dosimetry models are selected for human exposure simulations and
to perform interspecies extrapolation of laboratory animal toxicity studies. The rationale for
selection of the extrapolation models is provided. An attempt is made to ascertain whether
dosimetry modeling can provide insight into the apparent discrepancies between the
epidemiologic and laboratory animal data, to identify plausible dose metrics of relevance to the
available health endpoints, and to identify modifying factors that may enhance susceptibility to
inhaled particles. Simulations of variability due to key modifying factors (age, gender, disease
status) are also attempted. This information should be useful to the interpretation of health
effects data in Chapters 11 and 12.
The chapter deals exclusively and genetically with aerosols (i.e., both airborne droplets
and solid particles, including the hygroscopic, acidic variety). It briefly reviews selected studies
that have been reported in the literature on particle deposition and retention since the publication
of the 1982 Air Quality Criteria Documents on Particulate Matter and Sulfur Oxides and the
1989 Acid Aerosols Issue Paper (U.S. Environmental Protection Agency; 1982, 1989), but the
focus is on newer information.
10.2 CHARACTERISTICS OF INHALED PARTICLES
Information about particle size distribution aids in the evaluation of the effective inhaled
dose. Because the characteristics of inhaled particles interact with the other major factors
controlling comparative inhaled dose, this section discusses aerosol attributes requiring
characterization and provides general definitions.
An aerosol is a suspension of finely dispersed solids or liquids in air. It is intrinsically
unstable, and hence, tends to deposit both continuously and inelastically onto exposed surfaces.
From the perspective of health-related actions of aerosols, interest is limited to particles that can
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at least penetrate into the nose or mouth and that deposit on respiratory tract surfaces. For
humans, this constraint ordinarily eliminates very coarse particles, viz., greater than about 100
fj.m diameter. Particles between 1 jim and 20 jim diameter are commonly encountered in the
work place and the ambient air. Still smaller, i.e., submicron diameter particles (less than 1 jim
in diameter) are generally the most numerous in the environmental air, with the number
concentration of particles tending to increase markedly for smaller particles. Even particles
down to the nanometer (nm) size domain are found in the atmosphere and are of interest,
although until recently, these "ultrafine" particles were of greater interest to atmospheric
scientists than to biomedical scientists. Typically, "ultrafine" aerosols are produced by highly
energetic reactions (e.g., high temperature sublimation and combustion, or by gas phase
o
reactions involving atmospheric pollutants). Note that 10 nm = 100 Angstroms = 0.01 //m or
IxlO"6 cm diameter.
Because aerosols can consist of almost any material, descriptions of aerosols in simple
geometric terms can be misleading unless important factors relating to size, shape, and density
are considered. Aerosol constituents are usually described in terms of their chemical
composition and geometric or aerodynamic sizes. Additionally, aerosol particles may be defined
in terms of particle surface area. It is important to note that aerosols present in natural and work
environments all have polydisperse size distributions. This means that the particles comprising
the aerosols have a range of geometric size, aerodynamic size, and surface area and are more
appropriately described in terms of size distribution parameters. Aerosol sampling devices can
be used to collect bulk or size fractions of aerosols to allow defining the size distribution
parameters. In this procedure, the amount of particles in defined size parameter groups (number,
mass, or surface area) is divided by the total number, mass, or surface of all particles collected
and divided also by the size interval for each group. Data from the sampling device are then
expressed in terms of the fraction of particles per unit size interval. The next step is to use this
information to define an appropriate particle size distribution.
The lognormal distribution has been widely used for describing size distributions of
radioactive aerosols (Hatch and Choate, 1929; Raabe, 1971) and is also generally used as a
function to describe other kinds of aerosols. For many aerosols, their size distribution may be
described by a lognormal distribution, meaning that the distribution will resemble the bell-
shaped Gaussian error curve, if the frequency distribution is based on the logarithms of the
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particle size. The lognormal distribution is a skewed distribution characterized by the fact that
the logarithms of particle diameter are normally distributed. In linear form, the logarithmic
mean is the median of the distribution. The standard deviation, a, of this logarithmic normal
distribution is a logarithm, so that addition and subtraction of this logarithm to and from the
logarithmic mean is equivalent to multiplying and dividing the median by the factor og, with In
og = a. The factor og is defined as the geometric standard deviation. When any aerosol
distribution is "normalized", it acquires parameters and properties equivalent to those of the
Gaussian distribution. Accordingly, the only two parameters needed to describe the log normal
distribution are the median diameter and the geometric standard deviation, og, (ratio of the log
84%/log 50% size cut or log 50%/log 16% size cut, where the 50% size cut is the median). For
a distribution formed by counting particles, the median is called the count median diameter
(CMD). While there may be occasions when the number of the particles is of the greatest
interest, the distribution of mass in an aerosol according to particle size is of interest if particle
mass determines the dose of interest. Derivation of the particle mass distribution is essentially a
matter of converting a diameter distribution to a diameter-cubed distribution since the volume of
a sphere with diameter d is 7id3/6 and mass is simply the product of particle volume and
physical density.
The cumulative distribution of a lognormally distributed size distribution is conveniently
evaluated using log-probability graph paper on which the cumulative distribution forms a
straight line (Figure 10-3). This distribution can be used for all three lognormally distributed
particle size parameters discussed above, which are related as indicated in Figure 10-3. The
characteristic parameters of this distribution are the size and og. The CMD is characterized by
the fact that half of the particles in the size distribution are larger than the CMD and half of the
particles are smaller. Multiplying and dividing the CMD by og yields the particle size interval
for the distribution that contains about 68% of the particles by number.
When particles are not spherical, equivalent diameters can be used in place of the physical
diameters of particles. A calculated parameter, the projected area diameter (diameter of a circle
having a cross sectional area equivalent to the particles in the distribution of interest) is often
used as the equivalent diameter.
10-8
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103
5-
1:
E
~ 0.5
o
4-*
o
E
ra
Q
o
0.1:
0.05.
0.01
MMD
MMD = 2.0 M
SMD = 0.93
CMD = 0.20
cb=2-4
2 5 10 20 30 50 70 80 90 95 98
Percent Less Than Indicated Size
Figure 10-3. Lognormal particle size distribution for a hypothetical polydisperse aerosol.
The mass median diameter (MMD) and surface median diameter (SMD), also shown in
Figure 10-3, are additional ways to describe size distributions of lognormally distributed
aerosols. In these distributions, half of the mass or surface area of particles is associated with
particles smaller than the MMD or SMD; the other half of the particles is associated with
particles larger than the MMD or SMD, respectively.
The relationship of the various lognormal distribution parameters based on geometric
diameter of particles is unique, since the CMD, SMD, and MMD are all lognormal with the
same og, but with different means that can be calculated. The CMD and og can be determined
and extrapolated to MMD, and SMD using the following relationships
In(MMD) = In(CMD) + 3(lnoJ2,
(10-1)
and
10-9
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In(SMD) = In(CMD) + 2(lnog)2. (10-2)
For most aerosols, it is useful to define a particle's size in terms of its aerodynamic size
whereby particles of differing geometric size, shape and density are compared aerodynamically
with the instability behavior of particles that are unit density (1 gm/cm3) spheres. The
aerodynamic behavior of unit density spherical particles can be determined, both experimentally
and theoretically, consequently, the aerodynamic diameter constitutes a useful standard by which
all particles can be compared in matters of inertial impaction and gravitational settling. Thus, if
the terminal settling velocity of a unit density sphere of 10 //m diameter is measured in still air,
the velocity induced by gravity would be ~3 x 10"1 cm/s. If the gravitational settling of an
irregularly shaped particle of unknown density was measured and the same terminal velocity was
obtained, the particle would have a 10 //m aerodynamic diameter (dae). Its tendency to deposit
by inertial processes on environmental surfaces or onto the surfaces of the human respiratory
tract will be the same as for the 10 //m unit density sphere.
A term that is frequently encountered is mass median aerodynamic diameter (MMAD),
which refers to the mass median of the distribution of mass with respect to aerodynamic
diameter. With commonly-encountered aerosols having low to moderate polydispersity, og <2.5,
the Task Group on Lung Dynamics (TGLD) (1966) showed that mass deposition in the human
respiratory tract could be approximated by the deposition behavior of the particle of median
aerodynamic size in the mass distribution, the so-called MMAD. This is successful because the
particles which dominate the mass distribution are those which deposit mainly by settling and
inertial impaction.
In many urban environments, the aerosol frequency and mass distributions have been
found to be bimodal or trimodal (Figure 10-4), usually indicating a composite of several log
normal distributions where each aerosol mode was presumably derived from different formation
mechanisms or emission sources (John et al., 1986). Conversely, in the laboratory,
experimentalists often create aerosol distributions which are lognormal or normal, and very
frequently, they generate monodisperse aerosols consisting of particles of nearly one size. The
use of monodisperse aerosols of nearly uniform, unit density, spherical particles
10-10
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O)
_0
<
51
0)
.a
E
1.2
1.0
''o 0.8
-h.
0
r | o.e
0.4
o>
o
IB
S 0.2
o1-
o 4
O)
|3
0)
£
I 1
I I |IIH I I I
Volume
11
0.01
0.1 1
Particle diameter (urn)
10
Figure 10-4. These normalized plots of number, surface, and volume (mass) distributions
from Whitby (1975) show a bimodal mass distribution in a smog aerosol.
Historically, such particle size plots were described as consisting of a coarse
mode (2.5 to 15 /^m), a fine mode (0.1 to 2.5 ^m), and a nuclei mode (<
O.OSjum). The nuclei mode would currently fall within the ultrafine particle
range (0.005 to 0.1
greatly simplifies experimental deposition and retention measurements and also instrument
calibrations. With nearly uniform particles, the mass, surface area and frequency distributions
are nearly identical, another important simplification.
The terms count median aerodynamic diameter (CMAD) and surface median aerodynamic
diameter (SMAD) might be encountered. These distributions are useful in that they include
consideration of aerodynamic properties of the particles. If the particle aerodynamic or diffusive
diameter is determined when sizing is done, then the median of the particle size distribution is
the CMAD, or count median diffusive (or thermodynamic) diameter (CMDD or CMTD),
respectively. If the mass of particles is of concern, then the median that is derived is the MMAD
or mass median diffusive (or thermodynamic) diameter (MMDD or MMTD). Generally,
MMTDs or MMADs are generally used to evaluate particle deposition patterns in the respiratory
tract because deposition of inhaled aerosol particles, as discussed in detail later in this chapter, is
10-11
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determined primarily by particle diffusive and aerodynamic properties of the particles rather
than simply particle physical size, surface area, volume, or mass. Activity median aerodynamic
diameter (AMAD) is the median of the distribution of radioactivity or toxicological or biological
activity with respect to size. Both MMAD and AMAD are determined using aerosol sampling
devices such as multistage impactors. When particles become smaller than about 0.1 //m
diameter, their instability as an aerosol depends mainly on their interaction with air molecules.
Like particles in Brownian motion, they are caused to "diffuse". For these small particles and
especially for ultrafine particles, this interaction is independent of the particle density and varies
only with geometric particle diameter. Very small particles are not expressed in aerodynamic
equivalency, but instead to a thermodynamic-equivalent size. The thermodynamic particle
diameter (dra) is the diameter of a spherical particle that has the same diffusion coefficient in air
as the particle of interest. The activity median thermodynamic diameter (AMTD) is the diameter
associated with 50 percent of the activity for particles classified thermodynamically.
The selection of the particle size distribution to associate with health effects depends on
decisions about the importance of number of particles, mass of particles, or surface area of
particles in producing the effects. In some situations, numbers of particles or mass of particles
phagocytized by alveolar macrophages may be important; in other cases, especially for particles
that contain toxic constituents, surface area may be the most important parameter that associates
exposures with biological responses or pathology. These particle distributions should all be
considered during the course of evaluating relationships between inhalation exposures to
particles and effects resulting from the exposures.
Most of the discussion in the remainder of this chapter will focus on MMAD because it is
the most commonly used measure of aerosol distributions. If MMAD is not measured directly,
an alternative is to estimate MMAD from one of the particle size distributions that is based on
physical size of the particles (CMD, MMD, and SMD), which can all be readily converted to
MMAD. The approximate conversion of MMD to MMAD is made using the following
relationship (neglecting correction for slip)
MMAD = MMD • (particle density) . (10-3)
10-12
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By definition, MMDD = CMTD, because behavior of particles in this size category does not
usually depend on aerodynamic properties.
Because small particles have a large aggregate surface area, aerosols comprised of such
particles have increased potential for reactivity. For example, tantalum is a very stable,
unreactive metal, whereas aerosols of tantalum particles can be caused to explode by a spark.
The rates of oxidation and solubility are proportional to surface area as are the processes of gas
adsorption and desorption, and vapor condensation and evaporation. Accordingly, special
concerns arise from gas-particle mixtures and from "coated" particles. For a general review of
atmospheric aerosols, their characteristics and behavior, the publication Airborne Particles
prepared under the aegis of the National Research Council (1979) is recommended.
10.3 ANATOMY AND PHYSIOLOGY OF THE RESPIRATORY TRACT
The respiratory systems of humans and various laboratory animals differ in anatomy and
physiology in many quantitative and qualitative ways. These differences affect air flow patterns
in the respiratory tract, and in turn, the deposition of an inhaled aerosol. Particle deposition
connotes the removal of particles from their airborne state due to their inherent instabilities in air
as well as to addtional instabilities in air induced when additional external forces are applied.
For example, in tranquil air, a 10 jim diameter unit-density particle only undergoes
sedimentation due to the force of gravity. If a 10 jim particle is transported in a fast moving air
stream, it acquires an inertial force that can cause it to deposit on a surface projecting into the air
stream without significant regard to gravitational settling. For health-related issues, interest in
particle deposition is limited to that which occurs in the respiratory tract of humans and
laboratory animals during the respiration of dust-laden air.
Once particles have deposited onto the surfaces of the respiratory tract, some will undergo
transformation, others will not, but subsequently, all will be subjected either to absorptive or
non-absorptive particulate removal processes, e.g., mucociliary transport, or a combination
thereof. This will result in their removal from the respiratory tract surfaces. Following this,
they will undergo further transport which will remove them, to a greater or less degree, from the
respiratory tract. Such particulate matter is said to have undergone clearance. To the extent
10-13
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particulate matter is not cleared, it is retained. The temporal persistence of uncleared (retained)
particles within the structure of the respiratory tract is termed retention.
Thus, either the deposited or retained dose of inhaled particles in each region is governed
by the exposure concentration, by the individual species anatomy (e.g., airway size and
branching pattern, cell types) and physiology (e.g., breathing rate, and clearance mechanisms),
and by the physicochemical properties (e.g., particle size, distribution, hygroscopicity,
solubility) of the aerosol. The anatomic and physiologic factors are discussed in this section.
The physicochemical properties of particles were discussed in Section 10.2. Deposition and
clearance mechanisms will be discussed in Section 10.4.
The respiratory tract in both humans and various experimental mammals can be divided
into three regions on the basis of structure, size, and function: the extrathoracic (ET) region or
upper respiratory tract (URT) that extends from just posterior to the external nares to the larynx,
i.e., just anterior to the trachea; the tracheobronchial region (TB) defined as the trachea to the
terminal bronchioles where proximal mucociliary transport begins; and the alveolar (A) or
pulmonary region including the respiratory bronchioles and alveolar sacs. The thoracic (TH)
region is defined as the TB and A regions combined. The anatomic structures included in each
of these respiratory tract regions are listed in Table 10-1, and Figure 10-5 provides a
diagrammatic representation of these regions as described in the International Commision on
Radiological Protection (ICRP) Human Respiratory Tract Model (ICRP66, 1994).
Figure 10-6 depicts how the architecture of the respiratory tract influences the airflow in
each region and thereby the dominant deposition mechanisms. The 5 major mechanisms
(gravitational settling, inertial impaction, Brownian diffusion, interception and electrostatic
attraction) responsible for particle deposition are schematically portrayed in Figure 10-6 and will
be discussed in detail in Section 10.4.1.
In humans, the nasal hairs, anterior nares, turbinates of the nose, and glottic aperture in the
larynx are areas of especially high air velocities, abrupt directional changes, and turbulence,
hence, the predominant deposition mechanism in the ET region for large particles is inertial
impaction. In this process, changes in the inhaled airstream direction or magnitude of air
velocity streamlines or eddy components are not followed by airborne particles because of their
inertia. Large particles (>5 //m in humans) are more efficiently removed from the
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TABLE 10-1. RESPIRATORY TRACT REGIONS
Region
Anatomic Structure
Other Terminology
Extrathoracic (ET)
Tracheobronchial (TB)
Alveolar (A)
Nose
Mouth
Nasopharynx
Oropharynx
Laryngopharynx
Larynx
Trachea
Bronchi
Bronchioles (including
terminal bronchioles)
Respiratory bronchioles
Alveolar ducts
Alveolar sacs
Alveoli
Head airways region
Nasopharynx (NP)
Upper respiratory tract (URT)
Naso-Oro-Pharyngo-Laryngeal
(NOPL)
Lower conducting airways
Gas exchange region
Pulmonary region
Adapted from: Phalenet al. (1988).
airstream in this region. The respiratory surfaces of the nasal turbinates are in very close
proximity to and designed to warm and humidify the incoming air, consequently they can also
function effectively as a diffusion deposition site for very small particles and an effective
absorption site for water-soluble gases. The turbinates and nasal sinuses are lined with cilia
which propel the overlying mucous layer posteriorly via the nasopharynx to the laryngeal region.
Thus, the airways of the human head are major deposition sites for the largest inhalable particles
(>10 jam aerodynamic diameter) as well as the smallest particles (<0.1 micrometers diameter).
For the most part, the ET structures are lined with a squamous, non-ciliated mucous membrane.
Collectively, the movement of upper airway mucus, whether transported by cilia or gravity, is
mainly into the gastrointestinal (GI) tract.
As air is conducted into the airways of the head and neck during inspiration, it first passes
through either the nasal passages or mouth. Whereas nasal breathing is normal with most people
most of the time, the breathing mode usually depends upon the work load. Work loads which
tend to treble or quadruple minute ventilation i.e., go from 10 L/m to
10-15
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T
Extrathoracic
Region
Pharynx"!
Posterior
Nasal Pasage
J~Nasal Part
Oral Part
Tracheobronchial
Region
Ciliated Bronchi:
Epithelium
(Secretory and
Basal Cells)
Bronchiolar
Alveolar Interstitial
Bronchioles
Terminal Bronchioles
Respiratory Bronchioles
Alveolar Duct +
Alveoli
Alveolar Endothelium,
Epithelium and Interstitium
(Endothelial Cells, Type II
Epithelial Cells and Clara Celfe)
Figure 10-5. Diagrammatic representation of respiratory tract regions in humans.
-------
Directional
Change
Very
Abrupt
Air
Velocity
Impactiorj
lmpactioi|i
Less
Abrupt
M
Interceptioji
Impactioti V, *r
0
Electrostati
Precipitatio
Figure 10-6. Schematic representation of five major mechanisms causing particle
deposition where airflow is signified by the arrows and particle trajectories
by the dashed line.
Source: Adapted from Casarett (1975); Raabe (1979); Lippmann and Schlesinger (1984).
10-17
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30 to 40 L/m, cause most subjects to change from nasal to oronasal breathing. In either case, the
inspired air then passes through the pharyngeal region into the larynx.
From the larynx, inspired air passes into the trachea, a cylindrical muscular- cartilaginous
tube. The trachea measures approximately 1.8 cm diameter x 12 cm long in humans. The
trachea, like other conducting airways of the lungs, is ciliated and richly endowed with secretory
glands and mucus-producing goblet cells. The major or main stem bronchi are the first of
approximately 16 generations of branching that occur in the human bronchial "tree". For
modeling purposes, Weibel (1963; 1980) described bronchial branching as regular and
dichotomous, i.e., where the branching parent tube gives rise, symmetrically, to two smaller (by
3 r
approximately \/2) tubes of the same diameter. While this pattern provides a simplification for
modeling, the human bronchial tree actually has irregular dichotomous branching, wherein the
parent bronchi gives rise to two smaller tubes of differing diameter and length. The number of
generations of branching occurring before the inspired air reaches the first alveolated structures
varies from about 8 to 18 (Raabe et al., 1976; Weibel, 1980). The junction of conducting and
respiratory airways appears to be a key anatomic focus. Many inhaled particles of critical size
are deposited in the respiratory bronchioles that lie just distal to this junction, and many of the
changes characteristic of chronic respiratory disease involve respiratory bronchioles and alveolar
ducts.
Impaction remains a significant deposition mechanism for particles larger than 2.5 //m
aerodynamic equivalent diameter (dae) in the larger airways of the TB region in humans and
competes with sedimentation, with each mechanism being influenced by mean flow rate and
residence time, respectively. As the airways successively bifurcate, the total cross-sectional area
increases. This increases airway volume in the region, and the air velocity is decreased. With
decreases in velocity and more gradual changes in air flow direction as the branching continues,
there is more time for gravitational forces (sedimentation) to deposit the particle. Sedimentation
occurs because of the influence of the earth's gravity on airborne particles. Deposition by this
mechanism can occur in all airways except those very few that are vertical. For particles «4 //m
dae, a transition zone between the two mechanisms, from impaction to predominantly
sedimentation, has been observed (U.S. Environmental Protection Agency, 1982). This
transition zone shifts toward smaller particles for nose breathing.
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The surface area of the adult human TB region is estimated to be about 200 cm2 and its
volume is about 150 to 180 mL. At the level of the terminal bronchiole, the most peripheral of
the distal conducting airways, the mean airway diameter is about 0.3 to 0.4 mm and their
number is estimated at about 6* 104. As to the variability of bronchial airways of a given size,
Weibel's model (1963) considered 0.2 cm diameter airways and noted that such airways occur
from the 4th to 14th generations of branching, peaking in frequency around the 8th generation.
An insight into the variabilities in various lung models was provided by Forrest (1993) who
indicated that the number of terminal bronchioles incorporated in Weibel's model was about
66,000, whereas, Findeisen (1935) used 54,000 and Horsfield and Cumming (1968) estimated
only 28,000. The transitional airways of the human lung, the respiratory bronchioles and
alveolar ducts, undergo an average of another 6 generations of branching according to Weibel
(1980) before they become alveolar sacs. On this basis, the dichotomous lung model indicates
there should be about 8.4><106 branches (223), serving 3><108 alveoli. The "typical path" model of
Yeh and Schum (1980), adopted by the National Council on Radiation Protection (NCRP)
(Cuddihy et al., 1988), cites approximately 33,000 terminal bronchioles. The International
Commission on Radiological Protection (ICRP) utilized the dimensions from three sources in its
human respiratory tract model (ICRP66, 1994).
The parenchymal tissue of the lungs surrounds all of the distal conducting airways except
the trachea and portions of the mainstem bronchi. This major branch point area is termed the
mediastinum; it is where the lungs are suspended in the thorax by a band of pleura called the
pulmonary ligament, the major blood vessels enter and leave the hilus of each lung, and the site
of the mediastinal pleura which envelopes the heart and essentially subdivides the thoracic
cavity.
Humans lungs are demarcated into 3 right lobes and 2 left lobes by the pleural lining. The
suspension of the lungs in an upright human gives rise to a gradient of compliance increasing
from apex to base and thereby controls the sequential filling and emptying of the lungs.
Subdivisions of the lobes (segments) are not symmetrical due to a fusion of 2 (middle left lung)
of the 10 lobar segments of the lung and occasionally an underdeveloped segment in the lower
left lobe. Lobar segments can be related to specific segmental bronchi and are useful anatomical
delineators for bronchoalveolar lavage.
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The lung parenchyma is composed primarily of alveolated structures of the A region and
the associated blood vessels and lymphatics. The parenchyma is organized into functional units
called acini which consist of the dependent structures of the first order respiratory bronchioles.
The alveoli are polyhedral, thin-walled structures numbering approximately 3*108 in the adult
human lung. Schreider and Raabe (1981) provided a range of values, viz, 2 x 108 to 5.7 x 108.
The parenchymal lung tissue can be likened to a thin sheet of pneumocytes (0.5 to 1.0 jim
thickness) that envelopes the pulmonary capillary bed and is supported by a lattice of connective
tissue fibers: these fibers enclose the alveolar ducts (entrance rings), support the alveolar septa,
and anchor the parenchymal structures axially (e.g. from pulmonary veins) and peripherally
(from the pleural surface).
The alveolar walls or septa are constructed of a network of meandering capillaries
consisting mainly of endothelial cells, an overlying epithelium made of Type I cells or
membranous pneumocytes (95% of the surface) with Type II cells or metabolically-active
cuboidal pneumocytes (5% of the surface), and an interstitium or interseptal connective tissue
space that contains interstitial histiocytes and fibroblasts (Stone et al., 1992). For about one-half
of the alveolar surface, the Type I pneumocytes and the capillary endothelia share a fused
basement membrane. Otherwise, there is an interstitial space within the septa which
communicates along the capillaries to the connective tissue cuffs around the airways and blood
vessels. The connective tissue spaces or basal lamina of these structures are served by
pulmonary lymphatic vessels whose lymph drainage, mainly perivascular and peribronchial, is
toward the hilar region where it is processed en route by islets of lymphoid tissue and filtered
principally by the TB lymph nodes before being returned to the circulation via the subclavian
veins. From the subpleural connective tissue, lymphatic vessels also arise whose drainage is
along the lobar surfaces to the hilar region (Morrow, 1972).
The epithelial surface of the A region is covered with a complex lipo-proteinaceous liquid
called pulmonary surfactant. This complex liquid contains a number of surface-active materials,
primarily phospholipids, with a predominance of dipalmitoyl lecithin. The surfactant materials
exist on the respiratory epithelium non-uniformly as a thin film (<0.01 |im thick) on a hypophase
approximately 10 times thicker. This lining layer stabilizes alveoli of differing dimensions from
collapsing spontaneously and helps to prevent the normal capillary effusate from diffusing from
the interstitium into the alveolar spaces. The role of the lining layer as an environmental
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interface is barely understood, especially in terms of how the layer may modify the
physicochemical state of deposited particles and vice versa.
The epithelial surface of the A region, which can exceed 100 m2 in humans, maintains a
population of mobile phagocytic cells, the alveolar macrophage (AM), that have many important
functions, e.g. removing cellular debris, eliminating bacteria and elaborating many cytologic
factors. The AM is also considered to play a major role in non-viable particle clearance. The
resident AM population varies, inter alia, according to conditions of particle intake, as does their
state of activation. An estimate of the normal AM population in the lungs of non-smokers is
about 7x 109 (Crapo et al. 1982) while in the Fischer 344 rat, estimates are about 2.2x 107 to 2.91
x 107 AM (Lehnert et al., 1985; Stone et al., 1992). According to prevailing views, the
importance of AM-mediated particle clearance via the bronchial airways in the rat and human
lungs may be different (refer to Section 10.4.2.).
The respiratory tract is a dynamic structure. During respiration, the caliber and length of
the airways changes as do the angles of branching at each bifurcation. The structural changes
that occur during inspiration and expiration differ. Since respiration, itself, is a constantly
changing volumetric flow, the combined effect produces a complex pattern of airflows during
the respiratory cycle within the conducting airways and volumetric variations within the A
region. Even if the conducting airways were rigid structures and a constant airflow was passed
through the diverging bronchial tree, the behavior of air flow within these structures would
differ from that produced by the identical constant flow passed in the reverse or converging
direction. Consequently, important distinctions exist between inspiratory and expiratory
airflows through the airways, especially those associated with the glottic aperture and nasal
turbinates. Distinctions occurring in particle deposition during inspiration and expiration are not
as marked as those in airflow. This is because the particles with the greatest tendency to deposit,
will deposit during inspiration and will mostly be absent from the expired air.
At rest, the amount of air that is inspired, the tidal volume (VT), is normally about 500 mL.
If a maximum inspiration is attempted, about 3300 mL of air can be added; this constitutes the
inspiratory reserve volume (IRV). During breathing at rest, the average expired VT is essentially
unchanged from the average inspired VT. At the end of a normal expiration, there still remains
in the lungs about 2200 mL, the functional residual capacity (FRC). When a maximum
expiration is made at the end of a normal tidal volume, approximately 1000 mL of additional air
10-21
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will move out of the lung: this constitutes the expiratory reserve volume (ERV). Remaining in
the lungs after a maximal expiration is the residual volume (RV) of approximately 1200 mL.
These volumes and capacities are illustrated in Figure 10-7. From the perspective of air volumes
within the respiratory tract, estimates are based on both anatomic and physiologic measurements.
The ET airways have a volume in the average adult of about 80 mL, whereas the composite
volume of the transitional airways is about 440 mL. At rest, the total volume in the lungs at end
exhalation is usually around 2200 mL and is called the functional residual capacity (FRC). Both
the RV and FRC tend to increase with age and in some forms of lung disease (e.g., COPD). The
gas exchange volume of the lungs contacts with between 60 and 100 m2 of alveolar epithelium
depending on the state of lung inflation, viz, Alvsa = 22 (VL)2/3 where the surface area (Alvsa) is
in m2 and the lung volume (VL) in liters (or cubic decimeters). The alveolar volume is
juxtaposed with a pulmonary capillary blood volume (70 to 230 mL) which varies with cardiac
output and contacts an endothelial surface area of comparable size to that of the alveoli.
The average respiratory frequency of an adult human at rest is about 12 to 18 cycles per
min. This indicates a cycle length of 4 to 5 s: about 40% for inspiration and 60% for expiration.
With a 500 mL VT, this results in a minute ventilation (VE) of about 6 to 7.5 L/min: about 60 to
70% of the VE is considered alveolar ventilation due to the dead space volume constituting about
30 to 40% of the VT. With the foregoing assumptions, the mean inspiratory and expiratory air
flows will be about 250 mL/s and 166 mL/s, respectively. During moderate to heavy exercise,
the VE will increase by up to 10-fold or more (35 to 70 L/min or more). This is accomplished
initially and primarily by an increase in VT (VT reaches approximately 2.0 L and frequency
approximately 30 to 35 per min at a ventilation of 60 to 70 L per min). There is considerable
variation in response. One impact of such an assumed change in VE is that the duration of the
respiratory phases become shorter and more similar, consequently, the mean inspired and
expired air flows will both likely increase to about >2,000 mL/s. With nose breathing, an
inspiratory airflow of
10-22
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Maximal Inspiratory
Level
Resting Expiratory Level
Maximal Expiratory Level
Figure 10-7. Lung volumes and capacities. Diagrammatic representation of various lung
compartments, based on a typical spirogram. TLC, total lung capacity; VC,
vital capacity; RV, residual volume; FRC, functional residual capacity; 1C,
inspiratory capacity; VT, tidal volume; IRV, inspiratory reserve volume;
ERV, expiratory reserve volume. Shaded areas indicate relationships
between the subdivisions and relative sizes as compared to the TLC. The
resting expiratory level should be noted, since it remains more stable than
other identifiable points during repeated spirograms, hence is used as a
starting point for FRC determinations, etc.
Source: Ruppel (1979).
800 mL/s would be expected to produce linear velocities in the anterior nares greater than 10
m/s.
Because of the irregular anatomic architecture of the nasal passages, the incoming air
induces many eddies and turbulence in the ET airways. This is also true in the upper portions of
the TB region largely due to the turbulence created by the glottic aperture. As the collective
volume and cross sectional area of the bronchial airways increases, the mean airflow rates fall,
but "parabolic airflow", a characteristic of laminar airflow does not develop because of the
10-23
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renewed development of secondary flows due to the repetitive airway branching. Conditions of
true laminar flow probably do not occur until the inspired air reaches the transitional airways.
Whether air flow in a straight circular tube is laminar or turbulent is determined by a
dimensionless parameter known as the Reynolds number (Re) which is defined by the ratio
paDaU/ji where pa is the air density, Da is the tube diameter, U is the air velocity, and |i is the
viscosity of air. As a general rule, when Re is below 2000, the flow is expected to be laminar
(Owen, 1969). See Table 10-2.
Pattle (1961) was the first investigator to demonstrate that the nasal deposition of particles
was proportional to the product of the aerodynamic diameter (dae) squared and the mean
inspiratory flow rate (Q); where the aerodynamic diameter is the diameter of a unit density
sphere having the same terminal settling velocity (see Section 10.2) as the particle of concern.
Albert et al. (1967) and Lippmann and Albert (1969) were among the earliest to report
experimentally that the same general relationship governed inertial deposition of different
uniformly-sized particles in the conducting airways of the TB region. Recent papers by
Martonen et al. (1994a,b,c) have considered the influence of both the cartilaginous rings and the
carinal ridges of the upper TB airways on the dynamics of airflow. As in the case of the glottic
aperture, these structures appear to contribute to the non-uniformity of particulate deposition
sites within these airways. Concomitantly, Martonen et al. have pointed to the limitations
incurred by assuming smooth tubes in modeling the aerodynamics of the upper TB airways (see
also Section 10.5.1.5).
Smaller particles, i.e. those with an aerodynamic size of between 0.1 and 0.5 jam, are the
particles with the greatest airborne stability. They are too small to gravitate appreciably and are
too large to diffuse; hence they tend to persist in the inspired air as a gas would, but in teams of
alveolar mixing, they behave as "non-diffusible" gas. The study of these particles has provided
very useful information on the distribution of tidal air under different physiologic conditions
(Heyder et al., 1985). A recent analysis of airflow dynamics in human airways, conducted by
Chang and Menon (1993), concluded that the measurement of flow dynamics aids in the
understanding of particle transport and the development of enhanced areas of particle deposition.
Sedimentation becomes insignificant relative to diffusion as the particles become smaller.
Deposition by diffusion results from the random (Brownian) motion of very small
10-24
-------
TABLE 10-2. ARCHITECTURE OF THE HUMAN LUNG ACCORDING TO WEIBEL'S (1963)
MODEL A, WITH REGULARIZED DICHOTOMY
to
At flow of 1 L/sec
Region
Trachea0
Main bronchus
Lobar bronchus
Segmental bronchus
Bronchi with
cartilage in wall
Terminal bronchus
Bronchioles with
muscle in wall
Terminal bronchiole
Resp. bronchiole
Resp. bronchiole
Resp. bronchiole
Alveolar duct
Alveolar duct
Alveolar duct
Alveolar sac
Alveoli, 21 per duct
Generation
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Number
1
2
4
8
16
32
64
128
256
512
1,020
2,050
4,100
8,190
16,400
32,800
65,500
131 x 103
262 x 103
524 x 103
1.05 x 106
2.10x 106
4.19 x 106
8.39 x 106
300 x 106
Diameter
(mm)
18
12.2
8.3
5.6
4.5
3.5
2.8
2.3
1.86
1.54
1.30
1.09
0.95
0.82
0.74
0.66
0.60
0.54
0.50
0.47
0.45
0.43
0.41
0.41
0.28
Length
(mm)
120.0
47.6
19.0
7.6
12.7
10.7
9.0
7.6
6.4
5.4
4.6
3.9
3.3
2.7
2.3
2.0
1.65
1.41
1.17
0.99
0.83
0.70
0.59
0.50
0.23
Cum."
Length (mm)
120
167
186
194
206
217
226
234
240
246
250
254
257
260
262
264
266
267
269
270
271
271
272
273
273
Area"
(cm2)
2.6
2.3
2.2
2.0
2.6
3.1
4.0
5.1
7.0
9.6
13
19
29
44
70
113
180
300
534
944
1,600
3,200
5,900
12,000
Volume
(mL)
31
11
4
2
3
3
4
4
4
5
6
7
10
12
16
22
30
42
61
93
139
224
350
591
3,200
Cum.b Volume
(mL)
31
42
46
47
51
54
57
61
66
71
77
85
95
106
123
145
175
217
278
370
510
734
1,085
1,675
4,800
Speed
(cm/s)
393
427
462
507
392
325
254
188
144
105
73.6
52.3
34.4
23.1
14.1
8.92
5.40
3.33
1.94
1.10
0.60
0.32
0.18
0.09
Reynolds
Number
4,350
3,210
2,390
1,720
1,110
690
434
277
164
99
60
34
20
11
6.5
3.6
2.0
1.1
0.57
0.31
0.17
0.08
0.04
—
"Area = total cross sectional area.
bCum. = cumulative.
°Dead space, approx. 175 mL + 40 mL for mouth.
Source: Y.C. Fung (1990).
-------
particles caused by the collision of gas molecules in air. The terminal settling velocity of a
particle approaches 0.001 cm/s for a unit density sphere with a physical diameter of 0.5 //m, so
that gravitational forces become negligible at smaller diameters. The main deposition
mechanism is diffusion for a particle having physical (geometric) size <0.5 //m. Impaction and
sedimentation are the main deposition mechanisms for a particle whose size is greater than
0.5 //m. Hence, dae = 0.5 //m is convenient for use as the boundary between the diffusion and
aerodynamic regimes. Although this convention may lead to confusion in the case of very dense
particles, most environmental aerosols have densities below 3 g/cm3 (U.S. Environmental
Protection Agency, 1982). Diffusional deposition is important in the small airways and in the A
region where distances between the particles and airway epithelium are small. Diffusion has
also been shown to be an important deposition mechanism in the ET region for small particles
(Cheng etal., 1988, 1990).
With mouth-only breathing, the regional deposition pattern changes dramatically when
compared to nasal breathing, with ET deposition being reduced and both TB and A deposition
enhanced. Oronasal breathing (partly via the mouth and partly nasally), however, typically
occurs in healthy adults while undergoing exercise. Therefore, the appropriate activity pattern of
subjects for risk assessment estimation remains an important issue. Miller et al. (1988)
examined ET and thoracic deposition as a function of particle size for ventilation rates ranging
from normal respiration to heavy exercise. A family of estimated deposition curves was
generated as a function of breathing pattern (See Section 10.5.1.4.). Anatomical and functional
differences between adults and children are likely to interact with the major mechanisms
affecting respiratory tract deposition in a complex way which will have important implications
for risk assessment.
Humidification and warming of the inspired air begins in the nasal passages and continues
into the deep lung. This conditioning of the ambient air does not significantly affect particle
deposition unless the paniculate material is intrinsically hygroscopic, in which case, it is very
important. For both liquid and solid aerosol particles that are hygroscopic, there are physical
laws that control both particle growth and deposition, and these have been modeled extensively.
In a review of this general subject (Morrow, 1986), many experimental measurements of the
humidity (RH) and temperature of the air within the respiratory tract have been reported, but
because of the technical problems involved, uncertainties remain. Two major problems prevail:
10-26
-------
(1) the accurate measurement of temperature requires a sensor with a very rapid response time;
and (2) hygrometric measurements of conditions of near saturation (>99% RH) are the most
difficult to make. The latter technicality is of special significance, because the growth of
hygroscopic aerosols are greatest near saturation. For example, the effect of a difference in
humidity between 99.0% and 99.9% is more important than the difference between 20 and 80%
RH. A more complete discussion of models and experimental determinations of the deposition
of hygroscopic aerosols is given in Section 10.4.
The differences in respiratory tract anatomy summarized briefly in this section are the
structural basis for the species differences in particle deposition. In addition to the structure of
the respiratory tract, the regional thickness and composition of the airway epithelium (a function
of cell types and distributions) are important factors in clearance (Section 10.4). Characteristic
values and ranges for many respiratory parameters have been published for "Reference Man" by
the International Commission on Radiological Protection (ICRP) (1975) and they are also
available from many reference sources (Altose, 1980; Collett et al., 1988; Cotes, 1979). A
typical description of respiratory tract morphology, cytology, histology, structure, and function
is given in Table 10-3. This description of the respiratory tract is used in the human dosimetry
model applied in Section 10.7 (ICRP66, 1994). For additional information on human respiratory
tract structure, the papers of Weibel (1963; 1980), Hatch and Gross (1964), Proctor (1977),
Forrest (1993), and Gehr (1994) are recommended.
10.4 FACTORS CONTROLLING COMPARATIVE INHALED DOSE
As discussed in Section 10.1, comprehensive characterization of the
exposure-dose-response continuum is the fundamental objective of any dose-
response assessment. Within human and interspecies differences in anatomical
and physiological characteristics, the physicochemical properties of the
inhaled aerosol, the diversity of cell types that may be affected, and a myriad
of mechanistic and metabolic differences all combine to make the
characterization particularly complex for the respiratory tract as the portal of
entry. This section attempts to discuss these factors within the exposure-dose-
response context in order to present unifying concepts. These concepts are used
to construct a framework by which to
10-27
-------
TABLE 10-3. MORPHOLOGY, CYTOLOGY, HISTOLOGY, FUNCTION, AND STRUCTURE OF THE
RESPIRATORY TRACT AND REGIONS USED IN THE ICRP66 (1994) HUMAN DOSIMETRY MODEL
Functions
Air Conditioning
Temperature am
Humidity, and
Cleaning; Fast
Particle
Conduction
Air Conduction;
Gas Exchange;
Slow Particle
Clearance
Gas Exchange;
Very Slow
Particle
Clearance
Cytology (Epithelium)
Respiratory Epithelium with Goblet
Cells
Cell Types:
• Ciliated Cells
• Nonclllated Cells:
Goblet Cells
Mucous (Secretory) Cell!
Serous Cells
Basal Cells
Intermediate Cells
Respiratory Epithelium with Clara
Cells (No Goblet Cells)
Cell Types:
• Ciliated Cells
• Nonclllated Cells:
Clara (Secretory) Cells
Respiratory Epithelium Consisting
Mainly
of Clara Cells(Secretory) and Few
Ciliated Cells
Squamous Alveolar Epithelial Cells
(Type 1), Covering 93% of Alveolar
Cuboldal Alveolar Epithelial Cells
Covering 7% of Alveolar Surface Arei
Alveolar Macrophages
Histology (Walls)
Mucous Membrane, Respiratory
Ciliated, Mucous), Glands
Mucous Membrane, Respiratory
or Stratified Epithelium, Glands
Mucous Membrane, Respiratory
Epithelium Cartilage Rings,
Glands
Mucous Membrane, Respiratory
Epithelium, Cartilage plates,
Smooth Muscle Layer, Glands
Mucous Membrane, Respiratory
Epithelium, No Cartilage, No
Glands, Smooth Muscle Layer
Mucous Membrane, Single-Layer
Respiratory Epithelium, Less
Ciliated, Smooth Muscle Layer
Mucous Membrane, Single-Layer
Respiratory Epithelium of
Cuboldal Cells, Smooth Muscle
Layer
Wall Consists of Alveolar
Entrance Rings, Squamous
Epithelial Layer, Surfactant
Interalveolar Septa Covered by
Squamous Epithelium, Containin
Capillaries, Surfactant
Number
0
1
2-8
15
16-18
(c)
(c)
Anatomy
Anterior Nasal Passages
I /Nose
\S Mouth, *
f ^^jT
Trachea 1*
^LPharynx
\ Posterior
^^Esophagus
v
Main Bronchy^'x
Bronchi l^j
Bronchioles 1 1
II
2y
Terminal ^\ *
Bronchloles^X
Respiratory -J ^
Bronchioles S fj
DucS" ^^V "Vvy**1^
-------
evaluate the different available dosimetry models; to appreciate why they are constructed
differently, and to determine which are the most appropriate for extrapolation of the available
toxicity data. The section discusses the major factors controlling the disposition of inhaled
particles. Note that disposition is defined as encompassing the processes of deposition,
absorption, distribution, metabolism, and elimination.
It must be emphasized that dissection of the factors that control inhaled dose into discrete
topic discussions is deceptive and masks the dynamic and interdependent nature of the intact
respiratory system. For example, although deposition in a particular respiratory region will be
discussed separately from the clearance mechanisms for that region, retention (the actual amount
of inhaled agent found in the respiratory tract at any time) is determined by the relative rates of
deposition and clearance. Retention and the toxicologic properties of the inhaled agent are
related to the magnitude of the pharmacologic, physiologic, or pathologic response. Therefore,
although the deposition mechanisms, clearance mechanisms, and physicochemical characteristics
of particles are described in distinct sections, assessment of the overall dosimetry and toxic
response requires integration of the various factors.
Inasmuch as particles which are too massive to be inhaled occur in the environmental air,
the description "inhalability" has been used to denote the overall spectrum of particle sizes which
are potentially capable of entering the respiratory tract of humans and depositing therein. Except
under conditions of microgravity (spaceflight) and possibly some other rare circumstances, unit
density particles >100 jim diameter have a low probability of entering the mouth or nose in still
air. Nevertheless, there is no sharp cutoff to zero probability because air velocities into the nose
or mouth during heavy breathing, or in the presence of a high wind, may be comparable to the
settling velocity of >100-|im particles. Even though the settling velocity of particles of this size
is >25 cm/s, wind velocities of several m/s can result in them being blown into the nose or
mouth. Inhalability can be defined as the ratio of the number concentration of particles of a
certain aerodynamic diameter, dae, that are inspired through the nose or mouth to the number
concentration of the same dae present in the inspired volume of ambient air (ICRP66, 1994). The
concept of aerodynamic diameter is discussed in Section 10.2. In studies with head and torso
models, inhalability has been considered generally under conditions of different wind velocities
and horizontal head orientations.
10-29
-------
The American Conference of Governmental Industrial Hygienists (ACGIH) (1985)
expressed inhalability in terms of an intake efficiency of a hypothetical sampler. This
expression was replaced in 1989 by international definitions for inspirable (also called
inhalable), thoracic, and respirable fractions of airborne particle (Soderholm, 1989). Agreement
on these definitions has been achieved between the International Standards Organization (ISO)
and the ACGIH (Vincent, 1995). Health-related sampling should be based on one or more of the
three, progressively very-finer, particle size-selective fractions; inhalable, thoracic, and
respirable.
Each definition is expressed as a sampling efficiency (S) which is a function of particle
aerodynamic diameter (dae) and specifies the fraction of the ambient concentration of airborne
particles collected by an ideal sampler. For the inspirable fraction,
SI(dae) = 0.5(1 + e~°-°6
-------
It should be emphasized that these conventions do not purport to reflect deposition per se, but
are rather intended to be representative of the penetration of particles to a region and hence their
availability for deposition. The thoracic fraction corresponds to penetration to the TB plus A
regions, and the respirable fraction to the A region. Inhalability for laboratory animals is
discussed in Section 10.5.2.
Swift (1976) estimated the deposition of particles by impaction in the nose, based on a
nasal entrance velocity of 2.3 m/s and a nasal entrance width of 0.5 cm, and deduced that
particles >61 jim dae have a negligible probability of entering the nasal passages due to the high
impaction efficiency of the external nares. Experiments by Breysse and Swift (1990) in tranquil
air estimated a practical upper limit for inhalability to be ~ 40 jim dae for individuals breathing at
15 breaths per min at rest. No information on tidal volumes was provided. Studies reported by
Vincent (1990) of inhalability made use of a mannequin with mouth and nasal orifices that could
be placed in a wind tunnel and rotated 360 degrees horizontally. At low wind speeds, the intake
efficiency approached 0.5 for particle sizes between 20 jam and 100 jim dae. Vincent derived the
following empirical relationship from these studies
ri! (sampler) = 0.5 [1 + exp(-0.06 dae) = 1 x 10'5 U2'75 exp (0.055 dj, (10-9)
where r^ is the intake efficiency of the sampler, dae is the aerodynamic diameter, and U is the
wind speed. For particles with dae less than about 40 //m, intake efficiency generally tends to
decrease with increasing dae. However, for large particles, the intake efficiency tends to increase
with windspeed. For particles with dae < 10 //m, the ICRP modified Vincent's expression to
increase the accuracy in representing the data. Thus, in the 1994 ICRP66 model (ICRP66, 1994)
the intake efficiency of the head, % i.e., the particle inhalability, is represented by
rh = 1 - 0.5 (1 - [7.6 x 10 -4 (dj 2'8 + I]'1) + 1 x ID'5 U2'75 exp (0.055 dae),
(10-10)
where dae is in //m and U is the windspeed in (m s"1) (for 0 < U < 10 ms"7).
While there is some contention about the practical upper size limit of inhalable particles in
humans, there is no lower limit to inhalability as long as the particle exceeds a critical
10-31
-------
(Kelvin) size where the aggregation of atomic or molecular units is stable enough to endow it
with "particulate" properties, in distinction to those of free ions or gas molecules. Inter alia,
particles are considered to experience inelastic collisions with surfaces and with each other. The
lower limit for the existence of aerosol particles is assumed to be around 1 nanometers for some
materials (refer to Section 10.2.). If the parti culate material has an appreciable vapor pressure,
particles of a certain size may "evaporate" as fast as they are formed. For example, pure water
droplets as large as 1 jim diameter will evaporate in less than 1 second even when they are in
water-saturated air at 20° Celsius (Greene and Lane, 1957).
Description of a "respirable dust fraction" was first suggested by the British Medical
Research Council and implemented by C.N. Davies (1952) using the experimentally-estimated
alveolar deposition curve of Brown et al. (1950). This curve described the respirable dust
fraction as that which would be available to deposit in the alveolated lung structures including
the respiratory bronchioles, thereby making "respirable dusts" applicable to pneumoconiosis-
producing dusts. The horizontal elutriator was chosen as a particle size selector, and respirable
dust was defined as that dust passing an ideal horizontal elutriator. The elutriator cutoff was
chosen to result in the best agreement with experimental lung deposition data. The
Johannesburg International Conference on Pneumoconiosis in 1959 adopted the same standard
(Orenstein, 1960). Later, an Atomic Energy Commission working group defined "respirable
dust" by a deposition curve which indicated 0% deposition at 10 jam dae and 100% deposition for
particles <2.0 jim dae. "Respirable dust" was defined as that portion of the inhaled dust which
penetrates to the nonciliated portions of the lung (Hatch and Gross, 1964). The AEC respirable
size deposition curve was pragmatically adjusted to 100% deposition for <2 jim dae particles so
that the "respirable" curve could be approximated by a two-stage selective sampler and because
comparatively little dust mass was represented by these small particles (Mercer 1973a). This
definition was not intended to be applicable to dusts that are readily soluble in body fluids or are
primarily chemical intoxicants, but rather only for poorly soluble particles that exhibit prolonged
retention in the lung.
Other groups, such as the American Conference of Governmental Industrial Hygienists
(ACGIH), incorporated respirable dust sampling concepts in setting acceptable exposure levels
for other toxic dusts. Such applications are more complicated, since laboratory animal
10-32
-------
and human exposure data, rather than predictive calculations, form the data base for standards.
The size-selector characteristic specified in the ACGIH standard for respirable dust (Threshold
Limits Committee, 1968) was almost identical to that of the AEC, differing only at 2 //m dae,
where it allowed for 90% passing the first-stage collector instead of 100 percent. The difference
between them appeared to be a recognition of the properties of real particle separators, so that,
for practical purposes, the two standards could be considered equivalent (Lippmann, 1978).
The cutoff characteristics of the precollectors preceding respirable dust samplers are
defined by these criteria. The two sampler acceptance curves have similar, but not identical,
characteristics, due mainly to the use of different types of collectors. The BMRC curve was
chosen to give the best fit between the calculated characteristics of an ideal horizontal elutriator
and available lung deposition data; on the other hand, the design for the AEC curve was based
primarily on the upper respiratory tract deposition data of Brown et al. (1950). The separation
characteristics of cyclone type collectors simulate the AEC curve. Whenever the particle size
distribution has a og > 2, samples collected with instruments meeting either criterion will be
comparable (Lippmann, 1978). Various comparisons of samples collected on the basis of the
two criteria are available (Knight and Lichti, 1970; Breuer, 1971; Maquire and Barker, 1969;
Lynch, 1970; Coenen, 1971; Moss and Ettinger, 1970).
The various definitions of respirable dust were somewhat arbitrary, with the BMRC and
AEC definitions being based on the poorly soluble particles that reach the A region. Since part
of the aerosol that penetrates to the alveoli remains suspended in the exhaled air, respirable dust
samples are not intended to be a measure of A deposition but only a measure of aerosol
concentration for those particles that are the primary candidates for A deposition. Given that the
"respirable" dust standards were intended for "insoluble dusts", most of the samplers developed
to satisfy their criteria have been relatively simple two-stage instruments. In addition to an
overall size-mass distribution curve, multistage aerosol sampler data can provide estimates of the
"respirable" fraction and deposition in other functional regions. Field application of these
samplers has been limited because of the increased number and cost of sample analyses and the
lack of suitable instrumentation. Many of the various samplers, along with their limitations and
deficiencies, were reviewed by Lippmann (1978).
10-33
-------
PM10 dust is based on the PM10 sampler efficiency curve promulgated by the U.S.
Environmental Protection Agency. This sample is equivalent to the thoracic dust sample defined
by the American Conference of Governmental Industrial Hygienists (Raabe, 1984).
The medical field also refers to a "respirable fraction". Aerosols are widely used for both
therapy and diagnosis (Swift, 1993). Aerosols are used to deliver bioactive substances to the
respiratory tract to affect a physiological change (e.g., nasal or bronchial medication),
provocation tests in the diagnosis of bronchial asthma, and the administration of contrast
substances for radiological studies. In pharmaceutical applications, the "respirable fraction"
refers to particles with an aerodynamic diameter between 0.5 and 5 //m for most therapeutic
products, although larger size particles (up to 10 //m) are recognized as important in certain
situations (Hallworth, 1993; Lourenco and Cotromanes, 1982). Aerosols produced by
metered-dose-inhaler (MDI) systems are about 2.5 to 2.8 //m in size upon entering the lung (Kim
et al., 1985) and 40 to 50% of these aerosols are expected to deposit during normal tidal
breathing. The lung deposition, however, is usually higher in the abnormal lung, and can be
further increased by changing the mode of breathing.
10.4.1 Deposition Mechanisms
This section will review briefly the aerosol physics that both explains how and why
particle deposition occurs and provides the theoretician a capability to develop predictive
deposition models. Some of these models will be described in Section 10.5, together with recent
experimental results on particle deposition. The ability of the experimentalist to measure
deposition quantitatively has continued to advance, but theoretical models remain the only
practical way for predicting the impact of aerosol exposures and for delineating the patterns of
intra-regional deposition.
The motion of an airborne particle between 1 and 100 |im dae is primarily related to its
mass, and the resulting resistive force of air which is proportional to
|ivd, (10-11)
where |i is the viscosity of air, v is the velocity of the particle relative to the air, and d is the
particle diameter. This is a statement of Stokes law for viscous resistance which is
10-34
-------
appropriate to a sphere moving in air at low particle Reynolds numbers, i.e., less than 1. The
particle Reynolds number (Rep) is defined as
(10-12)
where pa is the density of air. When the particle velocity relative to air is sufficiently slow that
the airflow pattern around the sphere is symmetrical and only viscous stresses resist the sphere's
motion, Stokes law applies. As the value of Rep increases, asymmetrical flow about the moving
sphere and a pressure drop across the sphere, both progressively develop. These changes in flow
signify that the condition of inertial resistance prevails and Stokes law does not pertain (Mercer,
1973b).
For the range of particle sizes just discussed (1 to 100 jim), the motion of airborne particles
is characterized by a rapid attainment of a constant velocity whereby the viscous resistance of air
matches the force(s) on the sphere responsible for its motion. This constant velocity is termed
the terminal velocity of the particle. For the size region below 1 |im diameter, particle motion is
also based on the viscous resistance of air and described by its terminal velocity. In this particle
size region, the viscous resistance of air on the particle, using Stokes law, begins to be
overestimated and the particle's terminal velocity, underestimated. This general phenomenon is
termed "slip"; consequently, Slip Correction Factors have been developed. These slip
corrections become more important as the particle diameter nears, or is less than, the mean free
path of air molecules (« 0.068 //m at 25 °C and 760 mm Hg air pressure).
10.4.1.1 Gravitational Settling or Sedimentation
All aerosol particles are continuously influenced by gravity, but for practical purposes,
particles with an dae > 0.5 jim are mainly involved. Within the respiratory tract, an dae of 100 jim
will be considered as an upper cut-off. A spherical, compact particle within these arbitrary
limits will acquire a terminal settling velocity when a balance is achieved between the
acceleration of gravity, g, acting on the particle of density, p, (g/cm3) and the viscous resistance
of the air according to Stokes law
10-35
-------
(7t/6)pdjg = 37tjidvt. (10-13)
The left hand side of Equation 10-13 is the force of gravity on the particle, neglecting the effect
of the density of air. Solving for the terminal velocity, vt, gives
t = da2epg Ks / 18ji. (10-14)
In Equation 10-14 a slip correction factor, Ks, is added to account for the slip effect on particles
with diameters about or below 1 jim. For particles as small as 0.02 jim, the K,, used by Knudsen
and Weber increases vt six fold (cited by Mercer, 1973c).
The relationship for the terminal settling velocity, just described, is not restricted to
measurements in tranquil air. For example, moving air in a horizontal airway will tend to carry
the particle at right angles to gravity at an average velocity, U. The action of gravity on the
particle will nonetheless result in a terminal settling velocity, vt; consequently the particle will
follow, vectorially, the two velocities; and, provided the airway is sufficiently long or the
settling velocity is relatively high, the particle will sediment in the airway. For every orientation
of the airways with respect to gravity, it is possible to calculate the particle's settling behavior
using Stokes law.
10.4.1.2 Inertial Impaction
Sudden changes in airstream direction and velocity, cause particles to fail to follow the
streamlines of airflow as depicted in Figure 10-5. As a consequence, the relatively massive
particles impact on the walls or branch points of the conducting airways. The ET and upper TB
airways have been described as the dominant sites of high air velocities and sharp directional
changes; hence, they dominate as sites of inertial impaction. Because the air (and particle)
velocities are affected by the breathing pattern, it is easy to imagine that even small particles also
experience some inertial impaction. Moreover, as nasal breathing shifts to oral breathing during
work or exercise, the particle that would normally be expected to impact in the ET region will
pass into the TB region, greatly increasing TB deposition. That all
10-36
-------
impaction sites occur lower down in the TB region when such a shift takes place is also
expected.
The probability that a particle with a diameter, d, moving in an air stream with an average
velocity, U, will impact at a bifurcation is related to a parameter called the Stokes number, Stk;
defined as
pd2 U/9ji Da , (10-15)
or
2
pdae2 U/9ji Da. (10-16)
As far as particulate properties are concerned, the aerodynamic diameter (dae) is again the
significant parameter (see Section 10.2). In Landahl's lung deposition model (1950a) of
impaction in the TB region, impaction efficiency was proportional to
pd2lL sin 0, / Dai S,.!, (10-17)
where U; is the air velocity in the airway generation i, 6; is the branching angle between
generations i and i-1, Dai is diameter of the airway of generation i, and S^ is the total cross
sectional area of airway generation i-1.
Prevailing TB models have simplistically represented the airways as smooth, bifurcating
tubes. Martonen et al. (1993; 1994a,b,c) have predicted that the cartilaginous rings and carinal
ridges perturb the dynamics of airflow and help to explain the non-uniformity of particle
deposition.
It should be evident that both gravitational settling and inertial impaction cause the
deposition of many particles within the same size range. These deposition forces are always
acting together in the ET and TB regions, with inertial impaction dominating in the upper
airways and gravitational settling becoming increasingly dominant in the lower conducting
10-37
-------
airways, and especially for the largest of the particles which can penetrate into the transitional
airways and alveolar spaces.
For sedimenting particles with diameters between 0.1 jim to 1.0 |im, their Slip Correction
Factor will be greater than 1.0, although the magnitude of their respective vt will only range
from about 1 |im/s to 35 |im/s. Concurrently, 0.1 jim diameter particles are affected by diffusion
such that the root mean displacement they experience in one second is about 0.3 jim. The size
region, 1.0 jim down to about 0.1 jim, is frequently described as consisting of particles which are
too small to settle and too large to diffuse. Indeed, it is this circumstance that makes them the
most persistent and stable particles in aerosols and those which undergo the least deposition in
the respiratory tract. As any aerosol ages and continuously undergoes deposition without
particle replenishment, the ultimate aerosol will exist largely within this same size range, i.e.,
have a median size of about 0.5 jam diameter.
10.4.1.3 Brownian Diffusion
Particles <1 jim diameter are increasingly subjected to diffusive deposition as their size
decreases. Even particles in the nanometer diameter range are large compared to individual air
molecules, hence, the collisions resulting between air molecules, undergoing random thermal
motion, and the surface of a particle produce numerous very small changes in the particle's
spatial position. These frequent, minute excursions are each made at a constant or terminal
velocity due to the viscous resistance of air. The root mean square (r.m.s.) displacement that the
particle experiences in a unit of time along a given cartesian coordinate, x, y or z is a measure of
its diffusivity. For instance, a 0.1 jim diameter particle has a r.m.s. displacement of about 37 jim
during one s. This 1 |im displacement in one s does not describe a velocity of particle motion
because the displacement resulted from numerous relatively high velocity excursions.
The diffusion of particles by Brownian motion is described by the Einstein-Stokes'
equation
Ax = D, (10-18)
10-38
-------
where Ax is the root-mean-square displacement in one second along coordinate x, D is the
diffusion coefficient for the particle expressed in cm2/s, t is time in seconds. The diffusion
coefficient of a particle of diameter, d, is
D = KTKs/37i:jid, (10-19)
where K is the Boltzmann constant, and T the absolute temperature, collectively describing the
average kinetic energy of the gas molecules.
It is apparent that the density of the particle is ordinarily unimportant in determining
particle diffusivity which increases as Ks increases and d decreases. Instead of having an
aerodynamic equivalent size, diffusive particles of different shapes can be related to the
diffusivity of a thermodynamic equivalent size based on spherical particles (Heyder and
Scheuch, 1983). In terms of the architecture of the respiratory tract, diffusive deposition of
particles is favored by proximate surfaces and by relatively long residence times for particles,
both conditions occurring in the alveolated structures of the lungs, the A region. Experimental
studies with diffusive particles (<0.5 jim) in replicate casts of the human nose and theoretical
predictions both indicate a rising deposition efficiency for the nasal airways as d becomes very
small (Cheng et al., 1988).
10.4.1.4 Interception
The interception potential of any particle depends on its physical size. As a practical
matter, particles that approach sizes > 150 //m or more in one dimension will be too massive to
be inhaled. Airborne fibers (length/diameter > 3), however, frequently exceed 150 jim in length
and appear to be relatively stable in air. This is because their aerodynamic size is determined
predominantly by their diameter, not their length. Fibers, therefore, are the chief concern in the
interception process, especially as their length approaches the diameters of peripheral airways
(>150 nm).
The theoretical model of Asgharian and Yu (1988, 1989) for the deposition of fibrous
particles in the respiratory tract is complex. While the model includes interception as an
important process for long fibers, it also depends on a combination of inertial, gravitational
10-39
-------
and diffusional forces to explain fiber deposition. The deposition efficiencies of the three
deposition mechanisms cited have been developed for spherical particles, but these can be
extended to fibrous particles by considering orientation effects which are strongly related to the
direction of airflow. The orientation of fibers depends upon the velocity shear of the airflow and
Brownian motion.
For their analysis of orientational effects throughout the respiratory tract, Asgharian and
Yu (1988, 1989) defined the equivalent mass diameter, dem, of fibers as
(10-20)
where df is the fiber diameter and P is its aspect ratio (length/diameter). For example, a fiber
100 jim long and 3 jim diameter has a dem of 10 jim diameter. In Figure 10-8, two sets of TB
deposition predictions for the rat are reproduced from Asgharian and Yu (1989) that clearly
show an example of the relative importance of particle interception.
0.5n
0.5n
Figure 10-8. Estimated tracheobronchial (TB) deposition in the rat lung, via the trachea,
with no interceptional deposition. Graph A is shown in relation to total TB
deposition, via the trachea; Graph B for the same fibrous aerosol under
identical respiratory conditions including interception.
Source: Asgharian and Yu (1989).
10-40
-------
Several general reviews of particle deposition mechanisms in the human respiratory tract
have been published, e.g, Stuart (1973), Lippmann (1977), and Brain and Blanchard (1993), and
are recommended to the reader, as is the excellent review of particle deposition mechanisms
prepared by Phalen (1984).
10.4.1.5 Electrostatic Precipitation
The minimum charge an aerosol particle can have is zero, when it is electrically neutral.
This condition is rarely achieved because of the random charging of aerosol particles by the
omnipresent air ions. Every cubic centimeter of air contains about 103 ions in approximately
equal numbers of positive and negative ions. Aerosol particles that are initially neutral will
acquire charges from these ions by collisions with them due to their random thermal motion.
Aerosols that are initially charged will lose their charge slowly as the charged particles attract
oppositely charged ions. An equilibrium state of these competing processes is eventually
achieved. The Boltzmann equilibrium represents the charge distribution of an aerosol in charge
equilibrium with bipolar ions. The minimum amount of charge is very small, with a statistical
probability that some particles will have no charge and others will have one or more charges.
The electrical charge on some particles may result in an enhanced deposition over what
would be expected from size alone. This is due to image charges induced on the surface of the
airway by these particles or to space-charge effects whereby repulsion of particles containing
like charges results in increased migration toward the airway wall. The effect of charge is
inversely proportional to particle size and airflow rate. This deposition is probably small
compared to the effects of turbulence and other deposition mechanisms and is generally a minor
contributor to overall particle deposition, but it may be important in some laboratory studies.
This deposition is also negligible for particles below 0.01 //m because so few of these particles
carry any charge at Boltzmann equilibrium.
Many of freshly generated particles are electrostatically charged. Experimental studies in a
lung cast (Chan et al., 1978) and measurements in rats and humans (Melandri et al., 1977, 1983;
Tarroni et al., 1980; Jones et al., 1988; Scheuch et al., 1990) all showed that particle charge
increased deposition. For low particle number concentration (<105 cm"3), the deposition increase
is due to the presence of electrostatic image force acting on the
10-41
-------
particle by particle-wall interaction (Yu, 1985). Figure 10-8 shows the experimental data on
human deposition of Melandri et al. (1983) and Tarroni et al. (1980) for three particle sizes and
the modeling results by Yu (1985). The vertical axis in Figure 10-9 is the deposition increment,
defined as
AT = (DE-DE0)/(1-DE0),
(10-21)
where DE is total deposition at particle charge level, q, and DE0 is the total deposition of
particles at Boltzmann charge equilibrium. As seen for each particle size, deposition increments
increase linearly with q. Figure 10-9 also shows that there exists a threshold charge level above
which the increase in deposition becomes significant. For 1 jim particles, the threshold charge
was estimated to be about 54 elementary charges (Yu, 1985).
16
14
12
« 10
a
o
:•= e
(0
o
0.
Q 4
2
d = 1.0 |jm
0.3|jm
0.6|jm
20 40 60 80 100
Particle Charge, q
120
140
Figure 10-9. Deposition increment data versus particle electronic charge (q) for three
particle diameters at 0.3, 0.6, and 1.0 /j,m (unit density). The solid lines
represent the theoretical predictions.
Source: Yu(1985).
10-42
-------
10.4.1.6 Additional Factors Modifying Deposition
The available experimental deposition data in humans are commonly for healthy adult
Caucasian males using stable, monodisperse particles in charge equilibrium. When these
conditions do not hold, changes in deposition are expected to occur. In the following, the effects
of different factors on deposition are summarized based upon the information reported from
various studies.
Gender
The average size of the adult human femal thorax is smaller than the average thorax size in
adult human males. The diameter of the female trachea is approximately 75% that of the male
(Warwick and Williams, 1973), and the size of the bronchi is proportional to the size of the
trachea (Weibel, 1963). In addition, the minute ventilation and inspiratory flow rate are smaller
for females. It is therefore expected that deposition will be different in females than males.
Using radioactive-labeled polystyrene particles in the 2.5 to 7.5 jim size range, Pritchard et al.
(1986) measured total and regional deposition in 13 healthy nonsmoking female adults at mouth
breathing through a tube. Because deposition of particles in this particle size range in the ET
region is controlled by impaction, they reported the data as a function of d^e Q to accommodate
the difference in flow rate between male and female. The data of Pritchard et al. (1986) for
females are shown together with data obtained for a group of male nonsmokers using the same
technique in Table 10-4. At a comparative value of d^e Q, females were found to have higher ET
and TB deposition and smaller A deposition. The ratio of A deposition to total thoracic
deposition in females was also found to be smaller. The differences in depositions were
attributed by Pritchard et al. (1986) to the differences in the airway size between males and
females.
Age
As a human grows from birth to adulthood, both airway structure and respiratory
conditions vary with age. These variations are likely to alter the deposition pattern of inhaled
particles. Total deposition data for particles of 1 to 3.1 jim size range were reported by
Becquemin et al. (1987, 1991) for a group of 41 children at 5 to 15 years of age and by Schiller-
Scotland et al. (1992) for 29 children at two age groups (6.7 and 10.9 years).
10-43
-------
TABLE 10-4. DEPOSITION DATA FOR MEN AND WOMEN
Deposition as a Fraction of
Inhaled Material (%) ± Standard Error
Sex
Female
Male
(//m2 Lmin"1)
405 ± 47
430 ±41
Total
75.9 ± 1.7
81. 5± 1.8
ET
21.2 ±2.4
19.9 ±2.5
TB
16.9± 1.5
14.7 ± 1.7
A
37.5 ±2.5
46.9 ±2.7
Although Becquemin et al. (1987, 1991) did not find a clear dependence of total deposition on
age, slightly higher deposition was found by Schiller-Scotland et al. (1992), for each diameter
when children breathed at their normal rates (see Figure 10-10), than was found in adults.
Mathematical models for children have been developed by many workers (Hofmann, 1982;
Crawford, 1982; Xu and Yu, 1986; Yu and Xu, 1987; Phalen et al., 1988; Hofmann et al., 1989;
Yu et al., 1992; Martonon and Zhang, 1993). Phalen et al. (1988) reported morphometric data
of twenty TB airway casts of children and young adults from 21 days to 21 years. With the use
of these data, they calculated a higher TB deposition in children during inhalation for particle
diameters between 0.01 and 10 jim. If the entire respiratory tract and a complete breathing cycle
at normal rate are considered in the model, the results show that ET deposition in children is
higher than adults, but that TB and A deposition in children may be either higher or lower than
the adult depending upon the particle size (Xu and Yu, 1986).
Respiratory Tract Disease
Effect of airway diseases on deposition have been studied extensively. In 8 healthy
nonsmokers, Svartengren et al. (1986, 1989) found A deposition at different flow rates to be
lower (26% versus 48% of thoracic deposition) in subjects after induced bronchoconstriction.
The degree of bronchoconstriction was quantified by measurements of airway resistance using a
whole-body plethysmograph. An inverse relationship between airway resistance and A
deposition was found. Data from the same laboratory (Svartengren et al., 1990, 1991) using 2.6
|im dae particles with maximally deep slow inhalations at 0.5 L/min showed no
10-44
-------
n Q
o O.o
Q.
0
Q
« 0.6
o
0.4
I 0.2
0123
Particle Size (|jm)
- adults A 1:1 urn * 1: 2 pm * 1: 2.3
° 1:3 pm ^ II: 1 pm • II: 2 pm * II: 3 pm
Figure 10-10. Total deposition data in children with or during spontaneous breathing as a
function of particle diameter (unit density). Group I (10.6 ± 2.0 yrs);
Group II (5.3 ± 1.5 yrs). The adult curve represents the mean value of
deposition from the data of Stahlhofen et al. (1989).
Source: Schiller-Scotland et al. (1992).
significant differences in mouth and throat deposition in asthmatics versus healthy subjects, but
thoracic deposition was higher in asthmatics than in healthy subjects (83% versus 73% of total
deposition). TB deposition was also found to be higher in asthmatics. The results are similar to
those found in subjects with obstructive lung disease (e.g., Dolovich et al., 1976; Itoh et al.,
1981; Anderson et al., 1990).
Another extensive study of the relationship between deposition and lung abnormality was
made by Kim et al. (1988). One-hundred human subjects with various lung conditions (normal,
asymptomatic smoker, smoker with small airway disease, chronic simple bronchitis and chronic
obstructive bronchitis) breathed 1 jim test particles from a bag at a rate of 30 breaths/min. The
number of rebreathing breaths needed to produce a 90% loss of aerosol
10-45
-------
from the bag was determined. From these data, they estimated total deposition and found that
total deposition increased with increasing level of airway obstruction.
Particle Polydispersity
Aerosol particles are often generated polydisperse and can be approximated by a lognormal
distribution (Section 10.2). The mass deposition of spherical particles in the respiratory tract
depends upon mass median diameter (MMD), geometric standard deviation, og, and physical
density (Diu and Yu, 1983; Rudolf et al., 1988). For large particles (dae > 1 jam), deposition is
governed by impaction and sedimentation. The dependence on MMD and mass density can be
combined with the use of mass medium aerodynamic diameter (MMAD), as suggested by TGLD
(1966). However, this method is not valid for particles in the size range where diffusion
deposition becomes important. Figure 10-11 shows the calculated total and regional mass
deposition results by Yeh et al. (1993) for polydisperse aerosols of unit density with various og
as function of MMD at quiet mouth breathing. The variation of deposition with og depends
strongly on the MMD of the aerosol. At certain MMD's, variability with og is zero; however,
variations at other MMD's can be very large. One of the main effects of polydisperse deposition
is the flattening of the deposition curves as a function of particle size, as shown in Figure 10-11.
Particle Hygroscopicity
Another important particle factor that affects deposition is the hygroscopicity of the
particle. Many atmospheric particles such as acid particles are water soluble. As these particles
travel along the humid respiratory tract, they grow in size and, as a result, the deposition pattern
is altered. A discussion on deposition of hygroscopic particles follows in Section 10.4.3.
10.4.1.7 Comparative Aspects of Deposition
The various species used in inhalation toxicology studies that serve as the basis for dose-
response assessment do not receive identical doses in a comparable respiratory tract region (ET,
TB, or A) when exposed to the same aerosol or gas (Brain and Mensah, 1983). Such
interspecies differences are important because the adverse toxic effect is likely more
10-46
-------
1.0 -I
0.8-
« 0.6-
g 0.41
Q.
0.2-
0.0
Og= 1
Og=2
Og=4
0.001
0.01
I
0.1
I
10
100
MMD(|jm)
1.0 -I
0.01
0.1 1
MMD(|jm)
10
100
Figure 10-11. Calculated mass deposition from polydisperse aerosols of unit density with
various geometric standard deviations (og) as a function of mass median
diameter (MMD) for quiet breathing (tidal volume = 750 mL, breathing
frequency = 15 min *). The upper panel is total deposition and the lower
panel is regional deposition (NOPL = Naso-oro-pharyngo-laryngeal, TB =
Tracheobronchial, A = Alveolar). The range of og values demonstrates the
extremes of monodisperse to extremely polydisperse.
Source: Yeh et al. (1993).
10-47
-------
related to the quantitative pattern of deposition within the respiratory tract than to the exposure
concentration; this pattern determines not only the initial respiratory tract tissue dose but also the
specific pathways by which the inhaled material is cleared and redistributed (Schlesinger,
1985b). Differences in ventilation rates and in the URT structure and size and branching pattern
of the lower respiratory tract between species result in significantly different patterns of airflow
and particle deposition. Disposition varies across species and with the respiratory tract region.
For example, interspecies variations in cell morphology, numbers, types, distributions, and
functional capabilities contribute to variations in clearance of initially deposited dose. Tables
10-5, 10-6, and 10-7 summarize some of these differences for the ET, TB, and A regions,
respectively. This section only briefly summarizes these considerations. Comprehensive and
detailed reviews of species differences have been published (Phalen and Oldham, 1983; Patra,
1986; Mercer and Crapo, 1987; Gross and Morgan, 1992; Mercer and Crapo, 1992; Parent,
1992).
The geometry of the upper respiratory tract exhibits major interspecies differences (Gross
and Morgan, 1992). In general, laboratory animals have much more convoluted nasal turbinate
systems than do humans, and the length of the nasopharynx in relation to the entire length of the
nasal passage also differs between species. This greater complexity of the nasal passages,
coupled with the obligate nasal breathing of rodents, is generally thought to result in greater
deposition in the upper respiratory tract (or ET region) of rodents than in humans breathing
orally or even nasally (Dahl et al., 1991), although limited comparative data are available.
Species differences in gross anatomy, nasal airway epithelia (e.g., cell types and location) and
the distribution and composition of mucous secretory products have been noted (Harkema, 1991;
Guilmette et al., 1989). The extent of upper respiratory tract removal affects the amount of
particles or gas available to the distal respiratory tract.
Airway size (length and diameter) and branching pattern affect the aerodynamics of the
respiratory system in the following ways:
• The airway diameter affects the aerodynamics of the air flow and the distance from the
particle to the airway surface.
• The cross-sectional area of the airway determines the airflow velocity for a given
volumetric flow.
• Airway length, airway diameter, and branching pattern variations affect the mixing
between tidal and residual air.
10-48
-------
TABLE 10-5. INTERSPECIES COMPARISON OF NASAL CAVITY CHARACTERISTICS
Body weight
Nans cross-section
Bend in nans
Length
Greatest vertical diameter
Surface area (both sides of nasal
cavity)
Volume (both sides)
Bend in nasopharynx
Turbinate complexity
Sprague-Dawley Rat
250 g
0.7 mm
40°
23 cm
9.6 mm
10.4 cm2
0.4cm
15°
Complex scroll
Guinea Pig
600 g
2 5 mm2
40°
3.4 cm
12.8mm
27.4 cm2
039 cm3
30°
Complex scroll
Beagle Dog
10kg
16.7 mm2
30°
10cm
23 mm
220.7 cm2
20cm3
30°
Very complex membranous
Rhesus Monkey
7kg
22.9 mm2
30°
5.3 cm
27mm
61.6 cm2
8cm3
80°
Simple scroll
Human3
-70kg
140 mm2
7-8 cm
40-45 mm
181 cm2
16-19 cm3 (does not
include sinuses)
-90°
Simple scroll
aAdult male.
Source: Schreider (1983); Gross and Morgan (1992).
-------
TABLE 10-6. COMPARATIVE LOWER AIRWAY ANATOMY AS REVEALED ON CASTS
Mammal/
Body Mass
Human/70 kg
Rhesus
monkey/2 kg
Beagle dog/
10kg
i—1 Ferret/
"P 0.61 kg
O Guinea pig/
1kg
Rabbit/
4.5kg
Rat/0.3 kg
Golden
hamster/
0.14kg
Left Lung
Lobes
Upper and
lower
Superior,
middle, and
inferior
Apical,
intermediate,
and basal
NR'
Superior
and
inferior
Superior
and
inferior
One lobe
Superior
and
inferior
Right Lung
Lobes
Upper, middle,
and lower
Superior,
middle, and
inferior,
azygous
Apical,
intermediate,
and basal
NR
Superior,
middle, and
inferior
Cranial,
middle, caudal,
and postcaval
Cranial,
middle, caudal,
and postcaval
Cranial, middle,
caudal, and
postcaval
Gross Structure
Airway
Branching
Relatively
symmetric
Monopodial
Strongly
monopodial
strongly
monopodial
Monopodial
Strongly
monopodial
Strongly
monopodial
Strongly
monopodial
Trachea Major
Length/Diameter Airway
(cm) Bifurcations
12/2 Sharp for about
the first
10 generations,
relatively
blunt thereafter
3/0.3 Mixed blunt
and sharp
17/1.6 Blunt tracheal
bifurcation,
others sharp
10/0.5 Sharp
5.7/0.4 Very sharp
and high
6/0.5 Sharp
2.3/0.26 Very sharp and
very high
throughout lung
2.4/0.26 Very sharp
Typical Structure
(Generation 6)
Average Branch Angles
Airway (Major Daughter/
L/D Minor Daughter)
(ratio) (degrees)
2.2 11/33
2.6 20/62
1.3 8/62
2.0 16/57
1.7 7/76
1.9 15/75
1.5 13/60
1.2 15/63
Typical Number
of Branches
to Terminal Respiratory
Bronchiole Bronchioles
14-17 About 3-5 orders
10-18 About 4 orders
15-22 About 3-5 orders
12-20 About 3-4 orders
12-20 About 1 order
12-20 About 1-2 orders
12-20 Rudimentary
10-18 About 1 order
"NR = Not reported.
Source: Phalen and Oldham (1983); Patra (1986); Mercer and Crapo (1987).
-------
TABLE 10-7. ACINAR MORPHOMETRY
Species
Human
Rabbit
Guinea pig
Rat
Number of
Fixation Acini/Lung
27,992
75% TLC 23,000
80,000
TLC 26,000-32,000
FRC 43,000
17,900
55% TLC 18,000
5,100
FRC 4,097
2,500
2,487
FRC 2,020
70% TLC 5,993
V
(mm3)
1.33-30.9
160.8
15.6
187.0
51.0
2.54
3.46
1.25
1.09
1.0
5.06
1.9
1.46
Alveolar
D or L (mm)2 Number Duct
Alveoli/Acinus Generations References
15,000
10,714
7.04 (L) 14,000-20,000
5.1 (L) 7,100
8.8 (L) 10,344
6.0 (D) 8,000
1.95 (L)
1.56(D) 6,890
1.5(D) 5,243
1-5 (L)
6
9
2-5
8-12
9
9
6
9-12
10-12
6
Pump (1964)
Horsfield and Gumming (1968); Parker et
Hansen and Ampay a (1975); Hansen et al
Boy den (1972)
Schreider and Raabe (1981)
Haefeli-Bleuer and Weibel (1988)
Mercer, and Crapo (1992)
Kliment(1973)
Rodriguez et al. (1971)
Kliment(1973)
Mercer and Crapo (1992)
Kliment(1973)
Yehetal. (1979)
Mercer et al., 1987
Rodriguez et al. (1987)
al. (1971)
. (1975)
'Volume of lung at fixation (TLC, total lung capacity;
2Acinar size (D, diameter; L, length).
Source: Mercer and Crapo (1992).
FRC, functional residual capacity).
-------
The airways show a considerable degree of variability within species (e.g., size and
branching pattern) and this is most likely the primary factor responsible for the deposition
variability seen within single species (Schlesinger, 1985a).
Larger airway diameter results in greater turbulence for the same relative flow velocity
(e.g., between a particle and air). Therefore, flow may be turbulent in the large airways of
humans, whereas for an identical flow velocity, it would be laminar in the smaller laboratory
animal. Relative to humans, laboratory animals also tend to have tracheas that are much longer
in relation to their diameter. This could result in increased relative deposition in humans
because of the increased likelihood of laryngeal jet flow extending into the bronchi. Human
airways are characterized by a more symmetrical dichotomous branching than that found in most
laboratory mammals, which have highly asymmetrical airway branching (monopodial). The
more symmetrical dichotomous pattern in humans is susceptible to deposition at the carina
because of its exposure to high air flow velocities toward the center of the air flow profile.
Alveolar size also differs between species, which may affect deposition efficiency due to
variations on the distance between the airborne particle and alveolar walls (Dahl et al., 1991).
Addressing species differences in ventilation, which affects the tidal volume and
ventilation to perfusion ratios, is also critical to estimating initial absorbed dose. Due to the
expected variations in airflows within the respiratory tract, the variability among lungs in the
human or laboratory animal population, and the variations in respiratory performance that
members of the population experience during their normal activities, e.g. sleep and exercise,
must be considered in order to gain some insight into the variability that might be expected in
particle deposition, total and regional, of particles in the urban atmosphere. The experimentalist
must try to keep respiratory parameters relatively constant to obtain reasonably consistent
deposition data.
10.4.2 Clearance and Translocation Mechanisms
Particles that deposit upon airway surfaces may be cleared from the respiratory tract
completely, or may be translocated to other sites within this system, by various regionally
distinct processes. These clearance mechanisms, which are outlined in Table 10-8, can be
10-52
-------
TABLE 10-8. OVERVIEW OF RESPIRATORY TRACT PARTICLE CLEARANCE
AND TRANSLOCATION MECHANISMS
Extrathoracic region
Mucociliary transport
Sneezing
Nose wiping and blowing
Dissolution (for "soluble" particles) and absorption into blood
Tracheobronchial region
Mucociliary transport
Endocytosis by macrophages/epithelial cells
Coughing
Dissolution (for "soluble" particles) and absorption into blood
Alveolar region
Macrophages, epithelial cells
Interstitial
Dissolution for "soluble" and "insoluble" particles (intra-and
extracellular)
Source: Schlesinger (1995).
categorized as either absorptive (i.e., dissolution) or nonabsorptive (i.e., transport of intact
particles) and may occur simultaneously or with temporal variations. It should be mentioned
that particle solubility in terms of clearance refers to solubility within the respiratory tract fluids
and cells. Thus, an "insoluble" particle is considered to be one whose rate of clearance by
dissolution is insignificant compared to its rate of clearance as an intact particle. For the most
part, all deposited particles are subject to clearance by the same mechanisms, with their ultimate
fate a function of deposition site, physicochemical properties (including any toxicity), and
sometimes deposited mass or number concentration. Clearance routes from the various regions
of the respiratory tract are schematically outlined in Figures 10-12 and 10-13. Furthermore,
clearance is a continuous process and all mechanisms operate simultaneously for deposited
particles.
10.4.2.1 Extrathoracic Region
The clearance of insoluble particles deposited in the nonolfactory portion of nasal passages
occurs via mucociliary transport, and the general flow of mucus is backwards, i.e., towards the
nasopharynx (Figure 10-12). However, the epithelium of the most anterior portion of the nasal
passages is not ciliated, and mucus flow just distal to this is forward,
10-53
-------
'Nasal Passag
!°JL )
C^V
Posterior )
Extrinsic Clearance
Pharynx
G
Tracheobronchial Tre
Figure 10-12. Major physical clearance pathways from the extrathoracic region and
tracheobronchial tree.
Deposited Particle
Phagocytosis by
Alveolar Macrophages
I
ieni
larl
Endocytosis by
Type I Alveolar
Epithel al Cells
Movement within
Alveolar Lumen
Passage Through
Alveolar Epithelium
^ ^
ithelium ^ s I
-
Passage through
Pulmonary Capillary
Endothelium
Bronchiolar/ Bronchial
Lumen
Interstitium
*
Lymphatic Channels
Mucociliary Blanket I
Phagocytosis by
Interstitial
Macrophages ^
Lymph Nodes
Figure 10-13. Diagram of known and suspected clearance pathways for poorly soluble
particles depositing in the alveolar region.
Source: Modified from Schlesinger (1995).
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clearing deposited particles to a site (vestibular region) where removal is by sneezing (a reflex
response), wiping, or blowing (mechanisms known as extrinsic clearance).
Soluble material deposited on the nasal epithelium will be accessible to underlying cells if
it can diffuse to them through the mucus prior to removal via mucociliary transport. Dissolved
substances may be subsequently translocated into the bloodstream following movement within
intercellular pathways between epithelial cell tight junctions or by active or passive transcellular
transport mechanisms. The nasal passages have a rich vasculature, and uptake into the blood
from this region may occur rapidly.
Clearance of poorly soluble particles deposited in the oral passages is by coughing and
expectoration or by swallowing into the gastrointestinal tract. Soluble particles are likely to be
rapidly absorbed after deposition (Swift and Proctor, 1988).
10.4.2.2 Tracheobronchial Region
Poorly soluble particles deposited within the tracheobronchial tree are cleared primarily by
mucociliary transport, with the net movement of fluid towards the oropharynx, followed by
swallowing. Some poorly soluble particles may traverse the epithelium by endocytotic
processes, entering the peribronchial region (Masse et al., 1974; Sorokin and Brain, 1975).
Clearance may also occur following phagocytosis by airway macrophages, located on or beneath
the mucous lining throughout the bronchial tree. They then move cephalad on the mucociliary
blanket, or via macrophages which enter the airway lumen from the bronchial or bronchiolar
mucosa (Robertson, 1980).
As in the nasal passages, soluble particles may be absorbed through the mucous layer of
the tracheobronchial airways and into the blood, via intercellular pathways between epithelial
cell tight junctions or by active or passive transcellular transport mechanisms.
The bronchial surfaces are not homogeneous; there are openings of daughter bronchi and
islands of non-ciliated cells at bifurcation regions. In the latter, the usual progress of mucous
movement is interrupted, and bifurcations may be sites of relatively retarded clearance. The
efficiency with which such non-ciliated regions are traversed is dependent upon the traction of
the mucous layer.
Another method of clearance from the tracheobronchial region, under some circumstances,
is cough, which can be triggered by receptors located in the area from the
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trachea through the first few bronchial branching levels. While cough is generally a reaction to
some inhaled stimulus, in some cases, especially respiratory disease, it can also serve to clear the
upper bronchial airways of deposited substances by dislodging mucus from the airway surface.
10.4.2.3 Alveolar Region
Clearance from the alveolar (A) region occurs via a number of mechanisms and pathways,
but the relative importance of each is not always certain and may vary between species.
Particle removal by macrophages comprises the main nonabsorptive clearance process in
the A region. Alveolar macrophages reside on the epithelium, where they phagocytize and
transport deposited material. They come into contact with phagocytized material by random
motion, or more likely via directed migration under the influence of local chemotactic factors
(Warheit et al, 1988). Contact may be facilitated as some deposited particles are translocated,
due to pressure gradients or via capillary action within the alveolar surfactant lining, to sites
where macrophages congregate (Schurch et al., 1990; Parra et al., 1986).
Alveolar macrophages normally comprise «3 - 5% of the total alveolar cells in healthy
(non-smoking) humans and other mammals, and represent the largest subpopulation of
nonvascular macrophages in the respiratory tract (Gehr, 1984; Lehnert, 1992). However, the
actual cell count may be altered by particle loading. While a slight increase of deposited
particles may not result in an increase in cell number, macrophage numbers will increase
proportionally to particle number until some peak accumulation is reached (Adamson and
Bowden, 1981; Brain, 1971). Since the magnitude of this increase is related more to the number
of deposited particles than to total deposition by weight, equivalent masses of an identically
deposited substance would not produce the same response if particle sizes differed; thus,
deposition of smaller particles would tend to result in a greater elevation in macrophage number
than would larger particle deposition.
Particle-laden macrophages may be cleared from the A region along a number of pathways
(Figure 10-13). One route is cephalad transport via the mucociliary system after the cells reach
the distal terminus of the mucus blanket. However, the manner by which macrophages actually
reach the ciliated airways is not certain. The possibilities are chance
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encounter; passive movement along the alveolar surface due to surface tension gradients between
the alveoli and conducting airways; directed locomotion along a gradient produced by
chemotactic factors released by macrophages ingesting deposited material; or passage through
the alveolar epithelium and the interstitium, perhaps through aggregates of lymphoid tissue
known as bronchus associated lymphoid tissue (BALT) located at bronchoalveolar junctions
(Sorokin and Brain, 1975; Kilburn, 1968; Brundelet, 1965; Green, 1973; Cony et al., 1984;
Harmsen et al., 1985).
Some of the cells which follow interstitial clearance pathways are likely resident interstitial
macrophages that have ingested particles which were transported through the alveolar
epithelium, probably via endocytosis by Type I pneumocytes (Brody et al., 1981; Bowden and
Adamson, 1984). Particle-laden interstitial macrophages can also migrate across the alveolar
epithelium, becoming part of the alveolar macrophage cell population (Adamson and Bowden,
1978).
Macrophages that are not cleared via the bronchial tree may actively migrate within the
interstitium to a nearby lymphatic channel or, along with uningested particles, be carried in the
flow of interstitial fluid towards and into the lymphatic system (Harmsen et al., 1985). Passive
entry into lymphatic vessels is fairly easy, since the vessels have loosely connected endothelial
cells with wide intercellular junctions (Lauweryns and Baert, 1974). Lymphatic endothelium
may also actively engulf particles from the surrounding interstitium (Leak, 1980). Particles
within the lymphatic system may be translocated to tracheobronchial lymph nodes, which often
become reservoirs of retained material. Particles penetrating the nodes and subsequently
reaching the post-nodal lymphatic circulation may enter the blood.
Uningested particles or macrophages in the interstitium may traverse the alveolar-capillary
endothelium, directly entering the blood (Raabe, 1982; Holt, 1981); endocytosis by endothelial
cells followed by exocytosis into the vessel lumen seems, however, to be restricted to particles
<0.1 //m diameter, and may increase with increasing lung burden (Lee et al., 1989; Oberdorster,
1988). Once in the systemic circulation, transmigrated macrophages, as well as uningested
particles, can travel to extrapulmonary organs. Some mammalian species have alveolar
intravascular macrophages, which can remove particles from circulating blood and which may
play some role in the clearance of material deposited in the alveoli (Warner and Brain, 1990).
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Uningested particles and macrophages within the interstitium may travel to perivenous,
peribronchiolar or subpleural sites, where they become trapped, increasing particle burden. The
migration and grouping of particles and macrophages within the lungs can lead to the
redistribution of initially diffuse deposits into focal aggregates (Heppleston, 1953). Some
particles can be found in the pleural space, often within macrophages which have migrated
across the visceral pleura (Sebastien et al., 1977; Hagerstrand and Siefert, 1973). Resident
pleural macrophages do occur, but their role in clearance, if any, is not certain.
During clearance, particles can be redistributed within the alveolar macrophage population
(Lehnert, 1992). This can occur following death of a macrophage, and release of free particles
to the epithelium, followed by uptake by other macrophages. Some of these newly freed
particles may, however, translocate to other clearance routes.
Clearance by the absorptive mechanism involves dissolution in the alveolar surface fluid,
followed by transport through the epithelium and into the interstitium, and diffusion into the
lymph or blood. Some soluble particles translocated to and trapped in interstitial sites may be
absorbed there. Although the factors affecting the dissolution of deposited particles are poorly
understood, solubility is influenced by the particle's surface to volume ratio and other surface
properties (Morrow, 1973; Mercer, 1967). Thus, materials generally considered to be relatively
insoluble may still have high dissolution rates and short dissolution half-times if the particle size
is small.
Some deposited particles may undergo dissolution in the acidic milieu of the
phagolysosomes after ingestion by macrophages, and such intracellular dissolution may be the
initial step in translocation from the lungs for these particles (Kreyling, 1992; Lundborg et al.,
1985). Following dissolution, the material can be absorbed into the blood. Dissolved materials
may then leave the lungs at rates which are more rapid than would be expected based upon their
normal dissolution rate in lung fluid. For example, while insoluble (in lung fluid) MnO2
dissolves in the macrophage following ingestion, soluble manganese chloride (MnCy likely
dissolves extracellularly and is not ingested, resulting in manganese clearing at different initial
rates depending upon the form in which it was initially inhaled (Camner et al, 1985).
Differences in rates of clearance may also occur for particles whose rate of dissolution is pH
dependent (Marafante et al., 1987).
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Finally, some particles can bind to epithelial cell membranes or macromolecules, or other
cell components, delaying clearance from the lungs.
10.4.2.4 Clearance Kinetics
Deposited particles may be cleared completely from the respiratory tract. However, the
actual time frame over which clearance occurs affects the cumulative dose delivered to the
respiratory tract, as well as to extrapulmonary organs. Particle-tissue contact and retained dose
in the extrathoracic region and tracheobronchial tree are often limited by rapid clearance from
these regions. On the other hand, the retained dose from material deposited in the A region is
more dependent upon the physicochemical characteristics of the particles.
Various experimental techniques have been used to assess clearance rates in both humans
and laboratory animals (Schlesinger, 1985b). Because of technical differences and the fact that
measured rates are strongly influenced by the specific methodology, comparisons between
studies are often difficult to perform. However, regional clearance rates, i.e., the fraction of the
deposit which is cleared per unit time, are well defined functional characteristics of an individual
human or laboratory animal when repeated tests are performed under the same conditions; but,
as with deposition, there is a substantial degree of inter-individual variability.
Extrathoracic Region
Mucus flow rates in the posterior nasal passages are highly nonuniform. Regional
velocities in the healthy adult human may range from < 2 to > 20 mm/min (Proctor, 1980), with
the fastest flow occurring in the midportion of the nasal passages. The median rate in a healthy
adult human is about 5 mm/min, the net result being a mean anterior to posterior transport time
of about 10-20 min for poorly soluble particles deposited within the nasal passages (Stanley et
al., 1985; Rutland and Cole, 1981). However, particles deposited in the anterior portion of the
nasal passages are cleared more slowly, at a rate of 1-2 mm/h (Hilding, 1963). Since clearance
at this rate may take upwards of 12 h, such deposits are usually more effectively removed by
sneezing, wiping, or nose blowing, in which case clearance may occur in 0.5 h (Morrow, 1977;
Fry and Black, 1973).
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Tracheobronchial Region
Mucus transport in the tracheobronchial tree occurs at different rates in different local
regions; the velocity of movement is fastest in the trachea, and it becomes progressively slower
in more distal airways. In healthy non-smoking humans, and using non-invasive procedures and
no anesthesia, average tracheal mucus transport rates have been measured at 4.3 to 5.7 mm/min
(Leikauf et al., 1981, 1984; Yeates et al., 1975, 1981b; Foster et al., 1980), while that in the
main bronchi has been measured at -2.4 mm/min (Foster et al., 1980). While rates of movement
in smaller airways have not been directly determined, estimates for human medium bronchi
range between 0.2-1.3 mm/min, while those in the most distal ciliated airways range down to
0.001 mm/min (Yeates and Aspin, 1978; Morrow et al., 1967b; Cuddihy and Yeh, 1988).
It is not certain whether the transport rate for deposited poorly soluble particles is
independent of their nature, i.e., shape, size, composition. While particles of different materials
and sizes have been shown to clear at the same rate in the trachea in some studies (Man et al.,
1980; Patrick, 1983; Connolly et al., 1978), other studies (using instillation) have indicated that
the rate of mucociliary clearance may be greater for smaller particles (<2//m) than for larger
ones (Takahashi et al, 1992). Reasons for such particle-size related differences are not known.
There may, however, be more than one phase of clearance within individual tracheobronchial
airways. For example, the rat trachea shows a biphasic clearance pattern, consisting of a rapid
phase within the first 2-4 h after deposition, clearing up to 90% of deposited particles with a half
time of < 0.5 h, followed by a second, slower phase, clearing most of the remaining particles
with a half-time of 8-19 h (Takahashi et al, 1992).
The total duration of bronchial clearance, or some other time parameter, is often used as an
index of mucociliary kinetics, yet the temporal clearance pattern is not certain. In healthy adult
non-smoking humans, 90% of poorly soluble particles depositing within the tracheobronchial
tree were found to be cleared from 2.5 to 20 h after deposition, depending upon the individual
subject and the size of the particles (Albert et al., 1973). While particle size does not affect
surface transport, it does affect the depth of particle penetration and deposition and the
subsequent pathway length for clearance. Due to differences in regional transport rates,
clearance times from different regions of the bronchial tree will differ.
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While removal of a TB deposit is generally 99% completed by 48 h after exposure (Bailey et al.,
1985a), there is the possibility of longer-term retention under certain circumstances.
Studies with rodents, rabbits, and humans have indicated that a small fraction («1%) of
insoluble material may be retained for a prolonged period of time within the upper respiratory
tract (nasal passages) or tracheobronchial tree (Patrick and Stirling, 1977; Gore and Patrick,
1982; Watson and Brain, 1979; Radford and Martell, 1977; Svartengren et al., 1981). The
mechanism(s) underlying this long-term retention is unknown, but may involve endocytosis by
epithelial cells with subsequent translocation into deeper (submucosal) tissue, or merely passive
movement into this tissue. In addition, uptake by the epithelium may depend upon the nature, or
size, of the deposited particle (Watson and Brain, 1980). The retained particles may eventually
be cleared to regional lymph nodes, but with a long half time that may be > 80 days (Patrick,
1989; Oghiso and Matsuoka, 1979).
There is some suggestion of a greater extent of long term retention in the bronchial tree.
Stahlhofen et al. (1986), using a specialized inhalation procedure, noted that a significant
fraction, up to 40%, of particles which were likely deposited in the conducting airways were not
cleared up to six days post-deposition. They also noted that the size of the particles influenced
this retention, with smaller ones being retained to a greater extent than were larger ones
(Stahlhofen et al., 1987, 1990). Although the reason for this is not certain, the suggested
presence of a surfactant film on the mucous lining of the airways (Gehr et al., 1990) may result
in a reduced surface tension which, in turn, influences the displacement of particles into the gel
layer and, subsequently, into the sol layer towards the epithelial cells. Particles that reach these
cells may then be phagocytized, increasing retention time in the lungs. However, the issue of
retention of large fractions of tracheobronchial deposit is not resolved.
Long-term TB retention patterns are not uniform. There is an enhancement at bifurcation
regions (Cohen et al., 1988; Radford and Martell, 1977; Henshaw and Fews, 1984), the likely
result of both greater deposition and less effective mucus clearance within these areas. Thus,
doses calculated based upon uniform surface retention density may be misleading, especially if
the material is, lexicologically, slow acting. Solubilized material may also undergo long-term
retention in ciliated airways due to binding to cells or macromolecules.
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Alveolar Region
Clearance kinetics in the A region are not definitively understood, although particles
deposited there generally remain longer than do those deposited in airways cleared by
mucociliary transport. There are limited data on rates in humans, while within any species rates
vary widely due to different properties of the particles used in the various studies. Furthermore,
some of these studies employed high concentrations of poorly soluble particles, which may have
interfered with normal clearance mechanisms, producing rates different from those which would
typically occur at lower exposure levels. Prolonged exposure to high particle concentrations is
associated with what is termed particle "overload." This is discussed in greater detail in Section
10.4.2.7.
There are numerous pathways of A region clearance, and these may depend upon the
nature of the particles being cleared. Thus, generalizations about clearance kinetics are difficult
to make, especially since the manner in which particle characteristics affect clearance kinetics is
not resolved. Nevertheless, A region clearance can be described as a multiphasic process, each
phased considered to represent removal by a different mechanism or pathway, and often
characterized by increased retention half-times with time post-exposure.
Clearance of inert, poorly soluble particles in healthy, nonsmoking humans has been
generally observed to consist of two phases, with the first having a half-time measured in days,
and the second in hundreds of days. Table 10-9 presents some observed times for the longer,
second phase of clearance as reported in a number of studies. Differences in technique,
chemistry, and solubility of the particles in Table 10-9 are largely responsbile for the variations.
Although wide variations in retention reflect a dependence upon the nature of the deposited
material (e.g., particle size) once dissolution is accounted for, mechanical removal to the
gastrointestinal tract and/or lymphatic system appears to be independent of size, especially for
particles < 5 //m (Snipes et al., 1983). Although not evident from Table 10-9, there is
considerable intersubject variability in the clearance rates of identical particles, which appears to
increase with time post-exposure (Philipson et al., 1985; Bailey et al., 1985a). The large
differences in clearance kinetics among different individuals suggest that equivalent chronic
exposures to poorly soluble particles may result in large variations in respiratory tract burdens.
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TABLE 10-9. LONG-TERM RETENTION OF POORLY SOLUBLE PARTICLES IN
THE ALVEOLAR REGION OF NON-SMOKING HUMANS
Particle
Material
Polystyrene latex
Polystyrene latex
Polystyrene latex
Polystyrene latex
Teflon
Aluminosilicate
Aluminosilicate
Iron oxide (Fe2O3)
Iron oxide (Fe2O3)
Iron oxide (Fe3O4)
Size (//m)
5
5
0.5
3.6
4
1.2
3.9
0.8
0.1
2.8
Retention Half-Time3
(days) Reference
150 to 300
144 to 340
33 to 602
296
100 to 2,500
330
420
62
270
70
Booker etal. (1967)
Newton etal. (1978)
Jammettetal. (1978)
Bohningetal. (1982)
Philipson et al. (1985)
Bailey etal. (1982)
Bailey etal. (1982)
Morrow et al. (1967a,b)
Waite and Ramsden (1971)
Cohen etal. (1979)
^Represent the half-time for the slowest clearance phase observed.
While the kinetics of overall clearance from the A region have been assessed to some
extent, much less is known concerning relative rates along specific pathways, and any available
information is generally from studies with laboratory animals. The usual initial step in
clearance, i.e., uptake of deposited particles by alveolar macrophages, is very rapid. Ingestion
by macrophages generally occurs within 24 h of a single inhalation (Naumann and Schlesinger,
1986; Lehnert and Morrow, 1985). But the actual rate of subsequent macrophage clearance is
not certain; perhaps 5% or less of their total number is translocated from the lungs each day in
rodents (Lehnert and Morrow, 1985; Masse et al., 1974).
The rate and amount of particle uptake by macrophages is likely governed by particle size
and surface properties (Tabata and Ikada, 1988), although these experiments were performed
with peritoneal macrophages and not with alveolar macrophages. For example, the effect of
particle size was examined by incubating mouse peritoneal macrophages with polymer
microspheres (0.5 to 5 //m). Both the number of particles ingested per cell and the volume of
these particles per cell reached a maximum for particle diameters of 1-2 //m, declining on either
side of this range. In terms of particle surface, those with hydrophobic surfaces were ingested to
a greater extent than were those with hydrophilic surfaces. Phagocytosis also increased as the
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surface charge density of a particle increased, but for the same charge density there was no
difference in uptake between positively or negatively charged particles.
The time for clearance of particle-laden alveolar macrophages via the mucociliary system
depends upon the site of uptake relative to the distal terminus of the mucus blanket at the
bronchiolar level. Furthermore, clearance pathways, and subsequent kinetics, may depend to
some extent upon particle size. For example, some smaller ultrafine particles (perhaps < 0.02
//m) may be less effectively phagocytosed than are larger ones (Oberdorster, 1993). But once
ingestion occurs, alveolar macrophage-mediated kinetics are independent of the particle
involved, as long as solubility and cytotoxicity are low.
In terms of other clearance pathways, uningested particles may penetrate into the
interstitium, largely by Type I cell endocytosis, within a few hours following deposition (Ferin
and Feldstein, 1978; Sorokin and Brain, 1975; Brody et al., 1981). This transepithelial passage
seems to increase as particle loading increases, especially to a level above the saturation point for
increasing macrophage number (Adamson and Bowden, 1981; Ferin, 1977). It may also be
particle size dependent, since insoluble ultrafine particles (<0.1 //m diameter) of low intrinsic
toxicity show increased access to and greater lymphatic uptake than do larger ones of the same
material (Oberdorster et al., 1992). However, ultrafine particles of different materials may not
enter the interstitium to the same extent. Similarly, any depression of phagocytic activity or the
deposition of large numbers of smaller ultrafine particles may increase the number of free
particles in the alveoli, enhancing removal by other routes. In any case, free particles and
alveolar macrophages may reach the lymph nodes, perhaps within a few days after deposition
(Lehnert et al., 1988; Harmsen et al., 1985), although this route is not certain and may be species
dependent.
The extent of lymphatic uptake of particles may depend upon the effectiveness of other
clearance pathways. For example, lymphatic translocation probably increases when phagocytic
activity of alveolar macrophages is decreased (Greenspan, et al., 1988). This may be a factor in
lung overload, as discussed in Section 10.4.2.7. However, it seems that the deposited mass or
number of particles must reach some threshold below which increases in loading do not affect
translocation rate to the lymph nodes (Ferin and Feldstein, 1978; LaBelle and Brieger, 1961).
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The rate of translocation to the lymphatic system may be somewhat particle size
dependent. Although no human data are available, translocation of latex particles to the lymph
nodes of rats was greater for 0.5 to 2 //m particles than for 5 and 9 //m particles (Takahashi et
al., 1992), and smaller particles within the 3 to 15 //m size range were found to be translocated
at faster rates than were larger sizes (Snipes and Clem, 1981). On the other hand, translocation
to the lymph nodes was similar for both 0.4 //m barium sulfate or 0.02 //m gold colloid particles
(Takahashi et al., 1987). It seems that particles < 2 //m clear to the lymphatic system at a rate
independent of size, and it is particles of this size, rather than those > 5 //m, that would have
significant deposition within the A region following inhalation.
In any case, and regardless of any particle size dependence, the normal rate of translocation
to the lymphatic system is quite slow, on the order of 0.02-0.003%/day (Snipes, 1989), and
elimination from the lymph nodes is even slower, with half-times estimated in tens of years
(Roy, 1989).
Soluble particles depositing in the A region may be rapidly cleared via absorption through
the epithelial surface into the blood, but there are few data on dissolution and transfer rates to
blood in humans. Actual rates depend upon the size of the particle (i.e., solute size), with
smaller ones clearing faster than larger ones. Chemistry also plays a role, since water soluble
compounds generally clear at a slower rate than do lipid soluble materials.
Absorption may be considered as a two stage process, with the first stage dissociation of
the deposited particles into material that can be absorbed into the circulation (dissolution) and
the second stage the uptake of this material. Each of these stages may be time dependent. The
rate of dissolution depends upon a number of factors, including particle surface area and
chemical structure. Uptake into the circulation is generally considered as instantaneous,
although a portion of the dissolved material may be absorbed more slowly due to binding to
respiratory tract components. Accordingly, there is a very wide range for absorption rates
depending upon the physicochemical properties of the material deposited. For example, a highly
soluble particle may be absorbed at a rate faster than the particle transport rate and significant
uptake may occur in the conducting airways. On the other
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hand, a particle that is less soluble and remains in the lungs for years would have a much lower
rate, perhaps <0.0001%/day.
10.4.2.5 Factors Modifying Clearance
A number of host and environmental factors may modify normal clearance patterns,
affecting the dose delivered by exposure to inhaled particles. These include aging, gender,
workload, disease and irritant inhalation. However, in many cases, the exact role of these factors
is not resolved.
Age
The evidence for aging-related effects on mucociliary function in healthy individuals is
equivocal, with studies showing either no changes or some slowing in mucous clearance function
with age after maturity (Goodman et al., 1978; Yeates et al., 1981a; Puchelle et al., 1979).
However, it is often difficult to determine whether any observed functional decrement was due
to aging alone, or to long-term, low level ambient pollutant exposure (Wanner, 1977). In any
case, the change in mucous velocity between approximately age 20 and 70 in humans is about a
factor of two (Wolff, 1992) and would likely not significantly affect overall kinetics.
There are few data to allow assessment of aging-related changes in clearance from the A
region. Although functional differences have been found between alveolar macrophages of
mature and senescent mice (Esposito and Pennington, 1983), no age-related decline in
macrophage function has been seen in humans (Gardner et al., 1981).
There are also insufficient data to assess changes in clearance in the growing lung. Nasal
mucociliary clearance time in a group of children (average age = 7 yrs) was found to be ~ 10 min
(Passali and Bianchini Ciampoli, 1985); this is within the range for adults. There is one report
of bronchial clearance in children (12 yrs old), but this was performed in patients hospitalized
for renal disease (Huhnerbein et al., 1984).
Gender
No gender related differences were found in nasal mucociliary clearance rates in children
(Passali and Bianchini Ciampoli, 1985) nor in tracheal transport rates in adults
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(Yeates et al., 1975). Slower bronchial clearance has been noted in male compared to female
adults, but this was attributed to differences in lung size (and resultant clearance pathway length)
rather than to inherent gender related differences in transport velocities (Gerrard et al., 1986).
Physical Activity
The effect of increased physical activity upon mucociliary clearance is unresolved, with the
available data indicating either no effect or an increased clearance rate with exercise (Wolff et
al., 1977; Pavia, 1984). There are no data concerning changes in A region clearance with
increased activity levels, but CO2-stimulated hyperpnea (rapid, deep breathing) was found to
have no effect on early alveolar clearance and redistribution of particles (Valberg et al., 1985).
Breathing with an increased tidal volume was noted to increase the rate of particle clearance
from the A region, and this was suggested to be due to distension related evacuation of
surfactant into proximal airways, resulting in a facilitated movement of particle-laden
macrophages or uningested particles due to the accelerated motion of the alveolar fluid film
(Johnetal., 1994).
Respiratory Tract Disease
Various respiratory tract diseases are associated with clearance alterations. The
examination of clearance in individuals with lung disease requires careful interpretation of
results, since differences in deposition of tracer particles used to assess clearance function may
occur between normal individuals and those with respiratory disease, and this would directly
impact upon the measured clearance rates, especially in the tracheobronchial tree. In any case,
nasal mucociliary clearance is prolonged in humans with chronic sinusitis, bronchiectasis, or
rhinitis (Majima et al., 1983; Stanley et al., 1985), and in cystic fibrosis (Rutland and Cole,
1981). Bronchial mucus transport may be impaired in people with bronchial carcinoma
(Matthys et al., 1983), chronic bronchitis (Vastag et al., 1986), asthma (Pavia et al., 1985), and
in association with various acute infections (Lourenco et al., 1971; Camner et al., 1979; Puchelle
et al., 1980). In certain of these cases, coughing may enhance mucus clearance, but it generally
is effective only if excess secretions are present.
Normal mucociliary function is essential to respiratory tract health. Studies of individuals
with a syndrome characterized by impaired clearance, i.e., primary ciliary dyskinesia (PCD),
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may be used to assess the importance of mucociliary transport and the effect of its dysfunction
upon respiratory disease, and to provide information on the role of clearance in maintaining the
integrity of the lungs. The lack of mucociliary function in PCD is directly responsible for the
early development of recurrent respiratory tract infections and, eventually, chronic bronchitis
and bronchiectasis (Rossman et al., 1984; Wanner, 1980). It is, however, not certain whether
partial impairment of the mucociliary system will increase the risk of lung disease.
Rates of A region particle clearance appear to be reduced in humans with chronic
obstructive lung disease (Bohning et al., 1982) and in laboratory animals with viral infections
(Creasia et al., 1973). The viability and functional activity of macrophages was found to be
impaired in human asthmatics (Godard et al., 1982).
Studies with laboratory animals have also found disease related clearance changes.
Hamsters with interstitial fibrosis showed an increased degree of alveolar clearance (Tryka et al.,
1985). Rats with emphysema showed no clearance difference from control (Damon et al.,
1983), although the co-presence of inflammation resulted in prolonged retention (Hahn and
Hobbs, 1979). On the other hand, inflammation may enhance particle and macrophage
penetration through the alveolar epithelium into the interstitium, by increasing the permeability
of the epithelium and the lymphatic endothelium (Corry et al., 1984). Neutrophils, which are
phagocytic cells present in alveoli during inflammation, may contribute to the clearance of
particles via the mucociliary system (Bice et al., 1990).
Macrophages have specific functional properties, namely phagocytic activity and mobility,
which allow them to adequately perform their role in clearance. Alveolar macrophages from
calves with an induced interstitial inflammation (pneumonitis) were found to have enhanced
phagocytic activity compared to normal animals (Slauson et al., 1989). On the other hand,
depressed phagocytosis was found with virus-induced acute bronchiolitis and alveolitis (Slauson
et al., 1987). How such alterations affect clearance from the A region is not certain, since the
relationship between macrophage functional characteristics and overall clearance is not always
straightforward. While changes in macrophage function do impact upon clearance, the manner
by which they do so may not always be easily
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predictable. In any case, the modification of functional properties of macrophages appear to be
injury specific, in that they reflect the nature and anatomic pattern of disease.
Inhaled Irritants
Inhaled irritants have been shown to have an effect upon mucociliary clearance function in
both humans and laboratory animals (Schlesinger, 1990; Wolff, 1986). Single exposures to a
particular material may increase or decrease the overall rate of tracheobronchial clearance, often
depending upon the exposure concentration (Schlesinger, 1986). Alterations in clearance rate
following single exposures to moderate concentrations of irritants are generally transient, lasting
< 24 h. However, repeated exposures may result in an increase in intra-individual variability of
clearance rate and persistently retarded clearance. The effects of irritant exposure may be
enhanced by exercise, or by coexposure to other materials.
Acute and chronic exposures to inhaled irritants may also alter A region clearance (Cohen
et al., 1979; Ferin and Leach, 1977; Schlesinger et al., 1986; Phalen et al., 1994), which may be
accelerated or depressed, depending upon the specific material and/or length of exposure. While
the clearance of poorly soluble particles from conducting airways is due largely to only one
mechanism, i.e., mucociliary transport, clearance from the respiratory region involves a complex
of multiple pathways and processes. Because transit times along these different pathways vary
widely, a toxicant-induced change in clearance rate could be due to a change in the time for
removal along a particular pathway and/or to a change in the actual route taken. Thus, it is often
quite difficult to delineate specific mechanisms of action for toxicants which alter overall
clearance from respiratory airways. Alterations in alveolar macrophages likely underlay some of
the observed changes, since numerous irritants have been shown to impair the numbers and
functional properties of these cells (Gardner, 1984).
Since a great number of people are exposed to cigarette smoke, it is of interest to
summarize effects of this irritant upon clearance processes. Smoke exposed animals and humans
show increased number of macrophages recoverable by bronchopulmonary lavage (Brody and
Davis, 1982; Warr and Martin, 1978; Matulionis, 1984; Zwicker et al., 1978). However, the rate
of particle clearance from the A region of the lungs appears to be reduced in cigarette smokers
(Bohning et al., 1982; Cohen et al., 1979).
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While cigarette smoking has been shown to affect tracheobronchial mucociliary clearance
function, the effects range from acceleration to slowing. Some of the apparent discrepancies in
different studies is related to differences in the effects of short-term versus long-term effects of
cigarette smoke. Long term smokers appear to have mucociliary clearance which is slower than
that in nonsmokers (Lourenco et al., 1971; Albert et al., 1971) and which also show certain
anomalies, such as periods of intermittent clearance stasis. On the other hand, the short term
effects of cigarette smoke range from acceleration to retardation depending upon the number of
cigarettes smoked (Albert et al., 1971; Lippmann et al., 1977; Albert et al., 1974).
10.4.2.6 Comparative Aspects of Clearance
As with deposition analyses, the inability to study the retention of certain materials in
humans for direct risk assessment requires use of laboratory animals. Since dosimetry depends
upon clearance rates and routes, adequate toxicologic assessment necessitates that clearance
kinetics in these animals be related to those in humans. The basic mechanisms and overall
patterns of clearance from the respiratory tract appear to be similar in humans and most other
mammals. However, regional clearance rates can show substantial variation between species,
even for similar particles deposited under comparable exposure conditions (Snipes, 1989).
Dissolution rates and rates of transfer of dissolved substances into the blood may or may
not be species independent, depending upon certain chemical properties of the deposited material
(Griffith et al., 1983; Bailey et al., 1985b; Roy, 1989). For example, lipophilic compounds of
comparable molecular weight are cleared from the lungs of various species at the same rate
(dependent solely upon solute molecular weight and the lipid/water partition coefficient), but
hydrophilic compounds do show species differences.
On the other hand, there are distinct interspecies differences in rates of mechanical
transport in the conducting and A airways. While mucous transport rates in the nasal passages
seem to be similar in humans and the limited other species examined (Morgan et al., 1986;
Whaley, 1987), tracheal mucous velocities vary among species as a function of body weight
(Felicetti et al., 1981; Wolff, 1992).
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In the A region, macrophage-mediated clearance of poorly soluble particles is species
dependent, with small mammalian species generally exhibiting faster clearance than larger
species, with the exception of the guinea pig which clears slower than laboratory rodents. This
may result from interspecies differences in macrophage-mediated clearance of poorly soluble
particles (Valberg and Blanchard, 1992; Bailey et al., 1985b), transport of particles from the
A region to alveolar lymph nodes (Snipes et al., 1983; Mueller et al., 1990), phagocytic rates and
chemotactic responses of alveolar macrophages (Warheit and Hartsky, 1994), or the prevalence
of BALT (Murray and Driscoll, 1992). These likely result in species-dependent rate constants
for these clearance pathways, and differences in regional (and perhaps total) clearance rates
between some species are a reflection of these differences in mechanical processes. For
example, the relative proportion of particles cleared from the A region in the short and longer
term phases of clearance differs between laboratory rodents and larger mammals, with a greater
percentage cleared in the faster first phase in laboratory rodents. The end result of interspecies
differences in deposition and clearance is that the retention of deposited particles can differ
between species, and this may result in differences in response to similar particulate exposure
atmospheres.
10.4.2.7 Lung Overload
Some experimental studies using laboratory rodents employed high exposure
concentrations of relatively nontoxic, poorly soluble particles, which interfered with normal
clearance mechanisms, producing clearance rates different from those which would occur at
lower exposure levels. Prolonged exposure to high particle concentrations is associated with
what is termed particle "overload." This is defined as the overwhelming of macrophage-
mediated clearance by the deposition of particles at a rate which exceeds the capacity of that
clearance pathway. It is a nonspecific effect noted in experimental studies, generally in rats,
using many different kinds of poorly soluble particles (including TiO2, volcanic ash, diesel
exhaust particles, carbon black, and fly ash) and results in A region clearance slowing or stasis,
with an associated inflammation and aggregation of macrophages in the lungs and increased
translocation of particles into the interstitium (Muhle et al., 1990; Lehnert, 1990; Morrow,
1994). While some overload induced effects are reversible, the extent of such reversibility
decreases as the degree of overloading increases (Muhle et al., 1990). Once
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some critical particle burden is reached, particles of all sizes (those studies ranged from ultrafme
to 4 //m) show increased translocation into the interstitum (Oberdorster et al., 1992). This
phenomenon has been suggested to be due to the inhibition of alveolar macrophage mobility.
While the exact amount of deposition needed to induce overload is uncertain, it has been
hypothesized that it will begin, in the rat, when deposition approaches 1 mg particles/g lung
tissue (Morrow, 1988). When the concentration reaches 10 mg particles/g lung tissue,
macrophage-mediated clearance of particles would effectively cease. Overload may be related
more to the volume of particles ingested than to the total mass (Morrow, 1988; Oberdorster
et al., 1992b). Following overloading, the subsequent retardation of lung clearance,
accumulation of particles, inflammation, and the interaction of inflammatory mediators with cell
proliferative processes and DNA may lead to the development of tumors and fibrosis in rats
(Mauderly, 1994).
Alternative hypotheses exist for the events that define the onset of lung overload. One
hypothesis is that if repeated exposures to poorly soluble particles occurs, some critical lung
burden may be reached. Until the critical lung burden is reached, clearance is normal; above the
critical lung burden, clearance becomes progressively retarded and associated other changes
occur. The other hypothesis is that overload is a function of the amount of poorly soluble
particles which deposit daily, i.e., deposition rate (Muhle, 1988; Creutzenberg et al., 1989;
Bellmann et al., 1990). Clearance retardation was suggested to occur at exposure levels of 3
mg/m3 or higher. Thus, some critical deposition rate over a sufficient exposure duration would
result in retardation of clearance (Yu et al., 1989).
The relevance of lung overload to humans, and even to species other than laboratory rats
and mice, is not clear. While it likely to be of little relevance for most "real world" ambient
exposures of humans, it is of concern in interpreting some long-term experimental exposure
data. It may, however, be of some concern to humans occupationally exposed to some particle
types (Mauderly, 1994), since overload may involve all insoluble materials and affect all species
if the particles are deposited at a sufficient rate (Pritchard, 1989), (i.e., if the deposition rate
exceeds the clearance rate). In addition, the relevance to humans is also clouded by the
suggestion that macrophage-mediated clearance is normally slower and
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perhaps less important in humans than in rats (Morrow, 1994), and that there will be significant
differences in macrophage loading between the two species.
10.4.3 Acidic Aerosols
An Issue Paper on Acid Aerosols was published by the Environmental Protection Agency
in 1989. Section 3 of that document was devoted to the deposition and fate of acid aerosols.
Moreover, that Section provided an update of particle deposition data from both human and
laboratory animal studies, described hygroscopic aerosol studies reported between 1977 and
1987, and presented a thorough discussion of the neutralization of acid aerosols by airway
secretions and absorbed ammonia.
This section consists of two subsections: the first concerns the phenomenon of
hygroscopicity; and the second presents current information on acidic aerosol neutralization.
10.4.3.1 Hygroscopicity of Acidic Aerosols
Hygroscopicity can be defined as the propensity of a material for taking up and retaining
moisture under certain conditions of humidity and temperature. It is well known that action of
ocean waves continuously disperses tons of hygroscopic saline particles into the atmosphere and
these contribute to worldwide meteorologic phenomena. As industrialization has expanded, the
evolution of gaseous pollutants, especially the oxides of sulfur and nitrogen, has caused a greatly
increased atmospheric burden of aerosols mainly derived from gas-phase reactions. These
aerosols are predominantly both acidic and hygroscopic, consisting of mixtures of partially
neutralized nitric, sulfuric and hydrochloric acids: i.e., inorganic salts, such as nitrites,
bisulfates, sulfates and chlorides. In addition, small amounts of organic acid salts, e.g., formate
and acetate, are present as are a variety of trace elements, e.g., cadmium, carbon, vanadium,
chromium and phosphorus, whose oxides and other chemical forms tend also to be acid forming
(Aerosols, 1986).
Experimental studies on deposition of acid aerosols are limited. There have been two
studies in laboratory animals using H2SO4 aerosols. Dahl and Griffith (1983) measured regional
deposition of these aerosols in the size range from 0.4 to 1.2 jim MMAD generated at 20% and
80% relative humidities. Their data showed greater total and regional deposition of H2SO4
aerosols in rats compared to nonhygroscopic aerosols having the same MMAD's
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(Figure 10-14). Deposition of H2SO4 aerosols generated at 20% RH was also higher than those
generated at 80% RH, indicating that the increase in deposition was caused by the growth of the
particles in the highly humid environment of the respiratory tract.
However, a similar study by Dahl et al. (1983) found that deposition of H2SO4 aerosols in
beagle dogs at these two relative humidities was similar to that of nonhygroscopic aerosols
having the same size although deposition at 20% RH was again higher than that at 80% RH.
The inconsistent results were explained by Dahl et al. (1985) to be caused by the large
intersubject variability of deposition in dogs.
Two reviews (Morrow, 1986; Hiller, 1991) have been published on hygroscopic aerosols
which consider the implications of hygroscopic particle growth on deposition in the human
respiratory tract. Much of the treatment of hygroscopic particle growth is based on theoretical
models (e.g., Xu and Yu, 1985; Perron et al., 1988; Martonen and Zhang, 1993). Suffice it to
say, particulate sodium chloride has been commonly utilized in these models and to a lesser
extent, sulfuric acid droplets, and ammonium sulfate and ammonium bisulfate particles. There
are no major distinctions in the growth of these hygroscopic materials except that sulfuric acid
does not manifest a deliquescent point (when the particle becomes an aqueous droplet). It can be
seen in Figure 10-15 that the growth rate of hygroscopic particles is controlled by the relative
humidity (RH): the closer to saturation (100% RH), the faster the growth rate.
In humans, deposition of acid aerosols in the respiratory tract has only been estimated by
model studies. Martonen and Zhang (1993) estimated deposition of H2SO4 aerosols in the
human lung for various ages and three different activity levels. The H2SO4 aerosol was
considered to be in equilibrium with atmospheric conditions outside the lung prior to being
inhaled. The results of their calculation for rest breathing without considering extrathoracic
deposition are shown in Figure 10-16. Comparing to nonhygroscopic aerosols such as Fe2SO3,
deposition of H2SO4 aerosols in different regions of the lung may be higher or lower depending
upon the initial particle size. There is a critical initial size of H2SO4 in the 0.2 to 0.4 jim range.
For larger particles the influence of hygroscopicity of H2SO4 aerosols is to increase total lung
deposition, whereas for smaller particles the opposite occurs.
Hygroscopic particles or droplets of different initial size will experience different growth
rates: the smallest particles being the fastest to reach an equilibrium size. For
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era
re
100
(A
o
a
0 10
a>
o.
100
(A
O
a.
a>
Q10
4-1
C
0)
o
0)
a.
1
0.2 0.5 1.0 2.0 3.0
Droplet Size MMAD (|jm)
(a)
100
c
o
4^
"w
o
a
0)
Q10
4-1
C
0)
u
l_
0)
a.
1
0.2 0.5 1.0 2.0 3.0
Droplet Size MMAD (|jm)
(b)
0.2 0.5 1.0 2.0 3.
Droplet Size MMAD (|jm)
(C)
Figure 10-14. Regional deposition data in rats versus particle size for sulfuric acid mists and dry particles. Panel (a) = upper
airway deposition; (b) = lower airway deposition; and (c) = total deposition. Circles are 20% relative humidity;
squares are 80% relative humidity; triangles are dry nonhygroscopic particles. Solid curves represent the mean
of the data for sulfuric acid mists. Error bars and broken curves represent 95% confidence limits.
Source: Dahl and Griffith (1983).
-------
4.0
O)
c
(0
£
U
0)
_N
5)
U
r
ra
Q.
3.0
2.0
1.0
10
20
30
40
50
60
70
80
90 100
% Relative Humidity
Figure 10-15. Theoretical growth curves for sodium chloride, sulfuric acid, ammonium
bisulfate, and ammonium sulfate aerosols in terms of the initial (d0) and
final (d) size of the particle. Note that the H2SO4 curve, unlike those for the
three salts, has no deliquescence point.
Source: Tang and Munkelwitz (1977).
example, a 0.5 jam diameter particle will require approximately 1 s, whereas a 2.0 jam particle
will require close to 10 s. It is immediately evident that many inhaled hygroscopic particles will
not reach their equilibrium size (maximum growth) during the duration of a single respiratory
cycle (ca 4 s). Conversely, the growth of ultrafine particles does not resemble that for particles
>0.1 jim and thereby represents a special case. Moreover, the hygroscopic growth characteristics
of aqueous droplets, containing one or more solutes, depend not only on their initial size, but
their initial composition. The study of Cocks and Fernando (1982), using the condensation
model of Fukuta and Walter (1970), with ammonium sulfate droplets illustrate both of these last
points (Figure 10-17).
The direct measurement of the RH of alveolar air and the temperature of air at the alveolar
surface have been attempted, but because of technical limitations, the direct
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.2 1-0-r
0.8-
F6203 Age h^ SO4
—•— Adult —•-
—D— 98 mo — D-
—O— 48 mo — O-
—ft— 22 mo — A-
—•— 7 mo — •"
(A
O
a
Q
Is
!c
u
c
o
u
o
-------
4r
3 -
2 -
X0= 40%
X0= 40%
X0= 20%
X0= 20%
10
-3
10
-2
1C'1
Time (s)
10
Figure 10-17. Distinctions in growth (r/r0) of aqueous ammonium sulfate [(NH4)2SO4]
droplets of 0.1 and 1.0 /j,m initial size are depicted as a function of their
initial solute concentrations (X0).
Source: Cocks and Fernando (1982).
successful. For deep-lung temperature, Edwards et al. (1963) used solubility of a helium-argon
mixture in arterial blood. By this approach they found the mean pulmonary capillary
temperature in five normal subjects to be 37.52 °C. Because of individual variability, they also
provided an equation for estimating the deep lung temperature in an individual from a
measurement of rectal temperature.
Perron and co-workers (1983, 1985) made the logical assumption that the RH of the
alveolar air was determined by an equilibrium with the vapor pressure of blood serum at the
capillary level. The osmolarity of serum at 37 °C (287 ± 4 mmol/kg) provided these
investigators a sound basis for selecting 99.5% RH as the value to use in all of the modeling
estimations. In Figure 10-18 (from Xu and Yu, 1985) the calculated equilibrium diameters
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H = 0.995
I
I
I
I
I
0.01 0.02
0.05 0.1
0.2 0.5
d0 (Mm)
10
Figure 10-18. The initial diameter of dry sodium chloride particles (d0) and equilibrium
diameter achieved (d) are shown for three relative humidity assumptions.
Source: Xu and Yu (1985).
for sodium chloride particles on the basis of their initial size (d0) is depicted. The equilibrium
diameters (d00) that can be achieved theoretically for each particle size is shown as a function of
three different RH values. For an RH of 99.5%, the growth of salt particles with an initial size
greater than 0.5 jim, yields about a 6-fold increase in diameter.
Perron et al. (1988) calculated the RH in the human airways by employing a transport
theory for heat and water vapor using cylindrical coordinates. Several parameters of the theory
were chosen to best fit the available experimental data. These authors also used the transport
theory to model the growth and deposition of three salts, viz., NaCl, CoCl2-6H2O,
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and ZnSO4 7H2O, which were selected because these differentially hydrated particles have large,
moderate and small hygroscopic growth potentials, respectively. Figure 10-19 depicts the
growth of these three salts when their initial dry particle size is 1.0 jim diameter, the average
inspired airflow is 250 cc/s, and the inhalation is by mouth. In this depiction, the particle growth
is expressed as the ratio of the achieved aerodynamic diameter to the initial aerodynamic size.
ae,s
4.0-
3.0-
2.0-
1.0-
0.0
0.01
Q = 250 cm3 Is
mouth
inhalation
NaCI
CoCI4 •
•'
* f
; /I
(c)
0.1
1
Time (s)
10
100
Figure 10-19. The initial dry diameter (daes) of three different salts is assumed to be 1.0
//m. Their subsequent growth to an equilibrium diameter at 99.5%RH is
shown by the ratio (dae/dae s). The highly hydrated salts of cobalt chloride
and zinc sulfate exhibit a reduced growth potential compared to sodium
chloride.
Source: Perron et al. (1988).
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A recent experimental study by Anselm et al. (1990) used an indirect method, similar to
that employed earlier by Tu and Knudsen (1984), to validate the 99.5% RH assumption for
alveolar air. In this instance, monodisperse NaCl particles between 0.2 and 0.5 jim were
made by vibrating orifice generator and administered, by mouth, as boli during a constant
inspiratory airflow. During expiration, the particles suspended in the same volume element were
size classified. To determine equilibrium particle sizes, 600 mL of aerosol was inspired
followed by 400 mL of clean air. Expiration was initiated after different periods of breath
holding and the behavior of NaCl particles (loss and settling velocities) was compared to that of
a stable (nonhygroscopic) aerosol. Through this approach, the investigators found that the
diameters of the NaCl particles initially 0.2 jim and 0.25 jim, increased 5.55 and 5.79-fold,
respectively. These values were found to be consistent with a 99.5% RH.
To make the transport theory model estimations more pragmatic, Perron and coworkers
(1992, 1993) made estimations for heterodisperse aerosols of salts with the range of growth
potentials used in their 1988 study. Also, deposition estimates for H2SO4 aerosols,
incorporating variabilities in age-related airway morphometry and in physical activity levels,
have been reported by Martonen and Zhang (1993) using some innovative modeling
assumptions.
In his excellent review of hygroscopic particle growth and deposition and their
implications to human health, Hiller (1991) concluded that despite the importance of models,
there remains insufficient experimental data on total and regional deposition of hygroscopic
aerosols in humans to confirm these models adequately.
10.4.3.2 Neutralization and Buffering of Acidic Particles
The toxicity of acidic particles may be modulated following their inhalation. This may
occur within the inhaled air, by neutralization reaction with endogenous respiratory tract
ammonia, or following deposition, due to buffering within the fluid lining of the airways.
Reaction of Acidic Particles with Respiratory Tract Ammonia
Ammonia (NH3) is present in the air within the respiratory tract. Measurements taken in
exhaled air have found that the NH3 concentration varies, depending upon the site of
measurement, with levels obtained via oral breathing greater than those measured in the nose
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or trachea (Larson et al., 1977; Vollmuth and Schlesinger, 1984). Because of these
concentration differences between the oral and nasal passages, the route of acidic particle
inhalation likely plays a significant role in determining the hydrogen ion (IT) available for
deposition in the lower respiratory tract. Thus, for the same mass concentration of acidic
particles, inhalation via the mouth will result in more neutralization compared to inhalation via
the nose, and less FT available for deposition in the lungs (Larson et al., 1982). The toxicity of
acidic particles is likely due to the H+, as discussed in Chapter 11.
The possibility that endogenous ammonia could chemically neutralize inhaled acidic
particles to their ammonium salts prior to deposition on airway surfaces, thereby reducing
toxicity, was originally proposed by Larson et al. (1977) in relation to acidic sulfate aerosols.
Since, stoichiometrically, 1 //g of NH3 can convert 5.8 //g of H2SO4 to ammonium bisulfate
(NH4HSO4), or 2.9 //g of H2SO4 to ammonium sulfate [(NH4)2SO4], they determined, based upon
the range of NH3 levels measured in the exhaled air of humans, that up to 1,500 //g/m3 of inhaled
H2SO4 could be converted to (NH4)2SO4. For a given sulfate content in an exposure atmosphere,
both ammonium bisulfate and ammonium sulfate are less potent irritants than is sulfuric acid.
Complete neutralization of inhaled sulfuric acid or ammonium bisulfate would produce
ammonium sulfate. However, partial neutralization of sulfuric acid would reduce to varying
extents the amount of FT" available for deposition, thereby modulating toxicity. The extent of
neutralization has been shown to play a role in measured toxicity from inhaled sulfuric acid.
Utell et al. (1989) exposed asthmatic subjects to sulfuric acid under conditions of high or low
levels of expired ammonia. The response to inhaled acid exposure was greater when exposure
was conducted under conditions of low oral ammonia levels.
The extent of reaction of ammonia with acid sulfates depends upon a number of factors.
These include residence time within the airway, which is a function of ventilation rate, and
inhaled particle size. In terms of the latter, for a given amount of ammonia, the extent of
neutralization is inversely proportional to particle size, at least within the diameter range of
0.1-10 //m (Larson et al., 1993). In addition, for any given ammonia concentration, the extent of
neutralization of sulfuric acid increases as mass concentration of the acid aerosol decreases
(Schlesinger and Chen, 1994).
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Cocks and McElroy (1984) presented a model analysis for neutralization of sulfuric acid
particles in human airways. Particle acidity was a function of both dilution by particle growth
and neutralization by ammonia. As an example of their results, neutralization would be
complete in 3 sec for H2SO4 (3M) having a particle size of 0.5 //m and a mass concentration of
100 //g/m3, with the ammonia level at 500 //g/m3. If the NH3 level is reduced to 50 //g/m3,
neutralization would take longer.
Larson (1989) presented another model for neutralization of inhaled acidic sulfate aerosols
in humans. It was concluded that significant deposition of acid in the lower respiratory tract
would occur in the presence of typical respiratory tract NH3 levels, for both oral or nasal
inhalation of H2SO4 particles at 0.3//m. However, particles at 0.03//m should be completely
neutralized in the upper respiratory tract. While this latter seems to contradict findings of
significant biological responses in guinea pigs following exposure to ultrafine acid particles
(Chapter 11), this could reflect differences in residence times and ammonia levels between
different species. Furthermore, it is likely that under most circumstances, only partial
neutralization of inhaled sulfuric acid occurs prior to deposition (Larson et al., 1977). In any
case, these conclusions support toxicological findings of biological effects following inhalation
of sulfuric acid concentrations that should, based solely upon stoichiometric considerations, be
completely neutralized, and highlights the complexity of neutralization processes in the
respiratory tract.
Larson et al. (1993) examined the role of ammonia and ventilation rate on response to
inhaled (oral) sulfuric acid by estimating, using the model of Larson (1989), the acid
concentrations to which the lungs would be exposed during oral inhalation. They concluded that
combinations of high ammonia and low ventilation rate or low ammonia and high ventilation
rate produce smaller or larger amounts of acid deposition, respectively, even if the acid
concentration at the point of inhalation remained constant. The former condition resulted in
greater neutralization than did the latter.
Buffering by Airway Surface Fluid (Mucus)
Mucus lining the conducting airways has the ability to buffer acid particles which deposit
within it. The pH of mammalian tracheobronchial mucus has been reported to be within a range
of about 6.5 to 8.2 (Boat et al., 1994; Gatto, 1981; Holma et al., 1977).
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This variability may be due to differences in the methods used and species examined, as
well as the likelihood that the acid-base equilibrium differs at different levels of the
tracheobronchial tree, but may also reflect variations in secretion rate and the occurrence of
inflammation. The influence on pH of various other endogenous factors, such as secretion of
hydrogen or bicarbonate ions, and the role of specific mucus constituents, such as secreted acidic
glycoproteins and basic macromolecules, have not been extensively examined.
The buffering capacity of human sputum, a mixture of saliva and mucus, was examined by
Holma (1985), by titrating sputum equilibrated with 5% carbon dioxide at 37 °C and 100%
relative humidity (RH) with sulfuric acid. While the buffering capacity was variable, depending
upon the sputum sample examined, depression of pH from 7.25 to 6.5 required the addition of
approximately 6 //mol of hydrogen ion (H+) per milliliter of sputum. Assuming a
tracheobronchial mucus volume of 2.1 mL, between 8 and 16 //mol of H+, if evenly distributed
through the airways, would be required to depress mucus pH from 7.4 to 6.5. Since 1 //g H+ is
obtained from 49 //g of sulfuric acid, between 390 and 780 //g of sulfuric acid would be required
to cause this change in pH. With an inhalation exposure duration of 0.5 h, ventilation at 20
L/min and 50% deposition (in the total respiratory tract) of 100 //g/m3 sulfuric acid (at 1M), 0.6
//mol of H+ would be deposited in the lungs. However, the distribution of submicrometer acid
particles in the respiratory tract is not uniform and, therefore, greater changes in pH may be
anticipated on a regional basis in those areas having higher than average deposition. If, for
example, 30 //g of acid deposited in 0.2 mL of mucus, a greater change in pH would likely
occur.
The above example may apply to healthy individuals. However, the buffering capacity of
mucus may be altered in individuals with compromised lungs. For example, sputum from
asthmatics had a lower pH than that from healthy subjects, and a reduced buffering capacity
(Holma, 1985). This group may, therefore, represent a portion of the population which is
especially sensitive to inhaled acidic particles. The potential sensitivity of asthmatics to acid
particles is discussed in greater detail in Chapter 11.
While biological responses following the inhalation of acidic aerosols are likely due to the
H+ component of these particles, it has been suggested that pH may not be the sole determinant
of response to acid particles, but that response may actually depend upon total available
hydrogen ion, or titratable acidity, depositing upon airway surfaces. Fine et al.
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(1987) hypothesized that buffered acid aerosols (with a greater H+ pool) would cause a greater
biological response than would unbuffered acid aerosols having the same pH. Since airway
surface fluids have a considerable capacity to buffer acid, it was suggested that the buffered acid
would cause a more persistent decrease in airway surface fluid pH. Thus, it appears that the
specific metric of acidity used, i.e., pH or titratable acid, would, therefore, be reflected in the
relationship between amount of deposited acidity and resultant biological response.
10.5 DEPOSITION DATA AND MODELS
The background information in Sections 10.4 demonstrates that a knowledge of where
particles of different sizes deposit in the respiratory tract and the amount of their deposition is
necessary for understanding and interpreting the health effects associated with exposure to
particles. As was seen, the respiratory tract can be divided into the ET, TB and A regions on the
basis of structure, size and function. Particles deposited in the various regions have large
differences in clearance pathways and, consequently, retention times. This section discusses the
available data on particle deposition in humans and laboratory animals. Different approaches for
modeling these data are also discussed. Theoretical models must assume average values and
simplifying conditions of respiratory performance in order to make reasonable estimates. This
latter approach was initiated by the meteorologist Findeisen (1935) over fifty years ago, when he
developed a simplified anatomic model of the respiratory tract and assumed steady inspiratory
and expiratory air flows in order to estimate the interactions between the anatomy of the
respiratory tract and particle deposition based on physical laws. Despite much progress in
respiratory modeling, there are not major distinctions in total particle deposition predictions
among models and experimental verifications have been generally satisfactory.
10.5.1 Humans
The deposition of particles within the human respiratory tract have been assessed using a
number of techniques (Valberg, 1985). Unfortunately, the use of different experimental
methods and assumptions results in considerable variations in reported values. This section
10-85
-------
discusses the available particle deposition data in humans for either the total respiratory tract or
in terms of regional deposition.
10.5.1.1 Total Deposition
If the quantity of aerosol particles deposited in the entire respiratory tract is divided by that
inhaled, the result is called total deposition fraction or total deposition. Thus, total deposition
can be measured by comparing particle concentrations of the inhaled and exhaled, but the
regional involvement cannot be distinguished. By the use of test aerosol particles with
radiolabels, investigators have been able to separate deposition by region, beginning from the ET
region with either nasal and nasopharyngeal deposition for nose breathing or oral and pharyngeal
deposition for mouth breathing. The measurement of clearance of the radiolabeled particles
from the thorax can be used to separate fast clearance, usually assumed to be an indicator of TB
deposition, from the more slowly cleared A deposition (see below for more discussion).
Total human deposition data, as a function of particle size with nose and mouth breathing
compiled by Schlesinger (1988) are depicted in Figure 10-20. These data were obtained by
various investigators using different sizes of test spherical particles in healthy male adults under
different ventilation conditions. Deposition with nose breathing is generally higher than that
with mouth breathing because mouth breathing bypasses the filtration capabilities of the nasal
passages. For large particles with aerodynamic diameters dae greater than 1 jim, deposition is
governed by impaction and sedimentation and it increases with increasing dae. When dae > 10
|im, almost all inhaled particles are deposited. As the particle size decreases from 0.1 jim,
diffusional deposition becomes dominant and total deposition depends more upon the physical
diameter d of the particle. Decreasing particle diameter leads to an increase in total deposition in
this particle size range. Total deposition shows a minimum for particle diameters in the range of
0.1 fj.m to 0.5 jim where neither sedimentation nor diffusion deposition are effective. The
particle diameter at which the minimum deposition occurs is different for nose breathing and
mouth breathing and it depends upon flow rate and airway dimensions. For all particle sizes,
mixing of the tidal air and functional residual air can enhance particle deposition by providing a
mechanism for keeping the inhaled particles in the lung for a longer time and
10-86
-------
100
80
- 60
c
o
(A
O
I 40
20
v. O
I
O Human (Oral)
• Human (Nasal)
0.01
0.1 1.0
Particle Diameter (urn)
10
Figure 10-20. Total deposition data (percentage deposition of amount inhaled) in humans
as a function of particle size. All values are means with standard deviations
when available. Particle diameters are aerodynamic (MMAD) for those >
0.5
Source: Schlesinger (1988).
thereby increasing the probability of the particles to deposit. This factor is more significant for
particle sizes for which deposition is low. Good deposition experiments therefore should
account for mixing into the residual volume by requiring subjects to fully exhale.
Although various studies in Figure 10-20 all appear to show the same trend, there is a
significant amount of scatter in the data. Much of this scatter can be explained by the use of
different test particles and methods in the experimental studies, as well as different breathing
modes and ventilation conditions employed by the subjects. However, a good portion of the
scatter is caused by the differences in airway morphology and breathing pattern among
10-87
-------
subjects (Heyder et al., 1982, 1988; Yu et al., 1979; Yu and Diu, 1982a,b; Bennett and
Smaldone, 1987; Bennett, 1988). In addressing the health-related issues of inhaled particles, this
intersubject variability is an important factor which must be taken into consideration.
Indeed, for well controlled experiments and controlled breathing patterns (constant
inspiratory flow in half a cycle and constant expiratory flow in another half cycle and no pause),
total deposition data do not have the amount of scatter shown in Figure 10-20. Figure 10-21
shows the data by Heyder et al. (1986) and Schiller et al. (1986, 1988) reported by Stahlhofen et
al. (1989) at controlled mouth breathing for particle size ranging from 0.005 jam to 15 jam and
three different ventilation conditions. Total deposition was found higher for larger tidal volume
while the minimum deposition occurred at about 0.4 jim for all three ventilation conditions.
0.2-
0.0
Total Deposition
(unit density spheres)
mouth breathing
Symbols: Experimental data
Curves : Model calculations
Tidal volume
AA »0 BD
cm3 500 1,000 2,000
Volumetric flow rate cm g-1 250
Breathing frequency min1 15
250
7.5
250
3.75
0.01
0.1 1
Diameter of unit density spheres (urn)
10
Figure 10-21. Total deposition as a function of the diameter of unit density spheres in
humans for variable tidal volume and breathing frequency. Experimental
data are by Heyder et al. (1986) and Schiller et al. (1988). The curves
represent empirical fitting.
Source: Stahlhofen et al. (1988).
10-88
-------
10.5.1.2 Extrathoracic Deposition
The fraction of inhaled particles depositing in the ET region can be quite variable,
depending on particle size, flow rate, breathing frequency and whether the breathing is through
the nose or through the mouth. During exertion, the flow resistance of the nasal passages cause
a shift to mouth breathing in almost all individuals, thereby bypassing much of the filtration
capabilities of the head and leading to increased deposition in the lung (TB and A regions). For
nose breathing, the usual technique for measuring inspiratory deposition is to draw the aerosol
through the nose and out of the mouth while the subject holds his mouth open (Pattle, 1961;
Lippmann, 1970; Hounam et al., 1969, 1971). The aerosol concentration is measured before it
enters the nose and after it leaves the mouth. Neglecting mouth deposition during expiration,
inspiratory nasal deposition can be calculated from the concentration difference. Another
method to measure the nasal deposition is to use the lung as a part of the experimental system
(Giacomelli-Maltoni et al., 1972; Martens and Jacobi, 1973; Rudolf, 1975). The deposition of
particles in the nose is calculated from total deposition of particles in the entire respiratory tract
for mouth, nose, mouth-nose and nose-mouth breathing. Because mouth deposition is not
significant under the experimental conditions, this method allows the determination of nasal
deposition for both inspiration and expiration.
Deposition in the mouth for expiration is normally assumed to be negligible. For
inspiration, the deposition in mouth has been measured using radioactive aerosol particles
(Rudolf, 1975; Lippmann, 1977; Foord et al., 1978; Stahlhofen et al., 1980; Chan and
Lippmann, 1980; Stahlhofen et al., 1981, 1983). The amount of deposition is obtained from the
difference of activity measurements, one immediately after exposure and the other after the
deposited particles are removed with mouthwash or other means. Because the subjects in these
experiments breathe through a large bore tube, the deposition via the mouth occurs
predominantly in the larynx. Rudolf et al. (1984, 1986) have suggested to name this laryngeal
deposition. Mouth deposition by natural mouth breathing without using a mouthpiece was
measured in an earlier study by Dennis (1961) and recently by Bowes and Swift (1989) during
natural oronasal breathing at moderate and heavy exercise conditions. The data showed a much
greater deposition than breathing through a mouth-piece.
10-89
-------
For dae > 0.2 |im, ET deposition is usually expressed as a function of dae2Q,
where Q is the flow rate. This is the appropriate parameter for normalizing
impaction-dominated deposition when the actual flow rates in the experimental
studies are not identical. Even with this normalization, deposition data in the
extrathoracic region by various workers exhibit a very large amount of scatter as
shown in Figures 10-22 and 10-23, respectively, for inspiratory nasal and mouth
deposition. Besides uncertainty in measurement techniques, one major source of
this scatter, similar to the case of total deposition, comes from intersubject
and intrasubject variabilities. The intersubject variability may arise from the
difference in anatomical structure and dimensions, number of nasal hairs,
breathing pattern, etc., while the intrasubject variability may be caused by the
degree of mouth opening and by the nasal resistance cycle in which airflow may be
redistributed from one side to the other side, by as much as 20 to 80%.
Mathematical model studies on the deposition in the nose and mouth are very
limited. There have been only two attempts to determine nasal deposition during
inspiration (Landahl, 1950b; Scott et al., 1978). At present, formulas useful
for predicting ET deposition are derived empirically from experimental data
(Pattle, 1961; Yu et al., 1981; Rudolf et al., 1983, 1984, 1986; Miller et al.,
1988; Zhang and Yu, 1993). The formulas by Rudolf et al. (1983, 1984, 1986) given
below, with some modification, have been adopted by the International Commission
on Radiological Protection (ICRP, 1994) in their dosimetry model. Deposition
efficiency via the nose (r|N) or mouth (r|M) is expressed in terms of an impaction
parameter (dae2Q), as
% = 1 - [3.0x10 -'(d^Q) + I]-1 , (10-22)
or
TIM = 1 - [1.1x10 4(d O^VT0'2)1-4 + I]"1 • (10-23)
where dae is in the unit of |im, Q in cm3/s, and VT is the tidal volume in cm3.
Equation 10-22 applies to both inspiration and expiration since the data by
Heyder and Rudolf (1977) do not show a systematic difference between the two
efficiencies. The
10-90
-------
I
1.0
0.8 -
0.6 -
D Landahl&Tracewell 1949
V Rattle 1961
• Lippmann 1970
A Hounam et al. 1971
O Giacomelli-Maltoni et a I! 972
A Martens & Jacobi 1973
O Rudolf
1975
0.4 -
Figure 10-22.Inspiratory deposition of the human nose as a function of particle
aerodynamic diameter and flow rate (dae2Q). The curve represents
Equation 10-22.
Source: Stahlhofen et al. (1988).
inclusion of VT in Equation 10-23 is caused by the fact that the size of the ET
region during mouth breathing increases with increasing flow rate and with
increasing tidal volume.
For ultrafine particles (d < 0.1 |im), deposition in the ET region is
controlled by the mechanism of diffusion which depends only on the particle
geometric diameter, d. At this time, ET deposition for this particle size range
has not been studied extensively in humans. George and Breslin (1969) measured
nasal deposition of radon progeny in three subjects but the diffusion
coefficient of the progeny was uncertain. Schiller et al. (1986, 1988) later
obtained inspiratory nasal deposition from total deposition measurements using
a nose in -
10-91
-------
1.0
0.8-
0.6-
Q, cm?s'1 V, cnf
A ~500 ~1,000 Lippmann
+ 500 1,000
-1,000
1,000
250
500
1,000
1,500
• -500
D 333
O 250
250
250
A
O
D
1977
Foord et al. 1978
Chan & Lippmann 1980
Emmett et al. 1982
Stahlhofen etal.
750
0.4-
^dae2(f3V\WcrTr/4 s2'3)
Figure 10-23. Inspiratory extrathoracic deposition data in humans during mouth
breathing as a function of particle aerodynamic diameter, flow
rate, and tidal volume (dae2Q2/3VT"1/4). The curve represents
Equation 10-23.
Source: Stahlhofen et al. (1988).
mouth out and mouth in-nose out maneuver. However, their data cannot be
considered reliable because mouth deposition is not negligible compared to nose
deposition.
The only data available to date for ET deposition of ultrafine particles are
from cast measurements (Cheng et al., 1988, 1990, 1993; Yamada et al., 1988;
Gradon and Yu, 1989; Swift et al., 1992). Figure 10-24 shows these data on
inspiratory nasal deposition from several laboratories reported by Swift et al.
(1992) as a function of the diffusion parameter, D1/2Q"1/8, where D is the particle
diffusion coefficient in cm2/sec and Q is the flow rate in L/min. Swift et al.
(1992) also proposed an equation to fit the data in the form
10-92
-------
Cast A, Harwell
• Cast G, Harwell
O Cast C, ITRI
• Cast B, ITRI
A Cast A, Clarkson
V Cast B, Clarkson
A Cast G, Clarkson
0.05
0.1
0.15
0.2
0.25
0.3
D1/2Q-1/8 (Lmiri )
1 1/8 (erf s1 j/2
Figure 10-24. Inspiratory deposition efficiency data and fitted curve for human
nasal casts plotted versus Q1/8D1/2 (LminJ)1/8(cm2s~lf\ The solid
curve represents Equation 10-24 and the dotted lines are 95%
confidence limits on the mean.
Source: Swift et al. (1992).
IN
-exp[-12.65£>1/2Q
(10-24)
which was adopted by ICRP66 in the 1994 model. Expiratory nasal deposition for
particles between 0.005 jim to 0.2 jim was found to have the same trend as Figure 10-
24 but was approximately 10% higher than the inspiratory nasal deposition
(Yamada et al., 1988). Cheng et al. (1993) derived the following empirical
equations to fit the data for expiratory nasal deposition
10-93
-------
TIN = 1 - exp[ - 15.0Z)1/2Q -1/8]. (10-25)
Diffusional deposition in human oral casts was found to be smaller than that in
nasal casts (Cheng et al., 1990). Based upon these data, Cheng et al. (1993)
derived the following equation for oral deposition
TIM = 1 - exp (- 10.3Z)1/2Q -1/8) , (10-26)
on inspiration, and
TIM = l-exp(-8.51Z)1/2Q 1/8) , (10-27)
for deposition on expiration. Contrary to nasal deposition, deposition in the
mouth is slightly higher for inspiration than for expiration. Figure 10-25 shows
the inspiratory oral deposition data and Equation 10-26.
ICRP66 (1994) took a more conservative view of the experimental data on
deposition of small particles in the oral passageway. Oropharyngeal deposition
for mouth breathing was assumed to be only half the value for nose breathing so
that
r|m = 1 - exp (-6.33 D1/2 Q '1/8). (10-28)
10.5.1.3 Tracheobronchial Deposition
Particles escaping from deposition in the ET region enter the lung, but
their regional deposition in the lung cannot be precisely measured. All the
available regional deposition data have been obtained from experiments with
radioactive labeled poorly soluble particles above 0.1 jim in diameter. The
amount of activity retained in the lung as a function of time normally exhibits a
fast and slow decay component that have been identified as mucociliary and
macrophage clearance. Since the tracheobronchial airways are ciliated, the
rapidly
10-94
-------
1.0-
0.8-
o
0
'o
it 0.6-
UJ
c
o
'35
£ 0.4-
0)
0
0.2-
^^^H ^^^^B ^^^
O NaCI (Cheng et al., 1990)
• 212Pb (Cheng etal., 1993)
0.0001
0.0010
0.0100
0.1000
1.0000
10.0000
D1'2 Q-1/8 (cm2 /sec)72 (L/minf8
Figure 10-25. Inspiratory deposition efficiency data in human oral casts plotted
versus flow rate and particle diffusion coefficient [Q~1/8D1/2
(Lmin"1)"1'8 (cmV1)172]. The solid curve represents Equation 10-26
and the dotted lines are the 95% confidence limits.
Source: Cheng et al. (1993).
cleared fraction of initial activity can be considered as a measure of the amount
of material deposited in the TB region, whereas the slowly cleared fraction
corresponds to the material deposited in the A region. However, there is
experimental evidence that a significant fraction of material deposited in the
TB region is retained much longer than 24 h (Stahlhofen et al., 1986a,b; Scheuch
and Stahlhofen, 1988; Smaldone et al., 1988). This may be caused by the fact that
the TB airway surface is lined with ciliated epithelium, but not all of the
ciliated epithelium is covered with mucus all the time (Stahlhofen et al., 1989).
Other mechanisms for prolonged TB clearance include phagocytosis by airway
macrophages and
10-95
-------
deposition of particles further down into the A region due to mixing of flow
during inspiration. Thus, TB and A deposition measured based upon the clearance
of radioactive labeled particles have been suggested as the "fast-cleared" and
"slow-cleared" thoracic deposition (Stahlhofen et al., 1989).
Figure 10-26 shows the data from various investigators (Lippmann, 1977;
Foord et al., 1978; Chan and Lippmann, 1980; Emmett et al., 1982; and Stahlhofen
et al., 1980, 1981, 1983) on TB deposition or fast-cleared thoracic deposition
for mouth breathing as a function of dae reported by Stahlhofen et al. (1989).
Again, the data are quite scattered due to differences in experimental technique
and intersubject and intrasubject variabilities that have been cited
previously. Another cause for the scatter is from the difference in the flow rate
employed by various studies. For dae > 0.5 jim, deposition in the TB region is
caused by both impaction and sedimentation. Whereas the impaction deposition is
governed by the parameter dae2Q, sedimentation deposition is controlled by the
parameter dae2/Q. It is therefore not possible to have a single relationship
between deposition and dae for different flow rates.
Data in Figure 10-26 show that TB deposition does not increase monotonically
with dae. A higher dae leads to a greater ET deposition and consequently a lower TB
deposition. For the range of flow rates employed in various studies, the maximum
TB deposition occurs at about 4 jim dae. It is also seen that the data by Stahlhofen
et al. (1980, 1981, 1983) in Figure 10-26 are considerably lower than those from
other investigators. Chan and Lippmann (1980) cited two possible reasons for
this difference. One was that Stahlhofen and coworkers used constant
respiratory flow rates in their studies as opposed to the variable flow rates
used by others. The second reason was that different methods of separating the
initial thoracic burden into TB and A regions were used. Stahlhofen et al. (1980)
extrapolated the thoracic retention values during the week after the end of fast
clearance back to the time of inhalation; they considered A deposition to be the
intercept at that time, with the remainder of the thoracic burden considered as
TB deposition. This approach yields results similar to, but not identical with,
those obtained by treating TB deposition as equivalent to the particles cleared
within 24 h.
10-96
-------
DE
TB
1.0
0.8-
0.6-
0.4-
0.2-
Q. cm3 s'1 V. cm3
Lippmann 1977
Foordetal. 1978
Chan & Lippmanri980
Emmett et al. 1982
Stahlhofen etal.
1980
1981
J983
0.1
10
dae (Mm)
Figure 10-26. Tracheobronchial deposition data in humans at mouth breathing as a
function of particle aerodynamic diameter (dae). The solid curve
represents the approximate mean of all the experimental data; the
broken curve represents the mean excluding the data of Stahlhofen
etal.
Source: Stahlhofen et al. (1988).
10.5.1.4 Alveolar Deposition
The A deposition data as a function of dae for mouth breathing are shown in
Figure 10-27. These data are from the same studies that reported TB deposition in
Figure 10-25 but there is a better agreement between different studies than with
the TB data. Alveolar deposition is favored by slow and deep breathing. The data
of Stahlhofen et al. (1980, 1981, 1983) at 1000 cm3 tidal volume and 250 cm3/sec
flow rate thus are higher than other data. Figure 10-27 also shows (1) that A
deposition reaches the maximum at about
10-97
-------
DE,
t
1.0
0.8 -
0.6 -
0.4-
0.2 -
Q. ctrPs'1 V. cnf
A-500 -1,000 Lippmann 1977
+ 500 1,000 Foordetal. 1978
•-500 -1,000
n 333 1,000
Chan & Lippmanr1980
Emmett et al. 1982
10
dae (Mm)
Figure 10-27. Alveolar deposition data in humans as a function of particle
aerodynamic diameter (dae). The solid curve represents the mean of
all the data; the broken curve is an estimate of deposition for nose
breathing by Lippmann (1977).
Source: Stahlhofen et al. (1988).
3.5 |im dae and (2) that for dae between 0.2 jim and 1.0 jim, A deposition does not show
significant change although a minimum deposition may occur near 0.5 jim.
By switching from mouth breathing to nose breathing, alveolar deposition
will decrease. Lippmann (1977) made an estimate by analysis of the difference in
the ET deposition for nose and mouth breathing. The nose breathing (dashed line)
result is also shown in Figure 10-26. For dae greater than 7 jim, practically no
particles deposit in the A region in this breathing mode.
10-98
-------
During exercise, most subjects switch from nose breathing to breathing
partly through the mouth (Niinimaa et al., 1981). The amount of inhaled material
that deposits in the lungs is affected because the mouth and nose have different
filtration efficiencies. Niinimaa et al. (1981) found that in thirty subjects,
twenty switched to oro-nasal breathing (normal augmenters), typically at a
ventilation rate of about 35 L/min, five continued to breathe through the nose,
and the rest who were habitual mouth breathers breathed oro-nasally at all levels
of exercise. These data were reviewed by Miller et al. (1988) and used to
estimate thoracic deposition (TB and A deposition) at different ventilation
rates. At higher ventilation rates, Miller et al. (1988) predicted little
difference in thoracic deposition between normal augmenters and mouth
breathers, but for ventilation rates less than 35 L/min they predicted
substantially lower deposition in normal argumenters compared to mouth
breathers. Based upon this finding, ICRP (1994) recommended a different
breathing pattern for normal augmenters and mouth breathers that typifies the
breathing habits of adult males as a function of ventilation rate. The split in
airflow for the recommended breathing patterns by ICRP (1994) is shown in
Figure 10-28. Table 10-10 provides the same information on the percentages of
total ventilatory airflow passing through the nose versus mouth at reference
levels of physical exertion for a normal augmenter and a mouth breather adult
male. These are the same levels of exercise and values for fraction of nasal
ventilatory airflow used to construct the activity patterns in Section 10.7. In
the absence of specific data, it must be assumed that a similar breathing pattern
applies to young healthy subjects at equivalent levels of exercise. Alveolar
deposition at different ventilation rates can be estimated from Figure 10-28 or
Table 10-10. For example, a mouth breather doing light exercise (VE =1.5 m3/h)
has about 40% ventilatory air-flow passing through the nasal route. At a
particle size of 2 //m dae Figure 10-28 gives, respectively, 0.24 and 0.36 A
deposition for mouth and nose breathing. Thus, the resultant A deposition at
this ventilation rate is 0.4 x 0.36 + 0.6 x 0.24 = 0.288.
10.5.1.5 Nonuniform Distribution of Deposition and Local Deposition Hot Spots
The deposition data in different regions of the respiratory tract do not
provide information on deposition nonuniformity in each region and local
deposition intensity at a specific site. Such information may be of great
importance from a toxicology perspective.
10-99
-------
100
80
60
ra
4-1
O
I-
M-
o
0)
O)
ra
a 40
o
O
4-1
(0
0)
OL
\
a
.52
+- "o ^
•£, <5 «T
5* x *:
_i m —'
a
0 1 2 3^4 5
Ventilation Rate (VE)(m3- h'1)
Figure 10-28. Percentage of total ventilatory airflow passing through the nasal
route in human "normal augmenter" (solid curve) and in habitual
"mouth breather" (broken curve).
Source: International Commission on Radiological Protection (ICRP66, 1994).
10-10. FRACTION OF VENTILATORY AIRFLOW PASSING
THROUGH THE NOSE IN HUMAN "NORMAL AUGMENTER" AND
"MOUTH BREATHER"3
Level of Excertion
Sleep
Rest
Light exercise
Heavy exercise
F.
Nasal Augmenter
1.0
1.0
1.0
0.5
Mouth Breather
0.7
0.7
0.4
0.3
"(ICRP66, 1994) as derived from Miller et al. (1988).
10-100
-------
Because airway structure and its associated air flow patterns are exceedingly
complex (Chang and Menon, 1993), and ventilation distribution of air in
different parts of the lung is uneven (Milic-Emili et al., 1966), it is expected
that particle deposition patterns in ET, TB, and A regions are highly nonuniform.
Fry and Black (1973) measured regional deposition in the human nose using
radiolabelled particles and found that most of deposition occurred in the
anterior region of the nose. Schlesinger and Lippmann (1978) found nonuniform
deposition in the trachea to be caused by the airflow disturbance of the larynx.
In a single airway bifurcation model, measurements show that deposition occurs
principally around the carinal ridge (e.g., Bell and Friedlander, 1973; Lee and
Wang, 1977); Martonen and Lowe, 1983; Kim and Iglesias, 1989 a,b). A similar
result was observed in the alveolar duct bifurcations in rats and mice (Brody and
Roe, 1983). Figure 10-29 shows the data on local deposition pattern obtained by
Kim and Iglesias (1989) and Kim et al. (1989) in a bifurcating tube for both
inspiration and expiration. The peak deposition occurs in the daughter tube
during inspiration and the parent tube during expiration, but always near the
carinal ridge. In addition, airways are not smooth tubes. More recently,
Martonen et al. (1994 a,b,c) have called attention to the existence of
cartilaginous rings on the wall of airways in the tracheobronchial region. Using
a numerical analysis, they showed that such surface structure can lead to a
considerable alteration of the flow pattern and enhancement of deposition.
Deposition measurements in small laboratory rodents (Raabe et al., 1977)
also showed differences in lobar distribution with up to 60 percent higher
deposition than the average in the right apical lobe (corresponding to the human
upper lobe). The difference was greater for large particles than for small
particles. Raabe et al. (1977) further showed that these differences in relative
lobar deposition were related to geometric mean number of airway bifurcations
between trachea and terminal bronchioles in each lobe for rats and hamsters.
Since similar morphologic differences occur in the human lungs, nonuniform lobar
distribution should also occur.
10.5.1.6 Approaches to Deposition Modeling
Mathematical models of lung deposition have been developed in recent years
to help interpret experimental data and to make predictions of deposition for
cases where data are not available. A review of various mathematical models was
given by Morrow and Yu
10-101
-------
c
o
o
a
CD
O
"a
+*
o
100-,
80-
60-
40-
20-
IB )c
Stk
00.05
• 0.09 - 0.27
I
A
I I I
BCD
Branch Sections
I
E
c
o
100-1
80-
(0
o
u 60
40-
20-
O 0 = 30
A 0 = 45
Figure 10-29.
A B C D E
Branch Sections
Local deposition pattern in a bifurcating tube for inhalation (top
panel) and exhalation (bottom panel). Deposition in each section
is expressed as a percent of total deposition for the entire model.
Symbols and error bars in the top panel represent means and
standard deviations of the 0 = 30° and 45°. Symbols and error bars
in the bottom panel represent means and standard deviations of the
entire data obtained in the Stokes number range from 0.05 to 0.28.
Source: Kim and Iglesias (1989); Kim et al. (1989).
10-102
-------
(1993). There are three major elements involved in mathematical modeling.
First, a model of airways simulating the real structure must be specified.
Secondly, deposition efficiency in each airway due to various mechanisms must be
derived. Finally, a computational procedure must be developed to account for the
transport and deposition of the particles in the airways.
Three different approaches have been used in the mathematical modeling. The
first approach is a compartmental model first formulated by Findeisen (1935).
Starting with the trachea, Findeisen divided the airways into nine compartments
based upon the anatomical structure. Particles which did not deposit in one
compartment remained airborne and transported to the next compartment for
deposition. Findeisen's lung model and analysis were later modified by Landahl
(1950a, 1963) and Beeckmans (1965). Detailed calculations of regional
deposition with additional consideration of nasal deposition based upon the
Findeisen-Landahl-Beeckmans theory were later published in a report by the Task
Group on Lung Dynamics (TGLD) in 1966.
Because of advancement in measuring techniques, refined airway models have
become available (as discussed in Section 10.2). Several new models based upon
the compartmental analysis have been proposed (e.g., Gerrity et al., 1979; Yeh
and Schum, 1980; Martonen and Graham, 1987). The expressions used for deposition
efficiency of each compartment differed somewhat in these models. In the absence
of any careful comparison with the experimental data, it is difficult to assess
the applicability of these models to deposition prediction. However, one
difficulty often encountered in the compartmental model is the derivation of
deposition efficiency in each airway for combined mechanisms of impaction,
sedimentation and diffusion. A commonly used assumption is that each deposition
mechanism is independent, thus the joint efficiency can be written in the form
(10-29)
where % r|s, and r|D are, respectively, deposition efficiency in an airway or
compartment by the individual mechanisms of impaction, sedimentation and
diffusion, and r| is the joint efficiency. Yu et al. (1977) have shown, in a
detailed mathematical analysis of a combined sedimentation and diffusion
problem, that the above equation is an inaccurate expression for deposition when
r|s and r|D are not small and have about the same magnitude. Another
10-103
-------
difficulty in the compartmental model is that the air-mixing effect (i.e.,
mixing of tidal air and lung air) on deposition cannot be easily accounted for.
Such an effect is important for transient exposure. However, the compartmental
model is easy to formulate and to understand conceptually.
The second approach to deposition modeling was put forward by Yu and
coworkers (Taulbee and Yu, 1975; Yu, 1978; Yu and Diu, 1983) and later by Egan and
Nixon (1985, 1989). In this approach, the many generations of airways are viewed
as a chamber shaped like a trumpet. The cross-sectional area of the chamber
varies with airway depth measured from the beginning of the trachea, according to
anatomical data. The concentration of inhaled particles in the chamber as a
function of airway depth and time during breathing is described by a convective
diffusion equation with a loss-term accounting for airway deposition. This
equation can be solved either exactly (without longitudinal diffusion) or
numerically with appropriate initial and boundary conditions. Deposition at
different sites in the airways is then calculated once the concentration is
known.
The deposition model formulated in this manner has some advantages over the
compartmental model. The use of differential airway length in the model allows
the joint deposition efficiency per unit airway length to be the superposition of
efficiencies by each individual mechanism. Variation of airway dimensions
during breathing is accounted for in the model. The model is time-dependent and
can thus be applied to any breathing pattern and transient exposure condition.
Air-mixing and uneven airway path lengths can be accounted for with the use of an
equivalent longitudinal diffusion term in the convective-diffusion equation.
Finally, in the case of no longitudinal diffusion, the exact solution of the
convective-diffusion is obtainable, thus reducing the time required for
calculating deposition.
The airway geometry of the human lung is not identical within a population.
In a given lung, the dimension of the airways in a specified generation is also
not uniform and the bifurcation is not symmetric (Weibel, 1963). The above two
modeling approaches have been extended to account for the randomness of airway
geometry (Yu et al., 1979; Yu and Diu, 1982a,b; Koblinger and Hofmann, 1990;
Hofmann and Koblinger, 1990). Yu and Diu (1982b) compared their modeling results
with total and regional deposition data of Stahlhofen et al. (1981) and Heyder et
al. (1982) for controlled breathing and suggested that differences
10-104
-------
in lung morphology were probably the principal cause for intersubject
variability in deposition.
Another approach to deposition modeling is an empirical one proposed by
Rudolf et al. (1983, 1984, 1986, 1990) similar to that developed for ET
deposition. This model considers the lung as a series of two filters
representing the TB and A regions of the lung. The model requires no assumptions
about airway geometry, airflow pattern and distribution, or particle deposition
efficiency in each airway. However, the construction of the model relies heavily
on experimental data of regional deposition for a wide range of particle sizes
(monodisperse) and breathing conditions. These data are not always available.
An additional difficulty in empirical modeling is the development of deposition
equations in each region for combined deposition mechanisms. As discussed
earlier, impaction, sedimentation and diffusion deposition depend,
respectively, on the parameters dae2Q, Dae2/Q and D/Q, where D is a function of
particle geometric diameter. It is a very difficult task to come up with an
equation for deposition in terms of these parameters which can match all
experimental data. Furthermore, because only a few compartments are used in the
empirical model, more detailed deposition information such as deposition at a
specific airway generation cannot be predicted. However, as mentioned, with an
empirical model the geometry and relative importance of mechanisms and airflow
splits are all "correct" in the subjects tested and are reflected in the measured
deposition. This may be an advantage over theoretical models that must rely on
extremely limited information on geometry. As described in Appendix 10A, the
ICRP based their 1994 model of respiratory tract deposition on a theoretical
calculation of the type introduced by Taulbee and Yu (1975), which was found to be
consistent with the experimental data taken as a whole. However, for
mathematical simplicity in applying the results of these complex calculations,
which included the effects of airway dimension scaling for subject gender and
age, the ICRP developed a set of algebraic expressions to represent regional lung
deposition in terms of the controlling parameters, i.e., particle diameter,
density, shape factor, breathing mode (nose or mouth), tidal volume, respiratory
frequency, functional residual capacity, gender, and subject height.
10-105
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10.5.2 Laboratory Animals
Since much information concerning inhalation toxicology is collected from
laboratory animals, the comparative regional deposition in these laboratory
animals must be considered to help interpret, from a dosimetric viewpoint, the
possible implications of animal toxicological results for humans. In evaluating
deposition studies in terms of interspecies extrapolation, it is not adequate to
express the amount of deposition merely as a percentage of the total inhaled. For
some particle sizes, regional deposition in humans and laboratory animals may be
quite similar and appears to be species independent (McMahon et al., 1977; Brain
and Mensah, 1983). However, different species exposed to identical particles at
the same exposure concentration will not receive the same particle mass per unit
exposure time because of their differences in tidal volume and breathing rate.
In addition, because of differences in the lung weight and airway surface area,
the amount of deposition normalized to these quantities is also very different
between species.
It is difficult to systematically compare interspecies deposition patterns
obtained from various reported studies, because of variations in experimental
protocols, measurement techniques, definitions of specific respiratory tract
regions, and so on. For example, tests with humans are generally conducted under
protocols that standardize the breathing pattern, whereas those using
laboratory animals involve a wider variation in respiratory exposure conditions
(for example, spontaneous breathing versus ventilated breathing as well as
various degrees of sedation). Much of the variability in the reported data for
individual species may be due to the lack of normalization for specific
respiratory parameters during exposure. In addition, the various studies have
used different exposure techniques, such as nasal mask, oral mask, oral tube, or
tracheal intubation. Regional deposition may be affected by the exposure route
and delivery technique employed.
Figure 10-30 shows the regional deposition data versus particle diameter in
commonly used laboratory animals obtained by various investigators and compiled
by Schlesinger (1988). Although there is much variability in the data, it is
possible to make some generalizations concerning comparative deposition
patterns. The relationship between total respiratory tract deposition and
particle size is approximately the same in humans and most of these animals;
deposition increases on both sides of a minimum, which occurs for particles of
0.2 to 0.9 jim. Interspecies differences in regional deposition occur due to
anatomical and
10-106
-------
1UU
80
60
40
20
r\
1 1 1
O Rat
E Hamster
A Mouse
~ O Guinea Pig
_
ET
A
- I
" i v % JfErtSfc
0.01 0.1 1.0
60
1 40
+j
0
Q.
Q 20
1 1
ORat
- P Hamster
A Mouse
VGuinea Pig
Voog
-
-
lll&w
T __
1 D
^3/1
w -
f •
10
I
TB
0.01
0.1
1.0
10
60
40
20
' O Rat
D Hamster
A Mouse
^Guinea Pig
VDog
I
1
V
i
V
V
V
1 1
<
r
i
>
i
k
^
ij
^ 0.5 //m and geometric (or diffusion equivalent) for those <
0.5
Source: Schlesinger (1988).
10-107
-------
physiological factors. In most laboratory animal species, deposition in the ET
region is near 100 percent for dae greater than 5 jim (Raabe et al., 1988),
indicating greater efficiency than that seen in humans. In the TB region, there
is a relatively constant, but lower, deposition fraction for dae greater than 1 jim
in all species compared to humans. Finally, in the A region, deposition fraction
peaks at a lower particle size (dae about 1 |im) in laboratory animals, than in
humans.
Mathematical deposition models for rats, hamsters, and guinea pigs have
been developed by several investigators (e.g., Schum and Yeh, 1980; Xu and Yu,
1987; Martonen et al., 1992) in a similar manner as the human models without
including diffusion deposition in the ET region. Although the modeling results
are generally in agreement with experimental data, there is a considerable
uncertainty in the respiratory and anatomical parameters of the laboratory
animals used in the modeling studies. In addition, the airway branching patterns
in the animals are commonly monopodial as compared to the dichotomous branching
in the human lung. The deposition efficiency of an airway (the amount of
deposition in an airway divided by the amount entered) developed in the human
model may not be applicable to laboratory animal species. Despite some of these
difficulties, modeling studies in laboratory animals remain a useful step in
extrapolating exposure-dose-response relationships from laboratory animals to
the human (Yu et al., 1991).
Asgharian et al. (1995) developed an empirical model of particle deposition
in the A region based on the published data reviewed by Schlesinger (1985a).
Although restricted to the A region, the approach could be applied to other
regions. A deposition function (FA) was described using a polynomial regression
of the form
N
FA = £ ^(log^d)1 for d
-------
reason, Equation 10-31 was added to be consistent with the deposition data and
dcut.off was determined by setting Equation 10-30 to zero. Newton's method was
employed to find dcut.off for different cases. Particle deposition was then
integrated with particle distributions differing in median particle diameter
and og to calculate deposition mass fraction for specific polydisperse size
distributions.
Menache et al. (1996) developed an empirical model to estimate fractional
regional deposition efficiency. This model represents a revised version of
previously published models used for dosimetric interspecies extrapolation
(Jarabek et al., 1989, 1990; Miller et al., 1988) that have been useful to develop
inhalation reference concentration (RfC) estimates for dose-response
assessment of air toxics (U.S. Environmental Protection Agency, 1994). For
example, rather than linear interpolation between the published (Raabe et al.,
1988) means for deposition measured at discrete particle diameters, as
previously done for the rat deposition modeling, equations have now been fit to
the individual animal data for each of the discrete, monodisperse particle
exposures (U.S. Environmental Protection Agency, 1994; Menache et al., 1996).
A description of the complete study including details of the exposure may be
found elsewhere (Raabe et al., 1988). Briefly, the animals were exposed to
radiolabelled ytterbium (169Yb) fused aluminosilicate spheres in a nose-only
exposure apparatus. Twenty unanesthetized rodents or eight rabbits were exposed
to particles of aerodynamic diameters (dae) approximately 1, 3, 5, or 10 //m. Half
the animals were sacrificed immediately post exposure; the remaining half were
held 20 h post exposure. One-half of the animals at each time point were female.
The animals were dissected into 15 tissue compartments, and radioactivity was
counted in each compartment. The compartments included the head, larynx, GI
tract, trachea, and the five lung lobes. This information was used directly in
the calculation of the deposition fractions. Radioactivity was also measured in
other tissues including heart, liver, kidneys, and carcass; and additionally in
the urine and feces of a group of animals held 20 h. Data for the animals
sacrificed immediately post exposure were used to ensure that there was no
contamination of other tissue, whereas the data from the animals held 20 h were
used in the calculation of a fraction used to partition bronchial deposition
between the TB and A regions. Radioactivity was measured in the pelt, paws, tail,
and headskin as a control on the exposure.
10-109
-------
Although there are some other studies of particle deposition in laboratory
animals (see review by Schlesinger, 1985a), no other data have the level of
detail or the experimental design (i.e., freely breathing, unanesthetized,
nose-only exposure to monodisperse particle size distributions) required to
provide deposition equations representative of the animal exposures used in many
inhalation toxicology studies. However, many inhalation toxicology studies are
not nose-only exposures. While nose-only exposures are necessary to determine
fractional particle deposition, adjustments can be made to estimate deposition
fractions under whole-body exposure conditions. Similarly, deposition of
polydisperse size distributions can be estimated by integrating the size
distribution and monodisperse fractional deposition.
The advantages of using the data of Raabe et al. (1988) to develop the
deposition efficiency equations include:
• the detailed measurements were made in all tissues in the animal,
providing mass balance information and indicating that there was no
contamination of nonrespiratory tract tissue with radioactivity
immediately post exposure,
• the use of unanesthetized, freely breathing animals, and
• the use of monodisperse or near monodisperse particle size
distributions in the exposures
Regional fractional deposition, Fr, was calculated as activity counted in a
region normalized by total inhaled activity (Table 10-11). The proportionality
factor, fL, in Equations 10-33 and 10-34 was used to partition thoracic
deposition between the TB and A regions. It was calculated using the 0 and 20-h
data and is described in detail by Raabe and co-workers (1977).
These regional deposition fractions, Fr, however, are affected not only by
the minute volume (VE), MMAD and og, but also by deposition in regions through
which the particles have already passed. Deposition efficiency, r|r, on the other
hand, is affected only by MMAD, og and VE. The relationships between deposition
fraction and efficiency are calculated as provided below and are described in
more detail elsewhere (Menache et al., 1995). In the aerodynamic domain, that is
for particles with diameters >0.5 //m, efficiencies increase monotonically and
are bounded below by 0 and above by 1. The
10-110
-------
TABLE 10-11. REGIONAL FRACTIONAL DEPOSITION
P Activity Counted in a Region
[ Total Inhaled Activity
[head + GI tract + larynxL h
Extrathoracic (ET): FET = — (10-32)
Total Inhaled Activity
5
trachea, + fT x Y^ lobe. n,,
"0 h L Z-^ 1,0 h /-JQ ^g^
Tracheobronchial (TB): F^ = — v " ;
Total Inhaled Activity
5
(1 - fT) x Y) lobCio„
Alveolar (A): FA = ^ (1°"34)
Total Inhaled Activity
Source: U.S. Environmental Protection Agency (1994).
logistic function has mathematical properties that are consistent with the shape
of the efficiency function (Miller et al., 1988)
where E(r|r) is the expected value of deposition efficiency (r|r) for region r, and
x is expressed as an impaction parameter, dae2Q, for extrathoracic deposition
efficiency and as aerodynamic particle size, dae, for TB and A deposition
efficiencies. The flow rate, Q (mL/s), in the impaction parameter may be
approximated by (2VE/60). The parameters a and P are estimated using nonlinear
regression techniques.
To fit this model, efficiencies must be derived from the deposition
fractions that were calculated as described in Table 10-11. Efficiency may be
defined as activity counted in a region divided by activity entering that region.
Then, considering the region as a sequence of filters in steady state,
efficiencies may be calculated as follows
r|ET = FET (10-36)
10-111
-------
(10-37)
5
trachea^, h + fL x J^ lobCj 0 h
v~-
5
(1 ~~ tT ) X / i\ju\si n L
L/ ^ ' (10-38)
IA
(1 - IET) (1 - T!TB)
Using these calculated regional efficiencies in the individual animals, the
logistic function was fit for the ET, TB, and A regions for the five animal
species and humans. Figure 10-3 1 shows the deposition efficiency in the rat ET
region versus the impaction parameter, dae2Q. The logistic curve was fit to the
experimental data assuming negligible deposition on exhalation. The open
circles represent the data for animals having extreme studentized residuals
(>1.96) compared to the data for other animals (closed circles) in the ET region.
Deposition efficiency curves were fit for the TB and A regions also. In all three
regions, the curve fits provided good descriptions of the data with asymptotic R2
of 0.98 or greater (Menache et al., 1996). The root MSE, an estimate of the
average error in the regression model in the data units, ranged between 0.08 and
0.10. These differences are well within the limits of biological variability
seen in this study and other studies (Schlesinger, 1988). The parameter
estimates from these fits are listed in Table 10-12.
The fitted equations are then used to generate predicted efficiencies (fj) as
a function of impaction in the ET region and of dae in the TB and A regions.
Finally, the predicted efficiencies are multiplied together and adjusted for
inhalability, I, as shown in Equations 10-39 through 10-41 to produce predicted
deposition fractions (Fr) for monodisperse and near monodisperse (og < 1 .3)
particles
FET = I x flET (10-39)
Fra = I x (1 - fjET) x fjra (10-40)
FA = I x (1 - f^) x (1 - f^ x V (10-41)
10-112
-------
Figure 10-31.
1.0-1
0.8-
o 0.6-1
o
ui
ui 0.4-
0.2-
0.0-
A. Negligible Deposition
on Exhalation
10 100
Impaction [(|jm3 ml/s]
1,000
Regional deposition efficiency in the rat extrathoracic (ET)
region versus an impaction parameter (dae2Q) as predicted by model
of Menache etal. (1996).
Source: Menache et al. (1996).
Inhalability, I, is an adjustment for the particles in an ambient exposure
concentration that are not inhaled at all. For humans, an equation has been fit
applying the logistic function (Menache et al., 1995) to the experimental data of
Breysse and Swift (1990)
I = 1
1
1 + e
10.32-7.17
(10-42)
The logistic function was also fit to the data of Raabe et al. (1988) for
laboratory animals (Menache et al., 1995)
I = 1
1
1 + e
2.57-2.81
(10-43)
Figure 10-32 illustrates the relationship between the predicted
efficiencies and predicted depositions using this model for the rats. The
particles were assumed to be monodisperse.
10-113
-------
TABLE 10-12. DEPOSITION EFFICIENCY EQUATION ESTIMATED PARAMETERS
AND 95% ASYMPTOTIC CONFIDENCE INTERVALS
Species
Human
Rat
a
7.129
6.348(5.14,
7.56)
ET (Nasal)
-1.957"
-5.269 (-6.
4.35)
P
19,-
o
J
2,
o
J
a
.298a
.822 (2.54,
.11)
TB
-4.588a
-4.576 (-5
4.10)
P
.06,-
0,
2.
2.
a
.523*
,241 (1.72,
,77)
A
-1.3893
-10.463
8.19)
P
(-12.74, -
"Source: Miller et al. (1988).
-------
A default body weight (BW) for the rats of 0.38 kg was used to calculate a default
VE using allometric scaling (U.S. Environmental Protection Agency, 1994).
Regional deposition efficiencies and fractions were calculated for particles
with dae ranging from 1.0 to 10 //m. These calculated points were connected to
produce the smooth curves shown in Figure 10-30. The three panels on the left of
Figure 10-32 are plots of the predicted regional deposition efficiencies; the
three panels on the right show the predicted regional deposition fractions
derived from the estimated efficiencies and adjusted for inhalability. The
vertical axis for the predicted deposition efficiency panels range from 0 to 1.
Although the deposition fraction is also bounded by 0 and 1, the vertical axes in
the figure are less than 1 in the TB and A regions. The top two panels of Figure
10-32 are the predicted deposition efficiency and fraction, respectively, for
the ET region. These two curves are plotted as a function of the impaction
parameter described for Equation 10-35. The middle two and lower two panels show
the predicted deposition efficiencies and fractions for the TB and A regions,
respectively. These four curves are plotted as a function of dae.
When a particle is from a monodisperse size distribution, the dae and the
MMAD are the same. If, however, the particle is from a polydisperse size
distribution, the particle cannot be described by a single dae; the average value
of the distribution, the MMAD, must be used. In the aerodynamic particle size
range, the deposition efficiency curves all increase monotonically as a function
of the independent variable (i.e., either the impaction parameter or dae) and
have both lower and upper asymptotes. The curves describing the deposition
fractions, however, have different shapes that are dependent on the respiratory
tract region. Deposition fractions in all three regions are nonmonotonic—
initially increasing as a function of particle size but decreasing as particle
sizes become larger. This is because particles that have been deposited in
proximal regions are no longer available for deposition in distal regions. As an
extreme example, if all particles are deposited in the ET region, no particles
are available for deposition in either the TB or A regions. In the ET region, the
nonmonotonic shape for fractional deposition is due to the fact that not all
particles in an ambient concentration are inhalable.
As discussed in Section 10.2, particles in an experimental or ambient
exposure are rarely all a single size but rather have some distribution in size
around an average value.
10-115
-------
Predicted Regional Deposition Efficiency Predicted Regional Deposition Fraction
1.0-1 ^_ 1.00000
> 0.8
o
c
0)
O 0.6
UJ
0.4
0.2
0.0
0.80000
0.60000
0.40000
0.20000
0.00000
10 100 1000
Impaction [((Jm)2 ml/sec]
1 10 100
Impaction [((Jm)2 ml/sec]
1000
0.0
10
Aerodynamic diameter (|jm)
Aerodynamic diameter (|jm)
1.0
0.0
0.1 1
Aerodynamic diameter (|jm)
0.1 1
Aerodynamic diameter (|jm)
10
Figure 10-32.
Comparison of regional deposition efficiencies and fractions for
the rat. A default body weight of 0.38 kg (U.S. Environmental
Protection Agency, 1994) was used in these calculations. The
fractional deposition (solid line) and inhalability (dashed line)
are shown in the upper right panel.
10-116
-------
As this distribution becomes greater, the particle is said to be polydisperse.
The empirical model of Menache et al. (1996) was developed from exposures using
essentially monodisperse particles (which are treated as though they are exactly
monodisperse). It is therefore possible to multiply the particle size
distribution function (which is customarily considered to be the lognormal
distribution) by the predicted depositions (calculated as described in
Equations 10-39 through 10-41) and integrate over the entire particle size
range. Mathematically, this calculation is performed as described by
Equation 10-44
x exp
-1/2
Gog cl - log MMAD)2
Gog of
dd,.
where log refers to the natural logarithm, [^r]p is the predicted polydisperse
fractional deposition for a given MMAD and og, and [^r]m is the predicted
monodisperse fractional deposition for particles of size dae. The limits of
integration are defined from 0 to °° but actually include only four standard
deviations (99.95% of the complete distribution). For each particle size in the
integration, [Fr]m is calculated and then multiplied by the probability of
observing a particle of that size in a particle size distribution with that MMAD
and og. Rudolf and colleagues (1988) have also investigated the effect of
polydisperse particle size distributions on predicted regional uptake of
aerosols in humans and present a more detailed discussion of these and related
issues.
As discussed by Schlesinger (1985a), there are many sources of variability
that could explain differences in predicted deposition using the model of
Menache et al. (1996) and the observed deposition data in the studies reported by
Schlesinger (1985a). However, results from the model of Asgharian et al. (1995),
based on the data reported in Schlesinger (1985a), are similar to estimates
derived using the model of Menache et al. (1996).
Data from inhalation studies, particularly chronic inhalation exposures,
are often difficult to interpret in terms of respiratory tract deposition
efficiency, because the amounts of material retained in the respiratory tract
and other body organs are often determined by complex relationships between
initial lung deposition, lung retention, subsequent organ uptake and retention,
and body uptake by ingestion of material contaminating the body surface. As an
example, review of the literature indicates that data from most inhalation
(10-44)
10-117
-------
deposition studies are not appropriate for direct comparison or model validation
with the estimates from the Menache et al. (1996) model because the data are
normalized to the deposition in or on the animal rather than to what was inhaled
(Newton and Pfledderer, 1986; Dahlback et al., 1989), used anesthetized animals
(McMahon et al., 1977; Johnson and Ziemer, 1971; Raabe et al., 1977), or used
cannulated animals (Shiotsuka et al., 1987). Berteau and Biermann (1977)
exposed female Sprague Dawley rats to an aerosol with a mass median diameter
(MMD) of 2.1 //m and a og of 2.0 for 20 minutes. These authors calculated total
deposition in 8 animals to be 28 ± 9.3%. The model of Menache et al. (1996) would
predict approximately 60% deposition, assuming the MMD = MMAD. Berteau and
Biermann (1977) noted substantially lower deposition in rats than in mice for
this same study and proposed a decrease in VE as a possible reason. Some
adjustment of VE would bring the model prediction into closer agreement with the
data. Differences in exposure such as whole-body and group housing versus nose-
only could also contribute to some of the variability. Although there is
substantial disagreement between the model prediction and the experimental
measurement for this polydisperse aerosol, it seems likely that the experimental
data are unusually low.
Dahlback and Eirefelt (1994) exposed male Sprague Dawley rats to
monodisperse fluorescent polystyrene latex microspheres ranging in size from
0.63 to 5.7 //m count median diameter. Deposition was reported as the sum of nose,
esophagus, stomach, and lung normalized to the amount deposited in the sum of
these four compartments. Menache et al. (1996) compared their model predictions
with the experimental data for all particles > 1 //m. Because the experimental
data were expressed as regional deposition normalized to total respiratory tract
deposition, the model predictions were also normalized to total predicted
respiratory tract deposition. To distinguish this presentation from
presentation of deposition fractions elsewhere in this chapter, upper
respiratory tract (URT) deposition is defined as the sum of the nose, esophagus,
and stomach deposition divided by those three compartments plus the lung for the
data of Dahlback and Eirefelt (1994); and as deposition in the ET region divided
by deposition in the sum of the ET, TB, and A regions for the predictions using the
Menache et al. (1996). Lower respiratory tract (LRT) deposition may then be
defined as
LRT deposition = 1 - URT deposition. (10-45)
10-118
-------
The experimental and model-predicted deposition fractions are shown in Figure
10-33 for the data of Dahlback and Eirefelt (1994), as well as for the data of
Raabe et al. (1988) that were used to develop the model. The solid line is the
line of identity and represents the situation in which the predicted and observed
deposition match exactly. As can be seen in Figure 10-33, there is considerable
scatter in the data, particularly in the range associated generally with
particles of about 2 to 3 //m MMAD. Under the conditions for which the model would
predict 50 to 60 percent deposition, the observed deposition for both the URT and
LRT ranges from 10 to 80 percent. As noted earlier (Figure 10-31) deposition in
rats increases very rapidly from low to high values in this range. Similarly, in
humans, regional deposition associated with particles of 2 to 3 //m ranges from 10
to 20 percent to 60 to 80 percent (Figure 10-22, 10-26, and 10-27).
10.6 CLEARANCE DATA AND MODELS
As discussed in previous sections, the biologic effects of inhaled
particles are a function of their disposition. This, in turn, depends on their
patterns of both deposition (i.e., the sites within which they initially come
into contact with airway epithelial surfaces and the amount removed from the
inhaled air at these sites) and clearance (i.e., the rates and routes by which
deposited materials are removed from the respiratory tract). Removal of
deposited materials involves the competing processes of macrophage - mediated
clearance and dissolution - absorption. Deposition and clearance mechanisms
were discussed in Sections 10.5 and 10.6, respectively.
Respiratory-tract clearance begins immediately upon deposition of inhaled
particles. Given sufficient time, the deposited particles may be completely
removed by these clearance processes. However, single inhalation exposures may
be the exception rather than the rule. It is generally accepted that repeated or
chronic exposures are common for environmental aerosols. As a result of such
exposures, accumulations of the particles may occur. Chronic exposures produce
respiratory tract burdens of inhaled particles that continue to increase with
time until the rate of deposition is balanced by the rate of clearance. This is
defined as the "equilibrium respiratory tract burden". The accumulation
patterns are unique to each
10-119
-------
1-1
£ 0.8'
o
(B
O
^ 0.6'
o
Q.
4)
Q
T3
4)
£
4)
0.4-
0.2-
• Data if Raabe et al., 1988
O Data of Dahlback & Eirefelt, 1994
model underpredic
URT = URT/(URT + LRT)
O O
^ model overpredicts
(a)
0.2 0.4 0.6 0.8
Predicted URT Deposition Fraction
5 0.8-
o
(B
LRT = LRT/(URT + LRT)
• Data if Raabe et al., 1988
O Data of Dahlback & Eirefelt, 1994
model underpredict
model overpredicts
0.4 0.6
Predicted LRT Deposition Fraction
0.8
Figure 10-33. Experimental deposition fraction data and predicted estimates
using model of Menache et al. (1996). The solid line is the line of
identity and represents the situation in which the predicted and
observed deposition match exactly.
Source: Menache et al. (1996).
10-120
-------
laboratory animal species, and possibly unique to the inhaled material,
especially if the inhaled material alters deposition and/or clearance patterns.
It is important to evaluate these accumulation patterns, especially when
assessing ambient chronic exposures, because they dictate what the equilibrium
respiratory tract burdens of inhaled particles will be for a specified exposure
atmosphere. Equivalent concentrations can be defined as "species-dependent
concentrations of airborne particles which, when chronically inhaled, produce
equal lung deposits of inhaled particles per gram of lung during a specified
exposure period". This section presents available data and approaches to
evaluating exposure atmospheres that produce similar respiratory tract burdens
in laboratory animals and humans.
10.6.1 Humans
Models for deposition, clearance, and dosimetry of the respiratory tract of
humans have been available for the past four decades and continue to evolve. The
International Commission on Radiological Protection (ICRP) has recommended
three different mathematical models during this time period (ICRP 1959, 1979,
1994). The models changed substantially in structure, expanding from two
compartments in the 1959 model (ICRP, 1959) to five compartments in the 1994
model (ICRP, 1994). These models have been an important aspect of radiation
protection programs for inhaled radioactive materials. However, they make it
possible to calculate the mass deposition and retention by different parts of the
respiratory tract and provide, if needed, mathematical descriptions of the
translocation of portions of the deposited material to other organs and tissues
beyond the respiratory tract. The structure and complexity of the ICRP models
increased with each version. These increases in complexity reflect both the
expanded knowledge of the behavior and dosimetry of inhaled materials in the
respiratory tract that has become available and an increased need for models that
can be applied to a broader range of uses.
The 1959 model (ICRP, 1959) had a very simple structure in which the
respiratory tract was divided into an upper respiratory tract (URT), and a lower
respiratory tract (LRT). No information was given on the anatomical division
between the URT and the LRT. In the 1959 model, 50% of inhaled particles
deposited in the URT, 25% deposited in the LRT, and the remaining 25% was exhaled.
No information on the effects of the sites or magnitude of
10-121
-------
particle deposition was given, and relationships between particle size,
deposition, and clearance were not incorporated into the 1959 model. The URT was
considered an air passage from which all deposited particles cleared quickly by
mucociliary activity and swallowed. Particles deposited in the LRT were
classified as soluble or insoluble. For soluble particles, chemical
constituents of all 25% of the inhaled particles that reach the LRT were assumed
to be rapidly absorbed into the systemic circulation. For poorly soluble
particles, 12.5% were assumed to clear by mucociliary activity and be swallowed
during the first 24 h following deposition. The remaining 12.5% was assumed to be
retained with a biological half-time of 120 d. No clearance of particles to the
regional lymph nodes was included in the 1959 model.
The 1979 model (ICRP, 1979) was based on the Task Group Lung Model (TGLM)
report (Morrow et al., 1966) and was divided into three compartments
(nasopharyngeal, NP; tracheobronchial, TB; and pulmonary, PU). The NP region
included anatomical structures from the tip of the nose to the larynx. The TB
region extended from the trachea to the end of the terminal bronchioles. The PU
region (equivalent to the A regional as described in Table 10-1) was the
remaining, non-ciliated pulmonary parenchyma. Deposition probabilities were
given for the NP, TB, and PU regions for activity median aerodynamic diameters
(AMAD) of inhaled particles that covered about two orders of magnitude (0.2 - 10
|im). This incorporation of particle size considerations and the AMAD concept
were major improvements in the health protection aspects of modeling related to
inhaled radioactive particles. The 1979 ICRP model also incorporated
consideration for clearance rates using three classes (D, W, Y). Class D
particles cleared rapidly (T1/2 = 0.5 d), class W particles cleared at an
intermediate rate (T1/2 = 50 d), and class Y particles cleared slowly (T1/2 = 500 d).
It was also recognized that the competing processes of dissolution-absorption
and physical clearance operated on the deposited particles, but inadequate
information was available to differentiate between the two mechanisms. This
model also included a clearance pathway to the tracheobronchial lymph nodes. The
long-term clearance of particles by either physical transport processes or by
dissolution-absorption processes are described by the same clearance half-time.
A substantial increase in knowledge about the effects of particle size on
the deposition of inhaled particles occurred since the publication of the TGLM
report (Morrow et al.,
10-122
-------
1966). This new information is reflected in the latest ICRP66 model (IRCP66,
1994). This new ICRP66 model considers the respiratory tract as four anatomical
regions. The extrathoracic (ET) region is divided into two sub-regions: the
anterior nasal airways, which clear only by extrinsic processes such as nose
blowing, defined as ETl5 and the posterior nasal passages, pharynx, mouth and
larynx defined as ET2, which clears to the gastrointestinal tract via a
combination of mucociliary action and fluid flow. The airways within the lungs
are comprised of the bronchial (BB) and bronchiolar (bb) regions, which combined
are equivalent to the Tracheobronchial (TB) region described in Table 10-3. The
division of the TB region into two parts (bronchi and bronchi olar) by the ICRP
enables mass deposition in the small airways to be evaluated separately, and
possible related to such effects as small airways constriction. The
gas-exchange tissues are defined as the alveolar-interstitial (AI) region,
which is exactly comparable to the pulmonary region or A region (see Tables 10-1
and 10-3). There are two lymph node regions; LNET drains the extrathoracic region
and LNra drains the BB, bb, and AI regions.
Deposition in the four anatomical regions (ET, BB, bb, and AI) is given as a
function of particle size covering five orders of magnitude, and two different
types of particle size parameters are used. The activity median thermodynamic
diameter (AMTD) is used to describe the deposition of particles ranging in size
from 0.0005 to 1.0 micrometer; the AMAD is used to describe deposition for the
size range of 0.1 to 100 micrometer. The model applies to hygroscopic particles
by estimating particle growth in each region during inhalation. Reference
values of regional deposition are provided, and guidance is given for
extrapolating to specific individuals and populations under different levels of
activity. Deposition is expressed as a fraction of the number or activity of
particles of a given size that is present in a volume of ambient air before
inspiration, and activity is assumed to be log-normally distributed as a
function of particle size for a typical particle density of 3 g/cm3 and dynamic
shape factor of 1.5, although particle density and shape factor are included as
variables in the deposition calculations. As discussed in Section 10.5, the 1994
ICRP66 model also includes consideration of particle inhalability, which is a
measure of the degree to which particles can enter the respiratory tract and be
available for deposition.
After deposition occurs in a given region, two different clearance
processes act competitively on the deposited particles, except in the ETX region
where the only clearance
10-123
-------
process is extrinsic. These processes are particle transport, which includes
mucociliary clearance from the respiratory tract and physical clearance of
particles to the regional lymph nodes, and absorption, which includes movement
of material to blood including both dissolution-absorption and transport of
ultra fine particles. Rates of particle clearance which were derived from
studies with human subjects are assumed to be the same for all types of particles.
Particle clearance from the BB and bb regions includes two slow phases: (1) to
account for observations of slow mucociliary clearance in humans and (2) to
account for observations of long term retention of small fractions of deposited
material in the tracheobronchial tissues of both laboratory animals and humans.
The structure for the ICRP66 1994 model is shown in Figure 10-34. A summary of the
development of the ICRP66 1994 model is provided in Appendix 10A. This includes
comparison of model predictions against the available depostion data discussed
in Section 10.5.
A considerable amount of information has accumulated relevant to the
biokinetics of inhaled radioactive materials. The radiation associated with
these materials allows relative ease of analysis to determine temporal patterns
for retention, distribution, and excretion of inhaled radioactive particles and
their constituents. Non-radioactive particles are difficult to study because
the particles and their chemical constituents are generally difficult to detect
in biological systems, tissues, and excreta. Some studies have shown that the
physicochemical forms and sites of deposition of chemical toxicants influence
clearance rates. Also, adsorption of chemicals onto particles can influence
deposition patterns and alter rates of dissolution-absorption of the particles
and their constituents. For example, vapors that would not normally reach the A
region will do so if they are adsorbed onto particles. Also, adsorption onto
particles might slow the rates at which chemicals can be absorbed into lung
tissue or the circulatory system. Amounts of inhaled material may markedly
influence clearance as a consequence of particle overload. The cytotoxicity and
shapes of particles (i.e., fibers) also influence clearance. Additionally,
metabolic products of the inhaled materials may cause pathology and disease
states that may result in nonpredictable retention and clearance patterns.
Absorption into blood is material specific, acts in all regions except ETl5
and is assumed to occur at the same rates for all regions. Absorption into blood
is a two stage process. The first step (dissolution) involves dissociation of
the particles into a form that can
10-124
-------
The ICRP 1994 Human Respiratory Tract Model
o
*—k
to
Anterior
Nasal
(ET,)
Naso-
Oropharynx/
Larynx
(ET2)
Bronchi
(BB)
Bronchioles
(bb)
Alveolar
Interstitium
(Al)
Extrathoracic
^^^_^^^i
Surface
/
1
,
Lymp
Node
" 4 Pnitholium
oequesiereu /
in Tissue /
(Airway Wall) /
* / »S
L
y
m
P
h
N
o
d
e
s
* — EpitheliurrJ Slow
/ ^/
* — ^EpitheliurrJ Slow
Thoracic
JFast ^
a
Cleared
by Mucus
i
Fast
£
/
t___^_^.
/
1
Fast
T/T /T,
/
=
-------
be absorbed into blood; the second step involves absorption of the subunits of
the particles. Because these processes act independently on the regionally
deposited particles, each can be specified separately and allowed to compete
against the other processes involved in the model. This approach makes it
possible to use time-dependent functions to describe processes such as
dissolution-absorption. However, for ease of calculation it is assumed that
time dependent dissolution can be approximated by dividing the material into two
fractions with different dissolution rates: material in an initial state
dissolves at a constant rate, simultaneously changing to a transformed state in
which it dissolves at another rate. Uptake into blood is treated as
instantaneous for the material immediately absorbed after dissolution. Another
fraction of dissolved material may be absorbed more slowly as a result of binding
with tissue components. The model can use observed rates of absorption for
compounds for which there are reliable human or laboratory animal data. The
absorption of other compounds are specified as fast, moderate or slow. In the
absence of specific information, compounds are classified as fast, moderate or
slow according to their former classification as D, W or Y, respectively, under
the previous ICRP model. Greater attention to the transfer of particles to
regional lymph nodes is given in this model than in the 1979 model by
incorporating these clearance processes at each level in the respiratory tract,
not just in the A or pulmonary region as in the 1979 model. Additionally, while
the new ICRP66 model (ICRP66, 1994) was developed primarily for use with airborne
radioactive particles and gases, its use for describing the dosimetry of inhaled
mass of non-radioactive substances is also appropriate.
An alternative new respiratory tract dosimetry model that developed
concurrently with the new ICRP model is being proposed by the National Council on
Radiation Protection (NCRP). This model was described in outline by Phalen et
al. (1991) and at the time of writing, a full report of the model is undergoing
final approval by the NCRP. As with the 1994 ICRP66 model (ICRP66, 1994), the
proposed NCRP model addresses (1) inhalability of particles, (2) new sub-regions
of the respiratory tract, (3) dissolution-absorption as an important aspect of
the model, and (4) body size (and age). The proposed NCRP model defines the
respiratory tract in terms of a naso-oro-pharyngo-laryngeal (NOPL) region, a
tracheobronchial (TB) region, a pulmonary (P) region, and the lung-associated
lymph nodes (LN). As with the 1994 ICRP66 model, inhalability of aerosol
particles is considered, and
10-126
-------
deposition in the various regions of the respiratory tract is modeled using
methods that relate to mechanisms of inertial impaction, sedimentation, and
diffusion. The rates of dissolution-absorption of particles and their
constituents are derived from clearance data from humans and laboratory animals.
The effect of body growth on particle deposition is also considered in the model,
but particle clearance rates are assumed to be independent of age. The NCRP model
does not consider the fate of inhaled materials after they leave the respiratory
tract. Although the proposed NCRP model describes respiratory tract deposition,
clearance, and dosimetry for radioactive substances inhaled by humans, the model
can also be used for evaluating inhalation exposures to all types of particles.
Both the NCRP and ICRP had the benefit of contributions from respected
investigators in respiratory tract toxicology and biomedical aerosol research.
Similar mathematical assessments were arrived at by both commissions, although
detailed calculations for specific radionuclides can be different. Comparison
of regional deposition fraction predictions between the two models are shown in
Figures 10-35 through 10-37. As noted above, the various compartments of the two
models are equivalent. That is, the ET region as described in Table 10-3 is
equivalent to the ETX plus ET2 compartments of the ICRP66 1944 model and the NOPL
compartment of the proposed NCRP model. The TB region of Table 10-3 is equivalent
to the BB plus bb compartments of the ICRP66 1994 model and to the TB compartment
of the proposed NCRP model. The A region of Table 10-3 is equivalent to the AI
compartment of the ICRP66 1994 model and to the P compartment of the proposed NCRP
model. These differences in nomenclature are retained in these figures to aid
distinguishing the predictions from each. Figures 10-35 and 10-36 show
predictions for an adult male during mild exercise and at rest. Figure 10-37
shows predictions for a 5-year old child. These comparisons show that the
behavior of the models are quite comparable, that is, the predicted deposition
fraction for a given particle size is similar if the models use the same
ventilation parameters as input. In fact, in order to insure a uniform course of
action that provides a coherent and consistent international approach, the NCRP
recommends adoption of the ICRP66 1994 model for calculating exposures for
radiation workers and the public (e.g., for computing annual reference levels of
intake and derived reference air concentrations).
10-127
-------
0.001 0.01 0.1 1
Particle Diameter (\tn)
10
100
0.001
0.01 0.1 1 10
Particle Diameter (urn)
100
— NCRP Draft Model
ICRP66 (1994) Model
Figure 10-35.
Comparison of regional deposition fractions predicted by the proposed
National Council on Radiation Protection (NCRP) model with those of
the International Commission on Radiological Protection (ICRP)
Publication 66 (1994) model. Predictions are for unit density,
spherical particles inhaled through the nose by an adult male with a
tidal volume of 1250 mL, respiratory frequency of 20 min"1, and
functional residual capacity (FRC) of 3300 mL. See text for an
explanation of abbreviations for respiratory tract compartments.
10-128
-------
0.001
0.01 0.1 1
Particle Diameter (im)
10
100
0.001
0.01 0.1
Particle Diameter
10
100
NCRP Draft Model ICRP66 (1994) Model
Figure 10-36.
Comparison of regional deposition fractions predicted by the proposed
National Council on Radiation Protection (NCRP) model with those of
the International Commission on Radiological Protection (ICRP)
Publication 66 (1994) model. Predictions are for unit density,
spherical particles inhaled through the nose by an adult male with a
tidal volume of 750 mL, respiratory frequency of 12 min"1, and
functional residual capacity (FRC) of 3300 mL. See text for an
explanation of abbreviations for respiratory tract compartments.
10-129
-------
0.001 0.01 0.1 1
Particle Diameter dm)
10
100
0.001
0.01 0.1 1
Particle Diameter (urn)
10
100
NCRP Draft Model ICRP66 (1994) Model
Figure 10-37.
Comparison of regional deposition fractions predicted by the proposed
National Council on Radiation Protection (NCRP) model with those of
the International Commission on Radiological Protection (ICRP)
Publication 66 (1994) model. Predictions are for unit density,
spherical particles inhaled through the nose by a 5-year-old child with
a tidal volume of 244 mL, respiratory frequency of 39 min"1, and
functional residual capacity (FRC) of 767 mL. See text for an
explanation of abbreviations for respiratory tract compartments.
10-130
-------
10.6.2 Laboratory Animals
Several laboratory animal models have been developed to help interpret
results from specific studies that involved chronic inhalation exposures to non-
radioactive particles (Wolff et al., 1987; Strom et al., 1988; Stober et al.,
1994). These models were adapted to data from studies involving high level
chronic inhalation exposures in which massive lung burdens of low toxicity,
poorly soluble particles were accumulated and the models have not been adapted to
chronic exposures to low concentrations of aerosols in which particle overload
does not occur.
Snipes et al. (1983) adapted a materials balance simulation model to
evaluate repeated or chronic inhalation exposures. The simulation model
language for a single inhalation exposure was described by Pritsker (1974) and
uses a Fortran-based numerical integration of differential equations. The
integration method is a fourth order, variable step-size Runge-Kutta-England
routine for integrating systems of first order ordinary differential equations
with initial values. The model was used to describe the retention and clearance
of poorly soluble aerosol inhaled by mice, rats, and dogs (Snipes et al., 1983)
and guinea pigs (Snipes et al., 1984). A distinct advantage of this kind of model
is the requirement that dissolution-absorption rates for particles retained in
the respiratory tract are approximated as part of the modeling process. The
model output includes an estimate of the pulmonary burden of dust for each day of
interest following an inhalation exposure.
Compartments and pathways of the model used in this chapter were kept as
simple as necessary and were limited to those associated with the alveolar region
of the respiratory tract. Figure 10-38 depicts the model, where
D(t) = alveolar deposit of aerosol particles at time t (|ig/g lung);
MP(t) = mechanical transfer rate (fraction/day) for particles from the
alveolar region to the mucociliary escalator for clearance to the
gastrointestinal tract;
ML(t) = mechanical transfer rate (fraction/day) for particles from the
alveolar region to the thoracic lymph nodes;
S(t) = dissolution-absorption rate (fraction/day) for particles in the
alveolar region or thoracic lymph nodes.
10-131
-------
Airborne Particles
MP(t)
-^
Alveolar Region
S(t)
•»-
ML(t)
Thoracic Lymph
Nodes
S(t)
Figure 10-38.
Compartments of the simulation model used to predict alveolar
burdens of particles acutely inhaled by mice, hamsters, rats,
guinea pigs, monkeys, and dogs. Definitions for parameters are
provided in the text.
The retention of particles in the alveolar region as a function of time after
a single inhalation exposure is described by
dD(t)/dt = -D(t)-[MP(t) + ML(t)
(10-46)
with appropriate initial conditions for a single inhalation exposure. The
solution of differential equations in the GASP IV simulation language is based
upon numerical analysis techniques which adapt to produce solutions to a
prespecified accuracy on either an absolute or relative scale. To maintain the
specified accuracy the algorithm adjusts the size of the time step, making the
step smaller or larger depending upon the estimated error. If the algorithm
detects that the error is growing too large, it goes back to an earlier time and
proceeds with smaller steps.
The simulation models for acute exposures were adapted to chronic exposures
for the selected species using the assumption that each individual exposure
during a chronic exposure
10-132
-------
is the same with regard to deposition and clearance kinetics. Chronic exposures
were simulated by defining the exposure duration in days and summing the amounts
of dust retained in the lung from each daily inhalation exposure throughout the
defined chronic exposure period. The model for chronic inhalation exposures
therefore simply integrated the results of the individual exposures to predict
the burdens of dust in the alveolar region during the course of the chronic
exposures.
This model adequately accounted for the observed lung burdens of diesel
exhaust particles (DEP) achieved in rats over the course of a 2-year chronic
inhalation exposure to 0.35 mg DEP/m3 (Snipes, 1989). The specific lung burdens
of DEP achieved in the rats during the 2-year study were about 0.4 mg DEP/g lung,
which is less that the amount that is generally predicted to cause particle
overload. This model, and alternatives that are easily adapted to inhalation
exposure scenarios, appears to be useful for predicting alveolar clearance
patterns for a variety of inhaled materials as long as exposure concentrations
are reasonably low and particle overload has not occurred.
10.6.3 Species Similarities and Differences
Rates for particle translocation from the A region to thoracic lymph nodes
(TLNs) appear to vary considerably among species. Rats and mice have particle
translocation rates from the A region to TLNs that are quite different from those
of guinea pigs, dogs, and possibly humans (Snipes et al., 1983; 1984).
Translocation from the A region to TLNs begins soon after an acute inhalation
exposure. However, after a few days following the acute exposure, the transport
of particles from the A region to TLNs appears to be negligible in mice and rats
(Snipes et al., 1983), but continues at a constant rate in guinea pigs and dogs
(Snipes et al., 1983; 1984). No experimental information is available about the
rates of translocation of particles from the A region to TLNs in humans. However,
data for amounts of particles accumulated in the lungs of humans exposed
repeatedly to dusty environments (Stober et al., 1967; Carlberg et al., 1971;
Mclnroy et al., 1976; Cottier et al., 1987) suggest that poorly soluble particles
accumulate in TLNs of humans at rates that may be comparable to those observed for
guinea pigs, dogs, and monkeys. However, based on human autopsy data for
particles found in thoracic lymph nodes and lung tissue, the ICRP (1994)
determined a transport rate for particle from lung to lymph nodes that would
result in
10-133
-------
a lymph node/lung particle concentration ratio of 20 at 10,000 days after
inhalation. The transport rate was 2 x 10"5/day, i.e., lower than the rate for
dogs and monkey by approximately a factor often.
Physical movement of particles from the A region to the TLNs affords the
opportunity to transport particles out of the lung, but the result is to
sequester, or trap the particles in what is generally perceived to be a dead-end
compartment. Because the TLNs represent traps for particles cleared from the
lung, particles can accumulate to high concentrations in the TLNs. Thomas (1968,
1972) discussed the implications of particle translocation from the A region to
TLNs when the particles contain specific radionuclides, but he presented
information that is relevant to all types of particles. Translocation of
particles from the A region to the TLNs results in concentrations of particles in
the lymph nodes that can be more than 2 orders of magnitude higher than
concentrations in the lung. The implications of this consequence of inhalation
exposures have not been fully evaluated but may have important implications for
immunological responses in humans exposed to specific kinds of aerosols.
Many measurements of alveolar retention and clearance have been conducted
on humans and a variety of laboratory animal species. In some cases, at least two
laboratory animal species were exposed to the same aerosolized material, so
direct comparisons among species are possible. Few human inhalation exposure
studies have been performed using the same materials as used for the laboratory
animal studies. Therefore, only a limited number of direct comparisons are
possible between laboratory animals and humans.
Table 10-13 contains a summary of selected results for alveolar retention of
inhaled materials after single inhalation exposures to small masses of poorly
soluble particles. Studies of less than about 3 mo duration were not included.
The variability in these results was caused by several factors. In many cases,
the reported results did not allow division of the alveolar burden between short-
and long-term clearance. Also, for most studies, dissolution-absorption of the
exposure materials were not known or were not reported. The broad range of
particle sizes would have influenced deposition patterns, and
dissolution-absorption rates, but probably not physical clearance of particles
from the A region. The alveolar burden as a function of time in days after acute
inhalation is given by
10-134
-------
TABLE 10-13. COMPARATIVE ALVEOLAR RETENTION PARAMETERS FOR POORLY SOLUBLE
PARTICLES INHALED BY LABORATORY ANIMALS AND HUMANS
Species
Mouse
Hamster
Rat
Guinea pig
Aerosol
Matrix
FAP
FAP
FAP
Ru oxide
Pu oxide
FAP
Diesel soot
FAP
FAP
FAP
FAP
FAP
FAP
Asbestos
fibers
Latex
Pu oxide
Pu oxide
U02
U308
Co304
FAP
Diesel soot
Latex
Particle Size3
(jm
0.7
1.5
2.8
0.38
0.2
1.2
0.12
1.25
0.7
1.5
2.8
1.2
1.4
1.2-2.3
3.0
<1.0
2.5
2.7-3.2
-1-2
2.69
2.0
0.12
3.0
Measure
AMAD
AMAD
AMAD
CMD
CMD
CMD
MMAD
CMD
AMAD
AMAD
AMAD
AMAD
AMAD
AMAD
CMD
CMD
AMAD
AMAD
CMD
MMAD
AMAD
MMAD
CMD
P
d 0.93
0.93
0.93
0.88
0.86
0.73
0.37
0.62
0.91
0.91
0.91
0.83
0.76
0.39
0.20
0.75
0.67
0.70
0.22
Alveolar Burdenb
T,(d)
34
35
36
28
20
50
6
20
34
35
36
33
26
18
20
30
20
19
29
P,
0.07
0.07
0.07
e 0.12
0.14
0.27
0.63
0.38
0.09
0.09
0.09
0.17
0.24
1.00
0.61
0.80
0.25
1.00
0.33
0.30
0.78
1.00
1.00
T,(d)
146
171
201
230
460
220
80
180
173
210
258
310
210
46-76
63
180
250
247
500
125
385
>2,000
83
Study
Duration
(days)
850
850
850
490
525
463
33fO
492
850
850
850
365
180
101-171
190
350
800
720
768
180
1100
432
190
References
Snipes etal. (1983)
Snipes et al. (1983)
Snipes etal. (1983)
Bair (1961)
Bair (1961)
Bailey etal. (1985a)
Lee etal. (1983)
Bailey etal. (1985b)
Snipes etal. (1983)
Snipes etal. (1983)
Snipes etal. (1983)
Finch etal. (1994)
Finch etal. (1995)
Morgan etal. (1977)
Snipes etal. (1988)
Langham(1956)
Sanders etal. (1976)
Moms etal. (1990)
Galibin and Parfenov
(1971)
Kreyling et al. (1993)
Snipes etal. (1984)
Lee etal. (1983)
Snipes etal. (1988)
-------
TABLE 10-13 (cont'd). COMPARATIVE ALVEOLAR RETENTION PARAMETERS FOR POORLY SOLUBLE
PARTICLES INHALED BY LABORATORY ANIMALS AND HUMANS
Species
Dog, (cont'd)
Monkey
Human
Aerosol
Matrix
Coal dust
Coal dust
Ce oxide
FAP
FAP
FAP
FAP
FAP
Nb oxide
Pu oxide
Pu oxide
Pu oxide
Pu oxide
Pu oxide
Pu oxide
Pu oxide
Pu oxide
Tantalum
U3o8
Zr oxide
Pu oxide
Pu oxide
FAP
FAP
Particle
(jm
2.4
1.9
0.09-1.4
2.1-2.3
0.7
1.5
2.8
2.01
1.6-2.5
1-5
4.3
1.1-4.9
0.1-0.65
0.72
1.4
2.8
4.3
4.0
0.3
2.0
2.06
1.6
1
4
Size
Measure
MMAD
MMAD
MMD
AMAD
AMAD
AMAD
AMAD
AMAD
AMAD
CMD
MMD
MMAD
CMD
AMAD
AMAD
AMAD
MMD
AMAD
CMD
AMAD
CMAD
AMAD
CMD
CMD
Alveolar Burden
P
0.09
0.15
0.15
0.15
0.05
0.10
0.10
0.32
0.22
0.50
0.40
0.47
0.14
0.27
T,(d)
13
20
21
21
~1
200
3.9
87
32
20
1.9
4.5
40
50
P,
1.00
1.00
1.00
0.91
0.85
0.85
0.85
0.95
1.00
1.00
1.00
0.90
0.90
0.68
0.78
0.50
0.60
0.53
1.0
1.0
1.0
0.86
0.73
T,(d)
1,000
«700
8 >570
440
257
341
485
910
>300
1,500
300
400
1,000
680
1,400
1,800
1,600
860
120
340
500-900
770-1,100
350
670
b Study
Duration
(days)
160
301-392
140
181
850
850
850
1,000
128
280
300
468
~ 4,000
730
730
730
270
155
127
128
200
990
372-533
372-533
References
Gibbet al. (1975)
Morrow and Yuile (1982)
Stuart etal. (1964)
Boecker and McClellan,
(1968)
Snipes etal. (1983)
Snipes etal. (1983)
Snipes etal. (1983)
Kreylmg et al. (1988)
Cuddihy (1978)
Bair (1961)
Bairetal. (1962)
Morrow etal. (1967)
Park etal. (1972)
Guilmette et al. (1984)
Guilmette et al. (1984)
Guilmette et al. (1984)
Bair and McClanahan (1961)
Bianco etal. (1974)
Fish (1961)
Waligora(1971)
Nolibeetal. (1977)
LaBauveetal. (1980)
Bailey etal. (1985a)
Bailey etal. (1985a)
-------
TABLE 10-13 (cont'd). COMPARATIVE ALVEOLAR RETENTION PARAMETERS FOR POORLY SOLUBLE
PARTICLES INHALED BY LABORATORY ANIMALS AND HUMANS
Species
Human,
(cont'd)
Aerosol
Matrix
Latex
Latex
Pu oxide
Graphite and
Pu02
Pu oxide
Th oxide
Teflon
Zr oxide
Particle
(jm
3.6
5
0.3
6
<4-5
<4-5
4.1
2.0
Size
Measure
CMD
CMD
MMD
AMAD
CMD
CMD
CMD
AMAD
Alveolar Burden
P T,(d) P9
0.2 30 0.73
7
0.4 0.5 0.58
2
1.00
1.00
1.00
1.00
0.3 4.5-45 0.70
0
1.00
T2(d)
296
150-300
240
240-290
1,000
300-400
200-2,500
224
b Study
Duration
(days)
^480
160
300
566
427
427
300
261
References
Bohning et al.
(1982)
Booker et al. (1967)
Johnson et al.
(1972)
Ramsden et al.
(1970)
Newton (1968)
Newton (1968)
Philipson et al.
(1985)
Waligora(1971)
aSome aerosols were monodisperse, but most were poly disperse, with geometric standard deviations in the range of 1.5 to 4.
bAlveolar burden = P1-e"(ln2:"/Ti + P2-e"(ln2:"/T2, where Pj and P2 are fractions constrained to total 1.00, Tj and T2 equal retention half-times in (d),
and
t equals days after exposure. Retention half-times are approximations and are the net result of dissolution-absorption and physical
clearance
processes. In some examples, the original data were subjected to a computer curve-fit procedure to derive the values for Pj and Tj presented
in this table.
TAP = fused aluminosilicate particles.
dAMAD = activity median aerodynamic diameter.
eCMD = count median diameter.
fMMAD = mass median aerodynamic diameter.
8MMD = mass median diameter.
-------
. -(ln2)t/T +P ' 6-(ln2)t/T2,
l c 2
(10-47)
where Px and P2 are fractions constrained to total 1.0, Tj and T2 equal retention
half-times in days, and t equals days after acute exposure.
The information shown in Table 10-13 was used to approximate biological
clearance rates for particles inhaled by the species listed in Table 10-14. In
addition, approximations are included for the fractions of alveolar burdens
initially deposited in the A region that were subjected to short- or long-term
clearance. These trends clearly will not apply to all types of inhaled
particles. For example, in some cases, deposition and clearance may be
influenced by the physicochemical and/or biological characteristics of the
inhaled material. Further, the generalizations that led to Table 10-14 allow
comparisons for the consequences of chronic inhalation exposures among these
animal species and humans that might not otherwise be possible.
TABLE 10-14. AVERAGE ALVEOLAR RETENTION PARAMETERS
FOR POORLY SOLUBLE PARTICLES INHALED BY SELECTED
LABORATORY ANIMAL SPECIES AND HUMANS
Alveolar Retention Parameters"
Species
Mouse
Rat, Syrian hamster
Guinea pig
Monkey, dog, human
P,
0.9
0.9
0.2
0.3
T,
30
25
29
30
P,
0.1
0.1
0.8
0.7
T2
240
210
570
700
^Alveolar burden (fraction of initial deposition) =
(-ln2)t/T
where:
Pj and P2 = fractions of alveolar burden in fast and slow-clearing components;
Tj and T2 = retention half-times (days) for Pj and P2; and
t = time in days after an acute inhalation exposure.
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The mathematical expressions for fitting curves to data are dependent on the
study duration. The values for percent initial alveolar burden (% IAB) versus
time in the following table were obtained by simulating alveolar retention of
poorly soluble particles in the rat using the physical clearance rates from
Table 10-14. Two-component exponential curves were next fit for % IAB versus
time using the model results for days 1 to 150, 1 to 300, and 1 to 730. As
indicated in Table 10-15, the curve fitting parameters for the data for days 1 to
150 agree well with results typically seen in relatively short-term alveolar
clearance studies with rats.
TABLE 10-15. PHYSICAL CLEARANCE RATES
Days
1
7
14
28
35
42
49
56
63
70
100
150
200
250
300
400
500
600
730
%IAB P, T, P2 T2
96.96
81.21
66.89
47.00
40.03
34.43
29.87
26.14
23.06
20.49
13.26
7.80 71.6 18.4 29.4 78.3
5.39
4.10
3.30 84.4 22.0 15.6 131
2.36
1.78
1.37
0.99 91.0 25.6 9.0 221
Physical clearance patterns for alveolar burdens of particles are similar
for guinea pigs, monkeys, dogs, and humans. For these species, about 20 to 30% of
the initial burden of particles clears with a half-time on the order of 1 mo, the
balance clears with a half-time of several hundred days. Mice, Syrian hamsters,
and rats clear about 90% of the deposited
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particles with a half-time of about 1 month and 10% with a half-time greater than
100 days. The relative division of the alveolar burden between short-term and
long-term clearance represents a significant difference between most rodents
and larger mammals and has considerable impact on long-term patterns for
retention of material acutely inhaled, as well as for accumulation patterns for
materials inhaled in repeated exposures.
10.6.4 Models To Estimate Retained Dose
Models have routinely been used to express retained dose in terms of
temporal patterns for alveolar retention of acutely inhaled materials.
Available information for a variety of mammalian species and humans can be used
to predict deposition patterns in the respiratory tract for inhalable aerosols
with reasonable degrees of accuracy. Additionally, as indicated above, alveolar
clearance data for mammalian species commonly used in inhalation studies are
available from numerous experiments that involved small amounts of inhaled
radioactive particles. The amounts of particles inhaled in those studies were
small and can be presumed to result in clearance patterns characteristic of the
species unless radiation damage was a confounding factor, which was probably not
the case except where acute effects were an experimental objective.
A very important factor in using models to predict retention patterns in
laboratory animals or humans is the dissolution-absorption rate of the inhaled
material. Factors that affect the dissolution of materials or the leaching of
their constituents in physiological fluids, and the subsequent absorption of
these constituents, are not fully understood. Solubility is known to be
influenced by the surface-to-volume ratio and other surface properties of
particles (Mercer, 1967; Morrow, 1973). The rates at which dissolution and
absorption processes occur are influenced by factors that include chemical
composition of the material. Temperature history of materials is an important
consideration for some metal oxides. For example, in controlled laboratory
environments, the solubility of oxides usually decreases when the oxides are
produced at high temperatures, which generally results in compact particles
having small surface-to-volume ratios. It is sometimes possible to accurately
predict dissolution-absorption characteristics of materials based on
physical/chemical considerations. However, predictions for in vivo
dissolution-absorption rates for most materials, especially if they contain
multivalent cations or anions, should be confirmed experimentally.
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Phagocytic cells, primarily macrophages, clearly play a role in
dissolution-absorption of particles retained in the respiratory tract
(Kreyling, 1992). Some particles dissolve within the phagosomes due to the
acidic milieu in those organelles (Lundborg et al., 1984, 1985), but the
dissolved material may remain associated with the phagosomes or other organelles
in the macrophage rather than diffuse out of the macrophage to be absorbed and
transported elsewhere (Cuddihy, 1984). Examples of delayed absorption of
presumably soluble inorganic materials are beryllium (Reeves and Vorwald, 1967)
and americium (Mewhinney and Griffith, 1983). This same phenomenon has been
reported for organic materials. For example, covalent binding of benzo(a)pyrene
or metabolites to cellular macromolecules resulted in an increased alveolar
retention time for that compound after inhalation exposures of rats (Medinsky
and Kampcik, 1985). Certain chemical dyes are also retained in the lung
(Medinsky et al., 1986), where they may dissolve and become associated with
lipids or react with other constituents of lung tissue. Understanding these
phenomena and recognizing species similarities and differences are important
for evaluating alveolar retention and clearance processes and interpreting
results of inhalation studies.
In one study related to the issue of species differences in dissolution-
absorption, Oberdorster et al. (1987) evaluated clearance of 109Cd from the lungs
of rats and monkeys after inhalation of 109Cd-labeled aerosols of CdCl2 and CdO.
The inhaled Cd was cleared 10 times faster from lungs of the rats than from the
lungs of monkeys. Cadmium in the lungs of mammalian species is probably bound to
metallothionein, and these differences in rates of Cd clearance appear to be the
result of species differences in metallothionein metabolism. Bailey et al.
(1989) conducted a study that included an interspecies comparison of the
translocation of 57Co from the A region to blood after inhalation of "COjC^. The
results of this multi-species study suggest that mammalian species demonstrate
considerable variability with regard to rates of dissolution of particles
retained in lung tissue, degree of binding of solubilized materials with
constituents of lung tissue, and rates of absorption into the circulatory
system.
Dissolution-absorption of materials in the respiratory tract is clearly
dependent on the chemical and physical attributes of the material. While it is
possible to predict rates of dissolution-absorption, it is prudent to
experimentally determine this important clearance parameter to understand the
importance of this clearance process for the lung, TLNs,
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and other body organs that might receive particles or fibers, or their
constituents which enter the circulatory system from the lung.
10.6.4.1 Extrathoracic and Conducting Airways
Insufficient data are available to adequately model long-term retention of
particles deposited in the conducting airways of any mammalian species. It is
probable that some particles that deposit in the airways of the head and TB region
during an inhalation exposure are retained for long times and may represent
significant dosimetry concerns. Additionally, some of the particles that are
cleared from the A region via the mucociliary transport pathway may become
trapped in the TB epithelium during their transit through the airways.
Additional research must be done to provide the information needed to properly
evaluate retention of particles in conducting airways.
Based on the results of longitudinal studies of dogs who inhaled promethium
oxide particles, Stuart (1966) concluded that some particles were retained for
relatively long times in the heads. A study by Snipes et al. (1983) included
mice, rats, and dogs exposed by inhalation to monodisperse or polydisperse
134Cs-labeled fused aluminosilicate particles. In all three species, 0.001 to 1%
of the initial internally deposited burden of particles was retained in the head
airways and was removed only by dissolution-absorption. Tissue autoradiography
revealed that retained particles were in close proximity to the basement
membrane of nasal airway epithelium. In another study by Snipes et al. (1988),
3-, 9-, and 15-|im latex microspheres were inhaled by rats and guinea pigs. About
1 and 0.1% of all three sizes of microspheres were retained in the head airways of
the rats and guinea pigs, respectively. For rats, the 9- and 15-|im microspheres
cleared with half-times of 23 days; for guinea pigs, microspheres of this size
cleared with half-times of about 9 days. The 3-|im microspheres were cleared from
the head airways of the rats and guinea pigs with biological half-times of 173 and
346 days, respectively. The smaller particles are apparently more likely to
penetrate the epithelium and reach long-term retention sites.
Whaley et al. (1986) studied retention and clearance of radiolabeled, 3-|im
polystyrene latex particles instilled onto the epithelium of the maxillary and
ethmoid turbinates of Beagle dogs. Retention of the particles at both sites
after 30 days was about 0.1% of the amount
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initially deposited. Autoradiographs of turbinate tissue indicated that the
particles were retained in the epithelial submucosa of both regions.
It is also generally concluded that most inhaled particles that deposit in
the TB region clear within hours or days. However, results from a number of
studies in recent years challenge this supposition. These studies have
demonstrated that small portions of the particles that deposit in, or are cleared
through, the TB region are retained with half-times on the order of weeks or
months. Patrick and Stirling (1977) noted that about 1% of barium sulfate
particles instilled intratracheally into rats remained in the bronchial tissue
for at least 30 days. In a followup study, Stirling and Patrick (1980) used
autoradiography to demonstrate the temporal retention patterns for some of the
retained 133BaSO4 particles in TB airways. The particles were retained within
macrophages in the tracheal wall for at least 7 days after intratracheal
instillation of 133BaSO4. By two h after instillation, some of the particles were
buried in the tracheal wall. After 24 h, when most of the initial deposition of
particles had cleared, 74% of 133BaSO4 particles located by autoradiography were
in macrophages proximate to the basement membrane. After 7 days, practically all
of the remaining particles were incorporated into the walls of the airways. The
authors did not determine the mechanisms by which the particles were moved into
the airway epithelium. It is possible that the particles were phagocytized by
macrophages and transported into the airway epithelium. Another possibility is
direct uptake by epithelial cells of the airways. It is also probable that
intratracheal instillation procedures perturb airway epithelium and influence
the results of these kinds of studies.
Gore and Thorne (1977) exposed rats by inhalation to polydisperse aerosols
of UO2. At 2, 4, 7, and 35 days after inhalation of the UOj, autoradiography was
used to determine the locations of particles retained in the TB and A regions.
The authors did not report seeing particles of UO2 retained in the airways, but
did note two phases of clearance. The first phase was associated with a clearance
half-time of 1.4 days, the second phase with a clearance half-time of about 16
days. The faster clearance was presumably associated with particles deposited
on the conducting airways during the inhalation exposure; the longer-term
clearance was associated with clearance of UO2 particles from the A region. In a
separate study, Gore and Patrick (1978) evaluated the distribution of UO2
particles in the trachea and bronchi of rats for up to 14 days after inhalation of
aerosols similar to those used by Gore
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and Thorne (1977). Retention of UO2 at airway bifurcations was noted, as was
retention of particles in the trachea.
In another study, Gore and Patrick (1982) also compared the retention sites
of inhaled UO2 particles and intratracheally instilled barium sulphate
particles. Both types of particles were found in macrophages at sites near the
basement membrane of the airways of the TB region. The macrophages appeared to
have engulfed the particles in the airways, then passed through the airway
epithelium and remained in the vicinity of the basement membrane. About 4% of the
UO2 in lungs of rats was associated with intrapulmonary airways (Gore, 1983;
Patrick, 1983). Watson and Brain (1979) observed similar results with aerosols
of gold colloid and iron oxide. Both types of particles were found in bronchial
epithelium, but more of the iron oxide was observed, suggesting a possible
particle size effect, or a relationship between the process of material uptake
and chemical composition of the material. Both types of particles were found in
bronchial epithelial cells, but neither gold nor iron oxide particles were seen
in interstitial macrophages.
In another inhalation study, Briant and Sanders (1987) exposed rats to 0.7
fj-m AMAD chain-aggregate aerosols of U-Pu. These authors observed retained
particles of U-Pu in the larynx, trachea, carina, and bronchial airways
throughout the course of their 84-day study. The amounts retained varied, but
were at any time approximately 1% of the concurrent alveolar burden. The
alveolar burden of U-Pu cleared with a biological half-time of 100 days, and the
relative amounts of U-Pu in the airways suggested comparable particle clearance
rates from the airways. Particles of U-Pu retained in the airways were located in
epithelial cells.
Stahlhofen et al. (1981, 1986) conducted inhalation studies with humans to
directly assess deposition and retention of poorly soluble particles that
deposit in the TB region by inhalation. Human subjects inhaled small volumes of
aerosols using procedures that theoretically allowed deposition to occur at
specific depths in the TB region, but not in the A region. Results of those
studies suggested that as much as 50% of the particles that deposited in the TB
region clear slowly, presumably because they become incorporated into the airway
epithelium. Smaldone et al. (1988) reported the results from gamma camera
imaging analyses of aerosol retention in normal and diseased human subjects, and
also suggested that particles deposited on central airways of the human lung do
not completely
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clear within 24 h. There have also been a few reports indicating that poorly
soluble particles associated with cigarette smoke are retained in the epithelium
of the tracheobronchial tree of humans (Little et al., 1965; Radford and Martell,
1977; Cohen et al., 1988). The cumulative results of these studies strongly
suggest that a portion of particles that deposit on the conducting airways can be
retained for long periods of time, or indefinitely.
Long-term retention and clearance patterns for radioactive particles that
deposit in the head airways and TB region must be thoroughly evaluated because of
the implications of this information for respiratory tract dosimetry and risk
assessment (James et al., 1991; Johnson and Milencoff, 1989; Roy, 1989; ICRP,
1994). Similar concerns exist for non-radioactive particles that might be
cytotoxic or elicit inflammatory, allergic, or immune responses at or near
retention sites in conducting airways.
10.6.4.2 Alveolar Region
Model projections are possible for the A region using the cumulative
information in the scientific literature relevant to deposition, retention, and
clearance of inhaled particles. Table 10-16 summarizes reasonable
approximations for physical alveolar clearance parameters for six laboratory
animal species. Alveolar clearance curves produced using the parameters in
Table 10-16 agree with curves produced using the parameters in Table 10-14. An
advantage to using the parameters in Table 10-16 is that they separate physical
clearance from the A region into its two components, physical clearance via the
mucociliary clearance pathway to the GI tract and clearance to TLNs. To model the
biokinetics of a specific type of particle in the A regions of these laboratory
animal species, the physical clearance parameters in Table 10-16 were used in
conjunction with a dissolution-absorption parameter to derive rates for
effective clearance from the A region. As explained below, biokinetic modeling
for particles deposited in the A region of humans was done using the new ICRP66
respiratory tract model (ICRP66, 1994). To model the alveolar biokinetics of a
specific type of particle, the physical clearance parameters in Table 10-16 are
used in conjunction with a dissolution-absorption parameter to derive rates for
effective clearance from the A region.
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TABLE 10-16. PHYSICAL CLEARANCE RATES3 FOR MODELING
ALVEOLAR CLEARANCE OF PARTICLES INHALED BY
SELECTED MAMMALIAN SPECIES
Clearance via Mucociliary Clearance to Thoracic
Species Transport Pathway Lymph Nodes
Mouseb 0.023 exp'0'0081 + 0.0013 0.0007 exp'0'51
Ratb, Syrian hamster0 0.028 exp'0'0" + 0.0018 0.0007 exp'0'51
Guinea pigb 0.007 exp'0'031 + 0.0004 0.00004
Monkeyd, dogb 0.008 exp'a°22t + 0.0001 0.0002
Traction of existing alveolar burden physically cleared per day.
bAdapted from Snipes (1989)
°Clearance rates assumed to be the same as for rats.
dClearance rates assumed to be the same as for dogs.
10.7 APPLICATION OF DOSIMETRY MODELS TO DOSE-RESPONSE
ASSESSMENT
For the purposes of this document an attempt was made to ascertain whether
dosimetry modeling can provide insight into the apparent discrepancies between
the epidemiologic and laboratory animal data, to identify plausible dose metrics
of relevance to the available health
endpoints, and to identify modifying factors that may enhance susceptibility to
inhaled particles. In order to accomplish these objectives, this section
presents an application of dosimetry modeling to data typically available from
the epidemiologic and laboratory animal studies. Choice of a dosimetry model for
humans and laboratory animals, respectively, is discussed and these models are
used to simulate deposition and retained doses of various exposures. Different
dose metrics and their relevance to observed health endpoints are also
discussed.
Application of the chosen dosimetry models to calculate these estimates are
intended to illustrate the potential influence dosimetry may have on estimation
of dose to provide a linkage between the exposure and the available epidemiologic
and toxicologic data. At present, respiratory tract dosimetry must rely on many
simplifications and empiricisms, but even a somewhat rudimentary effort will
assist in linking dose to effects and in species extrapolations. As more
information on mechanistic determinants of dose, target tissues, and target dose
and tissue interaction relationships become available, the more complex and
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realistic the dosimetry construct will become. It is foreseen that choice of
dose metrics will go beyond dependence on average mass or number concentration in
the future as physiologically-based models become available. The human and
laboratory animal models chosen for the simulations represent semi-empirical
and empirical approaches to characterizing the available deposition and
retention data. Default values for key parameters such as ventilation rate and
body weight have been used in these simulation exercises. Disagreement with the
limited published deposition and retention data is considered to be within the
known variability among these parameters as well as biological detectability of
the current state of measurement. As with any data-driven process, when
additional data become available, the model structures can be reviewed and
revised as appropriate. Additional experimental measurements would provide
more information to strengthen the predictions and provide better description of
intersubject and interspecies variability.
10.7.1 General Considerations for Extrapolation Modeling
Major factors that affect the disposition (deposition, uptake,
distribution, metabolism, and elimination) of inhaled particles include the
physicochemical properties of the particles (e.g., particle diameter,
distribution, hygroscopicity) and anatomic (e.g., upper respiratory tract
architecture, regional surface areas, airway diameters, airway lengths,
branching patterns) and physiologic (e.g., ventilation rates, clearance
mechanisms) parameters of individual mammalian species. The relative
contribution of each of these factors is a dynamic relationship. Further, the
relative contribution of these determinants is also influenced by exposure
conditions such as concentration and duration. A comprehensive description of
the exposure-dose-response continuum is desired for accurate extrapolation.
Therefore, a dosimetry model should incorporate all of the various deterministic
factors into a computational structure. Clearly, many advances in the
understanding and quantification of the mechanistic determinants of particle
disposition, toxicant-target interactions, and tissue responses (including
species sensitivity) are required before an overall model of pathogenesis can be
developed for a specific aerosol. Such data exist to varying degrees, however,
and may be incorporated into less comprehensive models that nevertheless are
useful in describing delivered doses or in some cases, target tissue
interactions.
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10.7.1.1 Model Structure and Parameterization
Data on the mechanistic determinants of particle disposition, toxicant-
target interactions, and tissue responses to incorporate into a model vary in
degree of availability for chemicals and animal species. An ideal theoretical
mathematical model to describe particle deposition would require detailed
information on all of the influential parameters (e.g., respiratory rates, exact
airflow patterns, complete measurement of the branching structure of the
respiratory tract, alveolar region mechanics) across different humans or across
various laboratory species of interest. An empirical model (i.e., a system of
equations fit to experimental data) is an alternative approach. A third
approach, the hybrid approach adopted in ICRP66, is to fit a system of empirical
equations to the results of theoretical modeling. Depending on the relative
importance of these various mechanistic determinants, models with less detail
may be used to adequately describe differences in respiratory dosimetry for the
purposes of extrapolation.
An understanding of the bases for model structures also allows development
of a framework for the evaluation of whether one available model structure may be
considered optimal relative to another. A model structure might be considered
more appropriate than another for extrapolation when default assumptions or
parameters are replaced by more detailed, biologically-motivated descriptions
or actual data, respectively. For example, a model could be preferred if it
incorporates more chemical or species-specific information or if it accounts for
more mechanistic determinants. Empirical models may differ in the quality or
appropriateness of the data used to fit the descriptive equations. These
considerations are summarized in Table 10-17.
The sensitivity of the model to differences in structure may be gauged by
their relative importance in describing the response function for a given
chemical. For example, a model that incorporates many parameters may not be any
better at describing ("fitting") limited response data than a simpler model.
10.7.1.2 Intraspecies Variability
There are essentially three areas of concern in assessing the quality of
epidemiologic or toxicity data. These involve the design and methodological
approaches for (1) exposure
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TABLE 10-17. HIERARCHY OF MODEL STRUCTURES FOR
DOSIMETRY AND EXTRAPOLATION
Optimal model structure
Structure describes all significant mechanistic determinants of
particle disposition, toxicant-target interaction, and tissue response
Uses chemical-specific and species-specific parameters
Dose metric described at level of detail commensurate with the
epidemiologic or toxicity data
Default model structure
Limited or default description of mechanistic determinants of particle
disposition, toxicant-target interaction, and tissue response
Uses categorical or default values for chemical and species parameters
Dose metric at generic level of detail
Source: Adapted from U.S. Environmental Protection Agency (1994); Jarabek (1995).
measures, (2) effect measures, and (3) the control of covariables and
confounding variables. Although these topics are discussed in detail in other
chapters, it is also important to consider these concerns when evaluating
potential dosimetry models for extrapolation of epidemiologic or toxicity data.
For example, although the epidemiologic investigations attempt to relate an
exposure to a given health effect, the way the exposure is characterized may
influence the choice of an appropriate dosimetry model. Characterization of a
particular health effect in a human population may include pre-existing
pathologic conditions (e.g., lung disease) that may alter inhalation dosimetry
and have implications for model choice. The broad genetic variation of the human
population in processes related to chemical disposition and tissue response
(e.g., age, gender, disease status) may cause individual differences in
sensitivity to inhaled aerosols. Sensitivity analyses could be used to
determine ranges of dosimetry model outputs for specific ranges of input for
various parameters (e.g., range in ventilation rate due to gender).
10.7.1.3 Extrapolation of Laboratory Animal Data to Humans
Toxicological data in laboratory animals typically can aid the
interpretation of human clinical and epidemiological data because they provide
concentration- and duration-response information on a fuller array of effects
and exposures than can be evaluated in humans.
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However, historically, use of laboratory animal toxicological data has been
limited because of difficulties in quantitative extrapolation to humans. The
various species used in inhalation toxicology studies do not receive identical
doses in comparable respiratory tract regions (ET, TB, A) when exposed to the
same aerosol (same composition, //g/m3, MMAD, og). Such interspecies differences
are important because the adverse toxic effect is likely more related to the
quantitative pattern of deposition within the respiratory tract than to the
exposure; this pattern determines not only the initial respiratory tract tissue
dose but also the specific pathways by which the inhaled particles are cleared
and redistributed.
Both qualitative and quantitative extrapolation of laboratory animal data
to humans are of interest. Qualitative extrapolation refers to the "class" of
the effects. For example, if the function of rabbit alveolar macrophages is
depressed by sulfuric acid, will it also be depressed in humans, albeit at an
unknown exposure? This type of extrapolation is limited to known homologous
effects. For example, given the similarities in human and laboratory animal
alveolar macrophages, and likely toxicity mechanisms, the qualitative
extrapolation is reasonable. However, in some cases, the homology is not
understood adequately. For example, what is the laboratory animal model
homology to the mortality effects observed in the epidemiological studies?
Would PM exposures of aged animals or animal models of respiratory or cardiac
disease states more closely mimic the mortality observed among the elderly or
those with pre-existing cardiopulmonary disease? Several hypotheses exist, but
at present there is inadequate evidence for concensus.
Once a qualitative extrapolation has been justified, a quantitative
extrapolation can be initiated. In order for the laboratory animal data to be
useful to the risk assessment of PM, interspecies extrapolation should account
for differences in particle dosimetry and species sensitivity. Dosimetry, here,
is used broadly to represent the effective dose to target site which may be some
complex combination of regional delivered or retained particle burdens. Given
the identical exposure, these particle burdens may be different in different
species. Even if there is a comprehensive understanding of dose, there still
needs to be an understanding of species differences in sensitivity to that dose.
For example, perhaps one species has more efficient repair or chemical defense
mechanisms than another, making that one species less sensitive to a given dose.
10-150
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10.7.2 Dosimetry Model Selection
Available deposition models for humans and laboratory animals were
presented in Section 10.5.1 and 10.5.2, respectively. Clearance models,
required to calculate retained doses, were discussed in Section 10.6. This
section focuses on modeling efforts intended to present informative and
comparative data relevant to lung burdens that result in humans and laboratory
animals as a consequence of acute and chronic inhalation exposures. The
information and predictions are intended to illustrate examples of approaches to
lung dosimetry, metrics of deposited and retained particle burdens, and species
similarities and differences that influence exposure and dose metrics.
10.7.2.1 Human Model
The theoretically-based, semi-empirical lung deposition model of the
International Commission on Radiological Protection (ICRP66, 1994) was chosen
and used to model the dosimetry of inhaled particles in humans (Sections 10.7.4
and 10.7.5 below). A distinct advantage of this model is that it incorporates
both deposition and clearance mechansisms so that both deposited and retained
particles burdens can be calculated. LUDEP® software version 1.1 was used to run
the ICRP66 1994 model simulations (National Radiological Protection Board,
1994).
Although the highly-detailed theoretical models described in Section 10.5
might allow prediction to more localized regions of the respiratory tract,
information about the dimensions of the numerous gross and microscopic
structures of the respiratory tract are extremely limited. Human experimental
data are still available only for gross regional deposition, for the adult
Caucasian male, and for a limited range of particle size (dae from about 1 //m to 10
Aim), making validation of the most detailed theoretical models impossible at the
present time. For these reasons, the analysis of respiratory tract deposition by
gross anatomical region adopted by the ICRP was viewed as advantageous. The
parametric analysis of regional lung desposition, developed by Rudolf et al.
(1986, 1990) and described in Section 10.5, was used to represent the results of
complex theoretical modeling by relatively simple algebraic approximations. A
theoretical model of gas transport and particle deposition (Egan et al., 1989)
was applied to apportion particle deposition among the lower respiratory tract
regions (BB, bb, Al — see Section 10.6), and to quantify the effects of lung
10-151
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size and breathing rate. The structure of the respiratory tract is represented
explicitly by a morphometric anatomical model as described in Table 10-3 and
Figure 10-4. The 1994 ICRP model reasonably describes the experimental data
relating total thoracic deposition to particle size and breathing behavior. The
model also succeeds in simulating the variation of regional deposition with
particle size and breathing pattern that was inferred by Stahlhofen et al.
(1980,1983) from their measurements of thoracic depostion and retention. In
common with earlier theoretical models of Yeh and Schum (1980) and Yu and Diu
(1982b), the 1994 ICRP model predicts less thoracic deposition for particles in
the range of dae from 1 //m to 5 //m than the median values reported by Lippmann
(1977) and Chan and Lippmann (1980). These data are crucial since they represent
the largest group of experimental subjects studied to date. However, as
described in Appendix 10A, according to the analysis in ICRP66 (1994), there is
direct experimental evidence (Gebhart et al., 1988) that particulate material
used in the New York University (NYU) studies exhibits a degree of hygroscopic
growth in the respiratory tract. When allowance is made in the deposition
calculation for these supplementary data, the key set of experimental
measurements from NYU is also found to support the 1994 ICRP66 deposition model.
The problem of time-dependent functions to describe clearance from the various
regions in the respiratory tract was overcome by using a combination of
compartments with constant rates of clearance. Clearance from each region by
three routes (absorption into blood, transport to GI tract, and transport to
lymphatics) is accomplished by pathways with assigned rate constants.
Mathematical models such as the ICRP66 model do not provide site-specific
dosimetry at the level of individual lung lobes, but the objective of this
exercise is to provide useful insights about dose metrics such as average
concentrations and average numbers of particles per unit area of respiratory
regions. The ICRP model provides average concentration or average number values
on a regional basis, i.e., mass or number deposited or retained in the ET, TB, or A
regions. An important aspect of modeling and dosimetry is to relate the modeling
effort to the level or accuracy of measurements. Neither the available
deposition and clearance data nor the response data such as the mortality effects
provide a level of detail that support more physiologically-based parameters and
compartments.
The available deposition data were from radioactive tracer studies, in
which accurate measurements were obtained at very low particulate mass burdens.
As such, the particle
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mass deposited in the respiratory tract was negligible, and did not introduce
the possibility of experimental artifact due to particle overload phenomena.
Biphasic or multiphasic clearance processes do not necessarily imply specific
physiologic associations. The ICRP model makes use of convenient mathematical
approaches to vary the rates of specific processes involved in clearance. The
time dependence of clearance processes (both physical and dissolution-
absorption) may well be determined by a decrease in the availability of the
particles, e.g., because of (1) burial of the particles in the interstitial
tissue, (2) sequestering in macrophages in areas that have low probability of
physical clearance, or (3) altered dissolution-absorption rates related to
physical or chemical changes in the particle with time.
Both the NCRP and ICRP had the benefit of contributions from respected
investigators in respiratory tract toxicology and biomedical aerosol research.
Similar mathematical assessments were arrived at by both commissions, although
detailed calculations for specific radionuclides can be different. Comparisons
between the models presented earlier and in Appendix 10A show that the behavior
of the models are quite comparable, that is, the predicted deposition fraction
for a given particle size is similar if the models use the same ventilation
parameters as input. In fact, in order to ensure a uniform course of action that
provides a coherent and consistent international approach, the NCRP recommends
adoption of the ICRP 1994 model for modeling the effects of exposure for
radiation workers and the public (e.g., for computing reference levels of annual
intake and derived reference air concentrations corresponding to recommended
dose limits).
Some of the human parameter values used in the ICRP66 model (ICRP66, 1994)
and the LUDEP® software are provided in Appendix 10B. Surface area values were
derived by the ICRP based on the morphometry provided previously in Table 10-3.
LUDEP® allows simulations of either normal augmenter or mouth breather adult
male humans. The proportion of nasal airflow for these two types of breathing at
different levels of activity previously provided in Figure 10-27 and Table 10-11
in Section 10.5. The levels of activity to apportion nasal airflow are the same
as those used to construct the three different activity patterns (general
population; worker, light work; and worker, heavy work) shown in Table 10B-1.
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10.7.2.2 Laboratory Animal Model
The particle dosimetry model of Menache et al. (1996) descirbed in
Section 10.5.2 was chosen to calculate deposited dose estimates for rats as an
illustration of dosimetric adjustment for laboratory animal species.
Attributes of the model that were viewed as especially advantageous for this
exercise included the detailed measurements made in all tissues that served as
the source of deposition data (Raabe et al., 1988); that the deposition data were
available for unanesthetized, freely breathing animals; and that inhalability
was accounted for and used to adjust the logistic function to describe deposition
efficiency. This model represents a revised version of previous models (Miller
et al., 1988; Jarabek et al., 1989, 1990) that have been useful to develop
inhalation reference concentration (RfC) estimates for dose-response
assessment of air toxics (U.S. EPA, 1994). The same approach will be used to
calculate deposited doses as discussed below in greater detail (Section 10.7.4).
The range for application of the Menache et al. (1996) model to interspecies
extrapolation was restricted to 1 to 4 //m MMAD because this is the range that had
the most deposition data for model development and it is also the range most
likely of use for evaluating the available inhalation toxicology
investigations.
For calculation of retained doses, the simulation model based on Pritsker
(1974) and described in Section 10.6 was used. This clearance model was applied
to output of the Menache et al. (1996) deposition model in order to calculate
retained dose as discussed below in Section 10.7.5.
The broad spectrum of mammals used in inhalation toxicology research have
body weights ranging upwards from a few grams to tens of kg; these mammals also
exhibit a broad range of respiratory parameters. Table 10B-2 in Appendix 10B
lists body weights, lung weights, respiratory minute ventilation and
respiratory tract region surface areas for six laboratory animal species. Lung
weights and ventilation parameters are important variables for inhalation
toxicology because these parameters dictate the amounts of inhaled materials
potentially deposited in the lung, as well as the specific alveolar burdens (mass
of particles/g lung) that will result from inhalation exposures. The inverse
relationship between body size and metabolic rate is demonstrated by the values
for respiratory minute ventilation and body weight or lung tissue volume. For
example, liters of air inhaled per minute per gram of lung is about 20 times
higher for resting mice than for resting humans, which is an important
10-154
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factor to consider relative to potential amounts of aerosol deposited in the
respiratory tract per unit time during inhalation exposures.
10.7.3 Choice of Dose Metrics
As discussed in the preceding sections, inhaled dose, especially to
different regions or locations within the respiratory tract, is not necessarily
related linearly to the exposure concentration. For this reason, an internal
dose to characterize the dose-response relationship of PM is desired. In
general, the objective is to provide a metric that is mechanistically-motivated
by the observed response. Unfortunately, at this point in time, the crucial
definition and determination of the relevant dose has not been accomplished for
PM. Mechanistic determinants of the observed health effects have not been
adequately elucidated. The health effects data discussed later (Chapter 11, 12,
and 13) include effects that could be characterized as either "acute" (e.g.,
effects associated with mortality) or "chronic" (e.g., morbidity or laboratory
animal pathology after two-year bioassays). Dose may be accurately described by
particle deposition alone if the particles exert their primary action on the
surface contacted (Dahl et al., 1991), i.e., deposited dose may be an appropriate
metric for acute effects. For longer-term effects, the initially deposited dose
may not be as decisive a metric since particles clear at varying rates from
different lung compartments. To characterize these effects, a retained dose
that accounts for differences between deposition and clearance is more
appropriate.
Conventionally and conveniently, doses usually are expressed in terms of
particle mass (gravimetric dose). However, when different types of particles
are compared, doses may be more appropriately expressed as particle volume,
particle surface area, or numbers of particles, depending on the effect in
question (Oberdorster et al., 1994). For example, the retardation of alveolar
macrophage-mediated clearance due to particle overload appears to be better
correlated with phagocytized particle volume rather than mass (Morrow, 1988).
As shown in Figures 10-2 and 10-3, the smaller size fractions of aerosols are
associated with greater amounts of particles when characterized by surface area
or by number rather than by mass. That is, concentrations in this size fraction
are very small by mass but extremely high by number. The need to consider this is
accentuated when the high rate of deposition of small particles in the lower
respiratory tract (TB and A regions), the putative target for the
10-155
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mortality and morbidity effects of PM exposures, is also taken into account.
Anderson et al. (1990) have shown that the deposition of ultrafine particles in
patients with COPD is greater than in healthy subjects.
Miller et al. (1995) recently investigated considerations for both
intraspecies and interspecies dosimetry. Using a multipath dosimetric model,
simulations for different particle sizes (0.1, 1, and 5 //m) were performed and
different dose metrics calculated for the rat and both normal and compromised
human lung status. A summary table of this exercise is provided as Table 10-18.
These simulations support the conclusion that particle number per various
anatomical normalizing factors indicate a need to examine the role of fine
particles in eliciting acute morbidity and mortality, particularly in patients
with compromised lung status (Miller et al., 1995).
For the present document, average deposited particle mass burden in each
region of the respiratory tract has been selected as the dose metric for "acute"
effects in both humans and laboratory animals. Average retained particle mass
burden in each region for humans and in the lower respiratory tract for
laboratory animals has been selected as the dose metric for "chronic" effects.
These choices were dictated by the selection of the dosimetry models and the
availability of anatomical and morphometric information.
Because mass may not be the appropriate metric, especially to characterize
effects of the fine fraction, average particle number burdens and the number of
particles deposited per day were calculated in addition for humans. An attempt
to address the variability due to differences in the population was made by
calculating deposited particle mass burdens in each region for eight different
demographic groups that included a range of ages and one selected for
cardiopulmonary symptoms.
10.7.3.1 Interspecies Extrapolation
In order to gain insight on species similarities and differences that may
account for the apparent discrepancies between epidemiologic and laboratory
animal data, interspecies adjustments to the observed exposure levels must be
made for the dose metrics selected for "acute" and "chronic" effects. This
section discusses an approach to calculate human equivalent concentration (HEC)
estimates based on the observed laboratory animal toxicological data.
10-156
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TABLE 10-18. SPECIES COMPARISONS BY MILLER ET AL. (1995) OF VARIOUS DOSE METRICS AS A
FUNCTION OF PARTICLE SIZE FOR 24-HOUR EXPOSURES TO 150 ,ug/m3
Particle Dose Metric
Size
Mass/unit area
0.1 (j,m No. deposited
No./unit surface
area
No./ventilatory
unit
No./alveolusc
No./macrophagec
o
^ 1 (j,m Mass/unit area
~° No. deposited
No./unit surface
area
No./ventilatory
unit
No./alveolusc
No./macrophagec
5 (j,m Mass/unit area
No. deposited
No./unit surface
area
No./ventilatory
unit
No./alveolusc
Rat
3.74.3.76 x 10
1.2 x IO10
7.1 x io6
4.9 x IO6
303-598
262-399
1.1-1.2 x 10
3.5 x 10
2,130
1,470
0.12-0.18
0.08-0.12
2.8-4.4 x 10
7.1 x 10
4
3
0.0002
Human
a Normal
5.0 x -ft)'4
5.9 x IO11
9.5 x IO5
1.8 x IO7
1,190-
1,930
100-61
2.8 x 1Q-4
3.3" x IO6
532
9,910
0.7-1.1
0.06-0.09
9.1 x io4
8.5 x IO6
14
260
0.02-0.03
Lung Status
Compromised
NCd
4.3 x IO11
2.8 x IO6
5.3 x IO7
3,570-5,790
298-482
NCd -3
2.4 x IO8
1,590
29,700
2.0-3.3
0.2-0.3
NCd -4
6.4 x IO6
42
780
0.05-0.09
Ratio:
Normal
0.13
49
0.1
4
2-5
0.3-0.6
0.23-0.25
92
0.3
7
4-9
0.5-1.2
2.09-3.23
1,195
3.2
88
49-120
Human/Rat
Compromised
NC
37
0.4
11
6-15
0.8-1.8
NC
69
0.8
20
11-28
1.4-3.5
NC
897
9.7
263
145-359
-------
A HEC would be calculated by
HEC (//g/m3) = NOAEL[ADJ] (//g/m3) x DAFr, (10-48)
where the NOAEL[ADJ] is the no-observed-adverse-effect level (or other effect
level) of the laboratory animal study (this level, if from an intermittent
exposure regimen, is often adjusted for the number of hours per day and days per
week (#/24 x #/7) in order to model a continuous exposure) and DAFr is a
dosimetric adjustment factor for a specific respiratory tract region, r (ET, TB,
A). The DAFr is either the regional deposited dose ratio (RDDRr) for "acute"
effects of deposited particles or the regional gas dose ratio (RGDRj.) for
"chronic" effects of retained particles. The DAFr is a multiplicative factor
that represents the laboratory animal to human ratio of a specific inhaled
particle burden. The HEC is expected to be associated with the same delivered
particle burden to the observed target tissue as in the laboratory animal
species. A DAFr above the value of 1.0 indicates that the human receives a
relatively smaller deposited or retained particle burden than the particular
laboratory animal species. Values of the DAFr below 1.0 indicate that the human
receives a relatively larger deposited or retained particle burden than the
laboratory animal species, and application of the DAFr would adjust the
resultant HEC lower than the laboratory animal exposure level.
For deposited particle burdens, regional deposited dose (RDDr) can be
calculated as
RDDr = 10 3 x q x VE x Fr, (10-49)
where:
RDDr = dose deposited in region r (//g/min),
Q = concentration (//g/m3),
VE = minute ventilation (L/min), and
Fr = fractional deposition in region r.
If the RDD in laboratory animals is expressed relative to humans, the
resultant regional deposited dose ratio (RDDR,.) can be used as the DAFr in
Equation 10-48 to adjust an inhalation particulate exposure in a laboratory
species to a predicted HEC that would be
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expected to be associated with the same particle burden delivered to the rth
region of the respiratory tract. The RDDR,. can be calculated as a series of
ratios
DDR, = x x x no.50)
(10 3 x q)H (Normalizing Factor)A (y^ (Fr)H
where the normalizing factor can be selected based on consideration of the
mechanism of action. Because poorly soluble particles deposit along the surface
of the respiratory tract, the surface area of an affected respiratory tract
region (e.g., TB or A region) could be used as the normalizing factor. For the
purposes of calculating the RDDR,., the exposure concentration for the laboratory
animal (A) and human (H) are assumed to be the same because it is assumed that the
observed effect in the laboratory animal is relevant to human health risk. The
RDDR,. is used as a factor to adjust for interspecies differences in delivered
dose under the same exposure scenario. The first term in Equation 10-50,
therefore, equals one and will not be discussed further. The last term, the ratio
of deposition fractions in a given respiratory region, (Fr), is calculated using
the respective human and laboratory animal dosimetry models.
Because the ICRP66 model utilizes an activity pattern, Equation 10-50 must
be modified to account for the fraction of time spent at each different
ventilation rate, corresponding to each different activity levels, as
RDDRr = - - -
[ACT1
tmxVF xF +tr91xVF xFr +...+tnlxVp
W *%[!] rH[l] L4 UH&] rH[2] LnJ ^HM
where t[;] is the fractional time spent breathing minute volume [i],
'[i] +t[2] +-+tw =1- ^d (10-52)
(Normalizing Factor)H
^ e ^ x VDF x FT , ,,ne^
(Normalizing Factor). EA IA (10-53)
10-159
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where VDg^ js a ^a[\y average ventilation rate (L/min x 1440 min/day). It should
be noted that the human denominator is the fractional deposition value output
from the ICRP model simulations using the LUDEP® software using an activity
pattern.
Although clearance is dependent on the site of initial deposition,
calculation of retained dose is probably more appropriate for assessing chronic
heatlh effects. Different normalizing factors such as retained mass per region,
retained mass per surface area, or retained mass per other available
morphometric information may be worthwhile to explore. The regional retained
dose ratio (RRDRj.) for interspecies dosimetric adjustment is calculated as a
series of five ratios
(lo3xCi)A (Normalizing Factor)H (VE)A (Fr)A (AIt)A
x x x x
(10 3xCi)H (Normalizing Factor)A (VE)R (Fr)H) (AIt)H
(10-54)
where:
RRDR,. = relative //g of particles retained in region (r),
Ci = exposure atmosphere concentration (//g/m3),
Normalizing Factor = lung weight (g),
VE = minute ventilation (L/min),
Fr = fractional aerosol deposition in region r, and
(AL) = relative accumulated alveolar interstitial burden of particles as a
function of time from the start of a chronic exposure.
Again, since the ICRP66 model allows simulation of an activity pattern,
Equation 10-54 must be adjusted to account for the fraction of time spent at each
different ventilation rate corresponding to different activity levels so that
RRDR
LI
[ACI1 tm x VF x Fr x (AL) x tr91xVF x Fr x (AL)
L1J EHPJ rH[1] v * Hl L4 HHTO rH[2] l
H[l] l H[l] LZJ ^2] rH[2] l H[2]
+ ... + trnl x Vp x (AL)
W Ejj[n] v t'H[n]
(10-55)
10-160
-------
where t [;] is the fractional time spent breathing at minute ventilation [i],
(10-56)
(NormalizingFactorr)
a = ™ r • P t ^ x (V°E)A x (Fr)A x (AIt)A '
(NonnalizingFactorr)
A
and (VDE^ js a ^aiiy average ventilation rate (L/min x 1440 min/day).
The relative accumulated alveolar interstitial burden of particles as a
function of time from the start of a chronic exposure must be calculated for
specific exposure scenarios to account for species differences in clearance, as
well as the dissolution-absorption characteristics of the inhaled particles.
This ratio is not a constant and must be calculated for the chronic exposure time
of interest. Physical clearance functions and dissolution-absorption rates for
particles deposited in the A region are used to integrate daily deposition and
clearance over the chronic exposure time period of interest. The equations for
laboratory animals are derived using the information in Table 10-16. Physical
clearance parameters for humans are in the ICRP model (ICRP66, 1994) and the
calculation of A burden for humans can be made using LUDEP®.
Calculating these ratios (either deposited or retained) depends on particle
diameter (MMAD) and distribution (og) but not on aerosol concentration, i.e., it
assumes no altered deposition or clearance due to exposure concentration or
chemical-specific toxicity.
The calculation of the DAFr currently uses point estimates for all the terms
used to construct the ratios, that is, a default VE for each species, a default
regional surface area or lung weight for the normalizing factor, and an estimate
of fractional deposition or retained particle burden. These single values are
assumed to be representative of the average value of that term for a member of the
laboratory animal species or human population. As discussed in the previous
sections of this chapter, there are many sources of intraspecies variability
that contribute to the range of responses observed to a given external exposure
to an inhaled toxicant. Host factors may affect both the delivered dose of the
toxicant to the target tissue as well as the sensitivity of that tissue to
interaction with the toxicant. The procedures described in this interspecies
extrapolation section could provide some limited capability to
10-161
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examine the effects of population variability on the DAFr by changing the default
VE and surface areas or lung weights in an iterative fashion. However, because
of correlations between VE, surface area, and lung weight, such changes should
be made with caution. Confidence intervals were provided on the parameters for
the deposition efficiency equations. Iterative computational procedures could
be used to generate evelopes of regional fractional deposition that could be used
with distributions of VE, surface areas, and lung weights to provide ranges of
DAFr estimates. Actual implementation of this procedure is not straightforward
due to the complex nature of the correlation structures. Future versions of the
deposition and clearance models used to calculate the laboratory animal species
values could estimate distributions that reflect the range of available data for
key parameters.
10.7.4 Choice of Exposure Metrics
10.7.4.1 Human Exposure Data
Ambient exposure data provided elsewhere in Chapter 3 of this document were
selected to represent typical human exposures. Three different aerosols were
selected as presented in Appendix IOC. As discussed in Chapter 3, it is not known
at this time whether the intermodal mode for the trimodal aerosols is real or
whether it is an artifact of sampling procedures.
The first is the trimodal aerosol shown in Figure 10C-1. Table 10C-1 shows
the upper size cut (in //m) for various particle size intervals based on the
distribution of particle count, surface area, mass, or aerodynamic diameter
(dae). Recall from Section 10.2 that the 50% size cut for each of these diameters
would be the respective median diameter of the distribution, i.e., the 50% size-
cut diameter of the dae is the MMAD. Table 10C-2a,b,c shows the particle number,
surface, area, and mass distribution, respectively, for the aerosol from Figure
10C-1. The distribution of particle mass in Table 10C-2c was used as input to the
human dosimetry (ICRP66, 1994) model to estimate total particle mass deposition.
The two trimodal aerosols depicted in Figure 10C-2, panel (a) and (b) for
Philadelphia and Phoenix respectively, were also chosen and treated similarly.
Table 10C-3 shows the upper size cut (in //m) for various particle size intervals
from the Philadelphia aerosol (Panel a), based on the distribution of particle
count, surface area, mass, or aerodynamic diameter (dae). Table 10C-4a,b,c shows
the particle number, surface area, and mass
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distribution, respectively, from Figure 10C-2(a). The distribution of particle
mass in Table 10C-4c was used as input to the human dosimetry model (ICRP, 1994)
to estimate total particle mass deposition. Tables 10C-5 and 10-C6a,b,c are
analogous to Tables 10-C3 and 10C-4a,b,c but show the data for Phoenix (Figure
10C-2b).
10.7.4.2 Laboratory Animal Data
As noted previously, the range of application for the Menache et al. (1996)
model was limited to that typically used in laboratory animal studies that are
the basis of the toxicity data in Chapter 11. For calculation of deposited doses,
fractional deposition was estimated for a range of particle diameters (dae) and
two distributions (og), one representing a relatively monodisperse (og = 1.3) and
the other a polydisperse (og = 2.4) aerosol. Deposited doses for two different
particle diameters and distributions were then used in clearance models to
calculate retained doses (see Section 10.7.5).
10.7.5 Deposited Dose Estimations
The respective models discussed in Section 10.7.1 were used to estimate
deposition in each of the respiratory tract regions. Note that the ICRP66 human
model divides the ET region into compartments, ETX and ET2. The ICRP66 model also
divides the TB region into two compartments, the bronchi (BB) and bronchiole
(bb). The alveolar interstitial (AI) compartment is equivalent to the A region.
When compared to the laboratory animal data, deposition fractions for ETl and ET2
were summed to calculate ET deposition. Likewise, the BB and bb deposition
fractions were summed to calculate the TB fraction.
10.7.5.1 Human Estimates
Tables 10-19 through 10-24 present the regional deposition fractions (% deposition) and
regional deposited particle mass (//g) for each of the three ambient human exposure aerosols
depicted in Figures 10C-1, 10C-2a (Philadelphia), and 10C-2b (Phoenix). Data are shown for
normal augmenters (Tables 10-19, 10-21, and 10-23) versus mouth breathers (Tables 10-20,
10-22, and 10-24) for three different activity patterns.
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TABIi;iO-19.DAILYM4SSDEPOSmONOFPARll
-------
o
ON
TABI^lOmDAILYMASSDEPOSmONOFPARTKXESraOMAEROSOLDEF^
"MOUTH BREATHER" ADULT MALE HUMANS EXPOSED
TO A PARTICLE MASS CONCENTRATION OF 50 jig/m3
Contribution to Total Deposited Particle Mass from Each Aerosol Modea
Activity Pattern
General
population0
Workers, light
workd
Workers, heavy
work6
Region of
Respiratory Tract
ETj
ET2
BB
bb
AI
Total
ET2
BB
bb
AI
Total
ET,
ET2
BB
bb
AI
Total
Nuclei
Percent
Deposited11
0.5
1.1
0.4
2.4
7.2
11.6
0.5
1.1
0.4
2.3
7.4
11.6
0.5
1.0
0.3
2.2
7.5
11.6
Mode
Mass of
Particles (|ig)
5
11
4
24
71
116
6
12
4
26
84
133
6
14
4
29
101
155
Accumulation Mode
Percent
Deposition
0.3
0.5
0.2
1.1
4.2
6.3
0.3
0.5
0.2
1.0
4.1
6.1
0.3
0.5
0.2
0.9
4.1
5.9
Mass of
Particles (|ig)
3
5
2
11
42
63
3
6
2
11
47
70
4
7
2
12
54
79
Coarse
Percent
Deposition
7.3
16.2
4.2
2.1
6.2
36.0
6.8
16.8
4.8
2.1
5.8
36.3
6.4
17.2
5.4
2.0
5.4
36.5
Mode
Mass of
Particles (|ig)
72
162
42
21
62
358
78
192
55
24
66
415
86
230
72
27
73
488
TSTuclei mode MMAD = 0.0169 (jm, og = 1.6, density = 1.4 g/cm3, 15.6% of the aerosol mass; accumulation mode MMAD = 0.180 (jm, og = 1.8,
density = 1.2 g/cm3, 38.7% of the aerosol mass; coarse mode MMAD = 5.95 (jm, og = 1.87, density = 2.2 g/cm3, 45.7% of the aerosol mass
(see Tables 10C-1 and 10C-2c).
''Expressed as a percentage of the total mass of particles in the volume of ambient air inhaled.
'Average for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 33.3% sitting, and 33.3% light exercise. (See Table 10B-1).
dAverage for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 27.1% sitting, and 35.4% light exercise, 4.2% heavy exercise. (See Table
10B-1).
'Average for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 16.7% sitting, and 41.7% light exercise, 8.3% heavy exercise. (See Table
10B-1).
-------
TABLE 10-21. DAILY MASS DEPOSITION OF PARTICLES FROM PHILADELPHIA AEROSOL DEFINED IN
FIGURE 10C-2(a) IN THE RESPIRATORY TRACT OF "NORMAL AUGMENTER" ADULT MALE HUMANS
EXPOSED TO A PARTICLE MASS CONCENTRATION OF 50
Contribution to Total Deposited Particle Mass from Each Aerosol Mode3
Accumulation Mode
Activity Pattern
General
population0
Workers, light
work4
o
Oi
Workers, heavy
work6
Region of
Respiratory Tract
ETj
ET2
BB
bb
AI
Total
ETj
ET2
BB
bb
AI
Total
ETj
ET2
BB
bb
AI
Total
Percent
Deposited11
2.0
1.9
0.2
0.7
3.7
8.5
1.9
1.9
0.2
0.6
3.6
8.3
1.9
2.0
0.2
0.6
3.6
8.3
Mass of
Particles (|ig)
19
19
2
7
37
84
22
22
2
7
42
95
26
26
3
8
48
111
Intermodal
Percent
Deposition
1.9
2.6
0.2
0.2
1.1
6.0
1.8
2.6
0.2
0.2
1.1
5.9
1.8
2.6
0.3
0.2
1.1
6.0
Mode
Mass of
Particles (|ig)
19
26
2
2
11
60
21
30
3
2
13
68
24
35
4
2
14
80
Coarse
Percent
Deposition
13.0
13.4
0.2
0.1
0.1
26.8
12.2
14.2
0.3
0.1
0.1
26.8
11.6
14.7
0.3
0.1
0.1
26.8
Mode
Mass of
Particles (|ig)
130
134
2
1
1
267
139
162
3
1
1
307
156
197
5
1
1
359
Accumulation mode MMAD = 0.436 (jm, og = 1.51, density = 1.3 g/cm3, 48.2% of the aerosol mass; intermodal mode MMAD = 2.20 (jm, og = 1.16,
density =1.3 g/cm3, 7.4% of the aerosol mass; coarse mode MMAD = 28.8 (jm, og = 2.16, density = 1.3 g/cm3, 44.4% of the aerosol mass
(see Tables 10C-3 and 10C-4c).
''Expressed as a percentage of the total mass of particles in the volume of ambient air inhaled.
°Average for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 33.3% sitting, and 33.3% light exercise. (See Table 10B-1).
dAverage for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 27.1% sitting, and 35.4% light exercise, 4.2% heavy exercise. (See Table
10B-1).
"Average for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 16.7% sitting, and 41.7% light exercise, 8.3% heavy exercise. (See Table
10B-1)
-------
TABLE 10-22. DAILY MASS DEPOSITION OF PARTICLES FROM PHILADELPHIA AEROSOL DEFINED IN
FIGURE 10C-2(a) IN THE RESPIRATORY TRACT OF "MOUTH BREATHER" ADULT MALE HUMAN
EXPOSED TO A PARTICLE MASS CONCENTRATION OF 50
Contribution to Total Deposited Particle Mass from Each Aerosol Modea
Accumulation Mode
Activity Pattern
General
population0
Workers, light
workd
Workers, heavy
work6
Region of
Respiratory
Tract
ETj
ET2
BB
bb
AI
Total
ETj
ET2
BB
bb
AI
Total
ETj
ET2
BB
bb
AI
Total
Percent
Deposited1"
0.5
0.6
0.2
0.7
3.9
5.9
0.5
0.6
0.2
0.7
3.8
5.8
0.5
0.6
0.2
0.6
3.7
5.7
Mass of
Particles
(re)
5
6
2
7
39
59
6
7
2
8
43
66
7
8
3
8
50
76
Intermodal Mode
Percent
Deposition
0.7
1.0
0.3
0.3
1.9
4.2
0.6
1.1
0.4
0.3
1.8
4.2
0.6
1.1
0.5
0.3
1.8
4.3
Mass of
Particles (|ig)
7
10
3
3
19
42
7
12
5
3
21
48
8
15
6
4
24
57
Coarse Mode
Percent
Deposition
6.6
18.3
1.1
0.2
0.4
26.6
6.1
18.8
1.1
0.2
0.3
26.7
5.7
19.3
1.2
0.2
0.3
26.7
Mass of
Particles (|ig)
66
182
11
2
4
265
70
215
13
3
4
305
76
259
16
o
J
4
357
^Accumulation mode MMAD = 0.436 (jm, og = 1.51, density = 1.3 g/cm3, 48.2% of the aerosol mass; intermodal mode MMAD = 2.20 (jm, og = 1.16,
density =1.3 g/cm3, 7.4% of the aerosol mass; coarse mode MMAD = 28.8 (jm, og = 2.16, density = 1.3 g/cm3, 44.4% of the aerosol mass
(see Tables 10C-3 and 10C-4c).
''Expressed as a percentage of the total mass of particles in the volume of ambient air inhaled.
'Average for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 33.3% sitting, and 33.3% light exercise. (See Table 10B-1).
dAverage for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 27.1% sitting, and 35.4% light exercise, 4.2% heavy exercise. (See Table
10B-1).
eAverage for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 16.7% sitting, and 41.7% light exercise, 8.3% heavy exercise. (See Table
-------
oo
TABLE 10-23. DAILY MASS DEPOSITION OF PARTICLES FROM PHOENIX AEROSOL DEFINED IN
FIGURE 10C-2(b) IN THE RESPIRATORY TRACT OF "NORMAL AUGMENTER" ADULT MALE HUMAN
EXPOSED TO A PARTICLE MASS CONCENTRATION OF 50
Contribution to Total Deposited Particle Mass from Each Aerosol Modea
Accumulation Mode
Activity Pattern
General
population0
Workers, light
workd
Workers, heavy
work6
Region of
Respiratory
Tract
ETj
ET2
BB
bb
AI
Total
ETj
ET2
BB
bb
AI
Total
ETj
ET2
BB
bb
AI
Total
Percent
Deposited1"
0.4
0.4
0.1
0.7
2.7
4.2
0.4
0.4
0.1
0.6
2.6
4.1
0.4
0.4
0.1
0.6
2.6
4.0
Mass of
Particles
4
4
1
7
26
42
4
4
1
7
30
47
5
5
1
8
34
53
Intermodal Mode
Percent
Deposition
2.9
3.8
0.2
0.3
1.7
8.9
2.8
3.8
0.3
0.3
1.7
8.9
2.8
3.8
0.4
0.3
1.6
8.9
Mass of
Particles (|ig)
29
38
2
3
17
89
32
43
4
3
19
101
37
51
6
4
22
119
Coarse Mode
Percent
Deposition
20.3
21.9
0.6
0.4
1.2
44.4
19.1
22.8
1.0
0.4
1.2
44.3
18.3
23.4
1.3
0.4
1.1
44.4
Mass of
Particles (|ig)
202
218
6
4
12
441
218
260
11
4
13
507
244
313
17
5
14
594
aAccumulation mode MMAD = 0.188 (jm, og = 1.54, density = 1.7 g/cm3, 22.4% of the aerosol mass; intermodal mode MMAD = 1.70 ^im, og = 1.9,
density = 1.7 g/cm3, 13.8% of the aerosol mass; coarse mode MMAD = 16.4 (jm, og = 2.79, density = 1.7 g/cm3, 63.9% of the aerosol mass
(see Tables 10C-5 and 10C-6c).
Expressed as a percentage of the total mass of particles in the ambient air inhaled.
°Average for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 33.3% sitting, and 33.3% light exercise. (See Table 10B-1).
dAverage for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 27.1% sitting, and 35.4% light exercise, 4.2% heavy exercise. (See Table
10B-1).
eAverage for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 16.7% sitting, and 41.7% light exercise, 8.3% heavy exercise. (See Table
10B-1).
-------
TABLE 10-24. DAILY MASS DEPOSITION OF PARTICLES FROM PHOENIX AEROSOL DEFINED IN
FIGURE 10C-2(b) IN THE RESPIRATORY TRACT OF "MOUTH BREATHER" ADULT MALE HUMANS
EXPOSED TO A PARTICLE MASS CONCENTRATION OF 50
Contribution to Total Deposited Particle Mass from Each Aerosol Mode3
Accumulation Mode
Activity Pattern
General
population0
Workers, light
work4
Workers, heavy
work6
Region of
Respiratory Tract
ETj
ET2
BB
bb
AI
Total
ETj
ET2
BB
bb
AI
Total
ET,
ET2
BB
bb
AI
Total
Percent
Deposited1"
0.2
0.3
0.1
0.7
2.7
4.0
0.2
0.3
0.1
0.6
2.6
3.9
0.2
0.3
0.1
0.6
2.6
3.8
Mass of
Particles (ng)
2
3
1
7
27
40
2
4
1
7
30
44
2
4
1
8
35
50
Intermodal Mode
Percent
Deposition
1.0
1.7
0.5
0.5
2.7
6.4
1.0
1.7
0.6
0.5
2.6
6.4
1.0
1.8
0.8
0.4
2.5
6.5
Mass of
Particles (ng)
10
17
5
5
27
63
11
20
7
5
30
73
13
24
10
6
34
86
Coarse Mode
Percent
Deposition
9.8
25.5
3.1
1.2
3.0
42.7
9.2
26.3
3.4
1.1
2.8
42.8
8.5
27.0
3.7
1.1
2.6
42.9
Mass of
Particles (|ig)
98
254
31
12
30
425
105
301
39
13
31
490
114
362
50
14
34
574
Accumulation mode MMAD = 0.188 (jm, og = 1.54, density = 1.7 g/cm3, 22.4% of the aerosol mass; intermodal mode MMAD = 1.70 (jm, og = 1.9,
density = 1.7 g/cm3, 13.8% of the aerosol mass; coarse mode MMAD = 16.4 (jm, og = 2.79, density = 1.7 g/cm3, 63.9% of the aerosol mass
(see Tables 10C-5 and 10C-6c).
Expressed as a percentage of the total mass of particles in the volume of ambient air inhaled.
°Average for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 33.3% sitting, and 33.3% light exercise. (See Table 10B-1).
dAverage for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 27.1% sitting, and 35.4% light exercise, 4.2% heavy exercise. (See Table
10B-1).
"Average for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 16.7% sitting, and 41.7% light exercise, 8.3% heavy exercise. (See Table
10B-1).
-------
Recall from Section 10.4 that deposition of a particular aerosol (MMAD and og) in the
respiratory tract is a function of inhalability and deposition efficiency. This is illustrated
schematically in Figure 10-39. The inhalability function (Figure 10-39b) for a specific respiratory
tract region (or for the total respiratory tract as depicted in the figure) is integrated with the
deposition efficiency function (Figure 10-39c). These are integrated with an aerosol characterized
by its particle diameter and mass distribution data (Figure 10-39a) to estimate the mass deposition
fraction (Figure 10-39d) in that region.
As expected from experimental studies, these simulations predict different deposition
fractions for mouth breathing versus nasal breathing. This is most noticeable for deposition of the
intermodal and coarse modes of the Philadelphia and Phoenix aerosols (depicted in Figures IOC-
la and 10C-2b), which showed significant increases in BB and AI deposition fractions. The
MMAD for the intermodal and coarse modes were 2.20 and 28.8, respectively, for the
Philadelphia aerosol; and 1.70 and 16.4, respectively, for the Phoenix aerosol. Deposition in these
regions of the accumulation mode was less effected by mouth breathing as would be anticipated
for these smaller MMADs.
Activity pattern influenced the deposition fractions greatly. ET deposition of all three
modes increased with the ventiliation rates associated with work activity patterns. A noticeable
increase in both BB and A deposition occurred with percent changes of increased deposition
ranging up to 60%. Differences were also apparent in the nuclei and accumulation modes. For
the aerosol depicted in Figure 10C-1, the nuclei mode (MMAD = 0.0169 //m), deposition
fractions decreased in the bb and AI regions with the heavy work activity pattern compared to
that for the general population. For the Philadelphia aerosol, deposition of the accumulation
mode (MMAD = 0.436 //m) stayed the same in the BB region but decreased slightly in the bb and
A regions with the heavy work activity pattern. For the Phoenix aerosol, deposition of the
accumulation mode (MMAD = 0.188) increased in the bb and A compartments with the heavy
work activity pattern. Figures 10-40 and 10-41 show the daily mass deposition (//g/d) predicted
for normal augmenters versus mouth breathers and these different minute volume activity patterns
for the Philadelphia and Phoenix aerosols, respectively.
Differences among the aerosols were also apparent and reflected the differences in the
MMAD values and percent mass of each mode. Table 10-25 presents summary data for each
10-170
-------
0.025
0.1 1 10
Aerodynamic Diameter, urn
(B)
0.01
0.1 1 10
Aerodynamic Diameter, urn
100
\Aerodynam
aiC
_Respiratory Tract Deposition
^Efficiency Curve
(C)
0.01
\
0.1 1 10
Aerodynamic Diameter, urn
100
0.02
o 0.015
Particle Mass Deposited in Total Respiratory Tract
0.1 1 10
Aerodynamic Diameter, urn
100
Figure 10-39. Schematic showing integration of inhalability (b) with deposition efficiency
(c) functions. These functions are integrated with particle diameter and
distribution data (a) to estimate deposition fractions of particle mass in each
region of the respiratory tract (d). The particle mass fraction deposited in
the total respiratory tract is illustrated.
10-171
-------
0.1
1
MMAD
10
100
0.1
1
MMAD
10
100
~~ General Population (Normal)
— Heavy Worker (Normal)
1=1 Light Worker (Mouth)
— Light Worker (Normal)
• General Population (Mouth)
A Heavy Worker (Mouth)
Figure 10-40. Daily mass deposition (/^g/day) in tracheobronchial and alveolar regions for
normal augmenter versus mouth breather adult males using International
Commission on Radiological Protection Publication 66 (ICRP66) (1994)
minute volume activity patterns (general population; worker-light activity;
worker-heavy activity). The 1994 ICRP66 model simulated an exposure at
50 Mg/m3 to the Philadelphia aerosol described in Appendix IOC.
of the three chosen ambient aerosols. To better understand the deposition differences for each
mode, however, the previous Tables 10-19 through 10-24 should also be consulted.
10-172
-------
0.1
1
MMAD
10
100
MMAD
— General Population (Normal)
— Heavy Worker (Normal)
n Light Worker (Mouth)
Light Worker (Normal)
General Population (Mouth)
Heavy Worker (Mouth)
Figure 10-41. Daily mass deposition (/^g/day) in tracheobronchial and alveolar regions for
normal augmenter versus mouth breather adult males using International
Commission on Radiological Protection Publication 66 (ICRP66) (1994)
minute volume activity patterns (general population; worker-light activity;
worker-heavy activity). The 1994 ICRP66 model simulated an exposure at
50 Mg/m3 to the Phoenix aerosol described in Appendix IOC.
Intraspecies Variability
The different deposition predictions for normal augmenter versus mouth breathing humans
illustrates the variability that differences in ventilation rate introduces to deposition estimates. As
discussed in Section 10.4.1.6., age, gender, and disease status can influence
10-173
-------
TABLE 10-25. DAILY MASS DEPOSITION OF AEROSOL PARTICLES IN
THE RESPIRATORY TRACTS OF "NORMAL AUGMENTER" AND "MOUTH BREATHER"
ADULT MALE HUMANS EXPOSED TO 50 //g PARTICLES/m3
Aerosol Figure
Region of Respiratory
Activity Pattern Tract
10C-1
Normal
Augmenter
Mouth
Breather
10C-2(a)
Normal
Augmenter
(Philadelphia)
Mouth
Breather
10C-2(b)
Normal
Augmenter
(Phoenix)
Mouth
Breather
Mass of Particle Cwg)
General population* ETl
ET2
BB
bb
AI
Total
Workers, light workb ET;
ET2
BB
bb
AI
Total
Workers, heavy work0 ETl
ET2
BB
bb
AI
Total
179
207
15
42
136
577
194
240
24
46
157
661
137
290
86
57
188
760
80
178
48
56
175
537
87
210
61
61
197
618
96
251
78
68
228
722
168
179
6
10
49
411
182
214
8
10
56
470
206
258
12
11
63
550
78
198
16
12
62
366
83
234
20
14
68
419
91
282
25
15
78
490
235
260
9
14
55
572
254
307
16
14
62
655
286
369
24
17
70
766
110
274
37
24
84
528
118
325
47
25
91
607
129
390
61
28
103
710
"Average for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 33.3% sitting, and 33.3% light exercise. (See Table 10B-1).
bAverage for 24 h, as derived from ICRP-66 (1974): for 33.3% sleep, 27.1% sitting, 35.4% light exercise, 4.2% heavy exercise. (See Table 10B-1).
cAverage for 24 h, as derived from ICRP-66 (1994): for 33.3% sleep, 16.7% sitting, 41.7% light exercise, 8.3% heavy exercise. (See Table 10B-1).
-------
deposition in the respiratory tract. Because the simulations in the preceding section were
performed with parameters for adult males using an activity pattern for the general population, an
effort to develop activity patterns for different demographic groups was undertaken.
Previous efforts on establishing and revising the NAAQS for ozone and carbon monoxide
have attempted to simulate the movement of people through zones of varying air quality so as to
approximate the actual exposure patterns of people living within a defined area (Johnson et al.,
1989; 1990; 1995a,b). The approach has been implemented through an evolving methodology
referred to as the NAAQS exposure model (NEM). The NEM includes data on ventilation rates
for various cohort populations.
These cohort data were analyzed to create daily ventilation breathing pattern data for eight
demographic groups as follows:
1. Adult Male (18 to 44 years)
2. Adult Female (18 to 44 years)
3. Elderly Male (over 65 years)
4. Elderly Female (over 65 years)
5. Children (0 to 5 years)
6. Children (6 to 13 years)
7. Children (14 to 18 years)
8. Compromised
The compromised demographic group was limited to adults > 19 years of age. The
objective of identifying this cohort was to construct an activity pattern for subjects with symptoms
consistent with cardiopulmonary disease. Those who met this age criterion were included if they
answered "yes - it limits my activity" to one of the following questions from a study of the activity
patterns affecting exposure to air pollution (Johnson, 1989):
1. Has a doctor ever determined that you have asthma?
2. Has a doctor ever determined that you have a heart condition?
3. Has a doctor ever determined that you have angina?
4. Have you had a stroke?
5. Have you ever had a heart attack?
10-175
-------
6. Has a doctor ever determined that you have hypertension (high blood pressure)?
7. Has a doctor ever determined that you have chronic bronchitis?
8. Do you have any other diagnosed respiratory or heart ailment which limits your activity?
Respondents were also included if they answered "yes - it does not limit my activity" to question
numbers 1, 2, 3, 4, 5, or 7.
Figures 10B-1 through 10B-3 in Appendix 10B show the daily minute volume patterns for
each of these demographic groups. The average minute volume for each of 4 time periods: (1)
24:00 to 06:00; (2) 06:00 to 12:00; (3) 12:00 to 21:00; and (4) 21:00 to 24:00 was used as input
to the 1994 ICRP model in order to create a total 24-h daily breathing pattern for each
demographic group.
Figure 10-42 shows the fractional deposition in each of the three respiratory tract regions
for these demographic groups. Figure 10-43 shows the daily deposition rate (//g/day) of an
exposure to 50 //g/m3. Some variation between the cohorts exists in the mass deposition fraction
for particles in the aerodynamic size range of the ET region; the cohorts of children, especially the
0 to 5 year age group, show an increased deposition. In the A region, the cohort of children 14 to
18 years showed an enhanced deposition rate (/ug/d) for submicron-sized of particles in all three
regions of the respiratory tract, whereas the cohort of children 0 to 5 years showed a decreased
deposition rate relative to male and female adults. For larger particles (micron-sized and above),
the 14 to 18 year cohort showed no enhanced deposition rate in the tracheo bronchichial or
alveolar regions compared to adults, and younger children cohorts showed a progressive decrease
with decreasing age. When evaluated on the basis of daily mass deposition rate (//g/d), the cohort
of children ages 14 to 18 years showed an increase in deposition for all three regions of the
respiratory tract (Figure 10-43) compared to other cohorts, whereas the cohort of children 0 to 5
years showed a decrease. This is due primarily to differences in respiratory frequency.
Although constructed for differences in age, gender, and health status, the cohorts as
constructed represent differences for these factors only characterized in terms of differences in
hourly minute volume patterns. Other effects on dosimetry such as altered respiratory tract
architecture leading to altered flow pattern or differences in susceptibility of the target
10-176
-------
c
o
o
(0
o
0.
CD
O
0.001 0.01 0.1 1
Particle Diameter (|jm)
10
0.001 0.01 0.1 1
Particle Diameter (|jm)
10
0.001 0.01 0.1 1
Particle Diameter (|jm)
10
100
100
100
Male Worker ~~ Male over 65yr Compromised
Female Worker ° Female over 65yr * Child 14-1 Syr
Child 6-1 Syr * Child 0-5yr
Figure 10-42. Deposition fraction in each respiratory tract region as predicted by the
International Commission on Radiological Protection Publication 66
(ICRP66) (1994) model. Simulations used daily minute volume activity
patterns for different demographic groups as provided in Appendix 10B.
10-177
-------
as
Q
0.001
500
0.01 0.1 1
Particle Diameter (|jm)
10
100
— 400
in
o
CL.
to
Q
-------
tissue are not addressed in these simulations. As discussed earlier, Anderson et al. (1990) have
shown enhanced deposition in patients with COPD compared to healthy subjects. Miller et al.
(1995) used a more detailed theoretical multipath model and estimated enhanced deposition in a
compromised lung status model defined by decreased ventilation to respiratory tract region
adjustment. The simulations performed herein were limited to average mass particle burdens per
region of the respiratory tract. Nevertheless, these simulations do suggest differences for these
cohorts. For example, the cohort for children 14 to 18 years showed an enhanced deposition rate
(ug/d) in all three respiratory tract regions whereas children 0 to 5 years showed a decrease.
Relevance to PM10 Versus PM25 Sampling
The dosimetry of particles of different sizes in the human respiratory tract formed one of the
primary bases for selecting the PM10 size fraction in the 1987 review. Particles in this size range
pose the greatest risk to human health because they penetrate to the putative target regions in the
lower respiratory tract associated with mortality and morbidity, i.e., the TB and A regions.
Ambient aerosols have been established as bimodal distributions of particles. Fine and
coarse particles generally have different sources, formation mechanisms, physical properties,
chemical composition and properties, atmospheric lifetimes, and outdoor to indoor infiltration
ratios. The fine fraction has been suggested to provide a better exposure surrogate for the
epidemiological data (See Chapters 12 and 13). In addition, some of the properties of fine
particles may play a role in possible mechanisms of toxicity. For example, the fine mode accounts
for most of the particle number and much of the surface area. Also, several chemical classes of
concern such as acids and sulfates are found predominantly in the fine fraction. If particle number
and not mass alone is an important determinant of response, then a refined characterization of this
mode may enhance the ability to discern effects in the exposed populations.
Simulations were performed using the 1994 ICRP66 dosimetry model to illustrate the
relationship between deposition efficiency of the respiratory tract, mass burden of particles in the
thoracic portion of the respiratory tract, and the mass distribution of aerosols collected by a PM10
or PM2 5 sampler.
Figure 10-44 shows the predicted regional deposition fraction in the respiratory tract,
relative to unit mass concentration in ambient air, as a function of the aerosol size (represented by
the mass median aerodynamic diameter, MMAD, in //m). The top graph is for aerosols with a
10-179
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geometric standard deviation (og) of 1.8 and the other with a og of 2.4. Deposition fraction based
on model simulations are shown for the thoracic region (i.e., tracheobronchial plus alveolar
deposition, TB + A), as well as for the total respiratory tract deposition fraction. The difference
between total respiratory tract and total thoracic fractions represents the extrathoracic or upper
airway deposition fraction. In addition these figures show curves representing the fraction
collected by a PM10 sampler. This illustrates that the PM10 sample accounts for almost all of the
thoracic deposition, but does not account for many of the larger particles which would be
deposited in the ET region. Two curves for the PM10 collection fraction are shown illustrating
different wind speed characteristics (i.e., for 2 km/h or 8 km/h). It is seen that wind speed is not a
major factor. These curves represent the deposition fractions for healthy people who breathe
oronasally during exercise (normal augmenters) and healthy people who breathe predominantly
through their mouth (mouth breather). As before, it is clear that mouth breathers have a greater
deposition of particles >1 jim than do oronasal breathers.
Figures 10-45 and 10-46 expand on the information presented in 10-44 by illustrating
deposition fraction in each of the two thoracic regions, the alveolar and the TB region, again for
normal augmenters and for mouth breathers. In addition, the collection fraction for a PM2 5
sampler is illustrated. Whereas PM10 accounts for all particles in the thoracic size deposition
mode, the PM2 5 sample does not include some larger particles that would be deposited in the TB
and A regions of mouth breathers, under the simulated conditions (general population activity
pattern 8 h sleep, 8 h sitting, 8 h light activity [see Appendix 10B, Table 10B-l(b)]. Mouth
breathers do not represent a large percentage of the population, but are cited here to illustrate the
effect of breathing habit. Figure 10-46 provides the same information as Figure 10-45 but
expands the scale for micron-sized particles by excluding particles smaller than 0.1 jim.
These simulations (Figures 10-44 through 10-46) represent single mode aerosols of various
MMAD and two different og. However, the real world ambient aerosols are
10-180
-------
c
g
"o
to
c
o
"o
_OJ
~o
o
c
o
*J
'w
o
Q.
03
Q
M
M
to
0.001
0.01 0.1 1
MMAD (|jm) with og = 1.8
10
100
0
0.001
0.01 0.1 1
MMAD (|jm) with og = 2.4
100
Total Respiratory Tract — PM10 (2 km/h) — PM10 (8 km/h)
Thoracic (Normal) ° Thoracic (Mouth)
Figure 10-44. Respiratory tract deposition fractions and PM10 sampler collection versus
mass median aerodynamic diameter (MMAD) with two different geometric
standard deviations (og = 1.8 or og = 2.4). Thoracic deposition fraction
predicted for normal augmenter versus mouth breather adult male using a
general population (ICRP66) minute volume activity pattern and the 1994
ICRP66 model. Total respiratory tract deposition fraction also shown for
normal augmenter. PM10 sampler collection shown at two different wind
speeds (8 km/h or 2 km/h).
10-181
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Total Respiratory
Tract
0.01
0.1 1 10
MMAD (jjm)with og = 1.8
100
0.01
Total Respiratory
Tract
0.1 1 10
MMAD (|jm) with og = 2.4
100
TB (Normal) D Total Thoracic (Normal)
TB (Mouth) D Total Thoracic (Mouth)
0 Alveolar (Normal)
0 Alveolar (Mouth)
Figure 10-45. Respiratory tract deposition fractions and PM10 or PM2 5 sampler collection
versus mass median aerodynamic diameter (MMAD) with two different
geometric standard deviations (og = 1.8 or og = 2.4). Alveolar,
tracheobronchial, or total thoracic deposition fractions predicted for normal
augmenter versus mouth breather adult male using a general population
(ICRP66) minute volume activity pattern and the 1994 ICRP66 model.
10-182
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Total Respiratory
Tract
1 10
MMAD (pm) with og = 1.8
100
Total Respiratory
Tract
1 10
MMAD (pm) with og = 2.4
100
0 Alveolar (Normal)
0 Alveolar (Mouth)
A TB (Normal)
* TB (Mouth)
D Total Thoracic (Normal)
° Total Thoracic (Mouth)
Figure 10-46. Respiratory tract deposition fractions and PM10 or PM2 5 sampler collection
fractions versus mass median aerodynamic diameter (MMAD) with two
different geometric standard deviations (og = 1.8 or og = 2.4). Alveolar,
tracheobronchial, or total thoracic deposition fractions predicted for normal
augmenter versus mouth breather adult male using a general population
(ICRP66) minute volume activity pattern and the 1994 ICRP66 model.
10-183
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multi-modal, having a broad distribution of particle sizes and composition. Figure 10-47
illustrates graphically the process of taking the mass distribution for an ambient aerosol and the
deposition efficiency curve for a "typical" (general population adult male) human and deriving the
distribution of particle mass deposited in the lung. This is shown in the sequence of graphs in
Figure 10-47. The mass distribution of the ambient aerosol (Figure 10-47a) is combined with the
deposition efficiency curve (Figure 10-47b; similar to Figure 10-39) to obtain the thoracic mass
deposition for the ambient aerosol (Figure 10-47c). The corresponding process for collection
with a PM10 sampler is also shown. Figure 10-47a (ambient mass distribution) is combined with
the sampler efficiency curve (Figure 10-47d), resulting in Figure 10-47e, which shows the
collected mass distribution for the ambient aerosol. If Figure 10-47c is superimposed on Figure
10-47e, figures such as 10-48 and 10-49 will be generated.
Figures 10-48 and 10-49 illustrate the fractional mass deposition seen with representative
ambient aerosols for the cities of Phoenix and Philadelphia. These trimodal aerosols were
described in Chapter 3, and their parameters are provided in Appendix IOC. From these graphs it
is shown that the PM25 sampler distribution accounts for the particle mass in the fine (<1.0 |im)
mode and the transition mode (MMAD -2.5 jim) but does not account for the smaller mass of
coarse mode particles that would be deposited in the thorax (mainly affecting tracheobronchial
deposition in mouth breathers). Failure of the PM2 5 sampler to account for coarse mode particle
thoracic deposition is more evident for the Phoenix aerosol than for the Philadelphia aerosol.
Because mass deposition is not the only dose metric that is of interest, a similar modeling
exercise was conducted for particle number, using the Philadelphia and Phoenix aerosols.
Simulations were again performed with parameters for adult males and a general population
activity pattern. Figure 10-50 shows the predicted fraction of total number of particles inhaled
that is deposited in each region of the respiratory tract (ET, TB, A) for the Philadelphia aerosol.
Figure 10-51 shows the number of particles deposited each day in each respiratory tract region for
the Philadelphia aerosol assuming an exposure to a total paniculate mass concentration of 50
//g/m3. These figures show that a large fraction of the number of deposited particles is
contributed, as anticipated, by the fine fraction mode, and that this can represent a very large
number of particles deposited per day (on the order of
10-184
-------
0.025
« 0.02
(A)
Aerosol Mass vs. Particle Size Distribution
I I L
0.01
0.1 1 10
Aerodynamic Diameter (urn)
100
(B)
(D)
0.8
Characteristic Deposition Curve for Mouth Breather
0.8
o 0.6
T3
o 0.4
0.2
Characteristic Collection
Curve for PM10 Sampler
0.01
0.1 1 10
Aerodynamic Diameter (urn)
100
O-l—
0.01
0.1 1 10
Aerodynamic Diameter (urn)
100
(C)
(E)
0
S 0.015
Q
Fractional Mass
g p
Particle Mass Deposited In the Lungs (TB + A Regions
,-\ ,
/^
•^
0.01 0.1 1 10
Aerodynamic Diameter (urn)
100
c
o
•£ 0.015
o
U
i 0.01
"5
0
| 0.005
£
0
0.0
Particle Mas
:
s Collected by
* •
- -
* "
m m
•
V
1 0.1 1
PM10 Sample
S*.
/ '
/
•
•
10 10
Aerodynamic Diameter (urn)
Figure 10-47.
Schematic illustration of how ambient aerosol distribution data were
integrated with respiratory tract deposition efficiency (using 1994 ICRP66
model) or sampler efficiency to calculate deposition in respiratory tract
regions or mass collected by sampler.
10-185
-------
0.04
1 10
Aerodynamic Diameter (urn)
100
0.04
Aerodynamic Diameter
Alveolar
Total Thoracic
TB
Total Respiratory Tract
Figure 10-48. Mass deposition fraction in normal augmenter versus mouth breather
adult male with a general population minute volume activity pattern
predicted by the International Commission on Radiological Protection
Publication 66 (1994) model and the mass collected by PM10 or PM2 5
samplers for Philadelphia aerosol (described in Appendix IOC).
10-186
-------
0.02
I 0.015
o
CO
CO
0.01
0.005
0.02
1 10
Aerodynamic Diameter (\im)
100
1 10
Aerodynamic Diameter (urn)
100
Alveolar
Total Thoracic
TB
Total Respiratory Tract
Figure 10-49. Mass deposition fraction in normal augmenter versus mouth breather
adult male with a general population minute volume activity pattern
predicted by the International Commission on Radiological Protection
Publication 66 (1994) model and the mass collected by PMia or PM2 5
samplers for Phoenix aerosol (described in Appendix IOC).
10-187
-------
1E-02
1E-09
0.01
1E-02
1E-09
0.01
0.1 1 10
Aerodynamic Diameter (pm)
100
0.1 1 10
Aerodynamic Diameter (pm)
100
Extrathoracic
Tracheobronchial
Alveolar
Figure 10-50. Fractional number deposition in each respiratory tract region for normal
augmenter versus mouth breather adult male with a general population
activity pattern as predicted by the International Commission on
Radiological Protection Publication 66 (1994) model for an exposure to the
Philadelphia aerosol (described in Appendix IOC).
10-188
-------
(0
Q
L
O>
Q.
•c
0>
+*
0)
o
Q.
0>
Q
o
t
(0
Q.
M-
o
^
4)
E
n
Q
0)
Q.
•a
«
'w
o
Q.
4)
Q
in
"o
r
(0
Q.
>4-
o
^
o>
E
Normal Augmenter
.01
.01
0.1 1 10
Aerodynamic Diameter (pm)
100
0.1 1 10
Aerodynamic Diameter (pm)
100
Extrathoracic
Tracheobronchial
Alveolar
Figure 10-51. Number of particles deposited per day in each respiratory tract region for
normal augmenter versus mouth breather adult male with a general
population activity pattern as predicted by the International Commission
on Radiological Protection Publication 66 (1994) model for an exposure to
the Philadelphia aerosol (described in Appendix IOC) at a concentration of
50
10-189
-------
100,000,000) in the alveolar region. Figure 10-52 shows the predicted fraction of total number
of particles inhaled that is deposited in each respiratory tract region for the Phoenix aerosol, and
Figure 10-53 shows the number of particles deposited each day in each respiratory tract region for
this aerosol assuming an exposure to a total particulate mass concentration of 50 //g/m3. The
more disperse intermodal fraction of the Phoenix aerosol (see Figure 10C-2 in Appendix IOC)
contributes more particles to the fine mode size-range than that of the Philadelphia aerosol.
Hygroscopic Aerosols
The ICRP66 (1994) deposition model as so far described relates to the distribution of
activity or mass of aerosol particles with respect to their size on entering the respiratory tract.
However, in the case of a hygroscopic material, it is necessary to take account of the increase in
particle size that occurs when such materials are exposed to the near-saturated air in the
respiratory tract. The ICRP66 model can be applied for hygroscopic materials by replacing the
values of particle aerodynamic diameter, dae, and diffusion coefficient, D, in ambient air with the
values dae(j) and Dj attained in each region, j, of the respiratory tract.
Annexe D of ICRP66 describes how the growth of a hygroscopic particle can be
approximated in general terms as a function of its residence time in saturated air at body
temperature. For a residence time, tj, in region, j, measured from inspiration of the particle (i.e.,
entry to the nose or mouth), the particle aerodynamic diameter and diffusion coefficient attained
by hygroscopic growth are approximately related to dae(0) and D(0), the respective values in
ambient air (i.e., the external environment), and the values at equilibrium, dae(oo) and D(oo) are
- dae(0)]
exp
-{iotr}0'55
dae(0)
0.6
, and
(10-58)
= D(0) -
- dae(0)
[D(0)-D(oo)J
(10-59)
10-190
-------
1E-02
u
£ 1E-08
1E-09
0.01
0.1 1 10
Aerodynamic Diameter (|jm)
100
1E-02
•o
i 1E-03
« 1E-04
.a
E
1E-05
m
o
1E-06
o 1E-07
U
1E-08
1E-09
0.01
0.1 1 10
Aerodynamic Diameter (|jm)
100
Extrathoracic
Tracheobronchial
Alveolar
Figure 10-52. Fractional number deposition in normal augmenter versus mouth breather
adult male with a general population activity pattern predicted by the
International Commission on Radiological Protection Publication 66 (1994)
model for an exposure to the Phoenix aerosol (described in Appendix IOC).
10-191
-------
1E+09
n
Q
Q.
•o
4)
+-
'«
o
Q.
«
O
in
£
o
'•E
eg
a.
E
a
1E+00
0.01
1E+09
1E+08
1E+02
1E+01
1E+00
0.01
0.1 1 10
Aerodynamic Diameter (|jm)
100
0.1 1 10
Aerodynamic Diameter (|jm)
100
Extrathoracic
Tracheobronchial
Alveolar
Figure 10-53. Number of particles deposited per day in each respiratory tract region for
normal augmenter versus mouth breather adult male with a general
population activity pattern predicted by the International Commission on
Radiological Protection Publication 66 (1994) model for an exposure to the
Phoenix aerosol (described in Appendix IOC) at a concentration of
50 M/m3-
10-192
-------
To solve the model for a specific material, it is necessary to specify the degree of particle
size growth at equilibrium. This generally lies in the range of two- to fourfold growth, depending
on the amount of hygroscopic material associated with the particle. However, ICRP66 suggests
that it is likely to be adequate to assume by default a threefold growth factor at equilibrium, for
substitution in these equations. Note that the initial aerodynamic diameter, dae(0), is increased by
particle growth, whereas the initial diffusion coefficient, D(0), is decreased.
The effect of hygroscopic particle growth is generally to decrease total lung deposition for
submicron-sized particles, and to increase it for larger particles. As discussed in some detail in
Annexe D of ICRP66, the particle size in ambient air corresponding to minimum lung deposition
is reduced from about 0.4 jim for non-hygroscopic particles to about 0.1 jim for hygroscopic
particles (Tu and Knutson, 1984; Blanchard and Willeke, 1984).
Intrahuman Variability in Regional Deposition
The experimental data on regional deposition of particles in the human respiratory tract
indicate substantial intersubject variability, even if the particles are inhaled under identical
exposure conditions. In ICRP66, the upper and lower 95% confidence bounds of the data are
represented by a variable coefficient, a, which is incorporated into each algebraic expression for
deposition efficiency (see ICRP66, Chapter 5, Tables 12 and 13, pp. 45 and 46). In each case, the
coefficient is taken to be log-normally distributed, (i.e., a^ = amedian x Og2, and alower = amedian -
og2) where og is the fitted geometric standard deviation. Other confidence bounds on the
predicted regional deposition efficiency are given by substituting an appropriate value of the
coefficient, a, that is sampled from the defined log-normal distribution.
Representing the median (or expectation) value of the coefficient, a, for each region, j, by a,j,
then it is convenient to use a dimensionless scaling constant, Cj, as a multiplier or divisor of the
median value. In Table 14 of ICRP66 (Chapter 5, p. 49), the ICRP gives values of this scaling
constant that are estimated to describe the spread in the experimental data for regional respiratory
tract deposition. The scaling factors defining the upper and lower 95% confidence bounds of
regional deposition range from x or + by 1.4 in the expression for "thermodynamic" deposition
efficiency of the extrathoracic (ET) region, to x or + by 3.3 for the "aerodynamic" deposition
efficiency of the ET region. To evaluate the uncertainty distribution of the predicted deposition
10-193
-------
fractions in all five regions of the respiratory tract (i.e., ETl3 ET2, BB, bb, and AI) it is necessary
to select the respective values of Cj at random from their assumed log-normal distributions.
10.7.5.2 Laboratory Animal Estimates
Tables 10-26 through 10-31 provide the deposition fractions of various particle sizes
(MMAD) for either a relatively monodisperse (og = 1.3) versus a more polydisperse (og = 2.4)
distribution in humans or rats. Deposition fractions of these aerosols for an adult male human
normal augmenter and mouth breather with a general population activity pattern were calculated
using the ICRP66 model (ICRP66, 1994). The deposition fraction for each respiratory tract
region is presented: ET in Tables 10-26 and 10-27; TB in Tables 10-28 and 10-29; and A in
Tables 10-30 and 10-31. These regional deposition fractions are shown plotted in Figure 10-54.
The left side in each panel represents the deposition fractions for the relatively monodisperse
aerosol (og = 1.3) and the right side in each panel represents the more polydisperse aerosol (og =
2.4). Note that the y-axis scale changes from one panel to the other and from panel to panel.
As discussed in Section 10.5, polydispersity in the aerodynamic particle size range tends to smear
the regional deposition across the range of particles. The interspecies differences in fractional
deposition are readily apparent from these figures.
In the TB region, Figure 10-54 illustrates that at the smaller particle diameters (MMAD < 2
//m for og = 1.3) the rats have higher deposition fractions than normal augmenter (nasal breathing)
humans. At larger particle diameters (MMAD > 2.5 //m for og = 1.3), rats have very little
deposition in the TB or A regions due to the low inhalability of these particles. This may help
explain why inhalation exposures of rodents to high concentrations of larger particles have
exhibited little effect in some bioassays.
The information in Tables 10-26 through 10-31 and depicted in the panels of Figure 10-54
can be used to calculate the deposition fraction term in Equations 10-50 and 10-54. The average
ventilation rates and parameters such as surface area which could be used for normalizing factors
for laboratory animals are found in Appendix 10B, Table 10B-2.
10-194
-------
TABLE 10-26. EXTRATHORACIC DEPOSITION FRACTIONS OF INHALED
MONODISPERSE AEROSOLS (og=1.3) IN RATS AND HUMAN
"NORMAL AUGMENTER" AND "MOUTH BREATHER"
MMAD
1
1.5
2
2.5
3
3.5
4
Normal Augmenter Mouth Breather
0.273 0.074
0.443 0.141
0.566 0.209
0.651 0.270
0.711 0.326
0.754 0.375
0.785 0.420
Rat
0.18
0.55
0.74
0.77
0.76
0.73
0.70
TABLE 10-27. EXTRATHORACIC DEPOSITION FRACTIONS OF INHALED
POLYDISPERSE AEROSOLS (og=2.4) IN RATS AND HUMAN
"NORMAL AUGMENTER" AND "MOUTH BREATHER"
MMAD
1
1.5
2
2.5
3
3.5
4
TABLE
MMAD
1
1.5
2
2.5
3
3.5
4
Normal Augmenter Mouth Breather
0.326 0.126
0.442 0.193
0.524 0.250
0.582 0.299
0.624 0.340
0.655 0.374
0.678 0.404
Rat
0.30
0.42
0.49
0.53
0.55
0.56
0.56
10-28. TRACHEOBRONCHIAL DEPOSITION FRACTIONS OF INHALED
MONODISPERSE AEROSOLS (og=1.3) IN RATS AND HUMAN
"NORMAL AUGMENTER" AND "MOUTH BREATHER"
Normal Augmenter Mouth Breather
0.022 0.026
0.033 0.048
0.042 0.074
0.048 0.101
0.050 0.125
0.050 0.144
0.049 0.159
Rat
0.10
0.06
0.03
0.01
0.005
0.002
0.001
10-195
-------
TABLE 10-29. TRACHEOBRONCHIAL DEPOSITION FRACTIONS OF INHALED
POLYDISPERSE AEROSOLS (og=2.4) IN RATS AND HUMAN
"NORMAL AUGMENTER" AND "MOUTH BREATHER"
MMAD
1
1.5
2
2.5
3
3.5
4
Normal Augmenter Mouth Breather
0.028 0.049
0.032 0.068
0.035 0.084
0.036 0.096
0.036 0.104
0.036 0.110
0.035 0.114
TABLE 10-30. ALVEOLAR DEPOSITION FRACTIONS OF
Rat
0.06
0.05
0.04
0.031
0.025
0.021
0.017
INHALED
MONODISPERSE AEROSOLS (og=1.3) IN RATS AND HUMAN
"NORMAL AUGMENTER" AND "MOUTH BREATHER"
MMAD
1
1.5
2
2.5
3
3.5
4
Normal Augmenter Mouth Breather
0.119 0.140
0.146 0.120
0.150 0.237
0.142 0.256
0.126 0.258
0.109 0.248
0.092 0.230
TABLE 10-31. ALVEOLAR DEPOSITION FRACTIONS OF
Rat
0.06
0.10
0.06
0.02
0.011
0.005
0.002
INHALED
POLYDISPERSE AEROSOLS (og=2.4) IN RATS AND HUMAN
"NORMAL AUGMENTER" AND "MOUTH BREATHER"
MMAD
1
1.5
2
2.5
O
3.5
4
Normal Augmenter Mouth Breather
0.111 0.151
0.112 0.171
0.109 0.180
0.103 0.179
0.096 0.175
0.089 0.169
0.082 0.161
Rat
0.04
0.04
0.035
0.031
0.027
0.023
0.020
10-196
-------
(a)
.2 0.8
0.6
0.4
0.2
(b)
0.2
•2 0.15
o
s
I 0.1
w
o
Q.
a
a
M0.05
2 3
MMAD (|jm)
1234
MMAD (Mm)
0.8
5 0.6
| 0.4
in
o
a.
o
0
0.2
og = 2.4
1 2 3
MMAD (|jm)
U.1Z
= 0-1
o
S 0.08
u.
c
I 0.06
o
S 0.04
m
0.02
n
- Nose - — """"
Mouth ^f ""^
Rat /
/
./
S''--.
-
""""""" "••-..
Og = 2.4
234
MMAD (Mm)
. . u.o ,
(c) .p^
o
Q.
0.25
0.2
0.15
0.1
0.05
-
-
Nose
Mouth
Rat
>
/
/
/
t ^~
1
x"" ^"^
X
r
---.._ Og = 1-3
234
MMAD (Mm)
0.25
A Deposition Fractl
o o
i= P ^ P
Ol -* Ol IO
0
- Nose
Mouth
Rat
og - 2.4
1234
MMAD (Mm)
Figure 10-54. Predicted extrathoracic deposition fractions versus mass median
aerodynamic diameter (MMAD) of inhaled monodisperse (og = 1.3) aerosols
shown in left-side panels or polydisperse (og = 2.4) aerosols shown in right-
side panels for humans (nose versus mouth breathing) and rats (obligatory
nose breathers), for (a) the extrathoracic region, (b) tracheobronchial
region, and (c) alveolar region.
10-197
-------
Respiratory tract region surface areas for humans are found in Table 10B-1. The human male
adult general population activity pattern in Table 10B-1 corresponds to a daily ventilation
volume of 19.9 m3/day. This is the average ventilation rate that was used to run the LUDEP®
simulations and would be used in the denominator of Equations 10-51 or 10-55. The normal
augmenter or mouth breather deposition fractions found in Tables 10-26 through 10-31
represents the sum of the FrH factors in the denominator of the expression found in Equations
10-51 and 10-55. Likewise, the deposition fractions for the rat represent the FrA factor in
Equations 10-53 and 10-57.
Because particles initially deposit along the surface of the respiratory tract, regional surface
area is chosen as the normalizing factor for calculation of the regional deposited dose ratio
(RDDR), as described in Equation 10-50, in order to characterize "acute" effects. Assuming an
exposure to an aerosol with a MMAD of 1.0 //m and og = 1.3, Equation 10-51 can be used to
calculate RDDRA[ACT] estimates using the deposition fractions provided in Tables 10-26 through
10-31 and surface area and ventilation rate parameters provided in Tables 10B-1 and 10B-2 in
Appendix 10B. A RDDRA[ACT] value of 1.54 is calculated for rats using the alveolar surface area
as a normalizing factor. The RDDRA[ACT] value for each species would be applied to an
experimental exposure concentration from a laboratory toxicology study using rats to calculate a
human equivalent concentration.
Interspecies extrapolation to HEC values allows for comparison among species. For
example, if a rat exhibited an effect in the alveolar region when exposed to an aerosol with a
MMAD =1.0 //m and og = 1.3 at an exposure concentration of 100//g/m3, the resultant FIEC
value calculated for the rat would be 154 //g/m3. This HEC would result in a similar alveolar
deposited dose and thereby a similar effect in humans, assuming species sensitivity to a given
dose is equal. Although laboratory species may be exposed to the same aerosol at the same
concentration, each would have a different fractional deposition, which when normalized to
regional surface area, could result in different HEC estimates. Thus, taking into account species
differences in dosimetry is necessary before comparing effective concentrations when
interpreting toxicity data.
For tracheobronchial effects, the RDDR^^,^ would be used to adjust exposure
concentrations for interspecies differences in dosimetry. For an aerosol with an MMAD =1.0
//m and o = 1.3, the RODR^, value is 9.95 for rats. For an aerosol with an MMAD = 2.5
10-198
-------
and og = 2.4, the RDDR^^^ value is 1.89. The decrease in the value is due to the decreased
inhalability of the larger particle diameter and the effect of polydispersity. Similarly, the
RDDRA[ACT] value for an aerosol with an MMAD = 2.5 //m and og = 2.4is0.88 for rats, whereas
it was 1.54 for the more monodisperse aerosol.
10.7.6 Retained Dose Estimates
An important issue in inhalation toxicology is the relationship between repeated or chronic
inhalation exposures and the resulting alveolar burdens of exposure material achieved in the
human lung versus the lungs of laboratory animal species. It is generally assumed that the
magnitude of the alveolar burden of particles produced during an inhalation exposure is an
important determinant of biological responses to the inhaled particles. Therefore, understanding
the basis for differences among species in alveolar burdens that will result from well-defined
inhalation exposures will provide investigators with a better understanding of alveolar burdens
that would result from exposures of various mammalian species to the same aerosol.
Alternatively, the exposure conditions could be tailored for each species to produce desired
alveolar burdens of particles.
Predictable deposition, retention, and clearance patterns are possible for acute inhalation
exposures of laboratory animal species and humans. Repeated exposures also occur for humans
and are used routinely in laboratory animals to study the inhalation toxicology of a broad
spectrum of potentially hazardous particulates. The predicted biokinetics of particles acutely
inhaled can be readily extrapolated to repeated exposures. However, the predictions become
increasingly questionable as exposure conditions deviate from those used for acute inhalation
exposures. The following predictions for repeated inhalation exposures are therefore intended
to be relative, rather than absolute, and were made using the assumption that physical clearance
parameters for the A region are the same for acute and repeated inhalation exposures.
10.7.6.1 Human Estimates
The LUDEP® software version 1.1 for the 1994 ICRP66 model was also used to simulate
chronic exposures of adult male "normal augmenters" to the trimodal aerosols described in
Appendix IOC for Philadelphia (Figure 10C-2a, and Tables 10C-3 and 10C-4) and Phoenix
(Figure 10C-2b, and Tables 10C-5 and 10C-6). The simulations were of a continuous 24 h/d and
10-199
-------
7 d/week exposure at an air concentration of 50 //g/m3. For both aerosols, the particles in the
accumulation, intermediate, and coarse modes were assumed to have dissolution/absorption half
times of 10, 100, and 1000 days, respectively.
Predicted particle mass (//g) lung burdens as a function of exposure days are presented in
Figure 10-55a for the Philadelphia trimodal aerosol and in Figure 10-55b for the Phoenix
trimodal aerosol. The assumed dissolution/absorption rates and default values for clearance
parameters in the ICRP66 1994 model yielded predicted particle mass lung burdens from the
accumulation, intermediate, and coarse modes that reached equilibrium between deposition and
clearance after about 100, 700, and 7,000 days, respectively. Table 10-32 presents the predicted
ratios of particle mass in the lungs for each of the three modes and for the total amount of
particles. Individuals breathing the Phoenix aerosol would have about 0.7 the amount of the
accumulation mode particles in the their lungs as would individuals breathing the Philadelphia
aerosol, and about 1.5 times as much of the intermediate and 11 times as much of the coarse
modes. Overall, individuals exposed for long periods to the Phoenix aerosol would have almost
4 times as much total mass of particles in their lungs as would individuals exposed to the
Philadelphia aerosol. Interestingly, the biggest difference is in the predicted amounts of particles
from the coarse mode.
Another way to present these model simulation results is to express them in terms of
specific lung burden (//g dust / g lung) versus time. This is presented in Figure 10-56a for the
Philadelphia aerosol and in Figure 10-56b for the Phoenix aerosol. Note that the time of
exposure was converted to age in years. Assuming that humans of all ages and gender deposit
and clear about the same amounts of particles from these aerosols per day per gram of lung, this
presentation of data approximates the specific lung burdens of particle mass as a function of age
for young and old alike. For both aerosols, equilibrium amounts of dust are achieved after about
16-18 years. Assuming that clearance rates are not altered with age or these levels of particle
burden, this suggests that an individual who has lived in these environments for longer than
about 18 years has accumulated a specific lung burden of these particles and that the burdens
will remain relatively constant as long as exposure conditions and health status are not
appreciably changed. Note again that the data in Table 10-33 predict different relative amounts
of accumulated particles from the three modes.
10-200
-------
10,000
1,000-
8
<8
r
(0
Q.
100-
in-
(a) Philadelphia
x
x
Total
Coarse Mode
Intermediate Mode
Accumulation Mode
1
10
100
Days of Exposure
1,000
10,000
10,000
1,000
W
w
ffl
-------
TABLE 10-32. PREDICTED RELATIVE PARTICLE MASS (^g) IN
LUNGS OF ADULT MALE "NORMAL AUGMENTER" EXPOSED
CHRONICALLY TO PHOENIX TRIMODAL AEROSOL VERSUS
PHILADELPHIA TRIMODAL AEROSOL
Day
1
2
4
6
8
10
12
14
16
18
20
25
30
40
60
80
100
150
200
250
300
400
500
600
700
800
900
1000
1200
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
7000
8000
9000
10,000
Particle Mass (jj,g)
Accum.
0.71
0.71
0.71
0.71
0.71
0.71
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
0.72
Versus Mode:
Intermed.
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.52
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
1.53
Ratio of Phoenix to Philadelphia
Coarse
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
Aerosols
Total
1.14
1.14
1.16
1.18
1.20
1.23
1.25
1.27
1.29
1.31
1.32
1.37
1.42
1.50
1.64
1.75
1.84
2.01
2.15
2.26
2.36
2.55
2.70
2.83
2.94
3.04
3.12
3.19
3.28
3.41
3.51
3.57
3.60
3.62
3.63
3.64
3.64
3.64
3.64
3.65
3.65
3.65
3.65
10-202
-------
D)
o
E
IB
O
4)
Q.
*ra
w
w
IB
ra
Q.
10
1
0.1-
0.01-
.ooin
o.c
i i i i
(a) Philadelphia
.
^' ,.-''
x'' .-•'
// -•' x
/ , X/X — • Total
X Coarse Mode
X Accumulation Modi
x
X
I I I I
101 0.01 0.1 1 10 10
Age in Years
0)
C
3
4-
o
E
i_
O
i_
41
Q.
"5
^
M
(A
(0
E
"o
r
ra
0.
10
1-
0.1-
0.01-
i i i i
(b) Phoenix
^•''' ..•••""
xX ^^
x / • '
X / .•'"
x X -•''
/' s^"?^
/' j^^-''
/' Jx5*^***
/' // •'
/ .// .•'
X xxx Total
//- ..••'' Intermediate Mode
Coarse Mode
Accumulation Modi
.ooin i i i i
0.001 0.01 0.1 1 10 10
Age in Years
Figure 10-56. Specific lung burden (/zg particles/g lung) versus time (age in years)
predicted by the International Commission on Radiological Protection
Publication 66 (1994) model, assuming dissolution-absorption half-times of
10,100, and 1,000 days for the accumulation, intermodal, and coarse
modes, respectively, of continuous exposures to Philadelphia and Phoenix
aerosols (described in Appendix IOC) at 50 /zg/m3. Predictions shown for a
normal augmenter adult male with a general population activity level.
10-203
-------
10.7.6.2 Laboratory Animal Estimates
Deposition data for two different aerosols, one with an MMAD of 1.0 and og of 1.3, the
other with an MMAD of 2.55 and a og = 2.4 were chosen to calculate total alveolar retention
(Table 10-33). The aerosol with an MMAD of 1.0 //m and og of 1.3 was chosen as the smallest
particle diameter for which the laboratory animal dosimetry model calculates fractional
deposition and to represent a relatively monodisperse distribution. The aerosol with an MMAD
of 2.55 //m and a og of 2.4 was chosen to approximate a hypothetical PM10 aerosol in which the
PM25 to PM10 sample size cut ratio is 0.6 Dockery and Pope (1994).
TABLE 10-33. FRACTION OF INHALED PARTICLES DEPOSITED
IN THE ALVEOLAR REGION OF THE RESPIRATORY TRACT
FOR RATS AND ADULT MALE HUMANS
Fraction of Aerosol Deposited in Alveolar Region
Aerosol Parameters Rata Humanb
1.0//mMMAD, og= 1.3 0.063 0.119
2.55 //m MMAD, oa = 2.4 0.031 0.102
"From Tables 10-30 and 10-31.
bFrom (ICRP 66, 1994) average for general population activity pattern (8 h sleeping, 8 h sitting, and 8 h light
activity) for adult male "normal augmenter" (See Table 10-18).
Table 10-34 provides fractional deposition data in the alveolar region for three different
aerosols as predicted for the various demograhic groups. Table 10-35 provides the particle
deposition rates (//g/d) in the alveolar regional for a 24-h exposure to an airborne mass
concentration of 50 //g/m3. Although model simulations of retained particle burdens were not
performed for these various cohorts, differences in retained particle burdens can be expected
because the clearance modeling output is proportional to the deposition fractions used as input.
Note the greater deposition efficiency for the larger diameter aerosols in elderly males and in
those with respiratory disease.
Table 10-36 summarizes the common and specific parameters used for predicting alveolar
burdens for exposures of humans and rats of the two different aerosols at a concentration of 50
jig particles/m3. Exposures were assumed to take place 24 h/day at the
10-204
-------
TABLE 10-34. FRACTION OF INHALED PARTICLES DEPOSITED IN THE ALVEOLAR
REGION OF THE RESPIRATORY TRACT FOR DIFFERENT DEMOGRAPHIC GROUPS
Fraction of Aerosol Deposited in Alveolar Regiona
Aerosol Parameters
0.5 //mMMAD, og = 1
1.0//mMMAD, og = 1
2.55//mMMAD, oe =
3
3
2.4
Male
Worker
(18-44)b
0.085
0.135
0.118
Female Worker (18-44)
or Elderly Female
(over 65)c
0.079
0.125
0.108
Elderly
Male
over 65d
0.085
0.138
0.123
Male
Respiratory
Compromised6
0.086
0.139
0.126
Child
(14-18)f
0.079
0.120
0.091
Child
(6-13)8
0.067
0.098
0.073
Child
(0-5)h
0.069
0.094
0.062
to
o
^Calculated using ICRP Publication 66 lung deposition model with EPA's hourly lung ventilation rates for each demographic group.
bTotal daily volume of air breathed by a male worker is 19.4 m3.
Total daily volume of air breathed by a female worker is 16.5 m3, and 16.1 m3 for a female over age 65.
dTotal daily volume of air breathed by a male over 65 years old is 18.1 m3.
Total daily volume of air breathed by a an adult male with compromised respiratory system is 17.4 m3.
Total daily volume of air breathed by a a child of age 14-18 years is 25.5 m3.
Total daily volume of air breathed by a a child of age 6-13 years is 18.2 m3.
Total daily volume of air breathed by a a child of age 0-5 years is 11.6 m3.
TABLE 10-35. PARTICLE DEPOSITION RATES (//g/d) IN THE ALVEOLAR REGION (FOR 24-H
EXPOSURE TO AN AIRBORNE MASS CONCENTRATION OF 50
Daily Mass Deposition in Alveolar Region
Aerosol Parameters
0.5 //mMMAD, og
l.OjumMMAD, og
2.55 //m MMAD, a
= 1.3
= 1.3
, = 2.4
Male Worker
(18-44)
82.5
131.3
114.5
Female Worker
(18-44)
65.2
102.8
89.1
Male
over 65
76.9
124.7
111.3
Male
Respiratory
Compromised
74.8
121.2
109.6
Child
(14-18)
100.7
153.0
116.0
Child
(6-13)
61.0
88.7
66.4
Child
(0-5)
40.0
54.6
36.0
-------
TABLE 10-36. SUMMARY OF COMMON AND SPECIFIC INHALATION
EXPOSURE PARAMETERS USED FOR PREDICTING ALVEOLAR BURDENS
OF PARTICLES INHALED BY RATS AND HUMANS
A. Common Parameters:
Exposure atmosphere 50 (ig/m3
Particle MMAD, og 1.0//m, 1.3; or 2.55//m, 2.4
Particle dissolution-absorption half-time 10, 100, or 1,000 days
Chronic inhalation exposure pattern 24 h/day; 7 days/week
Duration of continuous exposure 2 years
B. Specific Parameters: Particle deposition rates in the alveolar region; data calculated using information in Tables
10-33 and Appendix 10B, Tables 10B-1 and 10B-2
Species
Rat
Human3
Daily Deposition
of 1.0 //m MMAD, op = 1.3
Mg Mg/g lung
1.14 0.26
118 0.11
of 2.
Mg
0.56
101
Daily Deposition
55 ,um MMAD, op = 2.4
//g/g lung
0.13
0.092
TBased on human deposition parameters from ICRP66 (ICRP, 1994) for an average general population activity
pattern (8 h sleeping, 8 h sitting, and 8 h light activity) for adult male
"normal augmenter" (See Table 10B-1 in Appendix 10B).
average minute respiratory ventilation and deposition fractions presented in Tables 10B-1, 10B-
2, and 10-34. Daily alveolar deposition was expressed in units of//g particles/g lung to
normalize deposition rates between the two species. Particle dissolution-absorption rates were
varied; half-times of 10, 100, and 1000 days were used to simulate particles that are relatively
soluble, moderately soluble, and poorly soluble. The A clearance parameters in Table 10-16
derived from the results of acute inhalation exposures of laboratory animals, were used to predict
the consequences of repeated exposures of these animals. For human modeling of acute or
repeated inhalation exposures, the clearance parameters as recommended by the ICRP (ICRP66,
1994) were used in the human model LUDEP® version 1.1 software.
Table 10-37 shows the calculated alveolar particle burdens of the 1.0 //m MMAD (og =
1.3) aerosol in rats and an adult human normal augmenter for a general population activity
pattern, assuming a particle dissolution-absorption half-time of 10, 100, and 1,000 days,
respectively. Table 10-38 shows the analogous calculated alveolar particle
10-206
-------
to
o
TABLE 10-37. ALVEOLAR PARTICLE BURDENS (//g) OF EXPOSURE TO
50 Mg/m3 OF 1.0 ^m MASS MEDIAN AERODYNAMIC DIAMETER (MMAD) AEROSOL,
ASSUMING PARTICLE DISSOLUTION-ABSORPTION HALF-TIME OF 10,100, OR 1,000 DAYS
Exposure Days
1
7
14
21
28
35
50
75
91
100
150
200
300
400
500
600
700
730
Rat
1.04
5.52
8.31
9.74
10.5
10.9
11.2
11.3
11.3
11.3
11.3
11.3
11.3
11.3
11.3
11.3
11.3
11.3
10 Days
Human
114
642
1020
1250
1380
1460
1540
1570
1580
1580
1580
1580
1580
1580
1580
1580
1580
1580
Rat
1.11
6.96
12.4
16.8
20.2
23.1
27.5
32.1
33.9
34.7
37.4
38.6
39.7
40.1
40.2
40.3
40.3
40.3
100 Days
Human
117
790
1510
2170
2780
3340
4400
5840
6600
6980
8610
9690
10900
11500
11700
11800
11900
11900
Rat
1.11
7.13
13.0
17.8
21.9
25.3
31.2
37.9
40.9
42.4
48.1
51.8
56.6
59.8
62.1
63.9
65.3
65.7
1000 Days
Human
117
808
1580
2310
3020
3700
5090
7210
8460
9160
12700
15900
21600
26400
30500
34100
37100
38000
-------
TABLE 10-38. ALVEOLAR PARTICLE BURDENS (//g) OF EXPOSURE TO
50 ^g/rn3 OF 2.55 ^m MASS MEDIAN AERODYNAMIC DIAMETER (MMAD) AEROSOL,
ASSUMING PARTICLE DISSOLUTION-ABSORPTION HALF-TIME OF 10,100, OR 1,000 DAYS
o
to
o
oo
Exposure Days
1
7
14
21
28
35
50
75
91
100
150
200
300
400
500
600
700
730
Rat
0.51
2.70
4.06
4.76
5.12
5.31
5.47
5.53
5.53
5.53
5.53
5.53
5.53
5.53
5.53
5.53
5.53
5.53
10 Days
Human
96.0
542
861
1050
1160
1230
1300
1320
1330
1330
1330
1330
1330
1330
1330
1330
1330
1330
Rat
0.54
3.40
6.07
8.19
9.89
11.3
13.5
15.7
16.6
17.0
18.3
18.9
19.4
19.6
19.6
19.7
19.7
19.7
100 Days
Human
99.1
666
1280
1830
2340
2820
3710
4930
5570
5890
7260
8170
9200
9660
9890
9980
10000
10000
Rat
0.54
3.49
6.34
8.71
10.7
12.4
15.2
18.5
20.0
20.7
23.5
25.3
27.7
29.2
30.4
31.2
31.9
32.1
1000 Days
Human
99.3
681
1330
1950
2540
3120
4290
6080
7140
7730
10700
13400
18200
22200
25800
28700
31300
32000
-------
burdens for the 2.55 //m MMAD (og = 2.4) aerosol. Note the different patterns for
accumulations of A burdens of particles for these species. These simulations suggest that
significant A burdens of particles can be reached with exposures to relatively low aerosol
concentrations of 50 |ig/m3. Particle burdens increase with time until an equilibrium burden is
achieved. This burden is achieved more rapidly for less soluble particles. The maximal
equilibrium particle burden is much higher for poorly soluble particles and also slightly higher
for the smaller diameter (1 //m) particles.
The exposure concentration is representative of environmental ambient aerosols that have
been recorded for numerous American and European cities. An important point to make is that
the composition of the ambient aerosols vary from one place to another and constituents of the
aerosols undoubtedly cover a broad range of solubilization and absorption characteristics.
Therefore, the composition of the retained particles would be expected to change with time and
the accumulated A burdens would consist of the more persistent types of particles or constituents
of particles present in ambient aerosols. The more soluble, and perhaps more toxic, constituents
of the aerosols will be rapidly absorbed into the circulatory system, metabolized, excreted, or
redeposited in body organs.
Data in Tables 10-37 and 10-38 were used together with the data in Table 10B-2 to
calculate the //g of particles per gram of lung tissue for each aerosol at each of the assumed
particle dissolution-absorption half-life times. Panels a, b, and c in Figure 10-57 show the
alveolar particle burdens normalized to lung tissue weight (//g particles per g lung tissue) for the
1.0 //m MMAD (og = 1.3) aerosol assuming particle dissolution-absorption half-times of 10,
100, and 1,000 days, respectively. Panels a, b, and c in Figure 10-58 show the alveolar particle
burdens normalized to lung tissue weight (//g particles per g lung tissue) for the 2.55 //m
MMAD (og = 2.4) aerosol assuming particle dissolution-absorption half-times of 10, 100, and
1,000 days, respectively. The rat alveolar burden is predicted to be greater than that of humans
if a dissolution-absorption half-time of 10 days is assumed but remains at lower alveolar particle
burdens than the humans if 100 or 1,000 days is assumed for the dissolution-absorption half-
time.
Figure 10-58 shows the rat and human alveolar particle burdens for the larger diameter and
more polydisperse aerosol (2.55 //m MMAD, og = 2.4). At short dissolution-absorption half-
times, the rat and human are predicted to have very similar alveolar particle burdens,
10-209
-------
10-3
01
c
3
(a)
T!
3
m 1-
a
a
a
0.1-
JOO-q
0.1
200
400
Days of Exposure
600
800
• Human
Rat
200
400
Days of Exposure
600
800
200
400
Days of Exposure
600
800
Figure 10-57. Predicted retained alveolar dose 0/g/g lung) in a normal augmenter human
or in a rat for exposure at 50 Mg/m3 to 1.0 //m mass median aerodynamic
diameter (MMAD) monodisperse (og = 1.3) aerosol, assuming a dissolution-
absorption half-time of (a) 10 days, (b) 100 days, or (c) 1,000 days.
10-210
-------
101
Rat
Human
800
800
200
400
Days of Exposure
600
800
Figure 10-58. Predicted retained alveolar dose 0/g/g lung) in a normal augmenter human
or in a rat for exposure at 50 Mg/m3 to 2.55 /j,m mass median aerodynamic
diameter (MMAD) polydisperse aerosol (og = 2.4), assuming a dissolution-
absorption half-time (a) of 10 days, (b) 100 days, or (c) 1,000 days.
10-211
-------
with the rat having a slightly greater burden at an assumed dissolution-absorpton half-time of
10-days. At an assumed dissolution-absorption half-time of 100 days, rat alveolar particle
burden less than that of humans. By 1000 days, the rat burden is considerably lower.
Panels (a) through (c) in Figure 10-59 show the rat to human alveolar retained dose ratios
(//g/d lung) for both aerosols and assuming particle dissolution-absorption half-times of 10, 100,
and 1,000 days, respectively. Because retention involves clearance processes that can translocate
particle mass, the particle mass burden was normalized to lung tissue weight (//g particles per g
lung tissue). These ratios could be calculated using Equation 10-54 and could be used for
interspecies extrapolation of "chronic" effects. Tables 10-38 and 10-39 provide the (AI^ term.
Tables 10-27 through 10-32 provide the (Frj term Normaiizing factor data and ventilation
rates for laboratory humans and laboratory animals are provided in Tables 10B-1 and 10B-2,
respectively. These figures present the RRDRA[ACT] values that would be applied to a given
concentration to calculate an FIEC for the rat for these simulated continuous exposures. It is
apparent that a substantial range of exposure concentrations would be required to produce the
same specific A burdens in these mammalian species, and the exposure concentrations depend
on the exposure protocol, or study duration. These results demonstrate the importance of
understanding respiratory, deposition, and physical clearance parameters of humans and
laboratory animals, as well as the dissolution-absorption characteristics of the inhaled particles.
This combination of factors results in significant species differences in A accumulation patterns
of inhaled particles during the course of repeated or chronic exposures which must be considered
in experiments designed to achieve equivalent alveolar burdens, or in evaluating the results of
inhalation exposures of different mammalian species to the same aerosolized test materials.
These retained dose ratios are different than those predicted for deposited dose, reflecting
both a difference in normalizing factor as well as differences in clearance rates and the
dissolution-absorption characteristics of the inhaled particles.
10.7.7 Summary
Major factors that affect the disposition (deposition, uptake, distribution, metabolism, and
elimination) of inhaled particles in the respiratory tract include physicochemical characteristics
of the inhaled aerosol (e.g., particle size, distribution, solubility,
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(0
E
£
o
"-5
tt
2-
2
= 1.0|jmMMAD,og=1.3
= 2.55 |jm MM AD, og= 2.4
(a)
(b)
200 400 600
Days of Exposure
800
Figure 10-59. Predicted alveolar region retained dose ratios in rats versus humans for
chronically inhaled exposure at 50 //g/m3 to 1.0 //m mass median
aerodynamic diameter (MMAD) monodisperse (og = 1.3) and 2.55 /j,m
MMAD polydisperse (og = 2.4) aerosols, assuming a dissolution- absorption
half-time of (a) 10 days, (b) 100 days, or (c) 1,000 days.
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hygroscopicity) and anatomic (e.g., architecture and size of upper and lower airways, airway
diameters, airway lengths, branching patterns) and physiological (e.g., ventilation rates,
clearance mechanisms) parameters of individual mammalian species.
Differences in susceptibility can be due to either differences in dosimetry (i.e., differences
in deposited and retained particle mass or number) or tissue sensitivity. The simulations
performed herein were limited to an exploration of differences in dosimetry. At present,
respiratory tract dosimetry must rely on many simplifications and empiricisms, but even a
somewhat rudimentary effort assists in linking exposure to potential effects, provides insight on
intrahuman variability, and aids interspecies extrapolations.
The objective of this exercise was to provide useful insights about dose metrics such as
average mass concentrations and average numbers of particles per unit area of respiratory
regions. Construction of more detailed theoretical or PBPK model structures to explore site-
specific dosimetry at the level of individual lung lobes awaits the availability of data with which
to estimate parameters.
Dose may be accurately described by particle deposition alone if the particles exert their
primary action on the surface contacted (Dahl et al., 1991), i.e., deposited dose may be an
appropriate metric for acute effects. For longer-term effects, the initially deposited dose may not
be as decisive a metric since particles clear at varying rates from different lung regions. To
characterize these effects, a retained dose that includes the effects of both deposition and
clearance is more appropriate. For the present document, average deposited particle mass
burden in each region of the respiratory tract was selected as the dose metric for "acute" effects
in both humans and laboratory animals. Average retained particle mass burden in each region
for humans and in the lower respiratory tract for laboratory animals was selected as the dose
metric for "chronic" effects. These choices were dictated by the availability of the dosimetry
models and the input of anatomical and morphometric information.
Ventilatory activity pattern and breathing mode (nose or mouth) were confirmed as major
factors affecting inhaled particle deposition. Variations in mass deposition fraction were shown
for adult males with a general population activity pattern versus adult male workers with light or
heavy activity patterns. Eight demographic groups were constructed that differed in ventilation
pattern by age, gender, and cardiopulmonary health status. In the alveolar (A) region, the cohort
of children 14 to 18 years showed slightly higher deposition of particles less than approximately
10-214
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0.1 (j,m when compared to the other cohorts, whereas the cohort of children 0 to 5 years showed
a decrease. When evaluated on the basis of daily mass deposition (//g/d), the cohort of children
ages 14 to 18 years showed an increase in deposition for all three regions of the respiratory tract
compared to other cohorts, whereas the cohort of children 0 to 5 years showed a decrease. This
is due primarily to differences in minute volume relative to lung size.
Other differences in dosimetry such as altered respiratory tract architecture with altered
flow pattern or differences in susceptibility of the target tissue are not addressed in these
simulations. As discussed earlier, Anderson et al. (1990) have shown enhanced deposition of
ultrafine particles in patients with COPD compared to healthy subjects. Miller et al. (1995) used
a more detailed theoretical multipath model and estimated enhanced deposition in a model of
compromised lung status defined by decreased ventilation to some parts of the respiratory tract.
The simulations performed herein were limited to average particle mass burdens in each region
of the respiratory tract. Nevertheless, these simulations do suggest differences for these cohorts.
For example, the cohort of children 14 to 18 years showed an enhanced deposition rate (ug/d)
for submicron-sized particles in all three respiratory tract regions whereas children 0 to 5 years
showed a decrease deposition rate relative to male and female adults. For larger particles
(micron-sized and above), the 14 to 18-year cohort showed no enhanced deposition rate in the
tracheobronchial or alveolar regions compared to adults, and younger children cohorts showed a
progressive decrease with decreasing age.
A number of simulations were performed in order to illustrate the relationship between
deposition efficiency of the respiratory tract, mass burden of particles in the thoracic portion of
the respiratory tract, and the mass distribution of aerosols collected by a PM10 or PM25 sampler.
Simulations were performed for single mode aerosols of different particle diameters. It is clear
that mouth (habitually oronasal) breathers have a greater deposition of particles >1 jim than do
normal augmenter (habitually nasal) breathers. Whereas PM10 accounts for all particles in the
thoracic size deposition mode, the PM2 5 sample does not include some larger particles that
would be deposited in the TB and A regions of mouth breathers, under the simulated conditions
(general population activity pattern 8 h sleep, 8 h sitting, 8 h light activity). Habitual oronasal
(mouth) breathers do not represent a large percentage of the population, but are cited here to
illustrate the difference effect of breathing habit.
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Because the real world situation is more complex and ambient aerosols are multi-modal
having a broad distribution of particle size and composition, similar simulations were performed
using ambient aerosols, as characterized for either Philadelphia or Phoenix. These simulations
of ambient aerosols showed that the PM25 sampler distribution accounts for the particle mass in
the fine (<1.0 |im) mode and the transition mode (MMAD -2.5 jim) but does not account for the
smaller mass of coarse mode particles that would be deposited in the thorax (mainly affecting
tracheobronchial deposition in mouth breathers). Failure of PM25 to account for coarse mode
particle thoracic deposition is more severe for the Phoenix aerosol than for the Philadelphia
aerosol.
Doses are conventionally expressed in terms of particle mass (gravimetric dose).
However, when different types of particles are compared, doses may be more appropriately
expressed as particle volume, particle surface area, or numbers of particles, depending on the
effect in question (Oberdorster et al., 1994). For example, the retardation of alveolar
macrophage-mediated clearance due to particle overload appears to be better correlated with
phagocytized particle volume rather than mass (Morrow, 1988). The smaller size fractions of
aerosols are associated with the bulk of surface area and particle number. That is, concentrations
in this size fraction are very small by mass but extremely high by number. The need to consider
alternative dose metrics such as number is accentuated when the high rate of deposition of small
particles in the lower respiratory tract (TB and A regions), the putative target for the mortality
and morbidity effects of PM exposures, is also taken into account. Simulations of particle
number deposition fraction for ambient aerosols characterized for Philadelphia and Phoenix
confirm that the fine mode contributes the highest deposition fraction in each region of the
respiratory tract. Particle numbers deposited per day were shown to be on the order of
100,000,000 and 1,000,000,000 for the fine mode of Philadelphia and Phoenix, respectively, for
hypothethical exposure to a total aerosol mass concentration of 50 //g/m3.
Inhalability is a major factor influencing interspecies variability. At the larger particle
diameters (MMAD > 2.5 //m for g = 1.3), the laboratory animal species have very little lower
respiratory tract deposition due to the low inhalability of these particles. This may help explain
why inhalation exposures of laboratory animals to high concentrations of larger diameter
particles have exhibited little effect in some bioassays.
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Simulations of retained particle burdens confirmed solubility as a major factor influencing
clearance. Assumptions with respect to dissolution-halftimes (10, 100, or 1,000 days) were
shown to dramatically influence the predicted particle mass burdens. Data on in vivo solubility
are needed to enhance modeling of clearance in all species. Retained particle burden
accumulates more rapidly and reaches a higher equilibrium burden when the particles are poorly
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APPENDIX 10A
PREDICTION OF REGIONAL DEPOSITION IN
THE HUMAN RESPIRATORY TRACT USING THE
INTERNATIONAL COMMISSION ON RADIOLOGICAL
PROTECTION PUBLICATION 66 MODEL
10A-1
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10A.1 INTRODUCTION
This Appendix gives an overview of how the regional deposition values that are calculated
using the ICRP's newly recommended model of the human respiratory tract (ICRP66, 1994)
compare with the available body of experimental data. A more complete description and
discussion of these data is given in Annexe D (James et al., 1994) of the ICRP66 report. That
Annexe also discusses both the theoretical model (Egan et al., 1989) of gas and aerosol particle
transport in the human respiratory tract, which underlies ICRP66's analysis of the experimental
data, and ICRP66's methodology in developing the recommended algebraic expressions to
predict regional deposition for various subjects.
The deposition of particles in the respiratory tract, and the underlying physical mechanisms
that determine regional deposition, have been intensively studied. However, in the main,
experimental data are available only for the adult Caucasian male, and for a limited range of
particle size (from about l-|im to 10-|im aerodynamic diameter), whereas the application of this
human respiratory tract model is required to be much broader. Because of the need to
extrapolate the available data to aerosol particles and vapors from atomic dimensions up to very
coarse wind-borne particles, and also to subjects of different body size and level of physical
exertion, the ICRP66 report applied both theoretical and/or empirical modeling methods, as
appropriate, to develop the recommended predictive deposition model.
Since the publication of ICRP's previous deposition model (TGLD, 1966; ICRP, 1979),
substantial progress has been made in theoretical modeling of aerosol transport and deposition
within the lungs (Taulbee and Yu, 1975; Pack et al., 1977; Yu, 1978; Nixon and Egan, 1987).
The development of this theoretical modeling approach was reviewed by Heyder and Rudolf
(1984). As a working hypothesis, the ICRP66 report utilized the particular formulation
described by Egan and Nixon (1985), and later improved by Egan et al. (1989), as the basis for
modeling regional aerosol deposition in the lungs of different subjects as a function of their
respiratory characteristics.
In parallel with this more fundamental approach to modeling in purely physical terms,
substantial developments have occurred in the analysis of measured particle deposition in the
respiratory tract in terms of empirically defined parameters (TGLD, 1966; Davies, 1972; Rudolf
et al., 1986, 1990). As a working hypothesis, the ICRP66 report utilized the parametric analysis
of regional lung deposition developed by Rudolf et al. (1990) to represent the results of complex
10A-2
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theoretical modeling by relatively simple algebraic approximations. The algebraic formulae so
developed and described in the Annexe to ICRP66 constitute ICRP's recommended respiratory
tract deposition model.
In ICRP66, and in this annex, the term "deposition" denotes the mean probability of an
inspired particle being deposited. The fraction of the number of inhaled particles deposited in
the whole respiratory tract is referred to as "total" deposition. The fraction of the number of
inhaled particles deposited in a single region of the respiratory tract is referred to as "regional"
deposition. The total deposition is therefore the sum of the regional deposition values. The term
"deposition efficiency" denotes the fraction of the number of particles that enter a single region
of the respiratory tract that is deposited in that region.
10A.2 EXTRATHORACIC DEPOSITION
The processes that govern deposition of particles in the extrathoracic region of the
respiratory tract, i.e., the nose, naso-oropharyngeal passages, and larynx, depend strongly on
particle size (as they do within the thoracic airways). In broad terms, particles with an
aerodynamic diameter larger than about 0.5 jim are deposited primarily by the so-called
"aerodynamic" transport processes of inertial motion, referred to as "impaction," and
gravitational settling, referred to as "sedimentation." For very large particles and fibers,
interception with surfaces in the extrathoracic airways also contributes to their deposition.
Particles with an equivalent physical diameter less than a few tenths of a micrometer are
deposited primarily by the "thermodynamic" transport process of Brownian "diffusion."
10A.2.1 Nasal Deposition
The aerodynamic filtration efficiency of the nose is much better documented than that of
any other part of the respiratory tract. A large number of studies have been reported for aerosols
with aerodynamic particle diameters above 0.2 jim. These studies have been reviewed by
Mercer (1975), Lippmann (1977), Yu et al. (1981), Schlesinger (1985a), and Stahlhofen et al.
(1989). As discussed in Annexe D of ICRP66, different experimental techniques and evaluation
procedures were used in the various studies, and the published data are not all directly
comparable. The artificial technique of measuring nasal deposition when aerosol particles were
drawn in continuously through the nose and exhausted through a filter at the mouth gave
10A-3
-------
generally lower values than other techniques which utilized normal breathing. Accordingly,
ICRP66 fitted the recommended empirical model of nasal deposition efficiency to the
experimental data obtained with normal breathing.
Figure 10A-1 shows the experimental data on the aerodynamic deposition efficiency of the
nose during normal inspiration, plotted as a function of the inertial impaction parameter, d^e V,
where dae is the aerodynamic particle diameter (in jim), and V is the volumetric flow rate (in cm3
s"1). Each of the studies by Lippmann (1970), Giacomelli-Maltoni et al. (1972), and Rudolf
(1975) exhibit a large degree of variability in nasal deposition measured in different subjects.
ICRP66 adopted the empirical analysis reported by Rudolf et al. (1986) and Stahlhofen et
al. (1989) to represent the trend of the mean of these data for aerodynamic deposition efficiency
of the nose on inhalation in terms of the impaction parameter, dae V. The recommended function
is shown in Figure 10A-l(a), together with the estimated 95% confidence bounds based on the
variability of the data. The fitted function accounts for the observed slow increase in deposition
efficiency for low values of dae V, and also predicts an asymptotic approach to unity for high
values of this impaction parameter. As shown in the figure, for intermediate values of dae V, the
predicted deposition efficiency is similar to that given by Pattle's (1961) log-linear
approximation, which was adopted by the Task Group on Lung Dynamics (TGLD, 1966).
Nasal deposition for submicron-sized particles has not been studied intensively in human
subjects. Accordingly, to define the "thermodynamic" deposition efficiency of the nose, ICRP66
relied on the experimental measurements made in hollow, anatomical casts of the nasal airways
(Swift et al., 1992). (See ICRP66 Annexe D for discussion of these data, and their empirical
representation).
10A.2.2 Oropharyngeal Deposition
Most experimental studies of oropharyngeal deposition have been performed with mouth
breathing through a tube, since this is a convenient method for aerosol administration. The oral
deposition was measured by repeated mouth-washings directly after inhalation. The remainder
of the extrathoracic deposition, i.e., that in the oropharynx and larynx, was measured by external
gamma counting. Emmett and Aitken (1982) showed that, for particles
10A-4
-------
4- Giacomelli-Maltom etal. (1972)
CD Martens and Jacob! (1973)
• Lippmann (1970)
X Rudolf (1975)
ICRP Publication 66 (1994)
--•TGLD(1966)
• , ,
*
1000
Impaction Parameter,
100,000
Stahlhofen etal. (1980,1981 a, 1983)
Lippmann (1977)
o Chan and Lippmann (1980)
ICRP Publication 66 (1994)
100 1000
Impaction Parameter, X
10,000
Figure 10A-1. Nasal deposition efficiency measured in adult Caucasian males during
normal breathing (A) and data on extrathoracic deposition when particles
are inhaled and exhaled through a mouthpiece (B). The solid curves show
the empirical model used in ICRP Publication 66 (1994). The outer curves
on either side represent the estimated 95% confidence bounds in predicted
extrathoracic deposition based on the variability of the data. The heavy
dashed line in (A) shows the expression for nasal deposition efficiency used
in the ICRP Publication 30 (1979) lung model (TGLD, 1966). The
impaction parameter, x, is described in the text as dae2 V° 6 VT ° 2
cm
1 2
s"'6).
Source: ICRP Publication 66 (1994).
10A-5
-------
less than about 10-|im aerodynamic diameter, the bulk of the extrathoracic deposition during
mouth breathing occurs in the larynx.
Figure 10A-l(b) compares the experimental data on extrathoracic deposition during mouth
breathing through tube mouthpieces obtained by Lippmann (1977), Chan and Lippmann (1980),
and Stahlhofen et al. (1980, 198la, 1983). Again, the measured variability in extrathoracic
deposition is high. The curves shown in the figure represent the empirical model adopted in
ICRP66 to describe the underlying trend of deposition efficiency as a function of an impaction
parameter, (see also Figure 10-22 of Chapter 10), together with the upper and lower 95%
confidence bounds of this estimate.
10A.2.3 Scaling for Body Size
Extrathoracic deposition has not been studied systematically in children, nor has the degree
to which the intersubject variability measured in adult subjects is related to variation in
anatomical dimensions. In the absence of data, ICRP66 utilized the dimensional scaling
procedure proposed by Swift (1989) to predict the effect of a subject's body size on nasal and
oropharyngeal deposition of particles in the aerodynamic size-range, and by Cheng et al. (1988)
to predict body-size effects on thermodynamic deposition efficiency, in relation to values
modeled for a reference adult male.
10A.3 REGIONAL LUNG DEPOSITION
Although the experimental data obtained for the adult human male are sufficient to model
empirically and accurately the deposition efficiency of the lungs as a whole, as a function of
breathing behavior and particle size (Rudolf et al., 1983, 1986), they are not complete enough
nor mutually consistent enough to define precisely the regional deposition in a reference adult
male, nor the effects of different airway size in other subjects. ICRP66 therefore used the
theoretical model developed by Egan and Nixon (1985), and Nixon and Egan (1987), as updated
by Egan et al. (1989), to predict the effects of breathing behavior and airway size on the
deposition of particles in discrete anatomical regions of the lungs, i.e., in the bronchial (BB),
bronchi olar (bb), and alveolar-interstitial (Al) airways, of various subjects. These theoretical
predictions formed the basis for the simplified algebraic model of regional deposition in the
10A-6
-------
lungs of various subjects that is recommended in ICRP66, and is applied in Chapter 10. The
model evaluates the combined effects of convective and diffusive gas transport, and aerosol loss
processes, within the airways of the lungs, on the basis of the mathematical formalisms
introduced by Taulbee and Yu (1975) and Pack et al. (1977).
10A.3.1 Comparison with Data from GSF Frankfurt Laboratory
Stahlhofen et al. (1980, 1981a,b, 1983) measured the fractional deposition of insoluble
monodisperse aerosols of iron oxide particles labeled with 198Au, in a total of nine different
subjects under closely controlled breathing conditions. In these tests, the subjects inhaled and
exhaled particles of various sizes through a mouthpiece, at a constant flow rate of either 250 cm3
s"1 or 750 cm3 s"1. Four different tidal volumes were studied: 250 cm3, 500 cm3, 1000 cm3 at the
flow rate of 250 cm3 s"1, and 1500 cm3 at the flow rate of 750 cm3 s"1. The fraction of inhaled
gamma activity deposited initially in the thorax was measured using a calibrated and
well-characterized array of collimated NaI(Tl)-detectors. The retention of the deposited iron
oxide particles in the lungs (obtained by correcting the thorax measurements for the activity of
particles cleared to the stomach) was followed in each subject for several days. In general, two
distinct phases of particle retention were observed: an initial rapid phase, succeeded by
continued slow clearance with a fitted half-time of several tens of days. The exponential
clearance curve fitted to the "slow-cleared" fraction was extrapolated back to the time of
exposure to define the complementary "fast-cleared" fraction of the initial lung deposit. The
"slow-" and "fast-cleared" fractions of the thoracic deposit are conventionally assumed to
represent particles deposited in the A region and tracheobronchiolar airways (BB and bb
regions), respectively.
To simulate these experimental data, ICRP66 utilized the theoretical deposition model of
Egan et al. (1989) to calculate the expected fractional deposition summed for all airways in the
A region and the combined BB and bb regions. Figures 10A-2 and 10A-3 compare the
theoretical predictions of tracheobronchiolar and alveolar-interstitial deposition, respectively,
with the "fast-" and "slow-cleared" fractions of thoracic deposition measured at the GSF
Frankfurt Laboratory.
It is seen from these figures that both measured fractions of the thoracic deposition exhibit
substantial variability under otherwise identical experimental conditions (as does the
10A-7
-------
c
o
u
ra
•o
0)
ra
4)
ui
(9
1.0
0.8
0.6
0.4
: 0.2
l/=250mLs'1;VT =1000mL
* Stahlhofen et al. (1980)
A Stahlhofen et al. (1981 a)
v Stahlhofen etal. (1981b)
— Deposition Theory
~ ~ Including Slow Mucus
v •*.
V= 750 mL s"1; VT = 1500
Stahlhofen etal. (1980)
0.8
0.6
0.4
0.2
-1.
l/=250mLs
1 Stahlhofen et al. (1983)
l/=250ml_s ,' l/T =250 ml
• Stahlhofen etal. (1983)
10 15 0 5
Particle Aerodynamic Diameter (|jm)
10
15
Figure 10A-2. Comparisons of the "fast-cleared" fraction of lung deposition measured at
the GSF Frankfurt Laboratory with the tracheobronchiolar deposition
predicted by the theoretical model (shown by the solid curves) of Egan et al.
(1989). The dashed curves show the effect on the predicted "fast-cleared"
fraction of allowing for slow clearance of a fraction of the number of
particles deposited in the tracheobronchiolar airways. This "slow-cleared"
fraction is assumed to tend to zero for large particles.
Source: ICRP Publication 66 (1994).
total thoracic deposition). It is also seen that, overall, the calculated deposition curves provide
an accurate prediction of the trends in measured values with particle aerodynamic diameter.
10A-8
-------
1.0
1/=250mLs-; VT =1000 ml
A Stahlhofen etal. (1980)
Stahlhofen era/. (1981 a)
Stahlhofen ef a/. (1981 b)
— Deposition Theory
- - Including Slow Mucus
V= 250 mL s'1; V-^ = 500 ml
Stahlhofen era/. (1983)
= 750 mL s'1; Vr = 1500 mL
Stahlhofen etal. (1980)
0.3
0.2
0.1
l/=250mLs'1;VT =250mL
A Stahlhofen ef al. (1983)
10 15 0 5
Particle Aerodynamic Diameter (u.m)
10
15
Figure 10A-3. Comparisons of the "slow-cleared" fraction of lung deposition measured
at the GSF Frankfurt Laboratory with the alveolar deposition predicted
by the theoretical model (shown by the solid curves) of Egan et al. (1989).
The dashed curves show the effect on the predicted "slow-cleared"
fraction of allowing for additional slow clearance of a fraction of the
number of particles deposited in the tracheobronchiolar airways.
Source: ICRP Publication 66 (1994).
In Figure 10A-2, except for the experiments carried out at a flow rate of 250 cm3 s"1
and a low tidal volume of 250 cm3 (Figure 10A-2(d)), it is seen that the predicted curves
match the measured "fast-cleared" fractions. The closest match is obtained for the
experiments carried out at a flow rate of 750 cm3 s"1 and tidal volume of 1500 cm3
10A-9
-------
approximates the breathing rate of ICRP66's "reference worker." The apparently poor match to
the data at low flow rate and low tidal volume arises principally from the two measurements for
12-|im-aerodynamic-diameter particles. Bronchial deposition efficiency for these particles
should clearly be substantially higher than for the next smallest particles (of 7.5-|im aerodynamic
diameter). The fact that the measured efficiency is lower suggests an experimental artifact in
correcting for extrathoracic particle losses.
On the whole, the predicted deposition fractions are seen to match the data with increased
accuracy as the particle aerodynamic diameter is increased. For several of the smallest particle
sizes studied, there is a general tendency for the predicted tracheobronchial deposition to be
higher than the measured "fast-cleared" fraction. However, for these particles (with
aerodynamic diameter less than about 5 jim), the fit of the predicted curves to the measured
values is significantly improved by allowing for the incomplete "rapid" clearance of particles
deposited in the human tracheobronchial tree that has been observed directly in other
experimental studies. Those studies were discussed in detail in Annexe E (Bailey and Roy,
1994) of ICRP66. Based on that discussion, ICRP66 concluded that, for particles with a
physical diameter of 2.5 jim or less, only 50% of the number deposited in the tracheobronchial
airways is cleared rapidly. The remaining 50% is cleared at a rate that is indistinguishable
experimentally from particles deposited in the alveolar-interstitial airways. For larger particles,
the fraction of the tracheobronchial deposition that is cleared slowly is found to decrease steeply
with particle size. The dashed curves shown in Figure 10A-2 make allowance for slow clearance
of a part of the tracheobronchial deposition. It is seen that, by making this allowance, the fit of
the predicted "fast-cleared" fraction to the measured values is improved.
Figure 10A-3 compares the experimental data and theoretical predictions of the
complementary "slow-cleared" fraction of lung deposition. For particles with aerodynamic
diameter 5 jam or greater, the fit between predicted and measured values is generally good.
Allowance for part of the predicted tracheobronchiolar deposition being cleared slowly is again
seen to improve the predictions for smaller particles.
10A-10
-------
10A.3.2 Comparison with Data for Polystyrene Particles
The GSF Laboratory used a so-called "academic" breathing pattern, in which the subject
inhaled and exhaled at a closely controlled rate. Other investigators exposed their subjects under
so-called "spontaneous" breathing conditions, where the subject maintains a more natural
variation in flow rate through the breathing cycle, but is trained to achieve a relatively constant
tidal volume and respiratory frequency. In this manner, Foord et al. (1978) measured the
fractional deposition of 99mTc-labelled polystyrene particles in the mouth and lungs of 15
different subjects. The lung deposition was divided into a "tracheobronchiolar" fraction, which
was assumed to consist of the activity cleared from the lungs within 24 h of inhalation, and the
remaining "pulmonary" fraction. These authors used three different sizes of particles, i.e.,
2.5-|im, 5-|im, and 7.5-|im diameter, and studied regional deposition for several different
breathing patterns. Figure 10A-4 shows their results for 6 subjects (with an average tidal
volume of 1 L, and a mean respiratory frequency of 10 min"1), together with the deposition of
99mTc-labelled polystyrene particles in the lungs of 12 different subjects measured by Emmett
and Aitken (1982), using the same breathing pattern.
The figure shows that, after correcting for the extrathoracic deposition measured for each
test, the recommended lung deposition model accurately matches the trend of tracheobronchiolar
"deposition" with particle size measured by Foord et al (1978). (See panel labeled "TB"). The
calculated curve here includes ICRP66's recommended allowance for an assumed fraction of
50% the TB deposition of the 2.5-|im particles not being cleared from the TB region within the
24-h measurement period. The tracheobronchiolar deposition reported by Emmett and Aitken
(1982), i.e., the activity deposited in the lungs that is cleared within 24 h, is generally higher
than that found by Foord et al. (1978), with relatively little variability between the three subjects
studied at each particle size.
The panel labeled "A" in Figure 10A-4 shows the measured values of activity deposited in
the lungs that was retained longer than 24 h. In this case, the data of Foord et al. are generally
higher than the modeled values, while Emmett and Aitken's values are lower by a similar factor.
Both sets of data show a similar trend of "slow-cleared" lung deposition with particle size to that
modeled, but with higher or lower absolute values, respectively, for the same breathing pattern.
10A-11
-------
0.8
§
s
0.6
8
ffl
.1
0.4
0.2 ~
TB
I
I
4 6 8 10
Aerodynamic Diameter dim)
12
468
Aerodynamic Diameter (jim)
10
Figure 10A-4. Comparison of fractional deposition measured by Foord et al. (1978)
(solid triangles) and Emmett and Aitken (1982) (open triangles) in
different subjects with values given by the International Commission on
Radiological Protection (ICRP) Publication 66 (1994) lung model (solid
curves). The fractional deposition shown has been adjusted to
correspond to zero extrathoracic deposition in the tracheobronchial (TB)
and alveolar (A) regions. The dashed curves represent the upper and
lower 95% confidence bounds of regional deposition predicted for an
individual subject by the ICRP lung model.
Source: ICRP Publication 66 (1994).
10A-12
-------
When the experimental data on thoracic deposition in "fast-" and "slow-cleared" fractions
are pooled, as is done in Figure 10A-4, the deposition model recommended in ICRP66
represents the data as a whole. It is also seen from Figure 10A-4 that ICRP66's estimated 95%
confidence bounds on regional lung deposition predicted for individual subjects include all but 3
of the data points.
10A.3.3 Comparison with Data for Submicron-Sized Particles
For particles in the submicron, thermodynamic size range (with equivalent diameter
between about 5 nm and 0.2 |im), extrathoracic deposition during mouth breathing (in the oral
cavity and larynx) is small compared to that in the lungs. Schiller et al. (1986) measured the
total respiratory tract deposition for several subjects exposed via a mouthpiece to monodisperse,
uncharged spherical particles of silver over a range of particle diameter extending from 5 nm to
about 0.2 jim. These experimental results were corrected by Gebhart et al. (1989) for the effects
of instrumental dead space, which tended to reduce the measured deposition fraction for
nanometer-sized particles. Egan and Nixon (1989) compared the resulting mean values of total
thoracic deposition with the values predicted by the theoretical model developed by Egan et al.
(1989). These authors showed that the theoretically modeled fractional deposition in the lungs
matches the measured values. Figure 10A-5 shows that the calculated values also represent the
data obtained earlier for hydrophobic submicron-sized spheres of aluminosilicate by Tu and
Knutson (1984).
10A.3.4 Influence of "Controlled" Versus "Spontaneous" Breathing
The data from the GSF Frankfurt Laboratory shown above apply to controlled breathing at
a constant inspiratory and expiratory flow rate, whereas, during normal spontaneous breathing,
the flow rate varies throughout each breath in an approximately sinusoidal manner. However,
Heyder et al. (1982) showed in a study of 20 different subjects that the mean total deposition for
spontaneous breathing is virtually identical to that for controlled breathing at the same average
flow rate. Heyder et al.'s data are given in Figure 10A-6, together with the values predicted for a
reference male subject by the ICRP66 lung model. It is seen that, for both controlled and
spontaneous mouth breathing, there is a large amount of variation
10A-13
-------
80
70
60
£, 50
§
s
to
g. 40
8
30
20
10
A Subject K-1000 mL
• Subject Y-1000 mL
° Subject Y-750 mL
ICRP 66-1000 mL
ICRP66-750mL
B
0
0.01
I
0.1
Particle Diameter (urn)
Figure 10A-5. Comparison of total respiratory tract deposition of submicron-sized
alumino-silicate particles measured by Tu and Knutson (1984) in two
subjects (at tidal volumes of 1000 mL or 750 mL), with the values
calculated as a function of particle diameter by Egan et al. (1989).
The ICRP Publication 66 (1994) lung model reproduces these calculated
values.
Source: ICRP Publication 66 (1994).
between different subjects, although in any one subject under controlled breathing conditions,
total deposition measurements are highly repeatable (Heyder et al., 1982).
10A-14
-------
Spontaneous Breathing
1.0
o
15
a
o
0.8 —
0.6 —
0.4 —
0.2 —
246
Particle Diameter (urn)
Controlled Breathing
1.0
0.8
0.6
0.4
0.2
B
Single Subject
Different Subjects
ICRPPublication66
I I i
024 68
Particle Diameter (urn)
Figure 10A-6. Comparison of the distributions of total respiratory tract deposition
measured in 20 different subjects (A) breathing spontaneously at rest or
(B) breathing at a controlled rate at rest. In case (A), the individual
mean flow rate varied from 220 to 740 mL/s, with a collective mean value
of 380 mL/s. In case (B), the mean flow rate was held constant at
400 mL/s for each subject. Each box shown in the figure represents one
experimental measurement. Shaded boxes represent repeat
measurements on a single subject (see inset key in bottom figure). The
curves show values predicted by the ICRP Publication 66 (1994) model.
Source: ICRP Publication 66 (1994).
10A-15
-------
10A.3.5 Comparison with Data for Iron Oxide Particles from New York
University
Lippmann (1977) and Chan and Lippmann (1980) reported measurements of lung
deposition and 24-h retention in a large number of different subjects at New York University
(NYU). These studies involved iron oxide particles tagged in aqueous suspension with 99mTc
(Wales et al., 1980). Each subject was allowed to breath normally, and the average tidal volume
and breathing frequency were monitored. Typical values of these respiratory parameters were
500 cm3 s"1 and 15 min"1, respectively.
Figure 10A-7 shows the values of "fast-" and "slow-cleared" lung deposition obtained in
these studies at NYU (adjusted from the measured value to zero extrathoracic deposition). In
common with the earlier theoretical lung deposition models described by Yeh and Schum (1980)
and Yu and Diu (1982b), and with the NCRP's currently proposed lung model, ICRP66's
deposition model predicts substantially less bronchial ("fast-cleared") deposition for particles of
aerodynamic diameter larger than 1 jim than is indicated by the bulk of the NYU data.
Likewise, the predicted alveolar ("slow-cleared") deposition for particles of about l-|im
aerodynamic diameter is also low compared to the NYU data.
These data from NYU provide an excellent measure of intersubject variability in the
deposition efficiencies of the tracheobronchiolar and alveolar-interstitial regions of the lungs.
However, according to ICRP66's review of the literature, the interpretation of the NYU results is
complicated by the possibility that the labeled iron oxide particles used may have grown
hygroscopically in the humid air of the respiratory tract. Monodisperse iron oxide particles are
produced by atomization of an aqueous suspension of colloidal iron oxide with a spinning top
generator (Albert et al., 1964; Lippmann and Albert, 1967; Stahlhofen et al., 1979). The
colloidal suspension is prepared by converting iron chloride in aqueous solution by hydrolysis to
iron oxide. In order to remove all traces of the dissolvable chloride, the aqueous iron oxide
colloid must be dialyzed extremely thoroughly.
Gebhart et al. (1988) used light-scattering photometry to examine the effect of the degree
to which a suspension of colloidal iron oxide is dialyzed on the hygroscopicity of the resulting
monodisperse particles, by comparing the physical properties of these particles on inhalation and
exhalation. These authors found that even when the particles are produced from extremely well
dialyzed iron oxide there is a distinct change in light-scattering
10A-16
-------
1 10
Aerodynamic Diameter (urn)
100
0.1
1 10
Aerodynamic Diameter (urn)
Chan & Lippmann (1980) • Lippmann (1977)
Figure 10A-7. Experimental data on deposition efficiency of the tracheobronchial (TB)
region and fractional deposition in the alveolar (A) region for the large
group of subjects studied at New York University (NYU). These subjects
inhaled monodisperse particles of iron oxide through a mouthpiece at a
tidal volume of approximately 1000 mL and respiratory frequency of
15/min. The measured values are normalized to zero extrathoracic
deposition. The curves show the corresponding values predicted by the
NCRP (proposed) and ICRP Publication 66 (1994) models. Two curves
are shown for the ICRP 66 model: (1) "no growth" represents the values
calculated on the assumption that the size of the iron oxide particles was
stable in the respiratory tract, and (2) "with growth" represents the
partial hygroscopic growth of similar particles indicated by the
experimental study of Gebhart et al. (1988). The lower figure (marked
as "A") also shows the characteristic particle collection efficiency curve
for a PM10 sampler.
Source: Adapted from ICRP Publication 66 (1994).
10A-17
-------
properties between the inhaled and exhaled particles. Since the total respiratory tract deposition
of these particles was indistinguishable from that of oil droplets of the same aerodynamic size in
ambient air, Gebhart et al. (1988) concluded that their measured shift in optical properties was
caused by the presence of a thin film of condensed water on the surface of the exhaled particles.
Using this same technique on a sample of the dialyzed iron oxide suspension prepared at
NYU by their published method (Wales et al., 1980), Gebhart et al. (1988) found a much greater
shift in light-scattering properties of the final monodisperse particles between inhalation and
exhalation. This observed shift in light-scattering properties was accompanied by increased total
respiratory tract deposition compared with that of oil droplets of the same aerodynamic size in
ambient air. The deposition measured under identical exposure conditions was found to increase
from 44% for the hydrophobic oil droplets to 68% for the iron oxide particles. The same change
in measured respiratory tract deposition would be obtained by inhaling oil droplets of 3.8-|im
aerodynamic diameter in place of the 2.4-|im-aerodynamic-diameter iron oxide particles.
The ICRP66 report includes a recommended method for extending the algebraic deposition
model to evaluate regional lung deposition for aerosols that are subject to hygroscopic particle
growth. Figure 10A-7 shows the effect on the modeled fast- and slow-cleared lung deposition
including in the calculation the rate of hygroscopic growth of the NYU iron oxide particles that
was derived from the results of the Gebhart et al. (1988) study. It is seen that this correction of
the modeled lung deposition improves substantially the overall fit of the predicted values to the
measurements.
10A-18
-------
APPENDIX 10B
SELECTED MODEL PARAMETERS
10B-1
-------
TABLE IQB-l(a). BODY WEIGHT AND RESPIRATORY TRACT REGION SURFACE AREAS
Respiratory Tract Surface Areas
Body Weight (kg) Lung Weight (g)
o
td
K>
73.0
TABLE
Activity
Pattern
Adult male,
general
population
Adult male,
light work
Adult male,
heavy work
1,100
10B-l(b). HUMAN ACTIVITY PATTERNS AND
Sleeping Sitting
(.45 m3/h) (.54 m3/h)
Hours Total m3 Hours Total m3
8 3.6 8 4.32
8 3.6 6.5 3.5
8 3.6 4 2.16
ET (cm2) TB (cm2)
470
2,690
ASSOCIATED RESPIRATORY MINUTE
Activity Light
(1.5m3/h)
Hours Total m3
8 12
8.5 12.75
10 15
Activity Heavy
(3.0m3/h)
Hours Total m3
0 0
1 3
2 6
A(m2)
54.0
VENTILATION
Total/Day
Hours Total m3
24 19.9
24 22.85
24 26.76
international Commission on Radiological Protection (ICRP66, 1994).
-------
TABLE 10B-2. BODY WEIGHTS, LUNG WEIGHTS, RESPIRATORY MINUTE VENTILATION, AND RESPIRATORY
TRACT REGION SURFACE AREA FOR SELECTED LABORATORY ANIMAL SPECIES
Lung
Body Weight Weight13
Species
Mouse (B6C3F1)
Syrian hamster
Rat (F344)
Guinea pig
Monkey
Dog
(kg)
0.037a
0.134a
0.380a
0.890a
2.5C
10.0d
(R)
0.43b
1.54b
4.34b
10.1b
28. Ob
110.0d
Minute
Ventilation13
Minute
Ventilation
per g lung
(L/min) (1/min • g lung)
0.044a
0.057a
0.253a
0.286a
0.789b
2.39b
0.063
0.049
0.040
0.034
0.028
0.022
Respiratory Region Surface Area
ET (cm2
3a
14a
15a
30a
NAe
NAe
) TB (cm
3.5a
20.0a
22.5a
200a
NAe
NAe
2) A(m2)
0.05a
0.30a
0.34a
0.90a
4.3f
42.5f
o
td
aU.S. Environmental Protection Agency (1994, 1988a). Default values for male laboratory animals in chronic bioassays.
bStahl, 1967: lung weight in g = 11.3 • (kg BW)°"; minute ventilation = 379 • (kg BW)08.
Thalen(1984).
dCuddihyetal. (1972).
"Not available.
fScaled from results of dogs and baboons in Crapo et al. (1983).
-------
8 12 16
Hour of the Day
24
zu •
To
ID
4A •
Elderly Male (over 65 yr)
••<
^•H
5L
h^M
S
>.6L
^
r
f
1:
•••*
3.8L
I f
^
13.0L
X,
8 12 16
Hour of the Day
20
24
8 12 16
Hour of the Day
24
Figure 10B-1. Daily minute volume pattern for male demographic groups. The average
rates for each of four time intervals are shown. Total volume (m3)
breathed in 24 hours for male worker (18-44 yr) is 19.4; for elderly male
(over 65 yr) is 18.1; and for compromised subjects is 17.4.
10B-4
-------
Female worker (18-44 yr)
8 12 16
Hour of the Day
20
24
Elderly Female (over 65 yr)
8 12 16
Hour of the Day
20
24
Figure 10B-2. Daily minute volume pattern for female demographic groups. The
average rates for each of four tune intervals are shown. Total volume
(m3) breathed in 24 hours for female worker (18-44 yr) is 16.5 and for
elderly female (over 65 yr) is 16.1.
10B-5
-------
-------
APPENDIX IOC
SELECTED AMBIENT AEROSOL
PARTICLE DISTRIBUTIONS
10C-1
-------
0)
8
7
E 6
o
E 5 -
3 3 -
EAAC_]
220
245
Electrical aerosol analyzer^>
2 -
1 -
0.002
0.01
1
10
100
DP (|jm)
Figure 10C-1. An example of histogram display and fitting to log-normal functions for
particle-counting size distribution data. Instruments used and the range
covered by each are shown. Counts are combined into reasonably-sized
bins and displayed. Lognormal functions, fitted to the data, are shown
with geometric mass median diameter (MMD) of each mode and the width
(og) of each mode. Data taken from a study of fine sulfate and other
particles generated by catalyst equipped cars as part of a cooperative study
by EPA and General Motors Corporation. Note the clear separation of the
nuclei mode (MMD = 0.018 /j,m), the accumulation mode (MMD = 0.21 /j,m)
and coarse mode (MMD = 4.9 /j,m). Fine particles, as defined by Whitby
(1978), include the nuclei and accumulation mode.
Source: Wilson et al. (1977).
10C-2
-------
o
TABLE 10C-1 DISTRIBUTION OF PARTICLE COUNT, SURFACE AREA OR MASS IN THE
TRIMODAL POLYDISPERSE AEROSOL DEFINED IN FIGURE 10C-1
(The tabulated numbers represent the upper size cut [in jim] for each particle size interval based on the distribution of particle
count vs. physical diameter [d p{c}], distribution of surface area vs. physical diameter [dp{s|], distribution of mass vs. physical
diameter [dn{m}], or distribution of mass vs. Aerodynamic diameter [dae{m}]a.)
Percent of Total Count,
Aerosol Mode
Accumulation11
Intermodal0
Coarse4
Particle Parameter
count; dp{c}
surface; dp{s}
mass; dp{m}
mass; dae{m}
count; dp{c}
surface; dp{s}
mass; dp{m}
mass; dae{m}
count; dp{c}
surface; dp{s}
mass; dp{m}
mass; dq(,{m}
1
0.0053
0.0058
0.0060
0.0056
0.044
0.050
0.053
0.044
0.915
1.06
1.14
1.40
5
0.0073
0.0080
0.0083
0.078
0.066
0.075
0.080
0.066
1.40
1.63
1.75
2.14
10
0.0087
0.0094
0.010
0.093
0.081
0.093
0.099
0.083
1.76
2.04
2.20
2.68
20
0.011
0.012
0.012
0.011
0.105
0.120
0.128
0.108
2.32
2.69
2.89
3.52
Surface Area or Mass Associated with Particles
30
0.012
0.013
0.014
0.013
0.127
0.145
0.154
0.131
2.83
3.28
3.53
4.29
40
0.014
0.015
0.016
0.015
0.149
0.170
0.181
0.155
3.35
3.88
4.18
5.08
50
0.016
0.017
0.018
0.017
0.173
0.197
0.210
0.180
3.93
4.55
4.90
5.95
60
0.018
0.019
0.020
0.019
0.201
0.228
0.244
0.211
4.60
5.34
5.75
6.98
70
0.020
0.022
0.023
0.022
0.235
0.268
0.286
0.248
5.45
6.32
6.81
8.27
Smaller than Size
80
0.024
0.026
0.027
0.025
0.283
0.323
0.345
0.301
6.66
7.71
8.30
10.1
90
0.029
0.032
0.033
0.031
0.367
0.418
0.447
0.437
8.76
10.2
10.9
13.2
Cut
95
0.034
0.037
0.039
0.037
0.454
0.517
0.551
0.485
11.0
12.7
13.7
16.6
99
0.047
0.051
0.054
0.051
0.676
0.768
0.820
0.725
16.8
19.5
20.9
25.3
^Values for dae were calculated iterative ly from dp using Equations D. 13 and D. 14 of ICRP Publication 66, Annexe D
(James et al, 1994).
bMass median aerodynamic diameter (MMAD) = 0.018 (jm; geometric standard deviation (og) = 1.6; density (p) =1.4 g/cm3.
CMMAD = 0.21
dMMAD = 4.9 ^
m; og = 1.8; p = 1.2 g/cm3.
; o = 1.87; p = 2.2 g/cm3.
-------
TABLE 10C-2a. DISTRIBUTION OF PARTICLE NUMBER IN THE
TRIMODAL POLYDISPERSE AEROSOL DEFINED IN FIGURE 10C-1
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% number fractiles.
The "nuclei mode" contains about 99.6% of the total number of particles;
the "accumulation mode" about 0.39%; and the "coarse mode" about Q.01%.)
Mode Number Fractile (%)
Nuclei3 1
5
10
20
30
40
50
60
70
80
90
95
99
Accumulation13 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
1.0
4.0
5.0
10
10
10
10
10
10
10
10
5.0
4.0
0.004
0.0159
0.0198
0.0397
0.0397
0.0397
0.0397
0.0397
0.0397
0.0397
0.0397
0.0198
0.0159
Upper Limit of Particle
Size Interval (|im)
0.0027
0.0038
0.0045
0.0055
0.0064
0.0073
0.0082
0.0092
0.0105
0.0122
0.0149
0.0177
0.0244
0.0156
0.0233
0.0289
0.0374
0.0450
0.0528
0.0613
0.0711
0.0834
0.101
0.130
0.161
0.241
10C-4
-------
TABLE 10C-2a (cont'd). DISTRIBUTION OF PARTICLE NUMBER IN THE
TRIMODAL POLYDISPERSE AEROSOL DEFINED IN FIGURE 10C-1
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% number fractiles.
The "nuclei mode" contains about 99.6% of the total number of particles;
the "accumulation mode" about 0.39%; and the "coarse mode" about Q.01%.)
Mode Number Fractile (%)
Coarse0 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
2.7 >
1.1 >
1.3 >
2.7 >
2.7 >
2.7 >
2.7 >
2.7 >
2.7 >
2.7 >
2.7 >
1.3 >
1.1 >
< 10'7
< ID'6
< 10'6
< 10'6
< ID'6
< 10'6
< 10'6
< ID'6
< 10'6
< ID'6
< 10'6
; 10'6
= ID'6
Upper Limit of Particle
Size Interval (|im)
0.283
0.432
0.543
0.716
0.873
1.03
1.21
1.42
1.68
2.05
2.71
3.40
5.21
aMass median diameter (MMD) = 0.018 (jm; geometric standard deviation (og) = 1.6;
density (p) =1.4 g/cm3.
bMMD = 0.21 ^m; og = 1.8; density (p) = 1.2 g/cm3.
CMMD = 4.9 ^m; o = 1.87; density (p) = 2.2 g/cm3.
10C-5
-------
TABLE 10C-2b. DISTRIBUTION OF PARTICLE SURFACE AREA IN THE
TRIMODAL POLYDISPERSE AEROSOL DEFINED IN FIGURE 10C-1
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% surface area fractiles.
The "nuclei mode" contains about 77.4% of the total particle surface area; the
'accumulation mode" about 21.9%; and the "coarse mode" about Q.64%.)
Mode Surface Area Fractile (%)
Nuclei3 1
5
10
20
30
40
50
60
70
80
90
95
99
Accumulation13 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.78
3.1
3.9
7.8
7.8
7.8
7.8
7.8
7.8
7.8
7.8
3.9
3.1
0.22
0.89
1.1
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
1.1
0.89
Upper Limit of Particle
Size Interval (|im)
0.0043
0.0059
0.0070
0.0086
0.0100
0.0113
0.0127
0.0144
0.0163
0.0189
0.0233
0.0277
0.0381
0.0312
0.0465
0.0575
0.0746
0.0899
0.105
0.122
0.142
0.167
0.201
0.260
0.322
0.481
10C-6
-------
TABLE 10C-2b (cont'd). DISTRIBUTION OF PARTICLE SURFACE AREA IN THE
TRIMODAL POLYDISPERSE AEROSOL DEFINED IN FIGURE 10C-1
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% surface area fractiles.
The "nuclei mode" contains about 77.4% of the total particle surface area; the
'accumulation mode" about 21.9%; and the "coarse mode" about Q.64%.)
Mode Number Fractile (%)
Coarse0 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.006
0.026
0.032
0.064
0.064
0.064
0.064
0.064
0.064
0.064
0.064
0.032
0.026
Upper Limit of Particle
Size Interval (|im)
0.618
0.947
1.19
1.57
1.91
2.27
2.65
3.11
3.69
4.50
5.92
7.44
11.4
aMass median diameter (MMD) = 0.018 (jm; geometric standard deviation (og) = 1.6;
density (p) =1.4 g/cm3.
bMMD = 0.21 ^m; og = 1.8; density (p) = 1.2 g/cm3.
CMMD = 4.9 ^m; o = 1.87; density (p) = 2.2 g/cm3.
10C-7
-------
TABLE 10C-2c. DISTRIBUTION OF PARTICLE MASS IN THE
TRIMODAL POLYDISPERSE AEROSOL DEFINED IN FIGURE 10C-1
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% mass fractiles.
The "nuclei mode" contains 15.6% of the total particle mass; the "accumulation
mode" 38.7%; and the "coarse mode" about 45.7%.)
Mode Mass Fractile (%)
Nuclei3 1
5
10
20
30
40
50
60
70
80
90
95
99
Accumulation13 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.16
0.63
0.79
1.58
1.58
1.58
1.58
1.58
1.58
1.58
1.58
0.79
0.63
0.39
1.56
1.95
3.91
3.91
3.91
3.91
3.91
3.91
3.91
3.91
1.95
1.56
Upper Limit of Particle
Size Interval (|im)
0.0053
0.0073
0.0087
0.0107
0.0124
0.0141
0.0159
0.0179
0.0203
0.0236
0.0290
0.0345
0.0474
0.0312
0.0465
0.0575
0.0746
0.0899
0.105
0.122
0.142
0.167
0.201
0.260
0.322
0.481
10C-8
-------
TABLE 10C-2c (cont'd). DISTRIBUTION OF PARTICLE MASS IN THE
TRIMODAL POLYDISPERSE AEROSOL DEFINED IN FIGURE 10C-1
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% mass fractiles.
The "nuclei mode" contains 15.6% of the total particle mass; the "accumulation
mode" about 38.7%; and the "coarse mode" about 45.7%.)
Mode Number Fractile (%)
Coarse0 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.46
1.85
2.31
4.62
4.62
4.62
4.62
4.62
4.62
4.62
4.62
2.31
1.85
Upper Limit of Particle
Size Interval (|im)
0.915
1.40
1.76
2.32
2.83
3.35
3.93
4.60
5.45
6.66
8.76
11.0
16.9
aMass median diameter (MMD) = 0.018 (jm; geometric standard deviation (og) = 1.6;
density (p) =1.4 g/cm3.
bMMD = 0.21 ^m; og = 1.8; density (p) = 1.2 g/cm3.
CMMD = 4.9 ^m; o = 1.87; density (p) = 2.2 g/cm3!.
10C-9
-------
0)
o
90.0
Philadelphia-WRAC
1.0 10.0
Aerodynamic Diameter, pe (|jm)
100.0
Phoenix-WRAC
Mode
1
2
3
MMAD oq %Mass
0.188 1.54 22.4
1.70 1.90 13.8
16.4 2.79 63.9
1.0 10.0
Aerodynamic Diameter, pe (|jm)
100.0
Figure 10C-2. Impactor size distribution measurement generated by Lundgren et al. with
the Wide Range Aerosol Classifier: (a) Philadelphia and (b) Phoenix. Note
the much larger, small size tail to the coarse mode in the dryer environment
of Phoenix.
Source: Lundgren and Hausknecht (1982).
10C-10
-------
o
O
TABLE 10C-3. DISTRIBUTION OF PARTICLE COUNT, SURFACE AREA OR MASS IN THE
TRIMODAL POLYDISPERSE AEROSOL FOR PHILADELPHIA DEFINED IN FIGURE 10C-2(a)
(The tabulated numbers represent the upper size cut [in jim] for each particle size interval based on the distribution of particle
count vs. aerodynamic diameter [dae{c}], distribution of surface area vs. aerodynamic diameter [dae{s|], distribution of mass vs.
aerodynamic diameter [dae{m}], or distribution of mass vs. equivalent physical diameter [dn{m}]a.)
Percent of Total Count,
Aerosol Mode
Accumulation11
Intermodal0
Coarse4
Particle Parameter
count; dae{c}
surface; dae{s}
mass; dae{m}
mass; dp{m}
count; dae{c}
surface; dae{s}
mass; dae{m}
mass; dp{m}
count; dae{c}
surface; dae{s}
mass; dae{m}
Mass; dp{m}
1
0.152
0.162
0.167
0.185
1.53
1.54
1.55
1.67
3.43
4.29
4.80
5.16
5
0.201
0.214
0.221
0.243
1.70
1.72
1.73
1.86
5.80
7.25
8.12
8.73
10
0.233
0.249
0.257
0.282
1.79
1.80
1.81
1.95
7.67
9.60
10.7
11.5
20
0.280
0.298
0.308
0.336
1.92
1.93
1.94
2.09
10.8
13.5
15.1
16.2
Surface Area or Mass Associated with Particles Smaller than Size Cut
30
0.319
0.340
0.351
0.383
2.01
2.03
2.04
2.20
13.8
17.2
19.2
20.6
40
0.357
0.381
0.393
0.428
2.09
2.11
2.12
2.28
16.9
21.2
23.7
25.5
50
0.396
0.422
0.436
0.474
2.17
2.19
2.20
2.37
20.6
25.7
28.8
30.9
60
0.440
0.469
0.484
0.526
2.26
2.28
2.29
2.47
25.0
31.3
35.0
37.6
70
0.492
0.525
0.541
0.587
2.35
2.37
2.38
2.56
30.8
38.6
43.2
46.4
80
0.561
0.597
0.618
0.670
2.47
2.49
2.50
2.69
39.4
49.2
55.1
59.2
90
0.673
0.717
0.741
0.802
2.63
2.66
2.67
2.87
55.3
69.0
77.3
83.0
95
0.781
0.831
0.860
0.930
2.78
2.80
2.81
3.02
73.1
91.4
102.1
109.7
99
1.03
1.10
1.13
1.22
3.06
3.09
3.11
3.34
122.5
153.5
171.5
184.2
^Values for dp were calculated iteratively from dae using Equations D. 13 and D. 14 of ICRP Publication 66, Annexe D (James et al., 1994).
bMass median aerodynamic diameter (MMAD) = 0.436 (jm; geometric standard deviation (og) = 1.51; density (p) =1.3 g/cm3.
CMMAD = 2.20 ^m; og = 1.16; p = 1.3 g/cm3.
dMMAD = 28.8 pm; o = 2.16; p = 1.3 g/cm3.
-------
TABLE 10C-4a. DISTRIBUTION OF PARTICLE NUMBER IN THE
TRIMODAL POLYDISPERSE PHILADELPHIA AEROSOL DEFINED IN
FIGURE 10C-2a (Each individual mode of the trimodal aerosol is separated into the size
fractions containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% number
fractiles. The "accumulation mode" contains about 99.95% of the total number of
particles; the "intermodal mode" about 0.05%; and the "coarse mode" about Q.004%.)
Mode Number Fractile (%)
Accumulation" 1
5
10
20
30
40
50
60
70
80
90
95
99
Intermodalb 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
1.0
4.0
5.0
10
10
10
10
10
10
10
10
5.0
4.0
4.8 x 1C'4
1.9 x 1C'3
2.4 x 1C'3
4.8 x 1Q-3
4.8 x 1Q-3
4.8 x 1C'3
4.8 x 1C'3
4.8 x 1C)'3
4.8 x 1C)'3
4.8 x icr3
4.8 x icr3
2.4 x icr3
1.9 x icr3
Upper Limit of Particle
Size Interval (|im)
0.0912
0.121
0.140
0.168
0.192
0.215
0.238
0.264
0.296
0.337
0.404
0.469
0.623
1.43
1.60
1.68
1.79
1.88
1.96
2.03
2.12
2.20
2.31
2.47
2.59
2.89
10C-12
-------
TABLE 10C-4a (cont'd). DISTRIBUTION OF PARTICLE NUMBER IN THE
TRIMODAL POLYDISPERSE PHILADELPHIA AEROSOL DEFINED IN
FIGURE 10C-2a (Each individual mode of the trimodal aerosol is separated into the size
fractions containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% number
fractiles. The "accumulation mode" contains about 99.95% of the total number of
particles; the "intermodal mode" about 0.05%; and the "coarse mode" about Q.004%.)
Mode Number Fractile (%)
Coarse0 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
4.4 x lO'5
1.8 x lO'4
2.2 x 1Q-4
4.4 x lO'4
4.4 x lO'4
4.4 x lO'4
4.4 x 1Q-4
4.4 x lO'4
4.4 x lO'4
4.4 x lO'4
4.4 x 1Q-4
2.2 x lO'4
1.8 x lO'4
Upper Limit of Particle
Size Interval (|im)
0.579
0.979
1.30
1.82
2.32
2.86
3.48
4.22
5.21
6.65
9.34
12.3
20.9
aMass median aerodynamic diameter (MMAD) = 0.436 (jm; geometric standard deviation (og) = 1.51;
density (p) =1.3 g/cm3.
bMMAD = 2.20 ^m; og =1.16; density (p) = 1.3 g/cm3.
CMMAD = 28.8 pm; og = 2.16; density (p) = 1.3 g/cm3.
10C-13
-------
TABLE 10C-4b. DISTRIBUTION OF PARTICLE SURFACE AREA IN THE
TRIMODAL POLYDISPERSE PHILADELPHIA AEROSOL DEFINED IN
FIGURE 10C-2a (Each individual mode of the trimodal aerosol is separated into the size
fractions containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% surface area
fractiles. The "accumulation mode" contains about 95.4% of the total particle surface
area; the "intermodal mode" about 2.5%; and the "coarse mode" about 2.1%.)
Mode Surface Area Fractile (%)
Accumulation" 1
5
10
20
30
40
50
60
70
80
90
95
99
Intermodalb 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.96
3.9
4.8
9.6
9.6
9.6
9.6
9.6
9.6
9.6
9.6
4.8
3.9
0.025
0.10
0.13
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.13
0.10
Upper Limit of Particle
Size Interval (|im)
0.128
0.170
0.197
0.236
0.269
0.301
0.334
0.371
0.415
0.473
0.568
0.659
0.875
1.50
1.66
1.75
1.88
1.96
2.05
2.13
2.21
2.30
2.41
2.57
2.73
3.02
10C-14
-------
TABLE 10C-4b (cont'd). DISTRIBUTION OF PARTICLE SURFACE AREA IN THE
TRIMODAL POLYDISPERSE PHILADELPHIA AEROSOL DEFINED IN
FIGURE 10C-2a (Each individual mode of the trimodal aerosol is separated into the size
fractions containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% surface area
fractiles. The "accumulation mode" contains about 95.4% of the total particle surface
area; the "intermodal mode" about 2.5%; and the "coarse mode" about 2.1%.)
Mode Surface Area Fractile (%)
Coarse0 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.02
0.08
0.11
0.21
0.21
0.21
0.21
0.21
0.21
0.21
0.21
0.11
0.08
Upper Limit of Particle
Size Interval (|im)
1.90
3.20
4.24
5.95
7.60
9.37
11.4
13.8
17.0
21.8
30.5
40.4
68.1
aMass median aerodynamic diameter (MMAD) = 0.436 (jm; geometric standard deviation (og) = 1.51;
density (p) =1.3 g/cm3.
bMMAD = 2.20 Mm; og =1.16; density (p) = 1.3 g/cm3.
CMMAD = 28.8 pm; o = 2.16; density (p) = 1.3 g/cm3.
10C-15
-------
TABLE 10C-4c. DISTRIBUTION OF PARTICLE MASS IN THE
TRIMODAL POLYDISPERSE PHILADELPHIA AEROSOL DEFINED IN
FIGURE 10C-2a (Each individual mode of the trimodal aerosol is separated into the size
fractions containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% mass fractiles.
The "accumulation mode" contains 48.2% of the total particle mass; the "intermodal
mode" 7.4%; and the "coarse mode" 44.3%.)
Mode Mass Fractile (%)
Accumulation" 1
5
10
20
30
40
50
60
70
80
90
95
99
Intermodalb 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.49
2.0
2.4
4.9
4.9
4.9
4.9
4.9
4.9
4.9
4.9
2.4
2.0
0.07
0.30
0.37
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.37
0.30
Upper Limit of Particle
Size Interval (|im)
0.152
0.201
0.233
0.280
0.319
0.357
0.396
0.440
0.492
0.561
0.673
0.782
1.04
1.53
1.70
1.79
1.92
2.01
2.09
2.17
2.26
2.35
2.47
2.63
2.78
3.06
10C-16
-------
TABLE 10C-4c (cont'd). DISTRIBUTION OF PARTICLE MASS IN THE
TRIMODAL POLYDISPERSE PHILADELPHIA AEROSOL DEFINED IN
FIGURE 10C-2a (Each individual mode of the trimodal aerosol is separated into the size
fractions containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% mass fractiles.
The "accumulation mode" contains 48.2% of the total particle mass; the "intermodal
mode" 7.4%; and the "coarse mode" 44.3%.)
Mode Mass Fractile (%)
Coarse0 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.45
1.8
2.2
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
2.2
1.8
Upper Limit of Particle
Size Interval (|im)
3.43
5.80
7.67
10.8
13.7
16.9
20.6
25.0
30.8
39.2
55.0
72.4
118.7
aMass median aerodynamic diameter (MMAD) = 0.436 (jm; geometric standard deviation (og) = 1.51;
density (p) =1.3 g/cm3.
bMMAD = 2.20 Mm; og =1.16; density (p) = 1.3 g/cm3.
CMMAD = 28.8 pm; o = 2.16; density (p) = 1.3 g/cm3.
10C-17
-------
o
O
i
oo
TABLE 10C-5. DISTRIBUTION OF PARTICLE COUNT, SURFACE AREA OR MASS IN THE TRIMODAL
POLYDISPERSE AEROSOL FOR PHOENIX DEFINED IN FIGURE 10C-2(b) (The tabulated numbers represent the upper
size cut [in um] for each particle size interval based on the distribution of particle count vs. aerodynamic diameter [dae{c|],
distribution of surface area vs. aerodynamic diameter [dae{s|], distribution of mass vs. aerodynamic diameter [d^jm}], or
distribution of mass vs. equivalent physical diameter [dn{m}]a.)
Percent of Total Count,
Aerosol Mode
Accumulation11
Intermodal0
Coarse4
Particle Parameter
count; dae{c}
surface; dae{s}
mass; dae{m}
mass; dp{m}
count; dae{c}
surface; dae{s}
mass; dae{m}
mass; dp{m}
count; dae{c}
surface; dae{s}
mass; dae{m}
mass; dp{m}
1
0.062
0.066
0.069
0.062
0.302
0.353
0.381
0.353
0.831
1.24
1.51
1.41
5
0.083
0.089
0.092
0.083
0.469
0.548
0.592
0.552
1.67
2.49
3.03
2.34
10
0.097
0.104
0.108
0.098
0.592
0.691
0.747
0.697
2.43
3.61
4.40
4.13
20
0.118
0.126
0.131
0.119
0.785
0.916
0.991
0.926
3.81
5.67
6.92
6.50
Surface Area or Mass Associated with Particles Smaller than Size Cut
30
0.135
0.145
0.150
0.137
0.962
1.12
1.21
1.13
5.28
7.85
9.58
8.99
40
0.152
0.163
0.169
0.155
1.14
1.34
1.45
1.36
6.97
10.4
12.7
11.9
50
0.169
0.182
0.188
0.172
1.35
1.57
1.70
1.59
9.04
13.4
16.4
15.4
60
0.189
0.203
0.210
0.193
1.58
1.85
2.00
1.87
11.7
17.4
21.3
20.0
70
0.212
0.228
0.236
0.217
1.89
2.20
2.38
2.23
15.5
23.0
28.1
26.4
80
0.243
0.261
0.271
0.250
2.31
2.70
2.91
2.73
21.4
31.9
38.9
36.5
90
0.295
0.316
0.327
0.303
3.06
3.58
3.87
3.63
33.7
50.0
61.1
57.4
95
0.345
0.369
0.383
0.355
3.87
4.52
4.89
4.59
48.8
72.6
88.4
83.0
99
0.461
0.495
0.511
0.475
5.96
6.95
7.52
7.06
97.4
144.8
176.9
166.2
^Values for dp were calculated iteratively from dae using Equations D. 13 and D. 14 of ICRP Publication 66, Annexe D (James et al., 1994).
bMass median aerodynamic diameter (MMAD) = 0.188 (jm; geometric standard deviation (og) = 1.54; density (p) = 1.7 g/cm3.
CMMAD = 1.70 ^m; og = 1.90; p = 1.7 g/cm3.
dMMAD = 16.4 ^m; o = 2.79; p = 1.7 g/cm3.
-------
TABLE 10C-6a. DISTRIBUTION OF PARTICLE NUMBER IN THE
TRIMODAL POLYDISPERSE PHOENIX AEROSOL DEFINED IN FIGURE 10C-2b
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% number fractiles.
The "accumulation mode" contains about 99.6% of the total number of particles; the
"intermodal mode" about 0.3%; and the "coarse mode" about Q.1%.)
Mode Number Fractile (%)
Accumulation3 1
5
10
20
30
40
50
60
70
80
90
95
99
Intermodalb 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
1.0
4.0
5.0
10
10
10
10
10
10
10
10
5.0
4.0
0.0034
0.014
0.017
0.034
0.034
0.034
0.034
0.034
0.034
0.034
0.034
0.017
0.014
Upper Limit of Particle
Size Interval (|im)
0.0353
0.0475
0.0556
0.0672
0.0771
0.0867
0.0967
0.108
0.122
0.139
0.169
0.197
0.264
0.0878
0.136
0.172
0.228
0.280
0.333
0.391
0.461
0.548
0.673
0.891
1.13
1.74
10C-19
-------
TABLE 10C-6a (cont'd). DISTRIBUTION OF PARTICLE NUMBER IN THE
TRIMODAL POLYDISPERSE PHOENIX AEROSOL DEFINED IN FIGURE 10C-2b
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% number fractiles.
The "accumulation mode" contains about 99.6% of the total number of particles; the
"intermodal mode" about 0.3%; and the "coarse mode" about Q.1%.)
Mode Number Fractile (%)
Coarse0 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
9.3 >
3.7 >
4.6 >
9.3 >
9.3 >
9.3 >
9.3 >
9.3 >
9.3 >
9.3 >
9.3 >
4.6 >
3.7 >
< ID'4
< 10'3
< 10'3
< 10'3
< 10'3
< 10'3
< 10'3
< 10'3
< 10'3
< 10'3
< 10'3
< 10'3
< 10'3
Upper Limit of Particle
Size Interval (|im)
0.0353
0.0711
0.103
0.162
0.224
0.296
0.385
0.499
0.658
0.912
1.43
2.08
4.18
aMass median aerodynamic diameter (MMAD) = 0.188 (jm; geometric standard deviation (og) = 1.54;
density (p) =1.7 g/cm3.
bMMAD = 1.70 ^m; og = 1.90; density (p) = 1.7 g/cm3.
CMMAD = 16.4 ^m; o = 2.79; density (p) = 1.7 g/cm3.
10C-20
-------
TABLE 10C-6b. DISTRIBUTION OF PARTICLE SURFACE AREA IN THE
TRIMODAL POLYDISPERSE PHOENIX AEROSOL DEFINED IN FIGURE 10C-2b
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% surface area fractiles.
The "accumulation mode" contains about 85.5% of the total particle surface area; the
"intermodal mode" about 7.4%; and the "coarse mode" about 7.0%.)
Mode Surface Area Fractile (%)
Accumulation" 1
5
10
20
30
40
50
60
70
80
90
95
99
Intermodalb 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.86
3.5
4.3
8.6
8.6
8.6
8.6
8.6
8.6
8.6
8.6
4.3
3.5
0.075
0.30
0.37
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.37
0.30
Upper Limit of Particle
Size Interval (|im)
0.0514
0.0689
0.0807
0.0977
0.112
0.126
0.141
0.157
0.176
0.202
0.244
0.285
0.385
0.202
0.311
0.392
0.520
0.637
0.758
0.892
1.05
1.25
1.53
2.03
2.57
3.97
10C-21
-------
TABLE 10C-6b (cont'd). DISTRIBUTION OF PARTICLE SURFACE AREA IN THE
TRIMODAL POLYDISPERSE PHOENIX AEROSOL DEFINED IN FIGURE 10C-2b
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% surface area fractiles.
The "accumulation mode" contains about 85.5% of the total particle surface area;
the "intermodal mode" about 7.4%; and the "coarse mode" about 7.0%.)
Surface Area
Mode Fractile (%)
Coarse0 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.07
0.29
0.36
0.71
0.71
0.71
0.71
0.71
0.71
0.71
0.71
0.36
0.29
Upper Limit of Particle
Size Interval (|im)
0.290
0.583
0.847
1.33
1.84
2.43
3.16
4.09
5.40
7.48
11.8
17.1
34.4
aMass median aerodynamic diameter (MMAD) = 0.188 (jm; geometric standard deviation (og) = 1.54;
density (p) =1.7 g/cm3.
bMMAD = 1.70 Mm; og = 1.90; density (p) = 1.7 g/cm3.
CMMAD = 16.4 ^m; o = 2.79; density (p) = 1.7 g/cm3.
10C-22
-------
TABLE 10C-6c. DISTRIBUTION OF PARTICLE MASS IN THE
TRIMODAL POLYDISPERSE PHOENIX AEROSOL DEFINED IN FIGURE 10C-2b
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% mass fractiles.
The "accumulation mode" contains 22.4% of the total particle mass; the "intermodal
mode" 13.8%; and the "coarse mode" 63.9%.)
Mode Mass Fractile (%)
Accumulation3 1
5
10
20
30
40
50
60
70
80
90
95
99
Intermodalb 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.23
0.91
1.1
2.3
2.3
2.3
2.3
2.3
2.3
2.3
2.3
1.1
0.91
0.14
0.56
0.70
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
0.70
0.56
Upper Limit of Particle
Size Interval (|im)
0.0618
0.0832
0.0973
0.118
0.135
0.152
0.169
0.189
0.213
0.243
0.295
0.345
0.462
0.302
0.469
0.592
0.785
0.962
1.14
1.35
1.58
1.89
2.31
3.06
3.87
6.00
10C-23
-------
TABLE 10C-6c (cont'd). DISTRIBUTION OF PARTICLE MASS IN THE
TRIMODAL POLYDISPERSE PHOENIX AEROSOL DEFINED IN FIGURE 10C-2b
(Each individual mode of the trimodal aerosol is separated into the size fractions
containing the 1, 5,10, 20, 30, 40, 50, 60, 70, 80, 90, 95, and 99% mass fractiles.
The "accumulation mode" contains 22.4% of the total particle mass; the "intermodal
mode" 13.8%; and the "coarse mode" 63.9%.)
Mode Mass Fractile (%)
Coarse0 1
5
10
20
30
40
50
60
70
80
90
95
99
Percent of Trimodal
Aerosol
0.65
2.6
3.2
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
3.2
2.6
Upper Limit of Particle
Size Interval (|im)
0.831
1.67
2.43
3.81
5.27
6.96
9.03
11.7
15.5
21.4
33.5
48.4
94.1
aMass median aerodynamic diameter (MMAD) = 0.188 (jm; geometric standard deviation (og) = 1.54;
density (p) =1.7 g/cm3.
bMMAD = 1.70 Mm; og = 1.90; density (p) = 1.7 g/cm3.
CMMAD = 16.4 urn; o = 2.79; density (p) = 1.7 g/cm3.
10C-24
-------
11. TOXICOLOGICAL STUDIES OF
PARTICULATE MATTER
11.1 INTRODUCTION
This chapter assesses results of exposure to paniculate matter (PM) in controlled human
clinical studies, selected occupational studies, and animal toxicology studies. It focuses mainly
on those studies published since the 1982 Air Quality Criteria Document for Particulate Matter
and Sulfur Oxides (U.S. Environmental Protection Agency, 1982), emphasizing coverage of
selected constituents of ambient air PM that may contribute to those types of health effects found
by epidemiological studies discussed in Chapter 12 of this document. The data discussed in
Chapter 12 indicate that increased levels of PM in the ambient atmosphere are associated with
increased mortality risk, especially among the elderly (aged 65+ years) and individuals with
preexisting cardiopulmonary diseases, such as chronic obstructive pulmonary disease (COPD),
pneumonia, and chronic heart disease. The epidemiology studies also provide evidence for
associations of ambient PM exposures with increased risk of respiratory and cardiovascular
morbidity effects (e.g., increased hospital admissions or emergency room visits for asthma or
other respiratory problems, increased incidence of respiratory symptoms, or alterations in
pulmonary function).
Chronic obstructive pulmonary disease is defined as a disease state characterized by the
presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction
is generally progressive, may be accompanied by airway hyperreactivity, and may be partially
reversible (American Thoracic Society, 1995). The biological responses occurring in the
respiratory tract following controlled PM inhalation encompass a continuum of changes,
including changes in pulmonary function, respiratory symptoms (i.e., wheeze, coughing, etc.),
inflammation, and tumor formation. The responses observed are dependent on the
physicochemical characteristics of the parti culate matter, the total exposure and the health status
of the host. However, many of the responses are usually seen only at distinctly higher level
exposures characteristic of occupational and laboratory animal studies but not at typically much
lower ambient particle concentrations.
11-1
-------
Particulate matter is a broad term that encompasses thousands of chemical species, many of
which have not been investigated in controlled laboratory animal or human studies. However, a
full discussion of all the types of particles that have been studied is well beyond the scope of this
chapter. Thus, criteria were used to select topics for presentation. High priority was placed on
studies that: (1) may elucidate health effects of major common constituents of ambient PM
(e.g., sulfates, carbon, silica) and/or (2) contribute to enhanced understanding of the
epidemiological studies (e.g., real-world particles, "surrogate" particles; or particles with low
inherent toxicity that may cause effects due to their generic nature as a particle, such as their
ultrafine size). Based on these criteria, full summaries of acid aerosols, ultrafme particles, real-
world particles, and "surrogate" particles are provided.
Diesel exhaust particles generally fit the criteria; but, because they are described in great
detail elsewhere (U.S. Environmental Protection Agency, 1994; Health Effects Institute, 1995),
they are only summarized briefly here. Diesel particles also differ from other particles in this
classification because they are regulated pursuant to mobile source sections of the Clean Air Act
(g/mi emission standards), although there is still a relationship of these regulations to the PM10
standard. Medium priority was placed on particles with high inherent toxicity that are of
concern primarily because of point source emissions and more local exposures (as contrasted to
ubiquitous pollutants). Metals having air concentrations greater than 0.5 //g/m3 were placed in
this class. The health effects of particles in this prioritization class are summarized far more
briefly here. It must be emphasized that this prioritization is not related to a judgement or
decision about potency or health risk. For example, it should not be inferred that on an
individual exposure basis, a "high priority" particle is of more inherent health concern than a
"medium priority" particle. The split is primarily related to regulatory issues. The Clean Air
Act requires a criteria document for criteria pollutants. Except for lead, individual metals are
not criteria pollutants. Rather, they are regulated as hazardous air pollutants under the Clean Air
Act. Thus, their inclusion here is only intended to be generally instructive because they can be
part of the complex mixture of PM in the ambient air.
As noted above, lead is a criteria air pollutant that, like paniculate matter, is also regulated
under Sections 108 and 109 of the Clean Air Act. Earlier extensive evaluations in Air Quality
Criteria for Lead (U.S. Environmental Protection Agency, 1977) led to setting of
11-2
-------
the current National Ambient Air Quality Standard (primary as well as secondary) for lead at
1.5 //g/m3 on a quarterly average basis (Federal Register, 1978 [51594]). Subsequent to
promulgation of that standard, the U.S. Environmental Protection Agency issued a revised Air
Quality Criteria for Lead (1986a) and a Supplement (U.S. Environmental Protection Agency,
1990). These and other such assessments found blood lead levels of 10 //g/dl in young children
and women of child bearing age (due to risk to the fetus in utero) to be associated with
unacceptable risk of slowed prenatal and postnatal growth and neuropsychological development.
Air levels below 0.50 to 0.75 //g/m3 lead have been proposed as adequate to protect against such
risk (World Health Organization, 1987). Typical ambient air levels of lead in U.S. urban areas
almost invariably now fall below 0.10 to 0.25 //g/m3. The reader is referred to the above-noted
air quality criteria documents/supplement and Federal Register notices concerning the lead
National Ambient Air Quality Standard for detailed information on particulate lead health
effects.
In some widespread geographic areas of the United States, silica can be among major
ambient PM constituents and is discussed briefly here. The reader is referred to more extensive
evaluation of silica elsewhere (U.S. Environmental Protection Agency, 1996). Asbestos fibers
are also well established as a fibrogenic pollutant and they are known to cause mesothelial
tumors following chronic exposures in laboratory animals. However, asbestos is not discussed
as a separate entity in the present document, but reviews on asbestos effects can be found
elsewhere (U.S. Environmental Protection Agency, 1986b; Mossman and Gee, 1989; Rom, et
al., 1991; Health Effects Institute, 1991).
The effects of exposure to combinations of particles or particles and gases are important to
understand because people are not exposed to single ambient air pollutants. The responses to
pollutant mixtures may be different from those of the individual chemical constituents. Effects
can be additive, antagonistic, or synergistic. Controlled exposure studies of humans or animals
rarely involve more than two pollutants simultaneously or sequentially. Significant exceptions
to this are the bodies of work on diesel and gasoline engine emissions, where the exposure has
been to the specific mixture. In studies involving more complex mixtures (e.g., ambient air) it is
difficult, if not impossible, to assess the relative contributions of individual specific components.
-------
The different nature of the data bases also influences the structure of the chapter. For example,
community epidemiology studies that sought associations between health effects and some type
of ambient PM metric are described in Chapter 12 to permit full portrayal and integrated
evaluation of the results. For the metals and diesel particles, discussed to reach a different goal,
epidemiological studies are included here in Chapter 11 to facilitate a full hazard identification,
and as appropriate, exposure-response information. Besides the summary of the effects portion
of the literature, this chapter also attempts to identify and characterize key factors that may have
significant influences on the health effects of PM.
Most of the investigations reported herein were conducted with laboratory animals, raising
the question of their quantitative extrapolation to humans. Of the dosimetric and species
sensitivity aspects of extrapolation, most is known about the former, which is presented in
Chapter 10. Both Chapters 10 and 11 must be jointly considered for interpretation. For
example, was one aerosol more toxic than another because it had a greater deposition in a
sensitive lung target site or because it had higher potency?
Similarly, most particles considered in the laboratory animal toxicology and occupational
studies are mainly in the fine and coarse mode size range. However, the enormous numbers and
huge surface area of the ultrafine particles demonstrate the importance of considering the size of
the particle. Ultrafine particles with a diameter of 20 nm when inhaled at the same mass
concentration have an approximately 6 orders of magnitude higher number concentration than a
2.5 //m diameter particle; particle surface area is also greatly increased (Table 11-1).
TABLE 11-1. NUMBERS AND SURFACE AREAS OF MONODISPERSE
PARTICLES OF UNIT DENSITY OF DIFFERENT SIZES AT A MASS
CONCENTRATION OF 10
Particle Diameter Particle Number Particle Surface Area
//m _ per cm3 Air _ //m2 per cm3 Air
0.02
0.1
0.5
1.0
2.5
2,400,000
19,100
153
19
1.2
3,016
600
120
60
24
Source: Oberdorster et al. (1995a).
11-4
-------
Most of the laboratory animal and occupational epidemiological studies summarized here
used high paniculate mass concentrations, relative to ambient, even when laboratory animal-to-
human dosimetric differences are considered. This raises a question about the relevance of, for
example, a rat study at 5,000 //g/m3 in terms of direct extrapolation to humans in ambient
exposure scenarios.
In spite of these difficulties, the array of laboratory animal studies does illustrate certain
toxicological principles for particles. To identify but a few here, the data base clearly shows that
the site of respiratory tract deposition (and hence particle size) influences the health outcome and
that toxicity is dependent on the chemical species (e.g., cadmium is different from sulfuric acid,
and cadmium chloride is different from cadmium oxide).
11.2 ACID AEROSOLS
The ubiquitous presence of acidic aerosols in the ambient air and concern about their
potential health effects led to considerable research over the past 15 years on the response of
humans and laboratory animals to exposure to acid aerosols. In Section 11.2.1, responses of
both healthy and sensitive humans to acid aerosols and acidic aerosol mixtures with other
pollutants are reviewed. Human studies primarily consider brief exposures, whereas the
laboratory animal toxicology studies discussed in Section 11.2.2 also consider the effects of
chronic exposure to acid aerosols and acidic aerosol mixtures.
Section 11.2 focuses mainly on sulfate-related species (e.g., sulfuric acid [H2SO4]).
Information on certain other aerosol species (e.g., nitrates) was reviewed in the previous PM/SOX
CD (U.S. Environmental Protection Agency, 1982), the EPA Acid Aerosols Issue Paper (U.S.
Environmental Protection Agency, 1989), and the Oxides of Nitrogen Criteria Document (U.S.
Environmental Protection Agency, 1993). Those earlier assessments yielded only very limited
information indicative of health effects being associated with exposures to aerosol species such
as sodium nitrate (NaNO3) or ammonium nitrate (NH4NO3) at levels very much in excess of
ambient (i.e., at three orders of magnitude [about 1000 times] above nitrate concentrations
typically found in ambient air). Ambient levels of airborne nitrate salts are typically less than 5
Mg/m3 and rarely exceed 50 //g/m3 (Sackner et al., 1979). Given that little, if any, important new
information on nitrate-related health
11-5
-------
effects has appeared in the past few years since the above noted assessments were completed,
they are not treated further here, except as components of some particle mixtures discussed later
in the chapter.
11.2.1 Controlled Human Exposure Studies
11.2.1.1 Introduction
Human clinical exposure studies utilize controlled laboratory conditions to test responses
to atmospheric pollutants. Advantages include the opportunity to study the species of interest
(i.e., humans), and the ability to carefully control the atmosphere with regard to pollutant
concentration, aerosol characteristics, temperature, and relative humidity. Concentrations can be
varied while other conditions are held constant to determine exposure-response relationships.
Mixtures of pollutants or sequential exposures to different pollutants can be used to elucidate
interactions.
Methods of inhalation used in clinical studies include mouthpiece, face mask, head-dome,
and environmental chamber. Breathing through a mouthpiece alters breathing patterns, and
bypasses the normal filtering and humidifying role of the nasal passages, thereby increasing
delivery of particles to the lower airways. Environmental chamber and head-dome exposures
allow the assessment of shifts between nasal and oral-nasal breathing that normally occur with
exercise.
Several factors limit the utility of human clinical studies. To meet legal and ethical
requirements, exposures must be without significant harm. Studies are typically limited to short-
term exposures, since long-term exposures are impractical, and may be more likely to cause
harm. Sample sizes are small, and therefore may not be representative of populations at risk.
Finally, individuals likely to be at greatest risk (i.e., the very young and very old, those with
severe obstructive lung disease, or combined heart and lung disease) have not been studied. The
data from human clinical studies should therefore be used together with information from
laboratory animal exposure studies, epidemiologic studies, and in vitro exposure studies, in the
process of health assessment.
The endpoints most commonly measured in human clinical studies are symptoms and
pulmonary function tests. The latter are well standardized, and their use in these studies has
been reviewed (Utell et al., 1993). Effects in clinical studies can be directly compared to
11-6
-------
acute changes in field studies, as has been done extensively in studies of ozone health effects
(U.S. Environmental Protection Agency, 1995).
Airway responsiveness is another endpoint commonly measured in human clinical studies.
This test measures changes in lung function in response to pharmacologic bronchoconstricting
agents, typically methacholine, carbachol, or histamine (see also Section 11.2.1.4). A
dose-response curve is obtained for the agent, and airway responsiveness is expressed as the dose
of the bronchoconstricting agent resulting in a specific change in lung function: e.g., the PD20 is
the provocative dose resulting in a 20% fall in forced expiratory volume in 1 sec (FEVj).
Individuals with asthma almost always have hyperresponsive airways, with a PD20 well below
the normal range. Increase in airway reactivity in response to pollutant exposure could reflect
airway inflammation or edema. However, smaller airway caliber as a consequence of the
exposure will also increase measured responsiveness because of factors related to airways
geometry. It is therefore important to measure responsiveness at a time when spirometric
function has returned to baseline. Likewise, performing airway challenge testing prior to
pollutant exposure may alter subsequent lung function responses to the pollutant by changing the
baseline airways caliber. Differences among laboratories in the protocols and provocative agents
used for airway challenge make comparison of experimental results problematic.
Endpoints in human clinical studies have extended beyond measures of air flow and lung
volume. Mucociliary clearance is measured using inhaled radio-labelled aerosols. As reviewed
in the Acid Aerosols Issue Paper (U.S. Environmental Protection Agency, 1989), exposure to
acid aerosols alters mucociliary clearance in humans as well as in several laboratory animal
species. Within the past decade, fiberoptic bronchoscopy has been used to examine the lower
respiratory tract in healthy volunteers exposed to pollutants. Cells that populate the alveolar
space, including alveolar macrophages (AM), lymphocytes, and polymorphonuclear leukocytes
(PMN), can be recovered by bronchoalveolar lavage (BAL); bronchial epithelial cells can be
sampled using bronchial brushing and endobronchial biopsies. Nasal lavage can be used to
quantitate inflammation in the nose.
Features of experimental design of particular importance with regard to human clinical
studies are method of exposure, exercise, and selection of control exposures. Exposure by
mouthpiece reduces humidification of inhaled air that normally occurs in the nasal passages;
11-7
-------
inhalation of dry cold air into the airways may cause bronchoconstriction in asthmatic subjects.
Exercise plays an important role in enhancing pollutant effects by causing a change from nasal
to oral-nasal breathing, hence decreasing upper airways deposition, and by increasing pollutant
dose through increased minute ventilation (VE).
Selection of control exposures is of particular importance. Typically, each subject serves
as his/her own control to eliminate intersubject variability. The control atmosphere depends on
the study objectives and may consist of clean air, or, when acidic aerosols are being tested, a pH
neutral aerosol, such as sodium chloride (NaCl), to distinguish non-specific effects of the aerosol
from pollutant or hydrogen ion (H+) effects. It is important that control exposures be performed
under similar conditions of temperature, relative humidity, VE, and time of day; that control and
pollutant exposure be separated by sufficient time to avoid carry-over effects; and that the order
of the exposures be randomized among the study group. Double blind procedures (by which
neither the investigators collecting data nor the subjects know the contents of exposure
atmospheres) should be used to the extent possible.
Human exposure studies of the effects of acid aerosols were reviewed in the Acid Aerosols
Issue Paper (U.S. Environmental Protection Agency, 1989). That review reached the following
conclusions:
(1) In healthy subjects, no effects on spirometry have been observed after exposure to
concentrations of H2SO4 less than 500 //g/m3, and no consistent effects have been
observed at levels up to 1,000 //g/m3 with exposure durations up to 4 h. Studies of a
variety of other sulfate and nitrate aerosols have similarly demonstrated an absence
of spirometric effects on healthy subjects.
(2) Combinations of sulfates with ozone or SO2 have not demonstrated synergistic
or interactive effects.
(3) Asthmatic subjects experience modest bronchoconstriction after exposure to -400 to
1000 //g/m3 H2SO4, and small decrements in spirometry have been observed in
adolescent asthmatics at concentrations as low as 68 //g/m3 for 30 min.
(4) Some studies suggest that delayed effects may occur in healthy and asthmatic
subjects following exposure to H2SO4.
(5) Effects of sulfate aerosols are related to their acidity, and neutralization by oral
ammonia tends to mitigate these effects.
11-8
-------
(6) Exposure to H2SO4 at concentrations as low as 100 //g/m3 for 60 min alters
mucociliary clearance.
(7) Airway reactivity increases in healthy and asthmatic subjects following exposure to
1,000 Mg/m3 H2SO4 for 16 min.
(8) Differences in estimated respiratory intake explain only a portion of the differences
in responses among studies.
In the five years since the publication of the Acid Aerosol Issue Paper, several of these
summary statements have been further confirmed. For example, recent studies confirm the
absence of spirometric effects following acute exposure to H2SO4 and other acid aerosols in
healthy subjects, at or below 1,000 //g/m3. The observation of effects on adolescent asthmatics
at levels as low as 68 //g/m3 has not been confirmed, and studies utilizing longer exposures have
raised further questions about the relationship between dosimetry and health effects. However,
additional evidence supports the conclusion that lung function effects in asthmatic subjects are
related to hydrogen ion exposure, which is in part determined by the degree of neutralization by
oral ammonia. Two recent studies examining sequential exposure to H2SO4 and ozone (Linn et
al., 1994; Frampton et al., 1995) suggest that acid aerosols may potentiate the response to ozone
in some asthmatic subjects. Finally, clinical studies of acid aerosols have been expanded to
include endpoints associated with fiberoptic bronchoscopy and BAL.
Table 11-2 summarizes, in alphabetical order by author, controlled human exposure studies
of particle exposure published since 1988. The majority of the human clinical studies have
focused on the pulmonary function effects of exposure to acid aerosols. These studies are
therefore summarized separately below, first reviewing studies of effects on healthy subjects,
followed by subjects with asthma. Subsequent sections deal with effects other than lung
function, and with studies of particulate pollutants other than acid aerosols.
11.2.1.2 Pulmonary Function Effects of Sulfuric Acid in Healthy Subjects
Since 1988, ten studies have examined the effects of H2SO4 exposure on pulmonary
function in healthy subjects. Exposure levels ranged from 100 //g/m3 to 2,000 //g/m3, with
exposure durations ranging from 16 min to 6.5 h on two successive days. All of these studies
confirmed the findings from previous studies of an absence of spirometric effects on
11-9
-------
TABLE 11-2. CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
Ref.
Anderson
etal.
(1992)
Aris et al.
(1990)
Aris et al.
(1991a)
Aris et al.
(1991b)
Subjects
15 healthy
15 asthmatic
18 to 45 years
19 asthmatic
20 to 40 years
10 healthy
nonsmokers
21 to 31 years
ozone
sensitive
18 asthmatics
23 to 37 years
MMAD2 GSD3
Exposures1 C"m) (/^m)
(1): air
(2):H2S04 =100//g/m3 1.0 2
(3): carbon black
=200 //g/m3
(4): acid-coated carbon
with = 100 ,ug/m3 H2SO4
Mouthpiece study:
HMSA5 0 to 1000 fj.M + H2SO4
50 ijM vs H2S04 50 /Al
Chamber study:
HMSA 1 Mm + H2SO4 5 Mm
vs H2SO4 5 Mm
HN03 500 //g/m3 or H2O, or =6
air followed by ozone
0.2 ppm
Mouthpiece study:
H2SO4 vs NaCl, =3000 //g/m3 0.4 vs =6
with varying particle
size, osmolarity,
relative humidity
Chamber study: H2SO4 vs
NaCl, 960 to 1400 //g/m3
6
with varying water
content
Temp
Duration Exercise (°C)
Ih VE^50 22
L/min
3 min. 100 W on
cycle
1 h =25
2 h 50 min of 22
each h
3 h
40 L/min
22
16 min With and
without
=24
exercise.
100 W on
1 h cycle =27
RH"
(%) Symptoms
50 Healthy
subjects more
symptomatic in
air.
100 HMSA did not
increase
symptoms in
comparison
with H2SO4
alone.
100 No effects of
fog exposure
50
No effects
<10 vs
100
Lung Function Other Effects
Largest No change in
decrements in airway
FVC with air responsiveness
exposure.
No effects on
SRaw6
No direct No change in
effects of fog airway
exposures. responsiveness
Greatest
decrements when
ozone preceded
by air.
Increases in
Sraw with low RH
conditions; no
pollutant-rela
ted effects
Comments
Smoking
status of
subjects
not
stated.
Fog may
have
reduced
ozone
effects on
lung
function.
Postulated
that
effects
seen in
other
studies
due to
secretions
or effects
on larynx
-------
TABLE 11-2 (cont'd). CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
Ref.
Avol et al.
(1988a)
Avol et al.
(1988b)
Avol et al.
(1990)
Balmes
etal.
(1988)
Gulp et al.
(1995)
Subjects
21 healthy
21 asthmatic
18 to 45 years
22 healthy
22 asthmatic
18 to 45 years
32 asthmatics
8 to 16 years
12 asthmatics
responsive to
hypoosmolar
saline
aerosol
25 to 41 years
16 healthy
20 to 39 yrs
MMAD2 GSD3 Temp RH"
Exposures1 C^m) C^m) Duration Exercise (°C) (%) Symptoms
Air 0.85 to 2.4 to Ih 10 min x 3 21 50 Healthy: Slight
H2SO4: 0.91 2.5 47 to increase in cough
Healthy: 363, 49 L/min with highest
1128, 1578 concentrations.
//g/m3
Asthmatic: 396, Asthma:
999, 1,460 ,ug/m3 dose-related
increase in lower
resp. symptoms.
H2O 9.7 to Ih 10 minx 3 9 100 Dose-related
H2SO4: 10.7 41 to 46 increase in lower
Healthy: 647, L/min resp. symp. in both
1,100, groups.
2,193//g/m3
Asthmatic: 516,
1,085,
2,034 //g/m3
Air 40 min 30 min 21 48 No pollutant effect
H2SO446, 127, 0.5 1.9 rest, 10
and 134 //g/m3 min
exercise
20L/min/m2
Mouthpiece, At rest -23
5,900 to
87, 100 ,u/m3:
NaCl 30 mOsm
H2SO430mOsm =5 to 6 1.5
HNO3 30 mOsm
H2SO4+HNO3 30 mOsm
H2SO4 300 mOsm
NaCl 1000 //g/m3 0.9 1.9 2 h 10 min x 4 22 40
H2S04 1,000 Mg/m3 =40 L/min
Lung Function Other Effects
Healthy: No
effects on lung
function or
airway
reactivity.
Asthma: iFEVj
0.26 L with H2S04
1,460 //g/m3
Healthy: No No effects on
effects on lung airway
function. responsiveness
Asthma: ipeak
flow 16% at
2,034 //g/m3
H2S04.
No pollutant
effect.
One subject
increased Sraw
14.2% with acid
exposure.
Concentration
of acid aerosol
required to
increase Sraw
by 100% lower
than for NaCl.
No difference
between acid
species.
Mucins from
bronchoscopy:
no effects on
mucin recovery
or changes in
glycoproteins
Comments
Half the
subjects
received
acidic gargle;
no difference
in effects.
Did not
reproduce
findings of
Koenig et al.,
1983.
Exposures did
not mimic
environmental
conditions.
No mitigation
by oral
ammonia.
-------
TABLE 11-2 (cont'd). CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
Ref.
Fine et al.
(1987b)
Fine et al.
(1987a)
Frampton
etal.
(1992)
Frampton
etal.
(1995)
Hanley
etal.
(1992)
Subjects
8 asthmatics
22 to 29 yrs
10 asthmatics
22 to 34 yrs
12 healthy
20 to 39 yrs
30 healthy
30 asthmatics
20 to 42 yrs
22 asthmatics
12 to 19 yrs
MMAD2 GSD3 Temp RH"
Exposures1 C"m) C"m) Duration Exercise (°C) (%)
Mouthpiece: 5. 3 to 6. 2 1.6 to 3 min. At rest
Buffered and 1.8
unbuffered HC1
and H2SO4 at
varying pH
Mouthpiece: 5. 6 to 6.1 1.6 to 1 min. At rest
Na2SO3Oto 1.7
10 mg/ml, pH 9,
6.6, 4; buffered
acetic acid pH 4;
SO2 0.25 to 8 ppm
NaCl 1,000 //g/m3 0.9 1.9 2 h 10 min x 4 22 40
H2S04 1,000 //g/m3 =40 L/min
NaClorH2SO4 0.45 4.05 3h 10 min x 6. 21 40
100 //g/m3 0.64 2.50 Healthy: 33
followed by to 40 L/min;
ozone 0.08, 0.12, 3h asthmatics:
or 0. 1 8 ppm 3 1 to 36 L/min
Mouthpiece: 22 65
(1): Air; 40 min. 10 min
H2SO470, 0.72 1.5
130 //g/m3 45 min. 30 min
(2): Air; =30 L./min
H2S04 70 //g/m3
with and without
lemonade
Symptoms
Cough with
inhalation
of
unbuffered
pH2
aerosols
4/12
subjects:
throat
irritation
with acid
exposure.
No
pollutant
effects
No effects
Lung Function
= 50% increase in
airway resistance
with buffered acid
aerosols at pH 2.
Little response to
unbuffered acids.
ForN^Sq,,
bronchoconstriction
greater at
lower pH; no
response to acetic
acid.
No pollutant
effects
Healthy subjects:
no significant
effects.
Asthmatics: ozone
dose-response
following H2SO4
pre-exposure, but
not NaCl
Significant
decreases in FEVj
(=37ml///molH+)
and FVC at 2 to 3
min but not 20 min
after exposure.
Other Effects
BAL findings:
No effects on
cell recovery,
lymphocyte
subsets, AM
function, fluid
proteins.
Significant
correlation
between
baseline
airways
responsiveness
and AFEV/H+
(R2=0.3).
Comments
Titratable
acidity
important
determinant of
response to acid
aerosols.
Suggests
effects related
to release of SO2
or bisulfite,
but not sulfite.
Large
variability in
oral NH3 levels.
-------
TABLE 11-2 (cont'd). CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
Ref.
Koenig
etal.
(1989)
Koenig
etal.
(1992)
Koenig
etal.
(1993)
Koenig
etal.
(1994)
Laube et al.
(1993)
Subjects
9 asthmatics with
exercise-induced
bronchospasm
12 to 18yrs
14 asthmatics
with
exercise-induced
bronchospasm
13 to 18yrs
8 healthy
9 asthmatic
60 to 76 yrs
28 asthmatics
12 to 19 yrs
7 healthy
20 to 3 1 yrs
MMAD2 GSD3
Exposures1 C"m) C"m) Duration Exercise
Mouthpiece: 0.6 1.5 40 min lOmin
Air;
H2S04 68 //g/m3;
SO20.1 ppm;
H2SO4+SO2.
HNO3 0.05 ppm
Mouthpiece: =23 L/min
Air; 0.6 1.5 45 or
H2SO4 35 or 70 //g/m3 90 min
Mouthpiece: 10 min
Air; 40 min 17.5 L/min
(NH4)2SO4 =70 Mg/m3; 0.6 1.5 for
H2SO4 =74 to 82 //g/m3 with asthmatics,
and without lemonade 19.7 for
healthy
Mouthpiece: 90 min x VE 3 x
Air; 2 days resting
ozone 0.12 ppm+NO2 0.3 ppm; 0.6 1.5
ozone 0. 12 ppm+NO2
0.3 ppm+H2SO4 68 //g/m3;
ozone 0. 12 ppm+NO2
0.3 ppm+HNO3 0.05 ppm
Head dome: 1 h 20 min
NaCl =500 //g/m3 10.3
H2SO4 = 500//g/m3 10.9
Temp RH"
(°C) (%) Symptoms Lung Function
25 65 No effects iFEV^/oafter
H2SO4 compared
with 2% after
air.
22 65 JFEVjeo/oafter
H2S04 35 Mg/m3
for 45 min, 3%
after 70 //g/m3
(NS). Smaller
changes after
90 min
exposures.
22 65 No significant
effects.
Correlation
between
increase in
resistance and
oral ammonia
levels in
asthmatics
(R2 = 0.575).
22 65 No No pollutant
pollutant effects
effects
22 to 25 99 No No pollutant
pollutant effects
effects
Other Effects Comments
Responses
unrelated
to CxTx VE
No effects on 6 subjects
airway with
responsiveness moderate or
severe
asthma did
not
complete
protocol
Tracheal
clearance
increased
(4/4 subjects).
Outer zone
clearance
increased
(6/7 subjects).
No effects on
airway
responsiveness
-------
TABLE 11-2 (cont'd). CONTROLLED HUMAN EXPOSURES TO ACID AEROSOLS AND OTHER PARTICLES
Ref.
Linn et al.
(1989)
Linn et al.
(1994)
Morrow et
al. (1994)
Utell et al.
(1989)
Subjects
22 healthy
19
asthmatic
18to48yrs
15 healthy
30
asthmatic
18 to 50 yrs
17
asthmatic
20 to 57 yrs
17 COPD
52 to 70 yrs
15
asthmatic
19 to 50 yrs
Exposures1
H20
H2S04 =2,000 Mg/m3
Air;
ozone 0.12 ppm;
H2SO4 100 //g/m31
ozone+H2SO4
NaCl = 100 //g/m3
H2S04 =90 Mg/m3
Mouthpiece:
NaCl 350 //g/m3;
H2S04 350 //g/m3, high
NH3;
H2S04, low NH,
MMAD2 GSD3 Temp
Cum) C«m) Duration Exercise (°C)
20 Ih 40 to 45 =10
10 L/min
1
6.5 h/d 50 minx 6 21
=0.5 ~2 x2d 29 L/min
2h Asthmatics: 21
10 min x
4 COPD: 7 min
x 1
0.80 1.7 30 min 10 min
VE3x
resting
RH"
(%) Symptoms
74 to Increased
100 total score
with larger
acid
particles.
50 Symptoms
unrelated
to
atmosphere
30 No
pollutant
effects.
20 to
25
Lung Function
No pollutant effects
i FEVj & FVC in ozone,
similar for healthy &
asthmatic subjects.
Greater fall in FEVj
for acid+ozone than
ozone alone,
marginally
significant
interaction.
Asthmatics: JFEVj
slightly greater
after acid than after
NaCl.
COPD: No effects.
Greater fall in FEVj
with low NH3 (19%)
than with high NH3
(8%).
Other Effects
No effects on
airway
reactivity
Increased
airway
responsivenes
s with ozone,
marginal
further
increase with
ozone+acid
Comments
4 asthmatic
subjects unable
to complete
exposures
because of
symptoms.
Average subject
lost 100 ml FEVj
with ozone, 189
ml with
ozone+acid
Original
findings
replicated in
13 subjects
'Exposures in environmental chamber unless otherwise stated.
2Mass median aerodynamic diameter. In some studies expressed as volume median diameter; see text.
3Geometric standard deviation.
"Relative humidity.
5Hydroxymethanesulfonic acid.
'Specific airways resistance.
BAL=Bronchoalveolar lavage.
AM=Alveolar macrophage.
-------
healthy subjects. Exposures at the highest concentrations (i.e. 1,000 //g/m3 or greater) were
associated with mild increases in respiratory symptoms (cough, substernal discomfort, throat
irritation), especially those exposures with particle sizes in the 10 to 20 //m range.
Two studies reported by Avol and colleagues (Avol et al., 1988a,b) examined effects of
1-h H2SO4 aerosol exposures in an environmental chamber. In the first study (Avol et al.,
1988b), 22 healthy nonsmoking subjects between the ages of 18 and 45 years, some reporting
allergies, were exposed for 1 h to large particle aerosols (volume median diameter (VMD) 9.7 to
10.3 //m, GSD not stated) consisting of H2O (control) or H2SO4 at 647, 1,100, and 2,193 //g/m3.
Three 10-min periods of moderate exercise (46 L/min) were included. All subjects were
exposed to each atmosphere, separated by one week. Half the subjects received an acidic gargle
to reduce oral ammonia levels prior to exposure; no difference in effects was observed with or
without the gargle, so data were combined in the analysis. Healthy subjects experienced a slight
concentration-related increase in lower respiratory symptoms (cough, sputum, dyspnea, wheeze,
chest tightness, substernal irritation), but no effect was found on spirometry or on airway
reactivity to methacholine measured 1 h after exposure.
A second study (Avol et al., 1988a) essentially duplicated this protocol for H2SO4 aerosols
with a smaller particle size (MMAD = 0.85 to 0.91 //m, geometric standard deviation [GSD =
2.4 to 2.5]). Twenty-one healthy subjects, 12 with allergies by skin testing, were exposed on
separate occasions to air and H2SO4 aerosol at each of three concentrations: 363, 1128, 1578
Mg/m3. A slight increase in cough was found at the two highest concentrations of H2SO4, but no
effects were found on spirometry, specific airway resistance (Sraw), or airway reactivity to
methacholine.
Linn et al. (1989) examined the effects of droplet size on 22 healthy subjects exposed
to nominally 2,000 //g/m3 H2SO4 for 1 h, with three, 10-min exercise periods. Distilled H2O was
used for control aerosols. Aerosol VMDs were 1,10, and 20 //m. Actual exposure
concentrations were 1,496, 2,170, and 2,503 //g/m3. Results were similar to the previous fog
studies by this group, with no significant effects on lung function or airway reactivity to
methacholine. Total symptom scores were increased with exposure to 10 //m and 20 //m H2SO4
particles, but not to 1 //m.
11-15
-------
Frampton et al. (1992) exposed 12 healthy nonsmokers to aerosols of NaCl (control) or H2SO4
(MMAD = 0.9//m, GSD = 1.9) at 1,175 //g/m3 for 2 h in an environmental chamber. Four
10-min exercise periods at VE of -40 L/min were included. Subjects brushed their teeth and
rinsed with mouthwash prior to and once during each exposure to reduce oral ammonia levels.
Mild throat irritation was described by 4 of 12 subjects after acid exposure and 3 of 12 subjects
after NaCl exposure. No effects on lung function were found.
Five other recent studies (Anderson et al., 1992; Koenig et al., 1993; Laube et al., 1993;
Linn et al., 1994; Frampton et al., 1995) have included healthy subjects in exposures to H2SO4
aerosols at levels below 1000 //g/m3; none have shown meaningful effects on lung function.
Anderson et al., (1992) studied the responses of 15 healthy subjects exposed for 1 h in a chamber
to air, 100 //g/m3 H2SO4, 200 //g/m3 carbon black, and carbon black coated with H2SO4,
(MMAD ~ 1 //m). Lemonade or citrus juice gargles were used to reduce oral ammonia levels.
Exposures containing acid were without effects on symptoms, lung function, or airway
reactivity. Healthy subjects were actually more symptomatic and demonstrated greater increases
in Sraw after air than after pollutant exposure, contrary to expectation. In a study designed to
examine effects of acid fog on pulmonary clearance, Laube et al., (1993) exposed seven healthy
volunteers to NaCl or H2SO4 at 470 //g/m3, MMAD ~ 11 //m, for 1 h with 20 min of exercise.
Acid exposure did not alter symptoms or lung function. Two chamber studies designed to
examine the effects of combined or sequential exposure to acid aerosols and ozone found no
direct effects of exposure to ~ 100 //g/m3 H2SO4 on lung function of healthy subjects, using
exposure durations of 3 h (Frampton et al., 1995) or 6.5 h for two successive days (Linn et al.,
1994). Both studies included exercise and acidic mouthwash to minimize oral ammonia. Also
of particular interest, Koenig et al, (1993) studied eight elderly subjects age 60 to 76 years
exposed to air, H2SO4, or ammonium sulfate at approximately 82 //g/m3 H2SO4 for 40 min,
delivered by mouthpiece. No effects were found on spirometry or total respiratory resistance.
Thus, for young healthy adults, brief exposures to H2SO4 at mass concentrations more than
an order of magnitude above ambient levels do not alter lung function. Some subjects report
increased lower respiratory symptoms, including cough, at 1000 //g/m3 and higher
11-16
-------
levels, particularly with larger particle sizes (> 5 //m). One small study suggests that the elderly
do not demonstrate decrements in lung function at low H2SO4 exposure levels of (approximately
82 //g/m3). There are no data on the responses to particle exposure for healthy adolescents or
children.
11.2.1.3 Pulmonary Function Effects of Sulfuric Acid in Asthmatic Subjects
Individuals with asthma often experience bronchoconstriction in response to a variety of
stimuli, including exercise, cold dry air, or exposure to strong odors, smoke, and dusts.
Considerable individual variability exists in the nature of stimuli that provoke a response, and in
the degree of responsiveness. Thus, for clinical studies involving asthmatic subjects, subject
selection and sample size deserve particular consideration. Differences among subjects may
explain, in part, the widely differing results between laboratories studying effects of acid
aerosols. For example, in some studies described below, asthmatic subjects were specifically
selected to have exercise-induced bronchoconstriction (Koenig et al., 1989, 1992, 1994; Hanley
et al., 1992), or responsiveness to hypo-osmolar aerosols (Balmes et al., 1988). The interval for
withholding medications prior to exposure differed among various laboratories and different
studies. In addition, the severity of asthma differed among studies; severity is often difficult to
compare because published information describing clinical severity and baseline lung function is
often incomplete. Table 11-3 lists the characteristics of asthmatic subjects exposed to acid
aerosols and other particles.
Several studies have suggested that asthmatics are more sensitive than healthy subjects to
effects of acid aerosols on lung function. Utell et al., (1982) found significant decrements in
specific airway conductance (SGaw) in asthmatic subjects exposed by mouthpiece for 16 min to
450 and 1,000 //g/m3 H2SO4 (MMAD 0.5 to 1.0 //m). Moreover, exposure to neutralization
products of H2SO4 produced smaller decrements in function, roughly in proportion to their
acidity (H2SO4 > NH4HSO4 > NaHSO4).
The role of H+ in the responsiveness of asthmatics to acid aerosols was explored by Fine et
al. (1987b), who found that titratable acidity and chemical composition, rather than pH alone,
are key determinants of response in asthmatics. Eight asthmatic subjects were challenged by
mouthpiece for 3 min at rest, with buffered or unbuffered hydrochloric acid (HC1) or H2SO4 at
varying pH levels, and changes in SRaw were measured. Solutions were
11-17
-------
TABLE 11-3. ASTHMA SEVERITY IN STUDIES OF ACID AEROSOLS AND OTHER PARTICLES
oo
Ref.
Anderson
etal.
(1992)
Aris et
al.
(1990)
Aris et
al.
(1991b)
Avol et
al.
(1988a)
Avol et
al.
(1988b)
Subject #
(F/M)
15
(6/9)
19
(8/11)
18
21
(9/12)
22
(9/13)
Age Range
(mean)
19 to
45 years
(29)
20 to
40 years
23 to
37 years
18 to
45 years
(30)
18 to
45 years
(26)
Exposures1
(1): Air
(2):H2SO4«100,ug/m3
(3): carbon black
~ 200 Mg/m
(4): acid-coated
carbon
Mouthpiece study:
HMSAOto l,OOOmM
+ H2SO4 50 mM vs
H2S04 50 mM
Chamber study:
HMSA 1 mM + H2SO4
5 mM vs H2SO4 5 mM
Mouthpiece study:
H2SO4 vs NaCl to test
changes in particle
size, osmolarity (30
to 300 mOsm),
relative humidity
Chamber study: H2SO4
vs NaCl with varying
water content
Air
H2SO4 396, 999, 1,460
//g/m3
H20
H2SO4516, 1,085,
2,034 ^g/rn3
Allergies
Not
stated
Not
stated
Not
stated
Positive
skin
tests in
20
Positive
skin
tests in
18
Medications
Not stated
All but one on
albuterol. 3 on
inhaled
steroids. No
meds 24 h before
study.
Most subjects on
albuterol.
Several on
inhaled
steroids. No
meds 24 h before
study.
11 on no regular
meds; 10 on
regular meds.
3 unable to hold
meds prior to
exposure.
"Majority had
mild extrinsic
disease" . 9 on
regular meds.
FEVj
(% pred.)
Not
stated
82±20
(SD)
79±23
(SD)
Not
stated
Not
stated
FEV/FVC Airway
(%) Responsiveness
69±14 (SD) Methacholine:
PD20 < 56
"breath-units"
Not stated Methacholine:
All responded
to <2 mg/ml
Not stated Methacholine:
All responded
to <1 mg/ml
73±14 (SD) Hyperresponsive
by
methacholine
challenge, not
further
specified
45 to 98 Methacholine:
PD20<295 "dose
units"
Exercise/VE
Intermittent
at ~ 50 L/min
Intermittent,
100 W on
cycle
ergometer
Mouthpiece
study: with
and without
exercise.
Chamber
study :
intermittent
exercise at
100 W on
cycle
ergometer.
10 min x 3
47 to
49 L/mm
10 min x 3 41
to 46 L/min
-------
TABLE ll-Srcont'dX
Ref.
Avol et al.
(1990)
Balmes
etal.
(1988)
Fine et al.
(1987b)
Fine et al.
(1987a)
Frampton
etal.
(1995)
Subject #
(F/M)
32
(12/20)
12
(6/6)
8
(6/2)
10
(5/5)
30
(20/10)
Age Range
(mean)
8 to
16 years
25 to
41 years
22 to
29 years
22 to
34 years
(26.7)
20 to
42 years
ASTHMA SEVERITY IN STUDIES OF ACID AEROSOLS AND OTHER PARTICLES
Exposures1
Air
H2SO446,127, and!34
Mg/m3
Mouthpiece, doubling
outputs, 5,900 to
87,100 ,ug/m3: NaCl
30 mOsm
H2SO4 30 mOsm
HNO3 30 mOsm
H2SO4+HNO3 30 mOsm
H2SO4 300 mOsm
Mouthpiece:
Buffered and
unbuffered HC1 and
H2SO4 at varying pH
Mouthpiece: Na2SO3
Oto 1 0,000 ,ug/ml,
pH 9, 6.6, 4;
buffered acetic acid
pH4;
SO2 0.25 to 8 ppm
NaCl or H2SO4
100 |ig/m3 followed by
ozone 0.08, 0.12, or
0.1 8 ppm
Allergies
All had
history of
allergy
Not stated
Not stated
Not stated
All had
positive
skin
tests.
tlgEin 10.
Medications
1 8 on regular
meds, 2 on no
meds, rest
intermittent.
None on steroids.
All on inhaled
meds, 3 on
inhaled
steroids. No meds
24 h before
study.
6 on inhaled meds
and/or
theophylline, no
steroids. No
meds 1 2 h before
study.
7 on inhaled
meds, no
steroids. No
meds 1 2 h before
study.
All on
intermittent or
daily
bronchodilators.
None on steroids.
Meds held 24 h
before study.
FEVj FEV/ Airway
(% pred.) FVC (%) Responsiveness
Less than Not stated Hyperresponsive
70 in by exercise, cold
25 subjects air, or
methacholine.
94±15 (SD) 61 to 89 Responsive to
hypoosmolar
saline aerosol,
methacholine
<2 mg/ml.
41 to 108 74±11 (SD) Methacholine:
All responded to
<3 mg/ml.
Not stated Not stated 9 subjects had
bronchoconstrict-
ion and greater
response to
aerosol with
lower pH.
Response to NaSO3
aerosols may be
due to release of
SO2 gas in
bisulfiteions.
81±4 (SE) 75±2 (SE) Positive
carbachol
challenge if
normal
spirometry
Exercise/VE
30 min rest,
10 min
exercise
20L/rmn/m2
At rest
At rest
At rest
10 min x 6 for
each exposure
-------
TABLE 11-3 (cont'd). ASTHMA SEVERITY IN STUDIES OF ACID AEROSOLS AND OTHER PARTICLES
to
o
Ref.
Hanley
etal.
(1992)
Koenig
etal.
(1989)
Koenig
etal.
(1992)
Koenig
etal.
(1993)
Subject # Age Range
(F/M) (mean) Exposures1
22 12 to Mouthpiece:
(7/15) 19years (1): Air orH2SO4
70, 130,ug/m3
(2): AirorH2SO4
70 ,wg/m3, with and
without lemonade
9 12 to Mouthpiece: Air
(3/6) 18 years H2SO4 68 ,ug/m3
SO2 0. 1 ppm
H2S04+S02
HNO3 0.05 ppm
14 13 to Mouthpiece:
(5/9) 18 years Air
H2SO4 35 or
70 Mg/m3
9 60 to Mouthpiece:
(7/2) 76 years (1): Air
(2): (NH4)2S04
«70 Mg/m3
(3&4): H2SO4
-74 ,wg/m3 with and
without lemonade
Allergies
"All had
allergic
asthma".
I IgE in 8.
5
"allergic
asthma"
"Allergic
asthma"
Not
stated
Medications
All but 2 on
meds, no
steroids. No
meds 4 h before
study.
Not stated
Not stated
All on
"bronchodilator
and/or anti-
inflammatory
treatment".
Steroids not
specified.
FEVj FEV/ Airway
(% pred.) FVC(%) Responsiveness
Not Not Methacholine: PD20
stated stated 0.25 to 25 mg/ml;
not available for
3 subjects.
1 8 were responsive
to exercise by
treadmill test
Not Not Methacholine: All
stated stated responded to
<20 mg/ml.
AllhadiFEV1>15%
with treadmill
test
Not Not Methacholine: PD20
stated stated 0.25 to 25 mg/ml;
not available for
1 subject; 8 had
pos. treadmill
tests, 4 history of
exercise
responsiveness, 2
did not meet stated
criteria for
exercise
responsiveness.
75 Not Methacholine:
stated PD20< 10 mg/ml
Exercise/VE
(1): 10 mm
(2): 30 mm
~ SOL. /min
"Moderate",
on
treadmill
for 10 min
Intermittent
~ 23 L/min
10 min
17.5 L/mm
-------
TABLE 11-3 (cont'd). ASTHMA SEVERITY IN STUDIES OF ACID AEROSOLS AND OTHER PARTICLES
Ref.
Koenig
etal.
(1994)
Linn
etal.
(1989)
Linn
etal.
(1994)
Morrow
etal.
(1994)
Subject # Age Range
(F/M) (mean)
28 12 to
(9/19) 19 years
19 18 to
(13/6) 48 years
(29)
30 18 to
(17/13) 50 years
(30)
17 20 to
57 years
(35)
Exposures1
Mouthpiece:
(1): Air
(2): ozone 0.1 2 ppm
+NO2 0.3 ppm
(3): ozone
0.12ppm+NO2
0.3 ppm+H2SO4
68 //g/m3
(4): ozone 0.12 ppm
+NO20.3ppm
+HNO3 0.05 ppm
H20
H2SO4 « 2,000 ,ug/m3
(1): Air
(2): ozone 0.1 2 ppm
(3):H2S04100//g/m3
(4): ozone+H2SO4
NaCl«100//g/m3
H2SO4~90//g/m3
Allergies
"Personal
history
of
allergic
asthma"
"Some"
subjects
had
history
of
allergy
Some
subjects
had
positive
skin
tests.
Positive
skin
tests
FEVj
Medications (% pred.)
3 on no meds, 87
rest on regular
meds. 4 on
inhaled
steroids.
All on Not
bronchodilators stated
at least
weekly. No
regular
steroid use. No
meds 1 2 h
before study.
Wide range of Not
medication stated
usage. Some on
inhaled
steroids. No
meds 4 h before
study.
Requirement Not
for stated
bronchodilators
FEV/FVC Airway
(%) Responsiveness
Not Methacholine:
stated PD20<25 mg/ml.
All but 1
responsive to
exercise by
treadmill test.
70±11 Hyperresponsive-
(SD) ness based on
methacholine
PD20<38 "breath
units", exercise
responsiveness, or
bronchodilator
response.
72 Responsive to
methacholine or
exercise, or
bronchodilator
response
65±8 (SD) Positive carbachol
challenge if
normal spirometry
Exercise/VE
Intermittent
VE3x
resting
Intermittent
40 to
45 L/min
50 min x 6
29 L/min
10 min x 4
-------
TABLE 11-3 (cont'd). ASTHMA SEVERITY IN STUDIES OF ACID AEROSOLS AND OTHER PARTICLES
Ref.
Subject Age Range
# (F/M) (mean) Exposures1
FEV,
Allergies Medications
FEV/FVC Airway
(% pred.) (%)
Responsiveness
'Exposures in environmental chamber unless otherwise stated.
Exercise/ VE
Utellet 15
al.
(1989)
Yang and 25
Yang (15/10)
(1994)
19 to
50 years
23 to
48 years
Mouthpiece: Not stated
(1): NaCl
350 ,ug/m3
(2): H2S04
350 Mg/m3 high NH3
(3):H2S04lowNH3
Mouthpiece: All TIgE
Bagged polluted
air,
TSP = 202 Mg/m3
All on
intermittent or
daily
bronchodilators.
None on steroids.
Meds held 24 h
before study.
No steroids.
Holding of
medications not
stated.
88±4 (SE) 70±3 (SE) Positive carbachol 10 mm VE 3
challenge if x resting
normal spirometry
Not stated Not stated Hyperresponsive to Rest
methacholine
to
to
-------
buffered with glycine, which, by itself, was found to have no direct effect on lung function.
Aerosol MMAD ranged from 5.3 to 6.2 //m (GSD 1.6 to 1.8), simulating acid fogs. There was
no group response to unbuffered acid, even at pH 2. However, SRaw increased in seven of eight
subjects after inhalation of H2SO4 and glycine at pH 2, suggesting that titratable acidity or
available FT, rather than pH, plays a role in mediating acid fog-induced bronchoconstriction.
Nevertheless, the response occurred at H2SO4 concentrations estimated in excess of 10,000
Mg/m3, more than an order of magnitude higher than the concentration producing a response in
the study of Utell et al. (1982).
Fine et al. (1987a) further examined the role of pH in sulfite-induced bronchoconstriction
in asthmatics. Ten subjects with asthma were challenged with increasing concentrations of
sodium sulfite (Na^C^) at three different pH levels. Challenge with buffered acetic acid
aerosols at pH 4 was used to control for the airway effects of acid aerosols. Subjects also
inhaled increasing concentrations of SO2 gas during eucapneic hyperpnea. Exposures consisted
of 1 min of tidal breathing on a mouthpiece at rest. Particle MMAD ranged from 5.6 to 6.1 //m.
Nine often subjects experienced bronchoconstriction with Na^C^with greater responses to
aerosols made from solutions with lower pH. No response was seen following acetic acid. The
authors concluded that bronchoconstriction in response to Na2SO3 aerosols may be caused by the
release of SO2 gas or by bisulfite ions, but not by sulfite ions and not merely by alterations of
airway pH. These studies of Fine et al., as pointed out by the authors, addressed potential
mechanisms for bronchoconstriction in response to acidic sulfates, but did not attempt to mimic
the effects of environmental exposures.
Hypo-osmolar aerosols can induce bronchoconstriction in some asthmatics. To test the
effects of varying osmolarity of acidic aerosols, Balmes et al. (1988) administered aerosols of
NaCl, H2SO4, HNO3, or H2SO4 + HNO3 to 12 asthmatic subjects via mouthpiece. All solutions
were prepared at an osmolarity of 30 mOsm, and delivered at doubling concentrations until
SRaw increased by 100%. An additional series of challenges with H2SO4 at 300 mOsm was
performed. The 12 subjects were selected from a group of 17 asthmatics on the basis of
responsiveness to challenge with hypo-osmolar saline aerosol. Aerosol particle size was similar
to coastal fogs, with MMAD ranging from 5.3 to 6.1. Delivered nebulizer output during
exposure was quite high, ranging from 5,900 to
11-23
-------
approximately 87,000 //g/m3. All hypo-osmolar aerosols caused bronchoconstriction. Lower
concentrations of hypo-osmolar acidic aerosols were required to induce bronchoconstriction than
with NaCl, and there was no difference between acidic species. No bronchoconstriction
occurred with isosmolar H2SO4, even at maximum nebulizer output (estimated H2SO4
concentration greater than 40,000 //g/m3). The authors concluded that acidity can potentiate
bronchoconstriction caused by hypo-osmolar aerosols. As in the studies of Fine et al. (1987a,b),
these exposures did not mimic environmental conditions.
Koenig and colleagues have studied the responses of adolescents with allergic asthma to
H2SO4 aerosols with particle sizes in the respirable range, and concentrations only slightly above
peak, worst-case ambient levels. In one study (Koenig et al., 1983), ten adolescents were
exposed to 110 //g/m3 H2SO4 (MMAD = 0.6 //m) by mouthpiece for a total of 40 min, 30 min at
rest followed by 10 min of exercise. The FEVj decreased 8% after exposure to H2SO4, and 3%
after a similar exposure to NaCl, a statistically significant difference. In another study (Koenig
et al., 1989), nine allergic adolescents were exposed to 68 //g/m3 H2SO4 (MMAD = 0.6 //m) for
30 min at rest followed by 10 min of exercise (VE = 32 L/min). Although only five subjects
were described as having "allergic asthma", all subjects had exercise-induced
bronchoconstriction; thus all subjects were asthmatic by generally accepted criteria (Sheffer,
1991). Effects were compared with similar exposures to air, 0.1 ppm SO2, 68 //g/m3 H2SO4 +
0.1 ppm SO2, and 0.05 ppm HNO3. The FEVj decreased 6% after exposure to H2SO4 alone, and
4% after exposure to H2SO4 + SO2, compared to a 2% decrease after air. Increases in total
respiratory resistance were not significant. These results were presented as preliminary findings,
in that a total of 15 subjects were to be studied; formal statistical comparison of H2SO4 versus air
was not presented. Findings from the full group of 15 subjects have not been published. These
studies suggest that allergic asthmatics with exercise-induced bronchoconstriction may be more
sensitive to effects of H2SO4 than adult asthmatics, and that small changes in lung function may
be observed at exposure levels below 100 //g/m3.
Two studies reported by Avol et al. (1988a,b) examined effects of H2SO4 aerosols and fogs
on asthmatic subjects. The results for healthy subjects in these studies were described in Section
11.2.1.2. In the first study, 21 adult asthmatics, 20 of whom had positive skin tests to common
allergens, were exposed to air or 396, 999, and 1,460 //g/m3 H2SO4
11-24
-------
(MMAD 0.85 to 0.91 //m) for one hour with intermittent exercise. The asthmatic subjects
experienced concentration-related increases in lower respiratory symptoms (most notably,
cough), with some persistence of symptoms at 24 h. The FEVj decreased by a mean of 0.26 L
after exposure to 999 //g/m3, and 0.28 L after exposure to 1,460 //g/m3. Results using analysis of
variance (ANOVA) were significant for concentration effects on change in FEVj and FVC.
However, decrements at 396 //g/m3 were identical to those seen with air exposure. The SRaw
approximately doubled following exposure to both air and 396 //g/m3 H2SO4, and approximately
tripled following exposure to 999 and 1,460 //g/m3. Although absolute change in SRaw related
to concentration was not significant, percent change in SRaw was not analyzed as was done for
FEVj and FVC; ANOVA of percent change for each of these measures may have proved more
sensitive. These findings are similar to those of Utell, et al. (1983b), who found significant
effects on SGaw following exposure to 450 and 1,000 //g/m3, and significant effects on FEVj at
1,000 //g/m3 (MMAD = 0.8 //m). However, exposures in the Utell study were performed at rest
for a considerably shorter duration (16 minutes).
The second study (Avol et al., 1988b) utilized an identical protocol to examine effects of a
large particle aerosol (MMAD = 10 //m). Twenty-two asthmatic subjects were exposed to fogs
containing 516, 1,085 and 2,034 //g/m3 H2SO4, compared with H2O. Although
concentration-related increases in respiratory symptoms were similar to those in the study of
submicron aerosols, no significant effects were found on FEVl3 FVC, or SRaw, even at the
highest concentration of greater than 2,000 //g/m3. The findings from these two studies suggest
that aerosols of submicron particle size may alter lung function to a greater degree than large
particle aerosols in asthmatic subjects. Deep breaths of air containing acid aerosol would often
provoke cough. However, the concentrations required to produce an effect (> 5000 //g/m3)
differ strikingly from the studies of adolescent asthmatics of Koenig and colleagues (1983,
1989).
Linn et al. (1989) utilized a similar exposure protocol to specifically examine effects of
particle size. Nineteen asthmatic adults were exposed for 1 h to a pure water aerosol or
approximately 2,000 //g/m3 H2SO4 at 3 difference droplet sizes: 1,10, and 20 //m. Subjects
exercised for 3 10-min periods at VE of 40 to 45 L/min. Grapefruit juice gargles were used to
minimize oral ammonia. As in previous studies by this group, symptoms increased in acid
11-25
-------
atmospheres with larger particles. Four of the 19 asthmatic subjects were unable to complete
one or more exposures because of respiratory symptoms. All but one of the aborted exposures
was in an acid aerosol-containing atmosphere: three subjects did not complete the 1 //m acid
exposure, one the 10 //m exposure, and three the 20 //m exposure. The authors reported
significant decrements in lung function in these subjects, requiring administration of a
bronchodilator. As stated by the authors, "the patterns of these appreciable clinical responses by
asthmatics suggests a causal relationship to acid exposure, without obvious dependence on
droplet size". These more dramatic responses to acid aerosols are not reflected in the mean
responses, and suggest the existence of a few particularly susceptible individuals. Mean
responses of FEVj to acid aerosol exposure were about -21%, with responses to exercise in clean
air of about -12%. Some subjects experienced decreases in FEVj in excess of 50%, as a result of
combined exercise and acid aerosol exposure. Analysis of variance found significant effects of
acid x time on SRaw and FEVj. There was no apparent effect of droplet size.
Utell et al. (1989) examined the influence of oral ammonia levels on responses to H2SO4.
Fifteen subjects with mild asthma inhaled H2SO4 aerosols (350 //g/m3, MMAD = 0.8 //m) via
mouthpiece for 20 min at rest followed by 10 min of exercise. Sodium chloride aerosol served
as control. Low oral ammonia levels were achieved using a lemon juice gargle and
toothbrushing prior to exposure, and high levels were achieved by eliminating oral hygiene and
food intake for 12 h prior to exposure. These procedures achieved a five-fold difference in oral
ammonia levels. The FEVj decreased 19% with low ammonia versus 8% with high ammonia
(p<0.001). The FEVj also decreased 8% with NaCl aerosol. These findings extended the
authors' previous findings (Utell et al., 1983b) of decrements in SGaw following exposure to 450
Mg/m3 H2SO4, and demonstrated the importance of oral ammonia in mitigating the clinical
effects of submicron H2SO4 aerosols.
The findings of Koenig et al. (1989) in adolescent asthmatics prompted an attempt by Avol
and colleagues (1990) to replicate the study using a larger group of subjects. Thirty-two subjects
with mild asthma, aged 8 to 16 years, were exposed to 46 and 127 //g/m3 H2SO4 (MMAD
~0.5fj,m) for 30 min at rest followed by 10 min of exercise at 20 L/min/m2 body surface area.
Subjects gargled citrus juice prior to exposure to reduce oral ammonia. Bronchoconstriction
occurred after exercise in all atmospheres, with no statistically
11-26
-------
significant difference between clean air and acid exposures at any concentration. Because these
exposures were undertaken in an environmental chamber with unencumbered oral/nasal
breathing, in contrast to mouthpiece exposure in the Koenig et al. studies (1983, 1989), a
subsequent study was performed to examine the effects of oral breathing only. Twenty-one of
these subjects were therefore exposed to 134 //g/m3 H2SO4 while breathing chamber air through
an open mouthpiece. Again, no acid effect was found. One subject who was "unusually
susceptible to exercise-induced bronchospasm" also showed the largest decrements in lung
function with both exposures to the highest acid concentrations. It is possible that the subjects
in the Koenig et al. (1989) study, all of whom demonstrated exercise-induced
bronchoconstriction during a specific exercise challenge test, represented a more responsive
subgroup of adolescent asthmatics. Only 15 of the 32 subjects in the Avol et al. (1990) study
were known to have exercise-induced bronchoconstriction. Indeed, subsequent data (Hanley et
al., 1992) suggest exercise responsiveness is predictive of H2SO4 responsiveness (see below).
Aris et al. (1990) examined the effects of hydroxymethanesulfonic acid (HMSA), which
has been identified as a component of west coast acidic fogs. They postulated that HMSA might
cause bronchoconstriction in asthmatics because, at the pH of airway lining fluid, it dissociates
into CH2O and SO2. In the first part of the study, nine asthmatics were serially challenged by
mouthpiece with 0, 30, 100, 300 and 1,000 //M HMSA in 50 //M H2SO4 (MMAD = 6.1 //m).
The SRaw was measured after each challenge. These findings were compared on a separate day
to a similar series of exposures to 50 //M H2SO4 alone. No effect was found for HMSA on
symptoms or airways resistance. An environmental chamber exposure study was then performed
in which 10 asthmatic subjects were exposed to 1 mM HMSA + 5 mM H2SO4 for 1 h with
intermittent exercise. The control was exposure to 5 mM H2SO4 alone. Three subjects
underwent additional exposures to NaCl aerosol. Particle MMAD was approximately 7 //m.
Both acid exposures slightly increased respiratory symptoms, but no significant effects on SRaw
were found.
In a subsequent series of studies, Aris et al. (1991b) examined the effects of varying
particle size, osmolarity, and relative humidity on airways resistance in response to H2SO4
aerosol. To study effects of particle size and osmolarity, 11 asthmatics inhaled five different
aerosols for 16 min by mouthpiece at rest: (1) H2SO4 at 300 mOsm (VMD approximately
6 jum); (2) H2SO4 30 mOsm (VMD approximately
11-27
-------
6 jum); (3) sodium chloride 30 mOsm (VMD approximately 6 //m); (4) H2SO4 (VMD
approximately 0.4 //m); and (5) H2SO4, (VMD approximately 0.4 //m). Sulfuric acid
concentrations were high, at approximately 3000 //g/m3. Airway resistance actually decreased
slightly with all aerosol exposures and there were no significant effects on respiratory symptoms.
In a second mouthpiece study, nine subjects were exposed at rest (part 1) to H2SO4 at
approximately 3000 //g/m3, with large (VMD ~6 //m) versus small (0.3 //m) particle size and
low (< 10%) versus high (100%) relative humidity. Sodium chloride aerosols under similar
conditions served as control. Because these exposures caused no decrements in SRaw, six
subjects underwent exposures to small particle, low humidity H2SO4 versus sodium chloride
while exercising at 40 L/min (part 2). Although SRaw increased significantly with exercise,
there was no difference between H2SO4 and sodium chloride exposures. These results are shown
in Figure 11-1. A significant increase in throat irritation was observed with the low humidity,
small particle H2SO4 inhalation in part 1 of this study (n=9) but was not replicated in part 2
(n=6).
Finally, an environmental chamber exposure study was undertaken to examine effects of
H2SO4 fogs (VMD approximately 6 //m) with varying water content on airways resistance. Ten
subjects were exposed for 1 h with intermittent exercise to H2SO4 and NaCl at low (0.5 //g/m3)
and high (1.8 //g/m3) liquid water content. The mean sulfate concentrations were 960 //g/m3 for
low water content fogs and 1,400 //g/m3 for high liquid water content fog. Surprisingly, SRaw
decreased slightly with most exposures, with no significant difference among the 4 atmospheres.
The authors speculated that the decrements in pulmonary function following exposure to acid
aerosols in previous studies may have been due to increases in airway secretions or effects on the
larynx rather than bronchoconstriction.
Responsiveness of adolescent asthmatic subjects to H2SO4 aerosols was further explored by
Hanley et al. (1992). Fourteen allergic asthmatics aged 12 to 19 years inhaled air or H2SO4 at
targeted concentrations of 70 and 130 //g/m3, for 30 min at rest and 10 min with exercise. In a
second protocol, nine subjects were exposed to targeted concentrations of 70 //g/m3 H2SO4, with
and without drinking lemonade to reduce oral ammonia. Actual exposure concentrations ranged
from 51 to 176 //g/m3 H2SO4. Exposures lasted 45 min, including two 15-min exercise periods.
Aerosol MMAD was 0.72 //m. For the purposes of
11-28
-------
LowRH
Small Particle
NaCI
LowRH
Small Particle
High RH
Large Particle
S04
DPre
• Post
LowRH
Small Particle
LowRH
Small Particle
NaCI
^ T
Figure 11-1. Mean plus or minus standard error of the mean specific airway resistance
(SR,,W) before and after a 16-min exposure for (A) nine subjects who inhaled
low relative-humidity (RH) sodium chloride (NaCI), low-RH sulfuric acid
(H2SO4), and high-RH H2SO4 aerosols at rest, and (B) six subjects who
inhaled low-RH NaCI and low-RH H2SO4 aerosols during exercise.
Source: Aris et al. (1991b).
11-29
-------
this document, mean changes in FEVj were calculated from individual subject data provided in
the published report. In the first protocol, FEVj fell 0.05 ± 0.08 L after air and 0.15 ± 0.14 L
after nominal 70 //g/m3 H2SO4. In the second protocol, FEVj fell 0.00 ± 0.23 L without
lemonade gargle and 0.13± 0.09 L with lemonade gargle. Results from the 22 subjects exposed
in the two protocols were combined for the published analyses, and changes in pulmonary
function were regressed against FT concentration for each subject. Decrements in FEVj and
FVC were statistically significant at 2 to 3 min after exposure, but not at 20 min after exposure.
Changes in Vmax50 and total respiratory resistance were not significantly different. The findings
corresponded to a fall in FEVj of approximately 37 ml///M FT. A significant correlation was
found between exercise-induced bronchoconstriction, determined prior to exposure using a
treadmill test, and the slope of A FEV1/H+. A similar observation linking baseline airways
reactivity to H2SO4 responsiveness had been made previously by Utell et al. (1983b).
Koenig et al. (1992) examined the effects of more prolonged mouthpiece exposures to
H2SO4 (MMAD = 0.6//m). Fourteen allergic asthmatic subjects aged 13 to 18, with
exercise-induced bronchoconstriction, were exposed to air or 35 and 70 //g/m3 H2SO4, for
45 min and 90 min, on separate occasions. Oral ammonia was reduced by drinking lemonade.
The exposures included alternate 15-min periods of exercise at three times resting VE. The
largest decrements in FEVj (6%) actually occurred with the shorter exposure to the lower
concentration of H2SO4 (35 //g/m3). Changes following exposure to 70 //g/m3 and following 90
min exposures were not significant. The authors concluded that duration of exposure did not
play a role in the response to H2SO4 aerosols. However, the absence of a concentration response
in the studies suggests that the statistical findings may be due to chance. Therefore, the study
does not appear to demonstrate a convincing effect of H2SO4 at these exposure levels.
Anderson et al. (1992) included 15 asthmatic adults in a study comparing the effects of
exposure for 1 h to air, 100 //g/m3 H2SO4, 200 //g/m3 carbon black particles, and acid-coated
carbon black (MMAD ~ 1.0//m). Decrements in FEVj were observed for all exposures,
averaging about 9%. Analysis of variance for FVC showed a significant interaction of acid,
carbon, and time factors (p = 0.02), but the largest decrements actually occurred with air
exposure.
11-30
-------
In the only study of elderly asthmatics, Koenig et al. (1993) exposed nine subjects, 60 to
76 years of age, by mouthpiece to air, (NH4)2SO4, or 70 //g/m3 H2SO4 (MMAD = 0.6//m), with
and without lemonade gargle. Exposures were 30 min at rest followed by 10 min of mild
exercise (VE = 17.5 L/min). Greater increases in total respiratory resistance occurred following
H2SO4 without lemonade than following the other atmospheres, but the difference between
atmospheres was not significant.
In a study comparing effects of H2SO4 exposure in subjects with asthma and COPD,
Morrow et al. (1994) exposed 17 allergic asthmatic subjects in an environmental chamber to 90
Mg/m3 H2SO4 or NaCl (MMAD<1 //m) for 2 h with intermittent exercise. Pulmonary function
was measured after each of four 10 min exercise periods, and again 24 h after exposure, before
and after exercise. Decrements in FEVj were consistently greater in H2SO4 than NaCl, although
the difference was statistically significant only following the second exercise period. FEVj
decreased ~ 18% after H2SO4 compared with ~ 14% after NaCl (p = 0.02). Reductions in SGaw
were significantly different only following the fourth exercise period (p = 0.009). No changes
were found in symptoms or arterial oxygen saturation, and there were no significant changes in
lung function 24 h after exposure.
Finally, two recent studies have examined combined exposures to H2SO4 and ozone, one
using a combined pollutant atmosphere for 6 h per day over 2 days, (Linn et al., 1994) and the
other using sequential 3 h exposures to H2SO4 followed 1 day later by ozone (Frampton et al.,
1995). These reports will be discussed in detail in section 11.2.1.7. However, neither study
found any significant changes in lung function in asthmatics exposed to 100 //g/m3 H2SO4 alone.
In summary, asthmatic subjects appear to be more sensitive than healthy subjects to the
effects of acid aerosols on lung function, but the effective concentrations differ widely among
laboratories. Although the reasons for these differences remain largely unclear, subject selection
and differences in neutralization of acid by NH3 may be important factors. Adolescent
asthmatics may be more sensitive than adults, and may experience small decrements in lung
function in response to acid aerosols at exposure levels only slightly above peak ambient levels.
Even in studies reporting an overall absence of effects on lung function, some individual
asthmatic subjects appear to demonstrate clinically important effects. Submicron aerosols
appear to have greater effects on spirometry and airway
11-31
-------
resistance than particles in the 10//-20 //m range. However, respiratory symptoms (cough,
irritation, etc.) are observed with both large and small aerosols.
11.2.1.4 Effects of Acid Aerosols on Airway Responsiveness
Human airways may undergo bronchoconstriction in response to a variety of stimuli.
Airway responsiveness can be quantitated by measuring changes in expiratory flow or airways
resistance in response to inhalation challenge. Typically, the challenging agent is a non-specific
pharmacologic bronchoconstrictor such as methacholine or histamine. Other agents include
carbamylcholine (carbachol), cold dry air, sulfur dioxide, hypo-osmolar aerosols, or exercise. In
allergic subjects, airway challenge with specific allergens can be performed, although the
responses are variable, and late phase reactions can result in bronchoconstriction beginning 4 to
8 h after challenge and lasting 24 h or more. Although many individuals with airway
hyperresponsiveness do not have asthma, virtually all asthmatics have airway
hyperresponsiveness, possibly reflecting underlying airway inflammation. Changes in clinical
status are often accompanied by changes in airway responsiveness. Thus alterations in airway
responsiveness may be clinically significant, even in the absence of direct effects on lung
function (Godfrey, 1993; Weiss et al., 1993). Molfino et al. (1992) have provided a brief review
of air pollution effects on allergic bronchial responsiveness.
As noted in section 11.2.1.3, two studies (Utell et al., 1983b; Hanley et al., 1992) have
suggested that the degree of baseline airway responsiveness may predict responsiveness to acid
aerosol exposure in asthmatic subjects. This section will deal only with studies examining
changes in airway responsiveness with exposure to particles.
Despite the absence of effects on lung function in healthy subjects, Utell et al. (1983a)
observed, in healthy nonsmokers, an increase in airway responsiveness to carbachol following
exposure to 450 //g/m3 H2SO4 (MMAD = 0.8). The increase occurred 24 h, but not immediately,
after exposure. In addition, some subjects reported throat irritation between 12 and 24 h after
exposure to H2SO4. These findings suggested the possibility of delayed effects. These
investigators also observed increases in airway responsiveness among asthmatic subjects
following exposure to 450 and 1000 //g/m3, but not 100 //g/m3 H2SO4. These findings have been
reviewed (Utell et al., 1991).
11-32
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Avol et al. (1988a,b) included airway responsiveness as an outcome measure in their
studies of healthy and asthmatic subjects exposed to varying concentrations of H2SO4.
No effects on responsiveness were reported, with either acidic fogs or submicron aerosols, at
H2SO4 concentrations as high as 2000 //g/m3. However, airway challenge was performed using
only two concentrations of methacholine. This limited challenge may have been insufficiently
sensitive to detect small changes in airway responsiveness.
Using a similar 2-dose methacholine challenge protocol, Linn et al. (1989) found no
change in airway responsiveness of healthy subjects following exposure to 2000 //g/m3 H2SO4
for 1 h, at particle sizes ranging from 1 to 20 //m. Anderson et al. (1992), in their study of
responses to 100 //g/m3 H2SO4, 200 //g/m3 carbon black, and acid coated carbon, found no
effects on airway responsiveness in healthy or asthmatic subjects. In this study, a conventional
methacholine challenge was used, administering doubling increases in methacholine
concentration until FEVj decreased more than 20%.
In a study primarily designed to examine effects of acid fog exposure on mucociliary
clearance, Laube et al. (1993) examined changes in airway responsiveness to methacholine in
7 asthmatic subjects exposed to 500 //g/m3 H2SO4 or NaCl (MMAD ~ 10 //m) for 1 h with 20
min of exercise. Responsiveness was measured at screening and 30 min after each exposure. No
difference was observed between H2SO4 and NaCl exposures.
A recent study (Linn et al., 1994) has suggested that exposure to ozone with H2SO4 may
enhance the increase in airway responsiveness seen with ozone exposure alone. Fifteen healthy
and 30 asthmatic subjects were exposed to air, 0.12 ppm ozone, 100 //g/m3 H2SO4 (MMAD
-0.5), and ozone + H2SO4 for 6.5 h on 2 successive days, with intermittent exercise. Airway
responsiveness was measured after each exposure day using a conventional methacholine
incremental challenge, and compared with baseline measured on a separate day. An ANOVA
using data from all subjects found an increase in airway responsiveness in association with ozone
exposure (p=0.003), but showed no significant change following exposure to air or H2SO4 alone.
Multiple comparisons did not reveal significant differences in airway responsiveness between
ozone and ozone + H2SO4 in healthy or asthmatic subjects. However, asthmatic subjects showed
the greatest increase in airway responsiveness following the first day of ozone + H2SO4, and
ANOVA revealed a significant interaction of clinical status, ozone, acid, and day (p=0.03).
Decreases in FEVj following methacholine
11-33
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challenge for healthy subjects were 8% after air, 6% after H2SO4, 9% after ozone, and 13% after
ozone + H2SO4. Changes were smaller following the second exposure day, suggesting
attenuation of responsiveness with repeated exposure, as seen in previous studies of ozone alone
(U.S. Environmental Protection Agency, 1995). These studies suggest that exposure to low
concentrations of H2SO4 may enhance ozone-induced increases in airway responsiveness in both
healthy and asthmatic subjects.
Koenig et al. (1994) sought to determine whether exposure to H2SO4 or HNO3 enhanced
changes in lung function or airway responsiveness seen with exposure to ozone + nitrogen
dioxide (NO2). Adolescent asthmatic subjects were exposed to air, 0.12 ppm ozone + 0.3 ppm
NO2, ozone + NO2 + 73 //g/m3 H2SO4 (MMAD = 0.6), and ozone + NO2 + 0.05 ppm HNO3.
Exposures were by mouthpiece for 90 min, with intermittent exercise, on two consecutive days.
Airway responsiveness was measured by methacholine challenge at screening and on the day
following the second pollutant exposure. No effects on airway responsiveness were found for
any atmosphere. However, challenge following pollutant exposure utilized only doses of
methacholine well below the level causing significant reductions in FEVj for these subjects at
baseline, making it unlikely that small or transient changes in responsiveness would be detected.
Six subjects did not complete the protocol because of illness, symptoms, and other factors which
may or may not have been related to pollutant exposure; these data were not included in the
analysis.
In summary, the data suggest that there is little, if any, effect of low concentration acid
aerosol exposure (regardless of particle size) on airway responsiveness in healthy or asthmatic
subjects. Observations of possible delayed increases in responsiveness in healthy subjects
exposed to 450 //g/m3 H2SO4 (Utell et al., 1983a), and H2SO4 enhancement of ozone effects on
airway responsiveness in healthy and asthmatic subjects (Linn et al., 1994) require confirmation
in additional studies, utilizing standard challenge protocols.
11.2.1.5 Effects of Acid Aerosols on Lung Clearance Mechanisms
Brief (1- to 2-h) exposures to H2SO4 aerosols have shown consistent effects on mucociliary
clearance in three species: donkeys, rabbits, and humans. The direction and magnitude of the
effect are dependent on the concentration and duration of the acid aerosol
11-34
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exposure, the size of the acid particle, and the size of the tracer particle. Clearance studies in
animals are discussed in Section 11.2.2.5.
Initial studies in healthy nonsmokers by Leikauf et al. (1981) found that exposure to 110
Mg/m3 H2SO4 (MMAD «0.5//m) for 1 h at rest accelerated bronchial mucociliary clearance of
7.5 //m tracer particles, while a similar exposure to 980 //g/m3 H2SO4 slowed clearance. A
second study (Leikauf et al., 1984) utilizing a smaller tracer particle (4.2 //m) to assess more
peripheral airways, found slowing of clearance with both 108 and 983 //g/m3 H2SO4, in
comparison with distilled water aerosol. Spektor et al. (1989) extended these studies, exposing
ten healthy subjects to H2SO4 (MMAD = 0.5//m) or distilled water aerosols for up to 2 h. Two
different 4.2 //m tracer aerosols were used, one administered before and the other after exposure.
Following a 2 h exposure to 100 //g/m3 H2SO4, clearance halftime tripled compared with control,
with reduced clearance rates still evident 3 h after exposure. These findings suggested that brief,
resting exposures to H2SO4 at ~ 100 //g/m3 accelerate clearance in large bronchi but slow
clearance in more peripheral airways in a dose-dependent fashion.
Data from studies in asthmatics are less clear. Spektor et al. (1985) exposed ten asthmatic
subjects to 0, 110, 319, and 911 //g/m3 H2SO4 (MMAD = 0.5//m) for 1 h. The effects were
difficult to interpret because of inhomogeneous distribution of the tracer aerosol in the more
severe asthmatics. However, clearance was decreased following the highest concentration of
acid exposure in the six subjects with the mildest asthma (not dependent on regular medications).
These responses were similar to those of healthy subjects reported above.
Laube et al. (1993) recently examined the effects of acid fog on mucociliary clearance in
asthmatics. Seven nonsmoking subjects with mild asthma (baseline FEVj 90 to 118% predicted)
were exposed in a head dome to 500 //g/m3 H2SO4 or NaCl (MMAD ~ 10 //m) for 1 h with 20
min of exercise. Mucociliary clearance was measured using inhalation of a technetium-99M
sulfur colloid aerosol after exposure to the test aerosol. Tracheal clearance was measured in four
subjects, and was increased in all four after H2SO4 exposure (no statistical analysis was
performed because of the small number of subjects). Outer zone lung clearance was increased in
six of seven subjects after H2SO4 exposure (p < 0.05). The
11-35
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dose of H+ inhaled orally correlated significantly with the change in outer zone lung clearance
(r = 0.79, p = 0.05).
11.2.1.6 Effects of Acid Aerosols Studied by Bronchoscopy and Airway Lavage
Fiberoptic bronchoscopy with BAL has proved a useful technique for sampling the lower
airways of humans in clinical studies of oxidant air pollutants. The type and number of cells
recovered in BAL fluid reflect changes in alveolar and distal airway cell populations, providing
a relatively sensitive measure of inflammation. Increases in serum proteins recovered in BAL
fluid can be a result of increased epithelial permeability, a consequence of injury and/or
inflammation. Alveolar macrophages obtained by BAL can be assessed in vitro for functional
changes important in inflammation and host defense. In addition, proximal airway cells and
secretions can be recovered using airway washes or proximal airway lavage (Eschenbacher and
Gravelyn, 1987).
Only one study has utilized bronchoscopy to evaluate the effects of exposure to acid
aerosols. Frampton et al. (1992) exposed 12 healthy nonsmokers to aerosols of NaCl (control)
or H2SO4 (MMAD = 0.9, GSD = 1.9) at 1000 //g/m3 for 2 h. Four 10-min exercise periods at
-40 L/min were included. Subjects brushed their teeth and rinsed with mouthwash prior to and
once during each exposure to reduce oral ammonia levels. Fiberoptic bronchoscopy with BAL
was performed 18 h after exposure. No evidence for airway inflammation was found. Markers
for changes in host defense, including lymphocyte subset distribution, antibody-dependent
cellular cytotoxicity of alveolar macrophages, and alveolar macrophage inactivation of influenza
virus, were not significantly different between H2SO4 and NaCl exposures.
In an effort to define possible effects of H2SO4 exposure on airway mucus, Gulp et al.
(1995) determined the composition of mucins recovered during bronchoscopy of subjects studied
by Frampton et al. (1992), as well as from some subjects not exposed. Secretions were lipid
extracted from airway wash samples and analyzed with regard to glycoprotein content, protein
staining profiles, and amino acid and carbohydrate composition. Mucin composition was similar
when non-exposed subjects were compared with NaCl-exposed subjects, indicating that aerosol
exposure per se did not alter mucus composition. No differences were found between H2SO4
and NaCl exposure with regard to absolute yields
11-36
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of high-density material, proportion of glycoproteins, presence of glycoprotein degradation
products, carbohydrate composition, or protein composition.
In these studies, bronchoscopy was performed 18 h after exposure in order to detect
delayed effects. Transient effects of exposure to acid aerosols on alveolar macrophage function
or mucous composition have therefore not been excluded.
11.2.1.7 Human Exposure Studies of Acid Aerosol Mixtures
In human subjects, previous studies have suggested that exposure to H2SO4 does not
potentiate responses to other pollutants. A number of more recent studies have also failed to
find interactions in effects of pollutant mixtures that include H2SO4. Anderson et al. (1992)
found no effects on lung function following exposure to 200 //g/m3 carbon black alone, or
carbon particles coated with H2SO4. Aris et al. (1990) found no effects on airways resistance of
exposure to mixtures of hydroxymethanesulfonic acid and H2SO4. Balmes et al. (1988) found no
differences between the effects of H2SO4 and HNO3 exposure in asthmatics, and no interaction
with exposure to both aerosols by mouthpiece. Koenig et al. (1989) found that exposure of
adolescent asthmatic subjects to 68 //g/m3 H2SO4 with 0.1 ppm SO2 did not increase the
responses seen with H2SO4 alone.
In one recent study funded by the Health Effects Institute, 28 adolescent asthmatic subjects
were exposed to air, 0.12 ppm ozone + 0.3 ppm NO2, ozone + NO2 + 68 //g/m3 H2SO4, and
ozone + NO2 + 0.05 ppm HNO3 (Koenig et al., 1994). Exposures were by mouthpiece for 90
min, with intermittent exercise, on two consecutive days. No significant effects on lung function
were seen for any of the atmospheres. However, six subjects did not complete the study protocol
for a variety of reasons; these subjects were characterized by the authors as having moderate to
severe asthma, based on results of methacholine challenge. Although the reasons for withdrawal
of these subjects were not clearly related to exposures, all discontinued participation following
exposure to pollutants rather than to clean air. As noted in the published comments of the
Health Effects Institute Health Review Committee accompanying the Koenig et al. report, "...the
conclusions of the study may have been based on a group of subjects more tolerant to oxidants,
acid aerosols, or both, than those constituting the original study group" (Koenig et al., 1994,
page 103).
11-37
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Two recent studies suggest that exposure to 100 //g/m3 H2SO4 may enhance airway effects
of exposure to ozone. Linn et al. (1994) exposed 15 healthy and 30 asthmatic subjects to air,
0.12 ppm ozone, 100 //g/m3 H2SO4 (MMAD «0.5 //m), and ozone + H2SO4 for 6.5 h on two
consecutive days. Each subject received all 4 pairs of exposures, each separated by one week.
Subjects were exposed in small groups in an environmental chamber, with six, 50-min exercise
periods each day. Acidic gargles were used to reduce oral ammonia. Lung function and
methacholine responsiveness were measured at the end of each exposure day. Reductions in
FEVj and FVC, and increases in airway responsiveness, were observed in association with ozone
exposure in both healthy and asthmatic subjects. Some subjects in both the asthmatic and
nonasthmatic group demonstrated greater declines in lung function after the first day of acid +
ozone than after ozone alone (Figure 11-2), although the group mean differences were only
marginally significant by ANOVA. From these data, a "hypothetical average subject", under the
specific conditions of the study, would be expected to lose 100 ml FEVj during ozone exposure
relative to clean air exposure, and would lose 189 ml FEVj during ozone + H2SO4 exposure.
When the responsive subjects were re-studied months later, increased responsiveness to acid +
ozone compared with ozone was again demonstrated, although individual responses to O3 +
H2SO4 in the original and repeat studies were not significantly correlated.
100 -
-100 -
2
S
= -200 -
-300 -
-400 -
0-6
H
• f -f
i i i
1 2
Clean
6-4
T
H *"" i/
{""A T...J 0 T
T f.f ^
/\ 1
i ^
i
i i i i i i i
12 12 1
s''[
i
2
Acid Ozone Ozone+Acid
|A"--AAsthmatics O— OlMonasthmatics
Figure 11-2. Decrements in forced expiratory volume in 1 s (plus or minus standard
error) following 6.5-h exposures on 2 successive days.
Source: Linn et al. (1994).
11-38
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Frampton et al. (1995) exposed 30 healthy and 30 asthmatic subjects to 100 //g/m3 H2SO4
or NaCl for 3 h followed the next day by 0.08, 0.12, or 0.18 ppm ozone for 3 h. All exposures
included intermittent exercise. Each subject received two of the three ozone exposure levels.
Exposure to H2SO4 or NaCl did not alter lung functions. As shown in Table 11-4, changes in
spirometry following exposure to ozone were small, consistent with the relatively low
concentrations, short exposure duration, and moderate exercise levels (VE 30.6 to 36.2 L/min
for a total of 60 min). Figure 11-3 shows the percentage changes in FVC 4 h after ozone
exposure; these changes were similar to those found immediately after exposure. With H2SO4
pre-exposure, FVC decreased following ozone in a concentration-response fashion. The
ANO VA revealed significant main effects of ozone exposure as well as a significant interaction
between aerosol and ozone exposure for effects on FEVj and FVC among the asthmatic subjects,
but not the healthy subjects. Four-way ANOVA revealed an interaction between ozone and
aerosol for the entire group (p=0.0022) and a difference between healthy subjects and subjects
with asthma (p=0.0048). Surprisingly, the largest decrements in FVC with the NaCl
preexposure were found with 0.08 ppm ozone, whereas no effect was seen at 0.18. With 0.18
ppm ozone preceded by H2SO4, the responses were similar to those seen at 0.08 with NaCl. The
authors concluded that, for asthmatic subjects, H2SO4 alters the response to ozone in comparison
with NaCl pre-exposure. Interpretation of these findings would be facilitated by a similar study
including air as a further control pre-exposure atmosphere. However, considered together, these
two studies (Frampton et al., 1995 and Linn et al., 1994) suggest that H2SO4 aerosol exposure
may enhance airway responsiveness to ozone.
11.2.1.8 Summary and Conclusions
Controlled human studies offer the opportunity to study the responses of human subjects
under carefully controlled conditions, but are limited to short-term exposures to pollutant
atmospheres without severe health risks. Outcome measures are limited by safety issues, but
have been extended beyond measures of lung function and symptoms to include mucociliary
clearance, BAL, and airway biopsies.
Human clinical studies of particle exposure remain almost completely limited to the study
of acid aerosols, primarily of H2SO4, with the majority of these focussing on
11-39
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TABLE 11-4. PULMONARY FUNCTION RESPONSES AFTER AEROSOL AND OZONE EXPOSURES IN
SUBJECTS WITH ASTHMA3
Time of Measurement
0.08 ppm Ozone
Baseline
After exercise
Immediately after exposure
2 Hours after exposure
4 Hours after exposure
0.12 ppm Ozone
Baseline
After exercise
Immediately after exposure
2 Hours after exposure
4 Hours after exposure
0.18 ppm Ozone
Baseline
After exercise
Immediately after exposure
2 Hours after exposure
4 Hours after exposure
FVC
NaCl
3.80±0.17
3.64 ±0.17
3. 51 ±0.18
3.67 ±0.17
3.67±0.15
3. 97 ±0.22
3.72 ±0.20
3. 72 ±0.21
3. 91 ±0.22
3. 87 ±0.22
3. 89 ±0.23
3.76 ±0.23
3. 76 ±0.23
3. 81 ±0.25
3. 90 ±0.24
(L)
H2S04
3.73±0.17
3.59±0.18
3.64 ±0.17
3. 70 ±0.16
3.74±0.18
3. 95 ±0.22
3.76±0.19
3.76 ±0.20
3. 85 ±0.21
3. 87 ±0.21
3. 99 ±0.22
3. 71 ±0.22
3.74 ±0.24
3. 87 ±0.23
3. 84 ±0.25
FEVj
NaCl
2.85±0.11
2.84 ±0.12
2.73 ±0.12
2.91 ±0.12
2.92 ±0.10
2.98 ±0.17
2.94 ±0.17
2.90 ±0.19
3.10±0.18
3. 07 ±0.18
2.92 ±0.16
2.90 ±0.19
2.90 ±0.19
3. 03 ±0.19
3. 06 ±0.17
(L)
H2S04
2.79 ±0.10
2.72 ±0.12
2.79±0.11
2.89±0.11
2.92 ±0.13
3. 05 ±0.17
3.01 ±0.16
2.97 ±0.18
3. 08 ±0.17
3. 04 ±0.18
3. 04 ±0.17
2.99 ±0.16
2.96 ±0.18
3. 03 ±0.17
2.99 ±0.18
sGaw (cm H2O/L/sec)
NaCl H2S04
0.204 ±0.021 0.209 ±0.020
-
0.176 ±0.024 0.177 ±0.022
-
-
0.220 ±0.015 0.236 ±0.020
-
0.186 ±0.019 0.209 ±0.025
-
-
0.183 ±0.016 0.207 ±0.016
-
0.170±0.016 0.179±0.018
-
-
1 Values are expressed as means ± SEM.
-------
0.2T
0.1"
O o
o
O)
IS
£
O
-0.1"
-0.2"
-0.3
NaCI
H2S04
0.08
0.12
0.18
ppm Ozone
Figure 11-3. Asthmatic subjects. The absolute change in FVC (means ± SE) 4-h after
exposure to each of the three ozone concentrations for the NaCI and H2SO4
aerosol preexposure conditions.
Source: Framptonet al. (1995).
symptoms and pulmonary function. Only two studies (Frampton et al., 1992; Gulp et al., 1995)
have utilized BAL to examine effects of particle exposure in humans. No studies have
examined effects of particle or acid aerosol exposure on airway inflammation in asthmatic
subjects. There are no studies examining the effects of particle exposure on antigen challenge in
allergic or asthmatic subjects.
Ten studies since 1988 have confirmed previous findings that healthy subjects do not
experience decrements in lung function following single exposures to H2SO4 of various particle
sizes at levels up to 2,000 //g/m3 for 1 h, even with exercise and use of acidic gargles to
minimize neutralization by oral ammonia. Mild lower respiratory symptoms occur at exposure
concentrations in the mg/m3 range, particularly with larger particle sizes. Acid aerosols alter
mucociliary clearance in healthy subjects at levels as low as 100 //g/m3, with effects dependent
on exposure concentration, acid aerosol particle size, and the region of the lung being studied.
Asthmatic subjects appear to be more sensitive than healthy subjects to the effects of acid
aerosols on lung function, but the effective concentration differs widely among studies.
11-41
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Adolescent asthmatics may be more sensitive than adults and may experience small decrements
in lung function in response to H2SO4 at exposure levels only slightly above peak ambient levels.
Although the reasons for the inconsistency among studies remain largely unclear, subject
selection and acid neutralization by NH3 may be important factors. Even in studies reporting an
overall absence of effects on lung function, occasional asthmatic subjects appear to demonstrate
clinically important effects. Two studies from different laboratories have suggested that
responsiveness to acid aerosols may correlate with degree of baseline airway
hyperresponsiveness. There is a need to identify determinants of responsiveness to H2SO4
exposure in asthmatic subjects. In very limited studies, elderly and individuals with chronic
obstructive pulmonary disease do not appear to be particularly susceptible to the effects of
submicron acid aerosols on lung function.
Two recent studies have examined the effects of exposure to both H2SO4 aerosols and
ozone on lung function in healthy and asthmatic subjects. Both studies found evidence that 100
Mg/m3 H2SO4 may potentiate the response to ozone, in contrast with previous studies.
Human studies of particles other than acid aerosols provide insufficient data to draw
conclusions regarding health effects. However, available data suggest that inhalation of inert
particles in the respirable range, including three studies of carbon particles, have little or no
effect on symptoms or lung function in healthy subjects at levels above peak ambient
concentrations.
11.2.2 Laboratory Animal Studies
11.2.2.1 Introduction
This section reviews the effects of acidic aerosols on laboratory animals. Almost all of the
available data have been derived from studies using acidic sulfates, namely ammonium bisulfate
(NH4HSO4) and sulfuric acid (H2SO4).
11.2.2.2 Mortality
The previous CD (U.S. Environmental Protection Agency, 1982) examined animal studies
of the acute lethality of acid aerosols (mainly H2SO4), and there are few new data to add here.
As for other toxicologic endpoints, large interspecies differences occurred, with the guinea pig
being the most sensitive, compared to the mouse, rat and rabbit. But high
11-42
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concentrations of H2SO4, generally in excess of 10,000 //g/m3, were required for lethality, even
in a species as sensitive as the guinea pig. Also, within a particular species of experimental
animal, the H2SO4 concentration required for lethality was dependent upon particle size, with
smaller particles being less effective than larger ones. As noted in the previous CD, the cause of
death due to acute, high-level H2SO4 exposure was laryngeal or bronchial spasm. Since these are
irritant responses, differences in the deposition pattern of smaller and larger acid droplets may
account for the aforementioned particle size dependence of lethal concentration; larger particles
deposit to a greater extent in the larynx and upper bronchial tree, where the bulk of irritant
receptors are located. As acid particle size is reduced, deeper pulmonary damage occurs prior to
death. Lesions commonly seen are focal atelectasis, hemorrhage, congestion, pulmonary and
perivascular edema, and desquamation of bronchiolar epithelium; hyperinflation is also often
evident.
Few data allow assessment of lethality for acid sulfate aerosols other than H2SO4. Pattle
et al. (1956) noted that if sufficient ammonium carbonate was added into the chamber where
guinea pigs were exposed to H2SO4 so as to provide excess NH3, protection was afforded to acid
levels which would have produced 50% mortality in the absence of NH3. This implies that
H2SO4 is more acutely toxic than its neutralization products [i.e., NH4HSO4 and/or (NH4)2SO4].
Pepelko et al. (1980a) found no mortality among rats exposed for 8 h/day for 3 days to
(NH4)2SO4 at 1,000,000 to 1,200,000 //g/m3 (2 to 3 //m, MMAD); but 40 and 17% mortality
occurred in guinea pigs exposed once for 8 h to 800,000 to 900,000, or 600,000 to 700,000
Mg/m3, respectively, of similarly sized-particles. Death was ascribed to airway constriction,
rather than to extensive lung damage. As with H2SO4, guinea pigs were more sensitive than
other species.
In summary, very high concentrations of acid sulfates are required to cause mortality in
otherwise healthy animals, with variations in effective concentrations depending on acid particle
size and the animal species tested.
11.2.2.3 Pulmonary Mechanical Function
Many studies examining the toxicology of inhaled acid aerosols at sublethal levels used
changes in pulmonary function as indices of response. A survey of the database since
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publication of the previous CD (U.S. Environmental Protection Agency, 1982) is presented in
Table 11-5.
One of the major exposure parameters which affects response is particle size. Studies by
Amdur (1974) and Amdur et al. (1978a,b), summarized in the previous CD, showed that the
irritant potency of H2SO4, (NH4)2SO4, or NH4HSO4, as measured by pulmonary resistance in
guinea pigs, increased with decreasing particle size (i.e., the degree of response per unit mass of
sulfate [SO4 ] at any specific exposure concentration increased as particle size decreased, at least
within the size range of 1 to 0.1 //m). If this is compared to the relationship between particle
size and mortality, it is evident that the relative toxicity of different particle sizes also depends
upon the exposure concentration. At high concentrations above the threshold for lethality, large
particles were more effective in eliciting response, while at lower (sublethal) levels, smaller
particles were more effective.
Pulmonary functional responses to H2SO4 described previously suggested a major site of
action to be the conducting airways, as evidenced by exposure-induced alterations in airflow
resistance. However, some earlier data also suggested that high exposure levels may affect more
distal lung regions, as evidenced by changes in pulmonary diffusing capacity (DLCO) noted in
dogs exposed to 889 //g/m3 (MMAD = 0.5//m) (Lewis et al., 1973). Deep lung effects of H2SO4
are also evident from studies of morphologic and lung defense endpoints, discussed in
subsequent sections.
Studies reported in the previous CD (U.S. Environmental Protection Agency, 1982)
indicated that the particle size of the acid aerosol affected the temporal pattern of any pulmonary
function response. For example, the response to 100 //g/m3 H2SO4 at 1 //m was slight and
rapidly reversible, while that with 0.3 //m droplets was greater and more persistent. At any
particular size, however, the degree of change in resistance and compliance in guinea pigs was
observed to be concentration related.
Although the earlier studies by Amdur and colleagues appeared to provide a reasonable
picture of the relative effects of acid particle size and exposure concentration on the
bronchoconstrictive response of guinea pigs at sublethal exposure levels, there is some conflict
between these results and reports by others discussed in the previous CD (U.S. Environmental
Protection Agency, 1982). Whereas the Amdur work supported a concentration dependence for
respiratory mechanics alterations (i.e., animals in each
11-44
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TABLE 11-5. EFFECTS OF ACIDIC SULFATE PARTICLES ON PULMONARY MECHANICAL FUNCTION
Particle
H2S04
H2S04
H2S04
H2S04
H2S04
H2S04
H2S04
(NH4)2S04
(NH4)2S04
Species, Gender,
Strain, Age, or
Body Weight
Rat
Rat
Rat
Guinea pig, M
Hartley
Rabbit, M
NZW
Guinea pig, M
Hartley,
260-325 g
Guinea pig, M
Hartley,
290-410 g
Guinea pig, M
Hartley, 10 wk
Rat, M
SD, 14 wk
Exposure
Technique (RH)
Whole body
Whole body
Whole body
Whole body
Nose-only (50%)
Nose-only (50%)
Head-only (50%)
Whole body
(50-60%)
Whole body
(50-60%)
Mass Concentration
(//g/m3)
2,370
6,350
6,590
1,000, 3,200
250
300
200
1,000
1,000
Particle Characteristics
Size (//m); ag
0.5 (MMD)
0.44 (MMD)
0.31 (MMD)
0.54 (MMD); 1.32
0.3 (MMAD); 1.6
0.08 (MMD); 1.3
0.06 (MMD); 1.4
0.4 (MMAD); 2.2
0.4 (MMAD); 2.3
Exposure Duration
14 weeks
6 weeks
13 weeks
24 h/d, 3-30 d
1 h/day, 5 days/week,
up to 12 mo
Ih
Ih
6 h/day, 5 days/week,
1 or 4 weeks
6 h/day, 5 days/week,
1 or 4 weeks
Observed Effect
NC: VT, f, RL, Cd, pH, PaCO2
iPaC02
TpH
Hypo- to hyperresponsive
airways
NC: RL
Hyperresponsive by 4 mo
NC: VC, 1C, VA, TLC;
i DLco, (3 h post exp)
NC: RL
NC: RV; TFRC, VC, TLC,
DLco, Cd, AN2
TRV, TFRC, AN2
Reference
Lewkowski et al. (1979)
Lewkowski et al. (1979)
Lewkowski et al. (1979)
Kobayashi and Shinozaki
(1993)
Gearhart and
Schlesinger(1986)
Chenetal. (1991)
Chen et al. (1992b)
Loscutoffetal. (1985)
Loscutoffetal. (1985)
Key to abbreviations:
NC: No significant change
T: Significant increase
i: Significant decrease
Cd: Dynamic compliance
DLco: Diffusing capacity, CO
f: Respiratory frequency
FRC: Functional residual capacity
1C: Inspiratory capacity
AN2: Change in distribution of ventilation as measured by nitrogen washout technique
PaCO2: Partial pressure of CO2 in arterial blood
pH: Arterial pH
RL: Pulmonary resistance
RV: Residual volume
TLC: Total lung capacity
VT: Tidal volume
VA: Alveolar volume
VC: Vital capacity
-------
exposure group responded uniformly and the degree of response was related to the exposure
concentration), others found that individual guinea pigs exposed to H2SO4 at similar sizes
showed an "all-or-none" constrictive response (i.e., in atmospheres above a threshold
concentration), some animals manifested major changes in pulmonary mechanics ("responders"),
while others were not affected at all ("nonresponders") (Silbaugh et al., 1981b). As the exposure
concentration was increased further, the percentage of the group which was affected (i.e., the
ratio of responders to nonresponders) increased, producing an apparent concentration response
relationship. However, the magnitude of the change in pulmonary function was similar for all
responders, regardless of exposure concentration. Sensitivity to this all-or-none response may be
related to an animal's baseline airway caliber prior to H2SO4 exposure, because responders had
higher pre-exposure values for resistance and lower values for compliance, compared to
nonresponders. In any case, the threshold concentration for the all-or-none response was fairly
high (>10,000 //g/m3 H2SO4). Reasons for the discrepancy with the studies of Amdur and
colleagues are not known; they may involve differences in guinea pig strains, ages, or exposure
conditions, or differences in techniques used to measure functional parameters. In any case, the
dyspneic response of the guinea pig responders is similar to asthma episodes in humans, in both
its rapidity of onset and in the associated characteristic obstructive pulmonary function changes.
A more recent approach used to evaluate the acute pulmonary functional response to
H2SO4 involves co-inhalation of CO2 (Wong and Alarie, 1982; Matijak-Schaper et al., 1983;
Schaper et al., 1984). This procedure assesses the response to irritants by measuring a decrease
in tidal volume (VT) (based upon changes in inspiratory volume and pressure) which is routinely
increased above normal by adding 10% CO2 to the exposure atmosphere. Although the exact
mechanism underlying a reduction in response to CO2 is not clear, the assumption is that the
change in ventilatory response after irritant exposure is due to direct stimulation of irritant
receptors. A concentration-dependent decrease in CO2-enhanced ventilation has been found in
guinea pigs following 1-h exposures to H2SO4 (~ 1 //m, MMD) at levels >40,100 //g/m3 (Wong
and Alarie, 1982). Subsequently, Schaper et al. (1984) exposed guinea pigs for 0.5 h to H2SO4
at 1,800 to 54,900 //g/m3 (0.6 //m, AED). At concentrations >10,000 //g/m3, the level of
response (i.e., the maximum decrease in ventilatory response to CO2) increased as a function of
exposure concentration.
11-46
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At concentrations below 10,000 //g/m3, there was no clear relationship between exposure
concentration and response; any effects were transient, occurring only at the onset of acid
exposure.
The results of the studies with CO2 differ from those of both Silbaugh et al. (1981b) and
Amdur and colleagues, in that there was neither an "all or none" response as seen by the former,
nor was there a concentration-response relationship observed at H2SO4 concentrations <10,000
Mg/m3, as reported by the latter. In addition, Amdur and colleagues observed sustained changes
in lung function, rather than a fading response, at low concentrations. The reasons for these
differences are unknown, but may partly reflect inherent sensitivity differences in the
measurement techniques used as noted above.
The specific mechanisms underlying acid sulfate-induced pulmonary functional changes
are not known, but may be due to irritant receptor stimulation resulting from direct contact by
deposited acid particles or from humoral mediators released as a result of exposure. In terms of
the latter, a possible candidate in mediation of the bronchoconstrictive response, at least in
guinea pigs, is histamine (Charles and Menzel, 1975). On the other hand, evidence for a direct
response to H2SO4 in altering pulmonary function was found using the CO2 co-inhalation
procedure. Schaper and Alarie (1985) noted that the responses to histamine and H2SO4 differed
in both their magnitude and temporal relationship, suggesting direct action of the inhaled acid, or
a role of other humoral factors.
Whatever the underlying mechanism, the results of pulmonary function studies indicate
that H2SO4 is a bronchoactive agent that can alter lung mechanics of exposed animals primarily
by constriction of smooth muscle; however, the threshold concentration for this response is quite
variable, depending upon the animal species and measurement procedure used. In general,
exposure to H2SO4 at levels <1,000 //g/m3 does not produce physiologically significant changes
in standard tests of pulmonary mechanics, except in the guinea pig. Although in this species
such effects may be markers of exposure, any health significance in normal individuals is not
clear. On the other hand, all subgroups of an exposed population may not be equally sensitive.
11-47
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Airway Responsiveness
Some lung diseases (e.g., asthma) involve a change in airway "responsiveness", which is an
alteration in the degree of reactivity to exogenous (or endogenous) bronchoactive agents,
resulting in increased airway resistance at levels of these agents which would not affect airways
of normal individuals. Such altered airways are called hyperresponsive. The use of
pharmacologic agents capable of inducing smooth muscle contraction, a technique known as
bronchoprovocation challenge testing, can assess the state of airway responsiveness after
exposure to a nonspecific stimulus such as an inhaled irritant. Human asthmatics and, to some
extent, chronic bronchitis, typically have hyperresponsive airways, but the exact role of this in
the pathogenesis of airway disease is uncertain. Hyperresponsiveness may be a predisposing
factor in clinical disease, or it may be a reflection of other changes in the airways which precede
it. In any case, current evidence supports the hypothesis that an increase in airway
responsiveness is a factor in the pathogenesis of obstructive airway disease (O'Connor et al.,
1989).
The ability of H2SO4 aerosols to alter airway responsiveness has been assessed in a number
of studies. Silbaugh et al. (1981a) exposed guinea pigs for 1 h to 4,000 to 40,000 //g/m3 H2SO4
(1.01 //m, MMAD) and examined the subsequent response to inhaled histamine. Some of the
animals showed an increase in pulmonary resistance and a decrease in compliance at H2SO4
concentrations > 19,000 //g/m3 without provocation challenge; only the animals showing this
constrictive response during acid exposure also had major increases in histamine sensitivity.
This suggested that airway constriction may have been a prerequisite for the development of
hyperresponsiveness. On the other hand, Chen et al. (1992b) found bronchial
hyperresponsiveness, but no change in baseline resistance, in guinea pigs exposed for 1 h to 200
//g/m3 H2SO4 (0.06 //m, MMD). Perhaps the smaller size of this aerosol was responsible for
producing effects at a lower concentration.
Kobayashi and Shinozaki (1993) exposed guinea pigs to fairly high H2SO4 levels, namely
1,000 and 3,200 //g/m3 (0.54 //m), 24 h/day for 3, 7, 14 or 30 days, and examined airway
response to inhaled histamine. Unlike the study of Silbaugh et al. (1981a) and similar to that of
Chen et al. (1992b), acid exposure did not change the baseline resistance measured prior to
bronchoprovocation challenge. Exposure to 3,200 //g/m3 of acid resulted in airway
hyporesponsiveness at 3 days, hyperresponsiveness at 14 days and a return to normal levels of
responsiveness by 30 days of exposure. Thus, acid exposure resulted in a transient alteration in
airway function. The authors speculated that the hyporesponsiveness, and eventual return to
11-48
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normal, was due to changes in mucous secretion in the airways, which would affect the ability of
the inhaled histamine challenge aerosol to contact airway receptors.
Airway responsiveness following chronic exposure to H2SO4 was examined by Gearhart
and Schlesinger (1986), who exposed rabbits to 250 //g/m3 H2SO4 (0.3 //m, MMD) for 1 h/day, 5
days/week, and assessed responsiveness after 4, 8 and 12 mo of exposure, using acetylcholine
administered intravenously rather than inhaled. Hyperresponsiveness was evident at 4 mo, and a
further increase was found by 8 mo; the response at 12 mo was similar to that at 8 mo, indicating
a stabilization of effect. There was no change in baseline resistance. Thus, repeated exposures
to H2SO4 produced hyperresponsive airways in previously normal animals.
The mechanism which underlies H2SO4-induced airway hyperresponsiveness is not clear.
However, some recent studies have suggested possibilities. One may involve an increased
sensitivity to mediators involved in airway smooth muscle control. For example, guinea pigs
exposed to H2SO4 showed a small degree of enhanced response to histamine, but a much more
pronounced sensitivity to substance P, a neuropeptide having effects on bronchial muscle tone
(Stengel et al., 1993). El-Fawal and Schlesinger (1994) exposed rabbits for 3 h to 50 to 500
//g/m3 H2SO4 (0.3 //m), following which bronchial airways were examined in vitro for
responsiveness to acetylcholine and histamine. Exposures at >75 //g/m3 produced increased
responsiveness to both constrictor agents. Detailed examination of the response in tracheal
segments suggested that the acid effect may result from interference with airway
contractile/dilatory homeostatic processes, in that there was a potentiation of the response of
airway constrictor receptors and a diminution of the response of dilatory receptors.
11.2.2.4 Pulmonary Morphology and Biochemistry
Morphologic alterations associated with exposure to acid aerosols are summarized in
Table 11-6.
11-49
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TABLE 11-6. EFFECTS OF ACIDIC SULFATE PARTICLES ON RESPIRATORY TRACT MORPHOLOGY
Particle
H2S04
H2S04
H2S04
H2S04
H2S04
H2S04
H2S04
H2S04
H2S04
H2S04
Species, Gender,
Strain, Age, or
Body Weight
Guinea pig
Guinea pig, M/F
Hartley, 2-3 mo
Rabbit, M
mixed,
2.5-2.7 kg
Rabbit, M
mixed,
2.5-2.7 kg
Rabbit, M
NZ White, 3-3. 5 kg
Rat
Rat
Rat
Rhesus monkey
Guinea Pig
Exposure
Technique (RH)
Whole body
(70-90%)
Whole body (80%)
Oral tube or
nose- only (80%)
Nose-only (80%)
Nose-only (60%)
Whole body
(40-60%)
Whole body (50%)
Whole body
(<60%)
Whole body
(<60%)
Whole body
(<60%)
Mass
Concentration
C"g/m3)
32,600
1,200, 9,000,
27,000
250-500
250
125
2,000
700-1,200
45,000
68,000
172,000
150,000
361,000
502,000
30,000
38,000
71,000
Particle Characteristics
Size (//m); an
1 (MMAD); 1.49
0.8-1 (MMAD); 1.5-1.6
0.3 (MMAD); 1.6
0.3 (MMAD); 1.6
0.3 (MMD); 1.6
0.3 (MMD); =2
0.03-0.04 (CMD); 1.8-2.1
0.52(CMD)
0.4 (MMAD)
0.45 (CMD)
0.3-0.5 (CMD)
0.43 (MMAD); 1.6
0.48 (MMAD); 1.5
0.31 (MMAD); 1.6
0.31 (MMAD); 1.6
0.52 (CMD)
Duration
4h
6h
1 h/day,
5 days/week,
4 weeks
1 h/day,
5 days/week
up to 52 weeks
2 h/day,
5 days/week
up to 12 mo
8 h/day,
82 days
Continuous,
up to 180 days
11 days
6 days
7 days
3 days
7 days
7 days
7 days
7 days
4 days
Observed Effect
Focal atelectasis; epithelial
desquamation in terminal bronchioles
At 27,000 lig/m3: interstitial edema only
in "responders"; no change in
"nonresponders" oral 1,000 and 10,000
//g/m3. Concentration-dependent increase
in height of tracheal mucus layer at all
concentrations.
Increased epithelial thickness in small
airways; increase in secretory cells in
mid
to small airways
Increase in secretory cell no. density
throughout bronchial tree increase in
number of small airways
No bronchial inflammation; increase in
secretory cell number density in small
airways at 12 mo
Some hypertrophy of epithelial cells,
mainly at alveolar duct level; no effect
on turnover rate of terminal bronchiolar
epithelial or Type II cells
No effect
No effect in nasal passages, trachea,
bronchi, alveolar region
No effect
At 71,000 //g/m3: focal edema, necrosis of
alveolar septa, inflammatory cell
infiltration; necrosis of bronchiolar
epithelium; focal epithelial necrosis in
larger bronchi; ciliary denudation. At
38,000 //g/m3: minimal effects; some
change in density and length of cilia
Reference
Brownstein
(1980)
Wolff etal.
(1986)
Schlesinger
et al. (1983)
Gearhart and
Schlesinger
(1988)
Schlesinger
et al. (1992b)
Juhos et al.
(1978)
Moore and
Schwartz (1981)
Schwartz et al.
(1977)
Schwartz et al.
(1977)
Schwartz et al.
(1977)
-------
TABLE 11-6 (cont'd). EFFECTS OF ACIDIC SULFATE PARTICLES ON RESPIRATORY TRACT MORPHOLOGY
Particle
H2S04
H2S04
H2S04
H2S04
H2S04
(NH4)2S04
(NH4)2S04
(NH4)2S04
(NH4)2S04
(NH4)2S04
(NH4)2S04
Species, Gender,
Strain, Age, or
Body Weight
Mouse
Rat
Rat, M/F,
F344/Crl
12-16 weeks
Rat, M
Fischer,
250-300 g
Guinea pig
Guinea pig, M,
Hartley
adult
Rat, M,
SD/Crl,
70-75 g
Hamster, M,
Syrian,
10 weeks
Rat, M,
adult
Rat, M, SD
adult
Rat
Exposure
Technique (RH)
Whole body
(<60%)
Whole body
Whole body (80%)
Whole body (55%)
Whole body (55%)
Whole body
Whole body
Whole body
Whole body
Whole body
Nose- only
Mass
Concentration
(«g/m3)
140,000
170,000
1,000-100,000
1,100, 11,000,
96,000
10,000
30,000
100,000
10,000
30,000
100,000
1,030
5000
187
300,000
1,030
70
Particle Characteristics
Size (//m); a.
0.32 (MMAD); 1.4
0.62 (MMAD); 1.7
0.6-1.1 (MMAD); 1.7-1.8
0.8-1 (MMAD); 1.6-1.8
0.89(MMD)
0.83 (MMD)
0.72 (MMD)
0.89 (MMD)
0.83 (MMD)
0.72 (MMD)
0.42 (MMD); 2.25
0.8-1 (MMD); 1.8-2.0
0.3 (MMD); 2.02
1-2 (MMAD)
0.42 (MMAD); 2.25
0.2 (MMAD)
Exposure
Duration
14 days
10 days
6h
6h
5 days
5 days
5 days
5 days
5 days
5 days
6 h/day,
5 days/week,
20 days
7 days
6 h/day,
5 days/week,
15 weeks
8 h/day,
1-14 days
6 h/day,
5 days/week,
20 days
4 h/day,
4 days/week,
8 weeks
Observed Effect
Lesions in larynx and upper trachea;
epithelial ulceration, edema,
inflammatory infiltration
At 100,000 //g/m3: some cilia loss;
ulceration of larynx. <100,000
//g/m3: no effect
Laceration of larynx and cilia loss
in bronchi at 96,000 //g/m3; no deep
lung lesions; some thickening of
mucus lining in trachea at 1 1,000 and
96,000 A^g/m3
No effect
No effect
} Mortality
}
Interstitial thickening;
hypertrophy and hyperplasia of Type
II cells and secretory
cells in bronchioli
No effect (proximal acinar region)
Emphysematic lesions; no hyperplasia
of bronchial glands or metaplasia of
goblet cells
No effect
Interstitial thickening
Increased alveolar septal thickness;
decreased average alveolar diameter
Reference
Schwartz et al. (1977)
Henderson et al.
(1980a)
Wolff etal. (1986)
Cavender et al.
(1977b)
Cavender et al.
(1977b)
Busch et al. (1984)
Last et al. (1983)
Godleski et al. (1984)
Pepelko et al. (1980a)
Busch et al. (1984)
Kleinman et al. (1995)
-------
Single or multiple exposures to H2SO4 at fairly high levels (>1,000 //g/m3) produce a
number of characteristic morphologic responses (e.g., alveolitis, bronchial and/or bronchiolar
epithelial desquamation, and edema). As with other endpoints, the sensitivity to H2SO4 is
dependent upon the animal species. Comparative sensitivities of the rat, mouse, rhesus monkey
and guinea pig were examined by Schwartz et al. (1977), using concentrations of H2SO4 >30,000
Mg/m3 at comparable particle sizes (0.3 to 0.6 //m) and assessing airways from the larynx to the
deep lung. Both the rat and monkey were quite resistant, while the guinea pig and mouse were
the more sensitive species. The nature of the lesions in the latter pair were similar, but differed
in location; this was, perhaps, a reflection of differences in the deposition pattern of the acid
droplets. Mice would tend to have greater deposition in the upper respiratory airways than
would the guinea pig (Schlesinger, 1985), which could account for the laryngeal and upper
tracheal location of the lesions seen in the mice. The relative sensitivity of the guinea pig and
relative resistance of the rat to acid sulfates is supported by results from other morphological
studies (Busch et al., 1984; Cavender et al., 1977b; Wolff et al., 1986).
Repeated or chronic exposures to H2SO4 at concentrations < 1,000 //g/m3 produce a
response characterized by hypertrophy and hyperplasia of epithelial secretory cells.
In morphometric studies of rabbits exposed to 125 to 500 //g/m3 H2SO4 (0.3 //m) for 1 to
2 h/day, 5 d/week (Schlesinger et al., 1983; Gearhart and Schlesinger, 1988; Schlesinger et al.,
1992b), increases in the relative number density of secretory cells (as determined by
histochemical staining) have been found to extend to the bronchiolar level, where these cells are
normally rare or absent. Depending upon the study, the changes began within 4 weeks of
exposure and persisted for up to 3 mo following the end of exposure. The mechanism
underlying increases in secretory cell numbers at low H2SO4 exposure levels is also unknown; it
may involve an increase in secretory activity of existing cells, or a transition from another cell
type.
An increase in the relative number of smaller airways (<0.25 mm) in rabbits was found by
4 mo of exposure to 250 //g/m3 (0.3 //m) for 1 h/day, 5 days/week (Gearhart and Schlesinger,
1988). Changes in airway size distribution due to irritant exposure, specifically cigarette
smoke, has been reported in humans (Petty et al., 1983; Cosio et al., 1977), and this seems to be
an early change relevant to clinical small airways disease.
11-52
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The specific pathogenesis of acid-induced lesions is not known. As with pulmonary
mechanics, both a direct effect of deposited acid droplets on the epithelium and/or indirect
effects, perhaps mediated by humoral factors, may be involved. For example, similar lesions
have been produced in guinea pig lungs by exposure to either histamine or H2SO4 (Cavender
et al., 1977a). In addition, some lesions may be secondary to reflex bronchoconstriction, to
which guinea pigs are very vulnerable, rather than primary effects separable from constriction.
Thus, damage at the small bronchi and bronchiolar level may be due not only to direct acid
droplet-induced injury, but to indirect, reflex-mediated injury as well (Brownstein, 1980).
Morphologic and cellular damage to the respiratory tract following exposure to acid
aerosols may be determined by methods other than direct microscopic observation. Analysis of
bronchoalveolar lavage fluid can also provide valuable information, and this procedure has seen
increasing use since publication of the previous CD. Levels of cytoplasm!c enzymes, such as
lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G-6PD), are markers of
cytotoxicity; increases in lavageable protein suggest increased permeability of the alveolar
epithelial barrier; levels of membrane enzymes, such as alkaline phosphatase, are markers of
disrupted membranes; the presence of fibrin degradation products (FDP) provides evidence of
general damage; and sialic acid, a component of mucoglycoprotein, indicates mucus-secretory
activity. (It should, however, be noted that lavage analysis may not be able to provide
identification of the site of injury nor indicate effects in the interstitial tissue.)
Henderson et al. (1980b) exposed rats for 6 h to H2SO4 (0.6 //m, MMAD) at 1,500, 9,500,
and 98,200 //g/m3, and found FDP in blood serum after exposure at all concentrations. No FDP
was found in lavage fluid, but since the washing procedure did not include the upper respiratory
tract (i.e., anterior to and including the larynx), FDP in the serum was concluded to be an
indicator of upper airway injury. A concentration-dependent increase in sialic acid content of
the lavage fluid was also observed, indicating increased secretory activity within the
tracheobronchial tree.
Chen et al. (1992a) exposed guinea pigs to fine (0.3 //m) and ultrafme (0.04 //m) aerosols
of H2SO4 at 300 //g/m3 for 3 h/day for 1 or 4 days. Animals were sacrificed 24 h after each of
these exposures. Following the single exposure to either size, lavage fluid showed increases in
LDH and total protein, and the change in LDH was evident at 24 h with
11-53
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the fine, but not the ultrafine, particles. These responses did not occur following the 4 day
exposure.
Wolff et al. (1986) exposed both rats and guinea pigs for 6 h to H2SO4 (0.8 to 1 //m,
MMAD), at concentrations of 1,100 to 96,000 //g/m3 for rats and 1,200 to 27,000 //g/m3 for
guinea pigs. No changes in lavageable LDH, protein, or sialic acid were found in the rat.
However, some of the guinea pigs exhibited bronchoconstriction after exposure to 27,000 //g/m3,
and only these animals showed increased levels of lavageable protein, sialic acid and LDH.
In other studies, no changes in lavageable protein were found in the lungs of rats exposed for 3
days to 1,000 //g/m3 (0.4 to 0.5 //m, MMAD) H2SO4 (Warren and Last, 1987), nor for 2 days to
5,000 //g/m3 (0.5 //m, MMAD) (NH4)2SO4 (Warren et al., 1986).
An important group of biological mediators of the inflammatory response, as well as of
smooth muscle tone, are the eicosanoids, (e.g., prostaglandins and leukotrienes). Modulation of
these mediators could be involved in damage to the respiratory tract due to inhaled particles.
Preziosi and Ciabattoni (1987) exposed isolated, perfused guinea pig lungs for 10 min to
aerosols of H2SO4 (no concentration or particle sizes were given). An increase in thromboxane
B2 but no change in leukotriene B4 in the perfusate was found. Schlesinger et al. (1990b)
exposed rabbits to 250 to 1,000 //g/m3 H2SO4 (0.3 //m) for 1 h/day for 5 days. Lungs were
lavaged and the fluid assayed for eicosanoids. A concentration-dependent decrease in levels of
prostaglandins E2 and F2a and thromboxane B2 were noted, while there was no change in
leukotriene B4. The effects, which were determined to be due to the hydrogen ion rather than the
sulfate ion, indicate that acid sulfates can upset the normally delicate balance of eicosanoid
synthesis/metabolism which is necessary to maintain pulmonary homeostasis. Since some of the
prostaglandins are involved in regulation of muscle tone, this imbalance may be involved in the
development of airway hyperresponsiveness found with exposure to acid sulfates.
Other biochemical markers of pulmonary damage have been used to assess the toxicity of
acid sulfate particles. The proline content of the lungs may provide an index of collagen
metabolism. No change in soluble proline content was found in rat lungs after exposure for 7
days to 4,840 //g/m3 (0.5 //m, MMAD) (NH4)2SO4, nor due to a 7 day exposure to 1,000 //g/m3
(0.5 //m) H2SO4 (Last et al., 1986). A series of studies assessed collagen synthesis in rat lung
minces after in vivo exposure; this is a possible indicator of the potential
11-54
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for pollutants to produce fibrosis. Exposure for 7 days to H2SO4 at 40, 100, 500, and
1,000 //g/m3 (0.4 to 0.5 //m, MMAD) resulted in an increase in collagen synthesis rate only at
100 //g/m3; higher levels had no effect (Warren and Last, 1987). No effect on collagen synthesis
by rat lung minces was found due to 7-day exposures to (NH4)2SO4 at 5,000 //g/m3 (0.8 to 1 //m,
MMAD) (Last et al., 1983).
Other parameters of pulmonary damage are changes in lung DNA, RNA, or total protein
content. No significant changes in any of these parameters were found in rats after exposure to
1,000 //g/m3 H2SO4 (<1 //m) for 3 days (Last and Cross, 1978), nor in protein content in rats
exposed for up to 9 days to a similar concentration of H2SO4 (Warren and Last, 1987).
11.2.2.5 Pulmonary Defenses
Responses to air pollutants often depend upon their interaction with an array of
non-specific and specific respiratory tract defenses. The former consists of nonselective
mechanisms protecting against a wide variety of inhaled materials; the latter requires antigenic
stimulation of the immune system for activation. Although these systems may function
independently, they are linked, and response to an immunologic insult may enhance the
subsequent response to nonspecific materials. The overall efficiency of lung defenses
determines the local residence times for inhaled deposited material, which has a major influence
upon the degree of pulmonary response; furthermore, either depression or over-activity of these
systems may be involved in the pathogenesis of lung diseases.
Studies of altered lung defenses resulting from inhaled acid aerosols have concentrated on
conducting and respiratory region clearance function and nonspecific activity of macrophages;
there are only a few studies of effects upon immunologic competence.
Clearance Function: Clearance, a major nonspecific defense mechanism, is the physical
removal of material that deposits on airway surfaces. As discussed in Chapter 10, the
mechanisms involved are regionally distinct. In the tracheobronchial region, clearance occurs
via the mucociliary system, whereby a mucus "blanket" overlying the ciliated epithelium is
moved by the coordinated beating of the cilia towards the oropharynx. In the alveolar region of
the lungs, clearance occurs via a number of mechanisms and pathways, but the major one for
both microbes and nonviable particles is the alveolar macrophage (AM).
11-55
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These cells exist freely within the fluid lining of the alveolar epithelium, where they move by
ameboid motion. The phagocytic ingestion of deposited particles helps prevent particle
penetration through the alveolar epithelium and subsequent translocation to other sites. These
cells contain proteolytic enzymes, which digest a wide variety of organic materials, and they also
kill bacteria through oxidative mechanisms. In addition, AMs are involved in the induction and
expression of immune reactions. Thus, the AM provides a link between the lung's non-specific
and specific defense systems. These cells also are in the effector chain for lung damage (e.g., by
release of proinflammatory cytokines).
Mucociliary Transport: The assessment of acid effects upon mucociliary clearance often
involved examination only of mucus transport rates in the trachea, since this is a readily
accessible airway and tracheal mucociliary clearance measurements are more straightforward to
perform than are those aimed at assessing clearance from the entire tracheobronchial tree. Table
11-7 outlines studies of acid sulfate effects upon tracheal mucociliary clearance.
Although many of the studies involved fairly high concentrations of acid aerosols, most
demonstrated a lack of effect. The most likely explanation for this is that the sizes of the
aerosols were such that significant tracheal deposition did not occur. This is supported by the
results of Wolff et al. (1981), who found tracheal transport rates in dogs to be depressed only
when using 0.9 //m H2SO4; no effect was seen with a 0.3 //m aerosol at an equivalent mass
concentration. In addition, the use of tracheal clearance rate as a sole toxicologic endpoint may
be misleading, inasmuch as a number of studies have demonstrated alterations in bronchial
clearance patterns in the absence of changes in tracheal mucous transport.
Studies assessing the effects of acid aerosols upon bronchial mucociliary clearance are also
outlined in Table 11-7. Responses following acute exposure to H2SO4 indicate that the nature of
clearance change (i.e., a slowing or speeding) is concentration (C) and exposure-duration (t)
dependent; stimulation of clearance generally occurs after low Ct exposures, and retardation
generally occurs at higher Ct levels. However, the actual Ct needed to alter clearance rate may
depend upon the anatomic location within the bronchial tree from which clearance is being
measured, in relation to the region which is most affected by the deposited acid. Studies in
humans indicated that low H2SO4 concentrations (i.e., ~ 100 to 500 //g/m3) may accelerate
clearance, compared to unexposed subjects, from the large proximal airways
11-56
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TABLE 11-7. EFFECTS OF ACIDIC SULFATE PARTICLES ON RESPIRATORY TRACT CLEARANCE
Particle
H2S04
H2S04
H2S04
H2S04
H2S04
H2SO4
NH4HS04
(NH4)2S04
(NH4)2S04
H2S04
H2S04
H2S04
H2S04
Species, Gender,
Strain, Age, or
Body Weight
Tracheal
Dog, M/F
Beagle,
3 years
Donkey, M/F
adult
Rat
Rat
Rat, M/F
F344/Crl
12-16 weeks
Guinea pig, M/F
Hartley
2-3 mo
Sheep
Donkey
Sheep
Bronchial
Rabbit, M
NZW/mixed,
2. 5-3 kg
Rabbit, M
mixed
2.5-2.7 kg
Rabbit, M
NZW
2. 5-3 kg
Rabbit, M
NZW
2. 5-3 kg
Exposure Technique
(RH)
Nose-only (80%)
Nasopharyngeal
catheter (45%)
Whole body (82%)
Nose-only (80%)
Whole body (80%)
Whole body (80%)
Head-only (20-30%)
Nasopharyngeal
catheter (45%)
Head-only (20-30%)
Oral tube (75%)
Oral tube or
nose-only (80%)
Nose-only (80%)
Nose-only (60%)
Mass Concentration
(//g/m3)
1,000
5,000
1,000
500
200-1,400
1,000-100,000
10,000-100,000
1,100, 11,000,96,000
1,400, 9,000, 27,000
1,000
300-3,000
1,100
100-2,200
250-500
250
125
Particle Characteristics
Size (//m); ag
0.3 (MMAD); 1.2
0.3 (MMAD); 1.2
0.9 (MMAD); 1.3
0.9 (MMAD); 1.3
0.4 (MMAD); 1.5
0.6-0.8 (MMAD); 1.5-2.6
0.4-0.6 (MMAD); 1.3-1.4
0.9-1 (MMAD); 1.6-1.8
0.8-0.9 (MMAD); 1.5-1.6
0.1(CMD);2.1
0.4 (MMAD); 1.5
0.1 (CMD);2.1
0.3 (MMAD); 1.6
0.3 (MMAD); 1.6
0.3 (MMAD); 1.6
0.3 (MMD); 1.6
Exposure
Duration
Ih
Ih
Ih
Ih
Ih
6h
0.5 h
6h
6h
4h
Ih
4h
Ih
1 h/days,
5 days/week,
4 weeks
1 h/day,
5 days/week,
12 mo
2 h/day,
5 days/week up to
12 mo
Observed Effect
NC
NC
i
i
NC
T
T
T at 96,000 //g/m3
i at 1,400 //g/m3
NC
NC
NC
T,i (depending
on concentration
and duration)
T ; persistent
i by 1 week;
progressive
slowing after
19 weeks;
persistent
T followed by i
PE; persistent
Reference
Wolff etal. (1981)
Schlesinger et al. (1978)
Wolff etal. (1980)
Wolff etal. (1986)
Sackner et al. (1981)
Schlesinger et al. (1978)
Sackner et al. (1981)
Chen and Schlesinger
(1983); Schlesinger et al.
(1984)
Schlesinger et al. (1983)
Gearhart and Schlesinger
(1988)
Schlesinger etal. (1992b)
-------
TABLE 11-7 (cont'd). EFFECTS OF ACIDIC SULFATE PARTICLES ON RESPIRATORY TRACT CLEARANCE
Particle
H2S04
H2S04
H2S04
NH4HSO4
(NH4)2S04
(NH4)2S04
H2S04
H2S04
H2S04
Species, Gender,
Strain, Age, or Exposure Technique Mass Concentration
Body Weight (RH) C"g/m3)
Bronchial
Rabbit, M oral tube 250; 250; 500
mixed nose-only
6 mo
Donkey Nasopharyngeal 200-1,400
catheter (45%)
Rat, M Nose-only (39%; 85%) 3,600
SD
200 g
Rabbit, M Oral tube (78%) 600-1,700
mixed
2.5-2.7 kg
Rabbit, M Oral tube (78%) 2,000
mixed
2.5-2.7 kg
Rat, M Nose-only (39%; 85%) 3,600
SD
200 g
Alveolar
Rat, M Whole body (30-80%) 3,600
SD
200 g
Rabbit, M Oral tube 1,000
NZW
2. 5-3 kg
Rabbit, M Nose-only (80%) 250
NZW
2. 5-3 kg
Particle Characteristics
Size (//m); ag Duration
0.3 (MMAD); 1.6 1 h/day,
5 days/week,
4 weeks
0.4 (MMAD); 1.5 Ih
1.0 (MMAD); 1.9-2.3 4h
0.4 (MMAD); 1.6 Ih
0.4 (MMAD); 1.6 Ih
0.4 (MMAD); 1.9-2.3 4h
1.0 4h
0.3 (MMAD); 1.5 1 h
0.3 (MMAD); 1.6 1 h/day,
5 days/week,
1, 57, 240 day
Observed Effect
T only some days at
250/oral and
500/nasal;
persistent T up to
14 days PE for all.
i in some animals at
all
concentrations;
progressive
slowing in some
animals with
continued
exposures.
NC
i at 1,700 A^g/m3
NC
NC
NC
T
T
Reference
Schlesinger et al. (1983)
Schlesinger et al. (1978)
Phalen et al. (1980)
Schlesinger (1984)
Schlesinger (1984)
Phalen et al. (1980)
Phalen et al. (1980)
Naumann and Schlesinger
(1986)
Schlesinger and Gearhart
(1986)
-------
TABLE 11-7 (cont'd). EFFECTS OF ACIDIC SULFATE PARTICLES ON RESPIRATORY TRACT CLEARANCE
Particle
Species, Gender,
Strain, Age, or
Body Weight
Exposure Technique
(RH)
Mass Concentration
(//g/m3)
Particle Characteristics
Size (//m); a
Exposure
Duration
Observed Effect
Reference
Alveolar (cont'd)
Rabbit, M
NZW
3-3.5 kg
Nose-only (80%)
500
0.3 (MMAD); 1.6
2 h/day,
14 days
Schlesinger and Gearhart
(1987)
Key to abbreviations:
NC: No significant change
T: Significant increase
i: Significant decrease
PE: Post exposure
-------
where little acid deposits, while slowing clearance from the distal ciliated airways where there is
greater acid deposition. At higher concentrations, mucociliary clearance from both the proximal
and distal bronchial tree becomes depressed (Leikauf et al., 1984).
Comparison of responses to H2SO4 show interspecies differences in the sensitivity of
mucociliary clearance to acid aerosols. As an example, the acceleration of tracheal transport
found by Wolff et al. (1986) in the rat with ~ 100,000 //g/m3 H2SO4 seems anomalous since, in
other species, levels > 1,000 //g/m3 depress mucociliary function. The reasons for this apparent
discrepancy are not known. The rat is less susceptible to the lethal effects of H2SO4, and it does
not have strong bronchoconstrictive reflex responses following H2SO4 exposures. These
characteristics suggest that the mucociliary system of the rat may also differ in sensitivity from
the other species studied, a view supported by the lack of effect of H2SO4 on bronchial clearance
found by Phalen et al. (1980) following exposure at 3,600 //g/m3 for 4 h and by the similarity in
bronchial clearance response in donkeys and rabbits to single 1-h exposures of H2SO4 (Table
11-7). Although the lack of response of tracheal transport in the guinea pig at H2SO4 levels
>1,000 //g/m3 is also surprising, its response at 1,000 //g/m3 is also different from that of the rat
and more in line with other species (Wolff, 1986).
The relative potency of acid sulfate aerosols, in terms of altering mucociliary clearance, is
related to their acidity (H+ content). Schlesinger (1984) exposed rabbits for 1 h to
submicrometer aerosols of NH4HSO4, (NH4)2SO4, and Na^CV Exposure to NH4HSO4 at
concentrations of -600 to 1,700 //g/m3 significantly depressed clearance rate only at the highest
exposure level. No significant effects were observed with the other sulfur oxides at levels up to
«2,000 //g/m3. When these results are compared to those from a study using H2SO4 (Schlesinger
et al., 1984), the ranking of potency was H2SO4 > NH4HSO4 > (NH4)2SO4, Na2SO4; this strongly
suggests a relation between the hydrogen ion concentration and the extent of alteration in
bronchial mucociliary clearance.
The mechanism by which deposited acid aerosol alters clearance is not certain. The
effective functioning of mucociliary transport depends upon optimal beating of cilia and the
presence of mucus having appropriate physicochemical properties, and both ciliary beating as
well as mucus viscosity may be affected by acid deposition. At alkaline pH, mucus is more fluid
than at acid pH, so a small increase in viscosity due to deposited acid could "stiffen"
11-60
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the mucus blanket, perhaps promoting the clearance mechanism and, thus, increasing its
efficiency (Holma et al., 1977). Such a scenario may occur at low H2SO4 exposure
concentrations, where ciliary activity would not be directly affected by the acid, and is
consistent with clearance acceleration observed at these concentrations with acute exposure.
However, the exact relation between mucus viscosity and transport rate is not certain.
High concentrations of H2SO4 may affect ciliary beating, as discussed in the previous CD
(U.S. Environmental Protection Agency, 1982; Schiff et al., 1979; Grose et al., 1980). An
additional mechanism by which deposited acid may affect mucociliary clearance is via altering
the rate and/or amount of mucus secreted. A small increase in mucus production could facilitate
clearance, while more excessive production could result in a thickened mucus layer which would
be ineffectively coupled to ciliary beat. Finally, the airways actively transport ions, and the
interaction between transepithelial ion transport and consequent fluid movement is important in
maintaining the mucus lining. A change in ion transport due to deposited acid particles may
alter the depth and/or composition of the sol layer (Nathanson and Nadel, 1984), perhaps
affecting clearance rate. In any case, the pathological significance of transient alterations in
bronchial clearance rates in healthy individuals is not certain, but such changes are an indication
of a lung defense response. On the other hand, persistent impairment of clearance may lead to
the inception or progression of acute or chronic respiratory disease and, as such, may be a
plausible link between inhaled acid aerosols and respiratory disease.
Short-term exposures to acid aerosols may lead to persistent clearance changes, as
indicated previously (Schlesinger et al., 1978). The effects of long-term exposures were
investigated by Schlesinger et al. (1983), who exposed rabbits to 250 or 500 //g/m3 H2SO4
(0.3 //m, MMAD) for 1 h/day, 5 days/week for 4 weeks, during which time bronchial
mucociliary clearance was monitored. Clearance was accelerated on individual days during the
course of the acid exposures, especially at 500 //g/m3. In addition, clearance was significantly
faster, compared to preexposure levels, during a 2 week follow- up period after acid exposures
had ceased.
Another long-term exposure at relatively low H2SO4 levels was conducted by Gearhart and
Schlesinger (1988). Rabbits were exposed to 250 //g/m3 H2SO4 for 1 h/day, 5 days/week for up
to 52 weeks, and some animals were also provided a 3 mo follow-up
11-61
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period in clean air. Clearance was slower during the first month of exposure and this slowing
was maintained throughout the rest of the exposure period. After cessation of exposure,
clearance became extremely slow and did not return to normal by the end of the follow-up
period. Differences in the nature of clearance change between this study and that of Schlesinger
et al. (1983) may be due to differences in exposure protocol daily (duration) and/or
concentration. In both studies, however, and as discussed earlier, histologic analyses indicated
the development of increased numbers of epithelial secretory cells, especially in small airways,
the likely consequence of which would be an increase in mucus production. In addition, the
slowing of clearance seen by Gearhart and Schlesinger (1988) was also associated with a shift in
the histochemistry of mucus towards a greater content of acidic glycoproteins; this would tend to
make mucus more viscous.
The longest duration study at the lowest concentration of H2SO4 yet reported is that of
Schlesinger et al. (1992b), in which rabbits were exposed to 125 //g/m3 H2SO4 for 2 h/day,
5 days/week for up to 52 weeks. The variability of measured bronchial clearance time was
increased with acid exposure, and acceleration of clearance was noted at various times during the
one-year exposure period. However, following a 6-mo observation period after exposures had
ceased, a trend towards slowing of clearance was noted (compared to both control and rates
during acid exposure). In addition, and consistent with previous studies, an increase in the
number density of epithelial secretory cells was observed in small airways (<0.5 mm) following
12 mo of acid exposure. This histological change had resolved by the end of the 6-mo
post-exposure period.
Alveolar Region Clearance and Alveolar Macrophage Function: Only a few studies
have examined the ability of acid aerosols to alter clearance of particles from the alveolar region
of the lungs (Table 11-7). Rats exposed to 3,600 //g/m3 H2SO4 (l//m) for 4 h showed no change
in clearance (Phalen et al., 1980). On the other hand, acceleration of clearance was seen in
rabbits exposed for 1 h to 1,000 //g/m3 H2SO4 (0.3 //m, MMAD) (Naumann and Schlesinger,
1986).
Two studies involving repeated exposures to acid aerosols have been reported. In one,
rabbits were exposed to 250 //g/m3 (0.3 //m, MMAD) H2SO4 for 1 h/day, 5 days/week, and inert
tracer particles were administered on days 1, 57 and 240 following the start of the acid exposures
(Schlesinger and Gearhart, 1986). Clearance (measured for 14 days after each
11-62
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tracer exposure) was accelerated during the first test, and this acceleration was maintained
throughout the acid exposure period. In the other study (Schlesinger and Gearhart, 1987),
rabbits were exposed 2 h/day for 14 days to 500 //g/m3 H2SO4 (0.3 //m, MMAD); retardation of
early alveolar region clearance of tracer particles administered on the first day of exposure was
noted. The results of these two studies suggest a graded response, whereby a low exposure
concentration accelerates early alveolar region clearance and a high level retards it, such as was
seen with mucociliary transport following acute H2SO4 exposure.
The mechanisms responsible for the altered alveolar region clearance patterns seen in the
above studies are not known. Observed clearance is the net consequence of a number of
differential underlying responses, which can include change in mucociliary transport rates and
altered functioning of AMs.
A number of studies have examined the functional response of AMs following acidic
sulfate aerosol exposures. To adequately perform their role in clearance, AMs must be
competent in a number of functions, including phagocytosis, mobility and attachment to a
surface. Alterations in any one, or combination, of these individual functions may affect
clearance function. Naumann and Schlesinger (1986) noted a reduction in surface adherence and
an enhancement of phagocytosis in AMs obtained by lavage from rabbits following a 1-h
exposure to 1,000 //g/m3 H2SO4 (0.3 //m). The acid exposure produced no change in the
viability or numbers of recoverable AMs.
In a study with repeated H2SO4 exposures, AMs were lavaged from rabbits exposed to
500 //g/m3 H2SO4 (0.3 //m) for 2 h/day for up to 13 consecutive days (Schlesinger, 1987).
Macrophage counts increased after 2 of the daily exposures, but returned to control levels
thereafter. Neutrophil counts remained at control levels throughout the study, suggesting no
acute inflammatory response. Random mobility of AMs decreased after 6 and 13 of the daily
exposures. The number of phagocytically active AMs and the level of such activity increased
after 2 exposures, but phagocytosis became depressed by the end of the exposure series.
Although such studies demonstrate that H2SO4 can alter AM function, they have not as yet been
able to provide a complete understanding of the cellular mechanisms which may underly the
changes in pulmonary region clearance observed with exposure to acid aerosols.
The relative potency of acidic sulfate aerosols in terms of altering AM numbers or function
has been examined. Aranyi et al. (1983) found no change in total or differential
11-63
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counts of free cells lavaged from mice exposed to 1,000 //g/m3 (NH4)2SO4 for 3 h/day for
20 days; this suggests a lack of inflammatory response to this sulfate aerosol. Additional studies
seem to suggest that the response to acid sulfates of AM is a function of the H+. Schlesinger
et al. (1990a) examined phagocytic activity of AMs recovered from rabbits exposed for 1 h/day
for 5 days to either 250 to 2,000 Aig/m3 H2SO4 (0.3//m) or 500 to 4,000 Aig/m3 NH4HSO4 (0.3
Aim); the levels were chosen such that the H+ concentration in the exposure atmospheres were
equivalent for both sulfate species. Phagocytic activity of AMs was reduced following exposure
to > 1,000 Aig/m3 H2SO4 or to 4,000 Aig/m3 NH4HSO4; exposure to 2,000 Aig/m3 NH4HSO4
resulted in increased phagocytic activity. While these exposure concentrations were quite high,
the interesting observation was that for a given level of sulfate, the response to H2SO4 was
greater than that to NH4HSO4. However, even when the data were assessed in terms of H+
concentration in the exposure atmosphere, it was noted that exposure to the same concentrations
of H+ did not result in identical responses for the two different acid sulfate species; H+ appeared
to be more effective as the H2SO4 species. On the other hand, when AMs were incubated in
acidic environments in vitro, the phagocytic activity response was identical, regardless of the
sulfate species used, as long as the pH was the same. These results suggested an enhanced
potency of H2SO4 during inhalation exposures. Experimental evidence provided by Schlesinger
and Chen (1994) indicated that this difference noted in vivo was likely a reflection of different
degrees of neutralization by respiratory tract ammonia of the two species of inhaled acid
aerosols. It was shown that, for a given concentration of ammonia and within a given residence
time within the respiratory tract, more total H+ remained available from inhaled sulfuric acid
than from inhaled ammonium bisulfate when the exposure atmospheres had the same total H+
concentration. Thus, the greater observed potency of inhaled sulfuric acid compared to
ammonium bisulfate for exposure atmospheres containing the same total IT" concentration is
likely due to a greater degree of neutralization of the latter, and a resultant greater loss ofH+
prior to particle deposition onto airway surfaces. Thus, the respiratory "fate" of inhaled acid
sulfate particles should be considered in assessing the relationship between exposure atmosphere
and biological response, since a lower IT" concentration will likely deposit onto lung tissue than
is inhaled at the mouth or nose.
11-64
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Interspecies differences in the effects of acid sulfates on AM function were examined by
Schlesinger et al. (1992a). Based upon in vitro exposures of AM to acidic media, a ranking of
response in order of decreasing sensitivity to acidic challenge and subsequent effect on
phagocytic activity was found to be: guinea pig>rat>rabbit>human.
As noted with other endpoints, the effect of H2SO4 upon AM function may be dependent
upon particle size. Chen et al. (1992a) observed that 300 //g/m3 H2SO4 enhanced the phagocytic
activity of AMs recovered from guinea pigs after 4 days (3 h/day) of exposure to fine particles
(0.3 //m), while an identical exposure to ultrafine particles (0.04 //m) depressed phagocytic
function.
The effects of acid sulfates upon the intracellular pH of AMs has been examined, because
this may be one of the determinants of the rate of many cellular functions (Nucitelli and Deamer,
1982). Internal pH of AMs recovered from guinea pigs exposed to 300 //g/m3 H2SO4 was
depressed after a single 3-h exposure to both 0.3 and 0.04 //m particles, but the depression
persisted for 24 h following exposure to the smaller size (Chen et al., 1992a). A depression in
pH was also noted 24 h following 4 days of exposure to the ultrafine, but not the fine, aerosol.
Thus, acid exposure produced a change in intracellular pH of the AMs and the effect was
particle size dependent.
It is possible that this and other differences in response between fine and ultrafine particles
reflect, to some extent, differences in the number of particles in aerosols of these two size
modes, in that at a given mass concentration of acid sulfate, there are a greater number of
ultrafine than fine particles. To examine this possibility, Chen et al. (1995) noted that changes
in intracellular pH of macrophages obtained following inhalation exposure to H2SO4 aerosols
were dependent both upon the number of particles as well as upon the total mass concentration
of H+ in the exposure atmosphere, with a threshold existing for both exposure parameters. The
role of size in modulating toxicity due to PM is discussed further in Section 11.4. It should,
however, be noted that aside from number, differences in deposition and neutralization may also
affect differential responses to fine and ultrafine particles.
A possible mechanism underlying the acid-induced alterations in intracellular pH was
examined by Qu et al. (1993), who exposed guinea pigs to 969 //g/m3 H2SO4 (0.3 //m MMD, og
1.73) for 3 h or to 974 //g/m3 for 3 h/day for 5 days. Macrophages were
11-65
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obtained following the end of each exposure protocol and examined for the ability of internal
pH to recover from an added intracellular acid load. Both H2SO4 exposures resulted in a
depression of internal pH recovery compared to air control. Subsequent analysis indicated that
this alteration in internal pH regulation was attributable to effects on the Na+/H+ exchanger
located in the cell membrane.
Macrophages are the source of numerous biologically active chemicals, and the effects of
acid sulfate upon some of these have been investigated. Zelikoff and Schlesinger (1992)
exposed rabbits to 50 - 500 //g/m3 H2SO4 (0.3 //m) for 2 h. AM recovered by lavage following
exposure were assessed for effects on tumor necrosis factor (TNF) release/activity and
production of superoxide radical, both of which are biological mediators involved in host
defense. Exposure to H2SO4 at > 75 //g/m3 produced a reduction in TNF cytotoxic activity, as
well as a reduction in stimulated production of superoxide radical. Subsequently, Zelikoff et al.
(1994) exposed rabbits for 2 h/day for 4 days to sulfuric acid at 500, 750 or 1,000 //g/m3. AM
recovered from animals exposed at the highest acid level showed a reduction in TNF and
interleukin (IL)-la production/activity, both immediately and 24 h following the last exposure.
On the other hand, increased release of TNF from macrophages obtained from guinea pigs was
observed immediately following a single 3 h exposure, and 24 h following a 3 h/day 4 day
exposure, to 300 //g/m3 H2SO4 (0.3 //m or 0.04 //m) (Chen et al., 1992a); in addition, production
of hydrogen peroxide by these cells was enhanced immediately after the 4 day exposure. These
differences in TNF may reflect interspecies differences in response to acid exposure and/or
differences in experimental conditions.
Resistance to Infectious Disease
The development of an infectious disease requires both the presence of the appropriate
pathogen, as well as host vulnerability. There are numerous anti-microbial host defenses with
different specific functions for different microbes (e.g., there are some differences in defenses
against viruses and bacteria). The AM represents the main defense against gram positive
bacteria depositing in the alveolar region of the lungs. The ability of acid aerosols to modify
resistance to bacterial infection could result from a decreased ability to clear microbes, and
a resultant increase in their residence time, due to alterations in AM function. To test this
possibility, a rodent infectivity model has been frequently used. In this
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technique, mice are challenged with a bacterial aerosol after exposure to the pollutant of interest;
mortality rate and/or survival time are then examined within a particular postexposure time
period. Any decrease in the latter or increase in the former indicates impaired defense against
respiratory infection. A number of studies which have used the infectivity model (primarily
with Streptococcus sp.) to assess effects of acid aerosols were discussed in the previous CD
(U.S. Environmental Protection Agency, 1982). It was evident that acute exposures to H2SO4
aerosols at concentrations up to 5,000 //g/m3 were not very effective in enhancing susceptibility
to this bacterially-mediated respiratory disease in the murine model. More recent studies with
mice, shown in Table 11-8, continue to support this conclusion.
However, a study using another animal suggests that H2SO4 may indeed alter antimicrobial
defense. Zelikoff et al. (1994) exposed rabbits for 2 h/day for 4 days to 500, 750,
or 1,000 //g/m3 H2SO4. Intracellular killing of a bacterium, Staphylococcus aureus, by AMs
recovered by lavage 24 h following the last exposure at the two highest acid concentrations was
reduced; bacterial uptake was also reduced at the same time point, but only at the highest acid
level. Thus, repeated H2SO4 exposures may reduce host resistance to bacteria in the rabbit, in
contrast to no effect on this endpoint in the mouse.
Specific Immune Response
Most of the database involving effects of acid aerosols on lung defense is concerned with
non-specific mechanisms. Little is known about the effects of these pollutants on humoral
(antibody) or cell-mediated immunity. Since numerous potential antigens are present in inhaled
air, the possibility exists that acid sulfates may enhance immunologic reaction and, thus, produce
a more severe response, and one with greater pulmonary pathogenic potential. Pinto et al.
(1979) found that mice which inhaled H2SO4 for 0.5 h daily and were then exposed weekly to a
particulate antigen (sheep red blood cells) exhibited higher serum and bronchial lavage antibody
liters than did animals exposed to the antigen alone; unfortunately, neither the exposure mass
concentration nor particle size of the H2SO4 was described. The combination of acid with
antigen also produced morphologic damage, characterized by mononuclear cell infiltration
around the bronchi and blood vessels, while
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TABLE 11-8. EFFECTS OF ACID SULFATES ON BACTERIAL INFECTIVITY IN VIVO
Particle
H2S04
H2S04
(NH4)2S04
Species, Gender,
Strain, Age, or
Body Weight
Mouse, F
CD-I
30 days
Mouse, F
CD-I
30 days
Mouse, F
CD-I
30 days
Exposure Mass Concentration
Technique (RH) (/ig/m3)
Head-only (31%) 543
Head-only (31%) 365
Whole body 1,000
Particle Characteristics
Exposure Duration Observed References
Size (//m); a. Effect
0.08 (VMD); 2.3 2h NC Grose etal. (1982)
0.06 (VMD); 2.3 2 h/day, 5 days NC Grose et al. (1982)
Submicrometer 3 h/day, 20 days NC Aranyi et al. (1983)
NC: No change
oo
-------
exposure to acid or antigen alone did not. Thus, the apparent adjuvant effect of H2SO4 may be a
factor promoting lung inflammation.
Osebold et al. (1980) exposed mice to 1,000 //g/m3 H2SO4 (0.04 //m, CMD) to determine
whether this enhanced the sensitization to an inhaled antigen (ovalbumin). The exposure
regimen involved intermittent 4 day exposures, up to 16 total days of exposure; no increase in
sensitization compared to controls was found. Kitabatake et al. (1979) exposed guinea pigs to
1,910 //g/m3 H2SO4 (<1 //m, MMAD) for 0.5 h twice per week for 4 weeks, followed by up to
10 additional paired treatments with the H2SO4 for 0.5 h each; the animals were then exposed to
aerosolized albumin for another 0.5 h. The breathing pattern of the animals was monitored for
evidence of dypsnea. Enhanced sensitization was found after ~4 of the albumin exposures. A
subsequent challenge with acetylcholine suggested hyperresponsive airways.
Fujimaki et al. (1992) exposed guinea pigs to 300, 1,000, and 3,200 //g/m3 H2SO4 for 2 or
4 weeks, following which lung mast cell suspensions were examined for antigen-induced
histamine release. Exposure for 2 weeks at the two highest concentrations resulted in enhanced
histamine release, but this response dissipated by 4 weeks of exposure. Thus, H2SO4, at high
concentrations, may affect the functional properties of mast cells; these cells are involved in
allergic responses, including bronchoconstriction.
11.2.3
Mixtures Containing Acidic Sulfate Particles
Most of the toxicological data concerning effects of PM are derived from exposures using
single compounds. Although such information is essential, it is also important to study
responses which result from inhalation of typical combinations of materials, because population
exposures are generally to mixtures. Toxicological interaction provides a basis whereby ambient
pollutants may show synergism (effect greater than the sum of the parts) or antagonism (effect
less than the sum of the parts). Thus, the lack of any toxic effect following exposure to an
individual pollutant should always be interpreted with caution, because mixtures may act
differently than expected from the same pollutants acting separately. Most toxicologic studies of
pollutant mixtures involved exposures to mixtures containing only two materials. These are
summarized first below for mixtures containing
11-69
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acidic aerosols (see Table 11-9); complex acid aerosol mixture studies (i.e., those using more
than 2 compounds) are then discussed.
The extent of any toxicological interaction involving acidic sulfate aerosols has been
shown to depend on the endpoint being examined, as well as on the co-inhalant. Most studies of
interactions using acidic sulfates employed ozone (O3) as the co-pollutant. Depending upon the
exposure regimen, endpoint, and animal species, either additivity, synergism, or antagonism has
been observed. These studies are summarized in the O3 criteria document (U.S. Environmental
Protection Agency, 1995). Interaction studies of H2SO4 and nitrogen dioxide (NO2) are
discussed in the nitrogen oxides criteria document pollutant (U.S. Environmental Protection
Agency, 1993). The nature of interactions was dependent on the protocol; no unifying principles
emerged. It is important to recognize that the nature of particle-pollutant interactions are
specific for a given endpoint and set of exposure conditions and no attempt should be made to
generalize from those specific observations discussed in the O3 and NOX criteria documents.
Kitabatake et al. (1979) exposed guinea pigs to H2SO4 aerosol (average 1910 //g/m3) or
SO2 + H2SO4 aerosol (average 145 ppm and 1890 //g/m3) for 30 min, twice a week for 4 weeks
prior to albumin exposure. After the preexposures, the guinea pigs were treated 10 times with
paired exposures to the sulfur oxides for 30 min followed by treatment with the antigen
(albumin) aerosol for another 30 min. The results indicate that exposures to high concentrations
of sulfur oxides (SO2 + H2SO4 aerosol or H2SO4 aerosol alone) may increase hyperreactivity to
albumin in guinea pigs.
In a study designed to determine if effects of exposure to H2SO4 aerosol were exacerbated
in the presence of other particulate matter, Henderson et al. (1980a) exposed rats to H2SO4
aerosol (MMAD = .8 //m, og = 1.7) in the presence or absence of 70,000 //g/m3 fly ash (MMAD
= 6.0 //m, og = 2.0). Lung damage in the rats was determined by BAL one day after exposure to
the fly ash and 1,000, 10,000, or 100,000 //g/m3 H2SO4 for 6 h. BAL from animals exposed to
high levels of sulfuric acid alone, to the ash alone, or to both showed an increase in sialic acid
and in acid phosphatase activity. Lactate dehydrogenase and glutathione reductase activities
were elevated in the combined exposures. The presence of a separate paniculate aerosol did not
greatly modify the response of the rat lung to H2SO4.
11-70
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TABLE 11-9. TOXICOLOGIC EFFECTS OF MIXTURES CONTAINING ACIDIC AEROSOLS
Co-Pollutant
Chemical //g/m3 ppm
ZnO (0.05 //m,
MMAD,
ag=1.86)
ZnO (0.05 CMD,
ag = 2)
O3 0.15
ZnO up to
2,760 //g/m
3 (0.05 fj.m
MMAD,
ag = 2.0)
SO2 145
Fly ash 70,000
(6 fj.m,
MMAD)
Acid Particle
Chemical
H2S04
H2S04
(coated
on
particles)
H2SO4 pure
H2S04
(coated
on
particle)
H2S04
H.SO,
H2S04
, , , , Exposure
,ug/mj(//m) . *,
Exposure Regime Conditions
25 or 84 3 h Nose-only
24 or 84 Nose-only
300 (0.08)
20-30 //g/m3 1 h Head-only
(0.05//mMMAD,
a = 2.0)
202 //g/m3
(0.06//mMMAD,
a = 1.36)
1,890 0.5 h, twice Head-only
(<1 //m, weekly for
MMAD) 4 weeks;
then 0.5 h twice
weekly with
antigen
or constrictor
challenge
1,000, 6 h Chamber
10,000,
100,000
(0.8//m,
MMAD,
ag= 1.7-1.8)
Species, Gender
Strain, Age and
Body Weight Endpoints
GP, M Hartley BAL eicosanoids
250-300 g PE
Guinea pig, M, Pulmonary
Hartley 260-325 function
g
Guinea pig Airway
responsiveness
to acetylcholine
Guinea pig Sensitization to
inhaled antigen
(albumin);
responsitivity
to acetylcholine
Rat Lavage indices
(LDH, acid
phosphatase,
glutathione
reductase)
Response to
Mixture Interaction Reference
Concentration Chen et al.
dependent T in (1989)
PGF2a compared to
ZnO alone
Animals Acid layered on Chen et al.
exposed to particle enhanced (1991)
acid had response to
greater subsequent O3 or
decrease in acid exposure
lung volume
and DLCO
Acid-coated Chen et al.
particles caused (1992b)
hyperresponsiveness
Similar changes at
10 x concentration
of coated
particles
Enhanced response Kitabatake et al.
compared (1979)
to H2SO4 alone
Minimal Henderson et al.
interaction: (1980a)
response largely
due to H2SO4;
increase in LDH and
glutathione
reductase only in
combined exposure
-------
TABLE 11-9 (cont'd). TOXICOLOGIC EFFECTS OF MIXTURES CONTAINING ACIDIC AEROSOLS
to
Co-Pollutant
Chemical
HN03
(vapor)
Diesel
exhaust
HN03
(vapor)
Diesel
exhaust
ZnO
//g/m3 ppm
380
460(0.15)
380
550
(0.1 5 Aim
MMAD)
up to
2500 Aig/m3
(0.05 //m
emd,
ag = 2)
Acid Particle Species, Gender
_, . , , , , Exposure Strain, Age and
Chemical Aig/m3 (Aim) F ' , 6.
Exposure Regime Conditions Bodv Weight bndpomts
H2SO4 180 5h/day, 5 days Rat, M, Macrophage
(no size Sprague-Dawley phagocytosis;
stated) receptor
activity
H2SO4 180 5h/day, 5 days Nose-only Rat, M, Macrophage
(no size Sprague-Dawley, phagocytosis;
stated) 6 wk morphology;
tracheobronchial
and
mucociliary
clearance
H2SO4 20-30 Aig 3 h/day for 5 Guinea pig Pulmonary
(coated days function
on ZnO
particles)
Response to
Mixture Interaction
Macrophage Not determined
phagocytosis,
Fc receptor
activity
decreased
No change in Not
cell turnover in determinable
nose, trachea,
alveolar
epithelium; no
deep lung
lesions;
J phagocytosis;
no clearance
effects
Reductions in
total lung vol.
vital capacity,
DLCO severity
inc. with
increasing
exposure
duration, inc.
protein, PMNs in
BAL
Reference
Prasad et al.
(1988)
Prasad et al.
(1990)
Amdur and Chen
(1989)
-------
A few studies have examined the effects of exposure to multicomponent (complex)
atmospheres containing acidic sulfate particles. Studies of mixtures containing O3 or NO2 are
summarized elsewhere (U.S. Environmental Protection Agency, 1993, 1995).
A series of studies discussed in the previous PM/SOX CD (U.S. Environmental Protection
Agency, 1982) involved exposure of dogs to simulated auto exhaust atmospheres (e.g., Hyde
et al., 1978) for 16 h/day for 68 mo followed by a 32- to 36-mo period in clean air. The mixture
consisted of 90 //g/m3 H2SO4+ 1,100 //g/m3 SO2, with and without irradiated auto exhaust
(which results in production of oxidants) and nonirradiated auto exhaust. The results were
dependent on the time of examination, exposure, and the endpoint. The primary finding was that
groups exposed to SO2 and H2SO4 showed emphysema like changes, observed 32- to 36-mo
postexposure. The authors considered the specific changes to be analogous to an incipient stage
of human centrilobular emphysema. SO2 alone would be unlikely to produce such a deep lung
response. Also, from the pulmonary function results, it did not appear that auto exhaust
exacerbated the effects of the SO2-H2SO4 mixture.
Prasad et al. (1988) exposed rats for 5 h/day for 5 days to an atmosphere consisting of 460
Mg/m3 diluted diesel exhaust (0.15 //m), 380 //g/m3 HNO3 vapor, and 180 //g/m2 H2SO4 (present
as a surface coat on the diesel particles). Reduced activity of macrophage surface (Fc) receptors
and phagocytosis were noted, but interaction could not be determined since the individual
components were not tested separately. In another related study, Prasad et al. (1990) examined
particle clearance, lung histology and macrophage phagocytic activity following nose-only
exposures of rats (Sprague-Dawley, M, 6 weeks) for 5 h/day for 5 days to atmospheres
consisting of 380 //g/m3 HNO3 vapor, 550 //g/m3 diluted diesel exhaust, and 180 //g/m3 H2SO4
coated on the diesel particles (0.15 //m). There was no change in tracheobronchial or pulmonary
clearance of tracer particles with this mixture, compared to air controls. While no deep lung
lesions nor any change in turnover rate of epithelial cells from the nose, trachea or alveolar
region were noted, there was a decrease in the percentage of total macrophages assessed which
had internalized diesel particles following exposure to the mixture, compared to cells recovered
from animals exposed to the diesel particles alone. Furthermore, phagocytosis was depressed up
to 3 days following exposure to the mixture.
11-73
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The enhanced effect of the particles with the surface acid coat is consistent with studies,
described below, with other acid-coated particles.
Amdur and Chen (1989) exposed guinea pigs to simulated primary emissions from coal
combustion processes, produced by mixing ZnO, SO2, and water in a high temperature
combustion furnace. The animals were exposed 3 h/day for 5 days to ultrafme (0.05 //m CMD,
og=2) aerosols of zinc oxide (ZnO) at up to 2,500 //g/m3 having a surface coating of H2SO4
resulting from this process (ZnO had no effect in this study). Levels of SO2 in the effluent
ranged from 0.2 to 1 ppm. Acid sulfate concentrations as low as 20 to 30 //g/m3 as equivalent
H2SO4 delivered in this manner resulted in significant reductions in total lung volume, vital
capacity, and DLco. The effects appeared to be cumulative, in that the severity was increased
with increasing exposure duration. These exposures also resulted in an increase in the protein
content of pulmonary lavage fluid and an increase in PMNs. The investigators noted that much
higher exposure levels of pure H2SO4 aerosol were needed to produce comparable results,
suggesting that the physical state of the associated acid in the pollutant mixture was an important
determinant of response. But one confounder in these studies was that the number concentration
was greater for the coated particles than for the pure acid particles and, as mentioned earlier,
both number and mass concentrations of the exposure atmosphere likely play roles in the
biological responses.
Other studies have examined responses to acid-coated particles. Chen et al. (1989)
exposed (nose-only) guinea pigs (male, Hartley, 250 to 300g) for 3 h to ultrafme ZnO (0.05 //m,
og=1.86) onto which was coated 25 or 84 //g/m3 H2SO4. Selected eicosanoids were examined in
lavage fluid obtained at 0, 72, and 96 h post-exposure. Immediately following exposure,
animals exposed to the higher acid concentration showed increased levels of prostaglandin F2a
compared to those found in animals exposed to ZnO alone. Levels of prostaglandins El and
6-keto-PGF 1 a, thromboxane B2 and leukotriene B4 were similar to those found in animals
exposed to the metal alone. During the post-exposure period, changes in prostaglandin El,
leukotriene B4 and thromboxane B2 were noted. But the authors suggested that there was no
causal relationship between these changes and alterations in pulmonary function noted earlier
(Amdur et al., 1986).
Chen et al. (1992b) exposed guinea pigs to acid-coated ZnO for 1 h, and examined airway
responsiveness to acetylcholine administered 1.5 h after exposure. In this study, the
11-74
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equivalent concentrations of H2SO4 were 20 and 30 //g/m3 coated on the 0.05 //m ZnO particles.
Animals were also exposed to pure H2SO4 droplets at 202 //g/m3 and having a similar size as the
coated particles (0.06 //m, og=l .36). Hyperresponsiveness was found in animals exposed to the
acid-coated particles, but not in those exposed to furnace gases (particle-free control) or to the
ZnO alone. A similar quantitative change was noted in those animals exposed to the pure
droplet at about 10 times the concentration of the coated particles (Amdur and Chen, 1989).
Amdur and Chen (1989) exposed guinea pigs for 3 h or for 3 h/day for 5 days to a similar
atmosphere as above and examined pulmonary function. Levels of 30 //g/m3 H2SO4 produced a
significant depression in diffusing capacity (DLco). Repeated exposures at the equivalent of
21 //g/m3 H2SO4 resulted in reduced DLco after the 4th exposure day; at the higher (30//g/m3)
level of coated acid, DLco decreased gradually from the first exposure day.
The interaction of acid coated particles with ozone was examined by Chen et al. (1991).
Guinea pigs (male, Hartley, 260 to 325 g) were exposed (nose-only) to sulfuric acid coated ZnO
particles (0.050 //m CMD, og=2) at 24 or 84 //g/m3 H2SO4 or pure acid (0.08 //m) at 300 //g/m3
for 2 h, followed by 2 h rest period and 1 h additional exposure (whole body) to air or 0.15 ppm
O3. Other animals were exposed to acid coated ZnO having an equivalent acid concentration (24
//g/m3) for 3 h/day for 5 days. This was followed by exposure for 1 h to 0.15 ppm O3 on day 9,
or to two additional 3 h exposures to 24 //g/m3 H2SO4 layered-ZnO on days 8 and 9. In the
single exposure series, animals exposed only to the higher coated acid concentration followed by
ozone showed greater than additive changes in vital capacity and DLco, while those exposed
first to the pure acid droplet did not show any change greater than that due to ozone alone.
Animals exposed repeatedly and then to the two added acid exposures showed greater reductions
in lung volumes and DLco than did those that did not receive the additional acid exposures.
Finally, animals exposed to ozone after acid showed reduced lung volumes and DLco not
observed in animals exposed to either ozone alone or acid alone. In terms of acid alone, neither
single exposure to the coated acid affected the endpoints, while exposure to the pure acid
decreased DLco. The investigators concluded that single or multiple exposures to the acid-
coated ZnO resulted in an enhanced response to subsequent exposures to acid or ozone and that
the manner in which the acid was
11-75
-------
delivered (i.e., as a pure droplet or as a surface coating) affected whether or not any interaction
occurred. However, it is likely that the number concentration of particles was greater in the zinc
oxide aerosol than in the pure acid aerosol, and the interaction may reflect this greater particle
number. It should also be noted that ZnO itself may have produced some biological response, or
contributed to any interaction with the acid, in some of the studies reported for some endpoints.
Wong et al. (1994) exposed rats (M; F-344, nose-only) for 4 h/day, 4 days/week for
8 weeks to a complex mixture consisting of 350 //g/m3 California road dust (5 //m MMAD) + 65
Mg/m3 (NH4)2SO4 (0.3 //m) + 365 //g/m3 NH4NO3 (0.6//m) + O3 (0.2 ppm), as well as to O3
alone. Animals were sacrificed at 4 or 17 days after the last exposure to assess stress inducible
heat shock protein as an indicator of early pulmonary injury. An increase in heat shock protein
was observed with the mixture at both time points, but the effect of O3 was greater than that due
to the mixture.
Mannix et al. (1982) examined the effects of a 4 h exposure of rats to a SO2-sulfate mix,
consisting of SO2 (13,000 //g/m3) plus 1,500 //g/m3 (0.5 //m, MMAD) of an aerosol containing
(NH4)2SO4 and Fe2(SO4)3. No change in particle clearance from the tracheobronchial tree or
pulmonary region was found.
11.3 METALS
11.3.1 Introduction
The metals discussed in this section are generally present in the ambient atmosphere of
U.S. urban areas in concentrations greater than 0.5 //g/m3 (see Chapter 3, Table 3-10) and
include arsenic, cadmium, copper, iron, lead, vanadium, and zinc. While other metals are
present in the ambient air, they are found at concentrations less than 0.5 //g/m3 and are not
reviewed here. There are no reported toxicological studies of acute effects of inhaled metals at
or below this concentration.
The information presented has primarily been obtained from occupational and laboratory
animal studies. Both of these data sources have limitations that affect their usefulness to
ambient particulate matter discussion. In the occupational studies, the exposures are not well-
characterized and may be confounded by exposure to other materials
11-76
-------
such as PAH, toxic gases, and other respirable particulate. Moreover, the concentrations of
metals experienced in occupational settings as well as the exposure concentrations and the doses
administered in the laboratory animal studies are generally hundreds to several thousand times
greater than the concentrations found in the ambient air (about 1-14 //g/m3).
These sections are intended as general summaries of each metal since the majority, with
the exception of lead, do not have current documentation or health risk standards. However,
review articles and criteria documents from other agencies are cited as sources of additional
information. While there are many studies available using higher concentrations and other
routes of administration than inhalation, a select summary only of the effects of inhaling metals
on humans and animals is presented in Table 11-10 where an attempt was made, where possible,
to focus on those studies that reported effects at the lowest exposures. Each section briefly
discusses data on acute and chronic effects from inhaling metals in humans and laboratory
animals. Endpoints (developmental effects and other non-respiratory endpoints) not
immediately related to the epidemiological findings presented in Chapter 12 are not included in
this discussion but are presented in the references cited. End points seen with routes of exposure
other than inhalation are not discussed.
11.3.2 Arsenic
Human Data: The toxicity data on inhalation exposures to arsenic are limited in number
and quality. Long-term occupational exposure to arsenic leads to a range of health effects such
as lung cancer, skin changes and peripheral nerve damage in workers. Most of the available
human inhalation data on arsenic are based on occupational exposures to arsenic trioxide.
In humans, acute symptoms are seen after airborne exposure to high levels of arsenic
trioxide in an occupational setting. Symptoms include severe irritation of the nasal mucosa,
larynx, and bronchi (Holmqvist, 1951; Pinto and McGill, 1953). It is not clear if these effects
were chemically related to arsenic or a result of irritation due to the dusts inhaled. Irritation of
mucous membranes of the nose and throat leading to hoarseness, laryngitis, bronchitis, or
rhinitis and sometimes perforation of the nasal septa have been reported in workers exposed to
arsenic dusts (Pinto and McGill, 1953), but effect levels cannot be set due to insufficient
exposure data. Increased peripheral vasospastic disorders and Raynaud's
11-77
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TABLE 11-10. RESPIRATORY SYSTEM EFFECTS OF INHALED
METALS ON HUMANS AND LABORATORY ANIMALS
Metal
(Ambient
Concentrations)3
Arsenic
(0.002-2.32
Mg/m3)
Subjects
In humans
In animals
Resp. tract irritation, laryngitis,
100-1,000 ,ug/m3.
Decreased bactericidal activity,
Effectsb
bronchitis, rhinitis. Effects absent at
inc mortality in streptococcal assay at 500-940
References
Agency for Toxic
Substances and
Disease Registry
(1993)
Aranyietal. (1985)
Cadmium
(0.0002-7.0
oo
In humans Acute exposure: resp. tract irritation, bronchiolitis, alveolitis, impaired
lung function, and emphysema; mild and reversible symptoms with exposure to 200-
500 //g/m3. Chronic exposure: kidneys and resp. tract affected; effects include
proteinuria and emphysema, with exposure to 20 ,wg/m3 for 27 years.
In animals Mild inflammation; AM and epithelial hyperplasia in rat at 500 //g/m3 for 3 h;
lesions repaired at 7-15 days postexposure. Effects similar to humans. Dose-
dependent fibrotic lesions in lungs of rats exposed to 300-1,000 ,ug/m3 for 12
weeks.
Hyperplasia of terminal bronchioles, cell flattening, inflammation and
proliferation of fibroblasts in rat at >300 ,wg/m3, 6 h/day, 5 days/week, 62 days.
BAL fluid changes at 1,600 ,ug/m3, 3 h/day, 5 days/week, 1-6 weeks indicative of
lung damage. Aggregates of PMNs in interstitium, thickening of alveolar septa.
Effects peaked at 2 weeks, then dec.
Inc number and size of AM in rat at 100 ,ug/m3, 22 h/day, 7 days/week, 30 days,
returning to normal 2 mo postexposure.
In rabbit at 400 ,ug/m3, 6 h/day, 5 days/week, 4-6 weeks, inc lung weight,
interstitial infiltration of PMNs and lymphocytes, intraalveolar accumulation
of large, vacuolated macrophages, inc phospholipid content.
In mouse at 30-90 ,ug/m3, 8 or, 19 h/day, 5 days/week, 42-69 weeks inc incidence of
alveolar lipoproteinosis, interstitial fibrosis, broncho alveolar hyperplasia.
Agency for Toxic
Substances and
Disease Registry
(1989)
Buckley and Bassett
(1987)
Kutzmanetal. (1986)
Hart (1986)
Glaseretal. (1986a)
Johansson et al.
(1984)
Heinrich et al.
(1989a)
-------
TABLE 11-10 (cont'd). RESPIRATORY SYSTEM EFFECTS OF INHALED METALS
ON HUMANS AND LABORATORY ANIMALS
Metal
(Ambient
Concentrations)3
Copper
(0.003-5.14
Mg/m3)
Iron
(0.13-13.80
Subjects Effectsb
In humans Subjective symptoms and clinical tests (CBC, LDH determination, urinalysis) after
outbreak of metal fume fever: fever, dyspnea, chills, headache, nausea, myalgia,
cough, shortness of breath, sweet metallic taste, vomiting, 1-10 h occup exposure.
Complaints of discomfort similar to onset of common cold; chills or warmth;
stuffiness of the head, 75-120 //g/m3, few weeks occup exposure.
In Mild respiratory tract effects in hamster: Decreased cilia beating frequency and
animals abnormal epithelium at 3,300 //g/m3, 3 h/day.
In mouse exposed for 3 h/day, 5 days/week, 1 -2 weeks slight alveolar thickening and
irregularities after 5 exposures at 120 ,ug/m3, extensive thickening with many walls
fused into irregular masses and dec mean survival time after 10 exposures at
130 ,ug/m3. Dec bactericidal activity in both exposure groups.
In humans Subjective symptoms, chest X ray: siderosis in 3 males. Note: concurrent exposure
to several other chemicals; > 10,000 ,ug/m3, 2 mo-12 years (occup).
34% prevalence of siderosis; complaints of chronic coughing and breathlessness,
3,500-269,000 ,ug/m3, 10 year (avg).
In Respiratory tract cell injury (not specified) in hamsters, alveolar fibrosis,
animals 14,000 //g/m3, 1 mo.
Impaired respiration in rats, blood nasal discharge at 6,800 and 22,000 ,ug/m3, 6
h/day 5 days/week, 4 weeks.
References
Agency for Toxic
Substances and
Disease Registry
(1990)
Agency for Toxic
Substances and
Disease Registry
(1990)
Agency for Toxic
Substances and
Disease Registry
(1990)
Sentz and Rakow
(1969)
Teculescu and Albu
(1973)
Creasia and
Nettesheim(1974)
BASF Corporation
(1991)
-------
TABLE 11-10 (cont'd). RESPIRATORY SYSTEM EFFECTS OF INHALED METALS
ON HUMANS AND LABORATORY ANIMALS
Metal
(Ambient
Concentrations)3
Subjects
Effectsb
References
Vanadium
(0.0004-1.46
oo
o
In humans Bronchial irritation (cough, mucous formation) postexposure at 60 //g/m3.
Cough at 100, 600 Mg/m3 8 h lasted about 1 week.
Productive cough, runny nose, sore throat, wheezing, 100-300 ,ug/m3, 2 years
(occup).
In humans Rhinitis, nasal discharge, irritated throat, bronchopneumonia,
"asthmatic" bronchitis, est <6,500, 1-2 years (occup)
In animals Alveolar proteinosis in rat at 17,000 //g/m3, 6 h/day, 5 days/week, 2 weeks;
dose-related inc lung weight, inc accumulation of macrophages, collagen
deposition, lung lipid content, and Type II pneumocytes.
Reduced lung function in monkey at 2,500 //g/m3, 6 h, inc pulmonary
resistance; inc leukocytes in bronchoalveolar lavage.
In rat, nasal discharge (sometimes containing blood), difficulty
breathing, dec BW; hemorrhages in lung, heart, liver, kidney, brain.
bronchitis, focal interstitial pneumonia in lungs. Effects mainly in lungs
at low concentration. Mild signs of toxicity at 2,800 //g/m3.
In rats Capillary congestion, perivascular edema, hemorrhages in lungs. Also focal
edema and bronchitis in some cases, lymphocyte infiltration of interstitial
spaces, constriction of small bronchi, 1,700-2,800 //g/m3, 2 h/every other
day, 3 mo.
Zenz and Berg (1967)
Lewis (1959)
Sjoberg (1950)
Lee and Gillies
(1986)
Knechtetal. (1985)
Roshchm(1967a)
Roshchm (1967a)
-------
TABLE 11-10 (cont'd). RESPIRATORY SYSTEM EFFECTS OF INHALED METALS
ON HUMANS AND LABORATORY ANIMALS
Metal
(Ambient
Concentrations)3
Subjects
Effectsb
References
Zinc
(0.015-8.328
oo
In humans Symptoms metal fume fever: Nausea, chills, shortness of breath and chest
pains at 320,000-580,000 ,wg/m3, 1-3 h.
Fever, chills, chest tightness, muscle/joint pain, sore throat, headache at
4-8 h postexposure; inc airway resistance of 16%, 4,900 ,ug/m3, 2 h/day, 1 day
(face mask).
Significant correlation between change in peak expiratory flow rate and dust
concentration, 6-8 h workshift.
BAL fluid changes; inc number of leukocytes, T cells, T suppressor cells, and
NK cells; me PMN leukocytes, with 77,000-153,000 ,ug/m3, 15-30 mm (occup).
Miminal substernal irritation and throat irritation during exposure, 3.6
,ug/m3, 2 h.
In animals BAL fluid: Inc protein, LDH, and p-glucuronidase, inflammation at 2,200
,ug/m3, 3 h/day 1 day in rat.
BAL fluid: Inc protein, LDH, and P-glucuronidase (suggesting altered
macrophage function), inflammation at 2,200 ,ug/m3, 3 h/day 1 day in guinea
Pig-
Impaired lung function (dec compliance and lung volume, inc pulmonary
resistance, dec CO diffusing capacity at 3,700 //g/m3, 3 h/day 6 day in guinea
Pig-
Inc lung weight; inflammation, and increased interstitial thickening,
fibroblasts, and interstitial infiltrates at 4,300 //g/m3.
Dec pulmonary compliance, followed by inc during 2-h postexposure, at 730
,ug/m3, 1 h in guinea pig.
Agency for Toxic
Substances and
Disease Registry
(1994)
Gordon et al. (1992)
Marquart et al.
(1989)
Blanc etal. (1991)
Lmnetal. (1981)
Gordon etal. (1992)
Lam etal. (1985)
Amduretal. (1982)
^Ambient air concentration range associated with metal particulate matter in the United States atmosphere (see Chapter 1, Table 1 -4).
bAbbreviations: dec = decreased; inc = increased; occup = occupational; PAH = polycyclic aromatic hydrocarbons; ALK = alkaline phosphatase;
BAL = bronchoalveolar lavage; AM = pulmonary alveolar macrophage; PMN = polymorphonuclear leukocyte; res = respiratory.
-------
phenomenon were found in Swedish arsenic workers exposed to airborne arsenic dusts
(Lagerkvist et al., 1986).
Laboratory Animal Data: Limited acute data were available on the inhalation toxicity of
arsenic in animals. Aranyi et al. (1985) exposed mice to an aerosol of arsenic trioxide for 3 h at
levels of 0, 270, 500, or 940 //g arsenic/m3. Additional groups were exposed for 3 h/day for 5
or 20 days. At the end of exposure, mice were challenged with an aerosol exposure of viable
streptococci, and death of exposed and controls was recorded over 14 days. Separate groups
were challenged with aerosols of35S-\abQ\QdKlebsiellapneumoniae to evaluate macrophage
function (bacterial killing) in a 3-h period. In the streptococcal assay, a concentration-related
increase in mortality occurred. Bactericidal activity was markedly decreased after a single
exposure to 940 //g arsenic/m3, but no consistent or significant effects were seen at lower
exposure levels after one or several exposures.
In a chronic inhalation study, male Wistar rats (20 to 40/group) were continuously exposed
to 0, 60, or 200 //g arsenic/m3 as arsenic trioxide for 18 mo (Glaser et al., 1986b). No effects on
body weight, hematology, clinical chemistry, or macroscopic and microscopic examination
outcomes were observed.
11.3.3 Cadmium
Recent reviews and health criteria documents have detailed the toxicological and
carcinogenic effects of cadmium by different routes of administration including inhalation
(Oberdorster, 1989a,b; Waalkes and Oberdorster, 1990; International Agency for Research on
Cancer, 1993). Acute and chronic health effects observed after cadmium exposure were mostly
related to occupational settings and occurred after exposures to concentrations far exceeding
those occurring environmentally. Average airborne cadmium concentrations in rural areas range
from 0.0002 to 0.006 //g/m3, and in urban areas concentrations from 0.002 to 0.025 //g/m3 have
been found which can increase in industrial areas by a factor of 3 to 5. Health effects at these
low airborne concentrations of cadmium have not been reported; the following summary
indicates that health effects observed in humans and animals are correlated with higher
occupational exposure concentrations ranging up to the mg/m3 levels. Thus, exposure to much
lower ambient environmental airborne concentrations of cadmium
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are unlikely to contribute to acute health effects. It should also be considered that exposure to
cadmium occurring in cigarette smoke by far exceeds background ambient air concentrations.
When evaluating health effects of inhaled cadmium compounds it should be considered that in
vivo solubility of the different cadmium compounds is different from their water solubility. For
example, CdO and CdS are both insoluble in water, yet CdO is rapidly soluble in the lung,
possibly in the acidic milieu of alveolar macrophages after phagocytosis, whereas CdS is highly
insoluble in the lung, behaving more like a low toxicity particle (Oberdorster, 1989b).
11.3.3.1 Health Effects
Human Data: Table 11-10 summarizes data from studies of occupationally-exposed
workers which show that the main target organs for cadmium toxicity are the kidney and the
respiratory tract. This table is restricted to those studies where exposures to airborne cadmium
concentrations were less than 100 //g/m3 since it is felt that effects observed from exposures to
higher airborne cadmium concentrations are irrelevant for low concentrations of environmental
cadmium and particulate matter. With respect to renal damage, these low environmental
concentrations will not lead to significant accumulation of cadmium in the kidney to reach the
critical concentration of 200 //g/g which will result in symptoms of kidney damage, e.g.,
proteinuria. Earlier studies found evidence of proteinuria after occupational exposures to 50
Mg/m3 for up to 12 years (Kjellstrom et al., 1977). More recent analyses found the threshold of
cadmium exposure for proteinuria at close to 1,000 //g/m3 x year (Blinder et al., 1985a,b; Mason
et al., 1988). Obviously, these exposure concentrations are far above those encountered
environmentally and will not be considered further in the context of this document.
Acute respiratory effects of inhaled cadmium have been reported as pneumonitis and
edema if exposure concentrations exceed 1,000 //g/m3 for periods of 1 h or more. Chronic
cadmium exposures resulting in emphysema and dyspnea have also been reported when
exposure concentrations are very high, exceeding for extended periods of time several hundred
Mg/m3. Chronic exposure concentrations below 100 //g/m3 at occupational settings have been
associated with induction of lung tumors (International Agency for Research on Cancer, 1993).
Recent analyses of English and Swedish cohorts as well as an American
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cohort found a statistically significant excess risk of lung cancer in the highest exposure groups
(Blinder et al., 1985c; Sorahan, 1987; Thun et al., 1985). Based on these studies, IARC
determined that cadmium is a human carcinogen. However, environmentally encountered
airborne cadmium concentrations are too low to induce lung cancer, unless it is postulated that a
combination of cadmium plus other air contaminants results in a synergistic carcinogenic effect.
Excess of prostate cancer due to occupational inhalation of cadmium observed in earlier
epidemiological studies have not been confirmed in later studies (IARC, 1993).
Laboratory Animal Data: Health effects of inhaled cadmium compounds are summarized
in Table 11-10. Like with the human studies, only those studies are listed where exposure
concentrations below 100 //g/m3 were used. These studies in laboratory animals confirm that
inhalation exposure to cadmium compounds can result in respiratory tract injury. Very high
exposure concentrations (mg/m3) are needed to cause acute effects such as lung edema and
alveolar epithelial cell necrosis, whereas lower exposure concentrations at -50 - 100 //g/m3 can
induce chronic inflammatory responses including bronchoalveolar hyperplasia, proliferation of
connective tissue leading to interstitial fibrosis (Takenaka et al., 1983). The most striking effect
at low exposure concentrations in rats is that different cadmium compounds were shown to cause
lung cancer (Takenaka et al., 1983; Glaser et al., 1990). These studies reported primary lung
tumors (bronchoalveolar adenoma, adenocarcinoma, squamous cell tumors) following exposure
to CdCl2, CdSO4, CdS and CdO inhaled as dust or fume. Exposure concentrations were as low
as 10 //g/m3, adding to the evidence from human occupational exposure studies that inhaled Cd-
compounds can induce lung tumors. In contrast to rats, mice and hamsters exposed to the
different cadmium compounds at similar concentrations did not induce lung tumors (Heinrich et
al., 1989a). The reason for the significant species differences may be the different inducibility
of metallothionein (MT) as well as different baseline levels of MT in the lungs of mice and rats
which was demonstrated by Oberdorster et al. (1994a). These authors found that a four-week
inhalation exposure to CdCl2 aerosols at an exposure concentration of 100 //g/m3 caused greater
and more persistent inflammation and cell proliferation in the lungs of mice than in rats. At the
same time MT was induced to a greater degree in mice, possibly protecting the lungs of this
species from the cytotoxic effects of inhaled cadmium.
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In summary, these studies demonstrate that measured low environmental cadmium
concentrations alone are not likely to be causally associated with acute effects on mortality and
morbidity observed in epidemiological studies; nor are they likely to cause long-term chronic
effects. Cadmium exposure at relatively high exposure concentrations has been shown to lead to
a decreased immune response in mice (Graham et al., 1978; Krzystyniak et al., 1987) which
could suggest that people with a compromised immune system may also be affected more than
healthy people by exposure to cadmium. However, environmental low level cadmium
concentrations have not been shown to induce these effects.
11.3.4 Copper
Human Data: The data on human exposure to copper by inhalation are limited. The
major target organ appears to be the respiratory system, but the data are limited to occupational
studies. Data are primarily based on subjective symptoms without indications of pulmonary
function changes as a result of occupational exposure to copper. The observed symptoms may
also be due to exposure to copper by both oral and inhalation routes since exposures were
confounded. The lack of control workers is also a limitation in evaluating the human data
available for copper exposure by inhalation. A combination of respiratory symptoms has been
reported following acute inhalation exposure to copper in humans. Armstrong et al. (1983)
reported the following symptoms (in order of number of workers affected): fever, dyspnea,
chills, headache, nausea, myalgia, cough, shortness of breath, a sweet metallic taste and vomiting
in factory workers accidentally exposed to copper dust or fumes for 1 to 10 h as a result of
cutting pipes known to contain copper. These symptoms are consistent with metal fume fever,
an acute disease induced by inhalation of metal oxides that temporarily impairs pulmonary
function but does not progress to chronic lung disease (Stokinger, 198la). Airborne copper
concentration during the exposure period was not reported. It was reported that 5 of 12 workers
hospitalized following the acute exposure had urine copper levels greater than 50 //g/L. Since
the major route of excretion of copper is biliary, the elevated urine copper levels reported
suggest that the exposure concentration was relatively high. Copper levels were not determined
for control workers in this study which limits the interpretation of the urinary copper values as
an indicator of copper inhalation exposure. Armstrong et al. (1983) also reported evidence of
minimal elevation of serum
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lactate dehydrogenase (in 3 of 14 workers evaluated) and leukocytosis (in 21 of 24 workers
evaluated). Nonspecific complaints of discomfort and chills were reported among several
workers within a few weeks of beginning operation of a copper plate polishing operation.
Exposure levels of 75 to 120 //g/m3 were measured (Gleason, 1968).
In a epidemiological study by Suciu et al. (1981), factory workers exposed to copper dust
received annual physical and clinical examinations during a 4 year exposure period. The
reported air copper levels were not reported for the first year, were 464,000 //g Cu/m3 in the
second year; 132,000 //g Cu/m3 in the third year; and 111,000 //g Cu/m3 in the fourth year.
Although inhalation was considered to be the major route of exposure for these workers, it was
likely that a portion of the airborne copper was trapped in the upper respiratory tract and
swallowed. This assumption was made based on the gastrointestinal effects that were observed
in these workers in addition to the respiratory effects. Respiratory effects reported included
symptoms of coughing, sneezing, yellowish-green expectoration, dyspnea, and thoracic pain.
Radiography revealed linear pulmonary fibrosis and in some cases nodulation. Limitations of
this study include the absence of a control group, poor description of study design and the lack
of statistical analysis of data.
Respiratory effects were also noted in a report by Askergren and Mellgren (1975). Nose
and throat examinations were performed in sheet-metal workers exposed to copper dust. Six of
11 workers had nasal mucosa characterized by increased vascularity and superficial epistatic
vessels. This was accompanied by symptoms of runny nose and mucosal irritation in the mouth
and eyes. However, the levels of airborne copper were not measured.
Laboratory Animal Data: As with human exposure, the respiratory system appears to be
the primary site of injury following inhalation exposure to copper. Drummond et al. (1986)
reported a decrease in tracheal cilia beating frequency following a single exposure to 3,300 //g
Cu/m3 (as a copper sulfate aerosol) in hamsters, but not in mice exposed to the same level.
Alveolar thickening was observed in mice exposed repeatedly and the severity of the effect
increased with the duration of exposure. Histological examination of the trachea revealed
abnormal epithelium in mice at 5 exposures at 120 //g Cu/m3, extensive thickening and
decreased mean survival time after 10 exposures at 130 //g Cu/m3.
Immunological effects were observed in mice (Drummond et al., 1986) and in rabbits
(Johansson et al., 1983) exposed to copper sulfate aerosols. Mice exposed to either a single
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concentration of 560 //g Cu/m3 or 10 exposures to 130 //g Cu/m3, and simultaneously challenged
with an aerosol of Streptococcus zooepidemicus had decreased survival time (Drummond et al.,
1986). Decreased bactericidal activity was also observed in mice after exposure to an aerosol of
Klebsiellapneumonia after single or repeated exposures to copper sulfate aerosols (Drummond
et al., 1986), suggesting that copper can inhibit the function of alveolar macrophages. After
inhalation exposure, Johansson et al. (1983) also observed a slight increase in the amount of
lamellated cytoplasmic inclusions in alveolar macrophages. Exposures of rabbits to copper
chloride aerosols for 4 to 6 weeks resulted in a minor increase in volume density of alveolar
Type 2 cells and minor levels of lymphocytic or eosinophilic inflammatory infiltrates (Johansson
etal., 1984).
11.3.5 Iron
Human Data: Most of the available human inhalation data on iron are based on
occupational exposures to iron oxide, with effects limited to respiratory symptoms and
dysfunction. There are no acute human inhalation data on the effects of iron exposure. Health
effects information via inhalation route is limited to iron pentacarbonyl. No information was
located on the soluble iron salts including ferric chloride, ferric nitrate, and ferric sulfate.
Occupational exposure occurs from mining of iron ores, consisting mainly of oxide forms.
During the mining and during smelting and welding process, workers are often exposed to dust
containing iron oxides and silica, as well as other metals and substances. It is known that
exposure to iron oxides results in roentgenological changes in the lung due to deposition of
inhaled iron particles (Doig and McLaughlin, 1936; Musk et al., 1988; Plamenac et al., 1974),
designated variously as siderosis, iron pneumoconiosis, hematite pneumoconiosis, iron
pigmentation of the lung, and arc welder lung (Blinder, 1986). Siderosis is prevalent in 5 to
15% of iron workers exposed for more than 5 years (Buckell et al., 1946; Schuler et al., 1962;
Sentz and Rakow, 1969). Exposure levels were reported to exceed 10,000 //g iron/m3 by Sentz
and Rakow (1969); but no exposure data were presented for the other studies. A Romanian
study (Teculescu and Albu, 1973) reported a 34% prevalence of siderosis in workers exposed to
ferric oxide dust (3,500 to 269,000 //g/m3); but radiological evidence of lung fibrosis was not
observed. Complaints of
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chronic coughing were reported by 80% of the workers. Morgan (1978) found a male subject
exposed chronically to ferric oxide (magnetite; Fe3O4) had symptoms of coughing and sputum
for 8-9 years and exhibited an abnormal chest x-ray, but pulmonary function tests revealed no
abnormalities. Stokinger (1984) reviewed the literature on occupational exposure to iron oxide
fumes, and concluded that most investigators considered the roentgenological pulmonary
changes, secondary to inhalation of iron dust (i.e., siderosis), as benign and did not suspect them
to progress to fibrosis. Although several case reports have described iron oxide workers, with
coughing and shortness of breath, exhibiting diffuse fibrosis in their chest x-rays (Charr, 1956;
Friede and Rachow, 1961; Stanescu et al., 1967), concurrent exposure to other chemicals may
have contributed to this finding (Chan-Yeung et al., 1982; Sitas et al., 1989).
Several studies report high incidence of lung cancer mortality among workers exposed to
iron oxide in mines and smelters; but, in all cases, there was simultaneous exposure to other
potentially carcinogenic substances (Boyd et al., 1970; Faulds, 1957). Improvements in dust
control and ventilation of mines after 1967 have also resulted in reduction of lung cancer
mortality in iron ore mine workers (Kinlen and Willows, 1988).
Iron oxide particles have been used both as a tracer and as a carrier particle for radioactive
tracers (e.g., Te) in human (Leikauf et al., 1984; Gerrard et al., 1986; Ilowite et al., 1989;
Bennett et al., 1992; Bennett and Zeman, 1994; Bennett et al., 1993) and laboratory animal
studies (Okuhata et al., 1994, Brain et al., 1994; Warheit and Hartsky, 1993; Domes and
Valberg, 1992; Warheit et al., 1991a,c; Bellmann et al., 1991; Lehnert and Morrow, 1985; Brain
et al., 1984; Valberg, 1984; Skornik and Brain, 1983) to measure different aspects of pulmonary
deposition and clearance. In general, the exposures were brief and the concentrations of iron
used in these studies were extremely high compared to those found in the ambient atmosphere.
There were no reported acute effects of exposure to these iron oxide particles.
Laboratory Animal Data: Two acute inhalation studies reported clinical signs relating to
respiratory distress in rats exposed to iron pentacarbonyl for 4 h or 1 mo (BASF Corporation,
1991; Bio/Dynamics Incorporated, 1988). However, histopathology was not performed on the
lungs. Acute exposure of rats to 500,000 //g iron/m3 as iron oxide for greater than 30 min also
resulted in coughing, respiratory difficulties, and nasal irritation
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(Hewitt and Hicks, 1972 as cited in Blinder, 1986) and histopathology of the lungs revealed iron
oxide particles in macrophage cells. Ten intratracheal installations of ferric oxide in hamsters
produced loss of ciliated cells, and hyperplasia and proliferation of non-ciliated epithelial cells in
the lungs (Port et al., 1973). Intratracheal instillation of iron oxides in female rats produced
tumors in 70% of the animals but did not reduce the life-span (Pott et al., 1994). At a longer
duration of 1 mo, hamsters inhaling 14,000 //g iron/m3 as ferric oxide dust (MMAD of 0.11 //m)
revealed respiratory tract cell injury and alveolar fibrosis (Creasia and Nettesheim, 1974).
See also the discussion below on transition metals (Section 11.3.8) regarding ferric iron
(Fe3+) complexed on the surface of silicates. There it is noted, for example that newly emerging
studies by Ohio et al. (1992) and others suggest that Fe3+ complexed on the surface of silicate
particles may be responsible for inflammatory responses associated with silicate inhalation.
11.3.6 Vanadium
Human Data: Acute and chronic inhalation studies in humans are generally limited to
occupational case studies and epidemiology studies in workers engaged in the industrial
production and use of vanadium. Based on these studies, the respiratory tract is the primary
target of vanadium inhalation. Most of the reported exposures are to vanadium pentoxide dusts.
Acute and chronic respiratory effects were most commonly seen following exposure to
vanadium pentoxide dusts. Mild respiratory distress (cough, wheezing, chest pain, runny nose,
or sore throat) was observed in workers exposed to vanadium pentoxide dusts or vanadium in
fuel oil smoke for as few as 5 h (Levy et al., 1984; Musk and Tees, 1982; Thomas and Stiebris,
1956; Zenz et al., 1962) or as long as 6 years (Lewis, 1959; Orris et al., 1983; Sjoberg, 1956;
Vintinner et al., 1955; Wyers, 1946). Most clinical signs reflect the irritative effects of
vanadium on the respiratory tract; only at concentrations > 1,000 //g vanadium/m3 were more
serious effects on the lower respiratory tract observed (bronchitis, pneumonitis). Rhinitis,
pharyngitis, bronchitis, chronic productive cough, wheezing, shortness of breath, and fatigue
were reported by workers following chronic inhalation of vanadium pentoxide dusts (Sjoberg,
1956; Vintinner et al., 1955; Wyers, 1946).
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Two volunteers exposed to 60 //g vanadium/m3 as vanadium pentoxide reported a delay of 7 to
24 h in the onset of mucus formation and coughing (Zenz and Berg, 1967).
Vanadium induced asthma in vanadium pentoxide refinery workers without previous
history of asthma, with symptoms continuing for 8 weeks following cessation of exposure (Musk
and Tees, 1982). Increased neutrophils in the nasal mucosa were reported in chronically
exposed workers (Kiviluoto, 1980; Kiviluoto et al., 1979, 1981c).
Chronic occupational exposure to vanadium dusts was also associated with some
electrocardiographic changes (Sjoberg, 1950). Vanadium dusts had no effect on hematology
following acute exposure (Zenz and Berg, 1967) or chronic exposure (Kiviluoto et al., 1981a;
Sjoberg, 1950; Vintinner et al., 1955). Blood pressure and gross neurologic signs were not
affected following chronic exposure to vanadium pentoxide dusts at levels up to 58,800 //g
vanadium/m3 (Vintinner et al., 1955), although other authors reported anemia or leukopenia
(Roshchin, 1964; Watanabe et al., 1966). Based on serum biochemistry and urinalysis, there
was no indication of kidney or liver toxicity in workers chronically exposed to 200 to 58,800 //g
vanadium/m3 as vanadium dusts (Kiviluoto et al., 1981a,b; Sjoberg, 1950; Vintinner et al.,
1955). Vanadium green discoloration of the tongue resulting from direct deposition of
vanadium is often reported (Orris et al., 1983; Lewis, 1959; Musk and Tees, 1982).
Laboratory Animal Data: Acute and chronic laboratory animal studies support the
respiratory tract as the main target of inhaled vanadium compounds. The animal data indicate
that vanadium toxicity increases with increasing compound valency, and that vanadium is toxic
both as a cation and as an anion (Venugopal and Luckey, 1978).
The mechanism of vanadium's effect on the respiratory system is similar to that of other
metals. In vitro tests show that vanadium damages alveolar macrophages (Castranova et al.,
1984; Sheridan et al., 1978; Waters et al., 1974; Wei and Misra, 1982) by affecting the integrity
of the alveolar membrane, thus impairing the cells' phagocytotic ability, viability, and resistance
to bacterial infection. Cytotoxicity, tested on rabbit alveolar macrophages in vitro, was directly
related to solubility in the order V2O5 > V2O3 > VO2. Dissolved vanadium pentoxide (6 //g/ml)
also reduces phagocytosis (Waters, 1977).
Respiratory effects in laboratory animals following acute inhalation of vanadium
compounds include increased pulmonary resistance and significantly increased
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polymorphonuclear leukocytes in bronchioalveolar lavage fluid. These effects were observed in
monkeys 24 h following a 6-h inhalation exposure to 2,800 //g vanadium/m3 as vanadium
pentoxide (Knecht et al., 1985). In addition, increased lung weight and alveolar proteinosis were
observed in rats after inhaling bismuth orthovanadate 6 h daily for two weeks (Lee and Gillies,
1986). Rabbits exposed to high concentrations of vanadium pentoxide dust for 1 to 3 days
exhibited dyspnea and mucosal discharge from the nose and eyes (Sjoberg, 1950). In a follow-
up experiment, rabbits had difficulty breathing following a daily 1-h exposure for 8 mo
(Sjoberg, 1950).
The effects of acute exposure to 5,600 to 39,200 //g vanadium/m3 as vanadium pentoxide
fume or 44,800 to 392,000 //g vanadium/m3 as vanadium pentoxide dust were investigated by
Roshchin (1967a); the exposure duration was not described in the available literature. For
vanadium pentoxide fume, "mild toxicity" occurred at 5,600 //g vanadium/m3, and deaths were
observed at the high level. The vanadium pentoxide dust was described as one-fifth as toxic as
the fume. Effects at the lower levels were mostly observed in the lungs. These included
irritation of respiratory mucosa, perivascular and focal edema, bronchitis, and interstitial
pneumonia. In a subchronic experiment, rats were exposed to vanadium pentoxide fume (1,700
to 2,800 (j,g vanadium/m3) or vanadium pentoxide dust (5,600 to 17,000 //g vanadium/m3) for 2
h every other day for 3 to 4 mo (Roshchin, 1967a). Histopathological effects were limited to the
lungs and were similar to those observed following acute exposure. The study author concluded
that vanadium inhalation resulted in irritation of the respiratory mucosa, hemorrhagic
inflammation, a spastic effect on smooth muscle of the bronchi, and vascular changes in internal
organs (at higher levels). Similar effects were observed with the trivalent vanadium compounds
vanadium trioxide and vanadium trichloride, although vanadium trichloride caused more severe
histological changes in internal organs (Roshchin, 1967b); further details were not available.
Rats exposed to vanadium pentoxide condensation aerosol (15 //g vanadium/m3)
continuously for 70 days developed marked lung congestion, focal lung hemorrhages, and
extensive bronchitis (Pazynich, 1966).
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11.3.7 Zinc
Inhalation of zinc compounds, most notably zinc oxide fumes, can result in significant
pulmonary irritation and inflammation referred to as metal fume fever. However, zinc is an
essential element with low intrinsic toxicity, and exposure concentrations have to be in the
mg/m3 range to induce these symptoms which are accompanied by increased inflammatory cell
and protein levels in pulmonary lavage both in experimental animals and humans (Gordon et al.,
1992). A number of studies in experimental animals and also in humans occupationally-exposed
to zinc fumes have been reported, and almost all of these were related to high exposure
concentrations which are irrelevant for low environmental exposure levels. A recent review of
the toxicity of inhaled metal compounds including zinc in the respiratory tract (Gordon, 1995)
describes a number of studies from which it can be concluded that inhaled zinc compounds
including zinc oxide are rapidly solubilized in the lung and do not appear to accumulate in the
respiratory tract. Elevated levels of zinc can be found in blood and urine of exposed workers as
well as in exposed animals. Occupational exposures at concentrations below 50 //g/m3 have not
resulted in the occurrence of metal fume fever (Marquart et al., 1989; Linn et al., 1981). Higher
exposure concentrations inhaled repeatedly result in the development of tolerance after initial
symptoms of zinc fume fever subside (Gordon et al., 1992). Effects observed after acute high
level exposures include dyspnea, cough, pleuritic chest pain, bilateral diffuse infiltrations,
pneumothorax and acute pneumonitis from respiratory tract irritations. However, exposure
concentrations have to be extremely high for the more severe symptoms to occur which has no
relevance for ambient low level paniculate pollutants.
11.3.8 Transition Metals
An area of current investigation is the potential for the particle-associated transition metals
to induce oxidant injury. The transition metals are characterized by being electronically stable in
more than one oxidation state and, as a result, have the ability to catalyze the oxidative
deterioration of biological macromolecules. Considering that the transition metals can catalyze
the oxidative deterioration of biological macromolecules it is plausible that inhalation of PM
containing these metals could cause oxidative injury to the
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respiratory tract. However, the data available thus far is derived from studies using in vitro
systems and intratracheal administration and can not be used for risk estimation.
Iron, the best studied of the transition metals, has the ability to catalyze the formation of
reactive oxygen species (ROS) and initiate lipid peroxidation (Aust, 1989; Minotti and Aust,
1987; Imlay et al., 1988; Halliwell and Gutteridige, 1986). Guilianelli et al. (1993) studied the
importance of iron to the toxicity of iron-containing particles in cultured tracheal epithelial cells.
Nemalite, the most cytotoxic of the three minerals tested, contained the most surface Fe2+.
Moreover, pretreatment with the iron chealating compound desferrioxamine, reduced the toxic
effects of nemalite.
Garrett et al. (198la) exposed rabbit alveolar macrophages in vitro to fly ash with and
without surface coatings of various metal oxides. Cellular viability and cellular adenosine
triphosphate content were reduced only with the metal-coated ash particles. Berg and
co-workers (1993) measured the release of ROS from bovine alveolar macrophages stimulated
with heavy metal-containing dusts <4 //m in diameter. Dusts, derived from waste incineration,
sewage sludge incineration, an electric power station, and from two factories, incubated with
alveolar macrophages caused a concentration-dependent increase in ROS release. The ratio of
superoxide anion (O2:) and hydrogen peroxide (!M)2) secreted varied, depending on the dust,
but the release of H2O2 correlated best, in descending order, with the content of iron, manganese,
chromium, vanadium, and arsenic in the dusts. The positioning of iron first in this array is
consistent with other studies examining the biological effects of iron coating the surface of
particles.
Certain particles, including silica, crocidolite, kaolinite, and talc, complex considerable
concentrations of ferric iron (Fe3+) onto their surfaces. The potential biological importance of
iron complexation was assessed by Ghio and co-workers (1992) who examined the effects of
surface Fe3+ on several indices of oxidative injury. Three varieties of silicate dusts were studied:
(1) iron-loaded, (2) unmodified, and (3) desferrioxamine-treated. The ability of silicates to
catalyze oxidant generation in an ascorbate/H2O2 system in vitro, to trigger respiratory burst
activity and leukotriene B4 release by alveolar macrophages, and induce lung inflammation in
the rat following intra-tracheal instillation all increased in proportion to the amount of Fe3+
complexed onto their surfaces. Ghio and Hatch (1993) noted that an extracellular accumulation
of surfactant following instillation of silica into the lungs of rats
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was associated with the concentration of Fe3+ complexed to the surface of the particles, and that
surfactant-enriched material was a target for oxidants, the production of which was catalyzed by
Fe3+. Moreover, iron, drawn from body stores, has been shown to complex to the surface of
intratracheally instilled silica particles and increase concentrations of iron in bronchoalveolar
lavage fluid, lung tissue and plasma, and decrease antioxidant molecules in lung tissue, including
ascorbate, urate, and glutathione (Ohio et al., 1994).
Surface complexed iron has been implicated in pulmonary injury due to a variety of
environmental particles (Costa et al., 1994a,b; Tepper et al., 1994). Three particle types (Mt. St.
Helen's volcanic ash, ambient particles of Dusseldorf, Germany, and residual oil fly ash), which
represented a range of inflammatory potential, were intratracheally instilled into rats. Both the
degree of acute inflammation (as measured by assessing PMNs, eosinophils, LDH and protein in
lavage) and nonspecific bronchial responsiveness correlated with the iron (specifically Fe+3)
loading of the particles. An interesting observation was that surface iron was correlated with
particle acidity, yet when instillation of H2SO4 at comparable pH was performed, the lavage
analysis indicated much less inflammation with the pure acid compared to the high surface iron
particles. In fact, neutralization of the fly ash instillate (which could occur if similar particles
were inhaled, due to endogeneous respiratory tract ammonia) actually enhanced particle toxicity,
while the pulmonary response diminished when iron was removed from the fly ash by acid
washing. These preliminary results generally support the notion that oxidant generation by iron
present on the surface of particles may increase lung injury; but, clearly, other factors are likely
to contribute to this response.
Tepper et al. (1994) reported that the concentration of iron (Fe3+) complexed on the surface
of a particle was associated with the ability of the particle to support electron transfer and to
generate oxidants in vitro and to increase lung inflammation and airway hyperresponsiveness in
vivo. Particles with or without iron complexed on the surface were instilled into the lungs of
rats and evaluated for their potential to produce inflammation and airway hyperactivity. The
effects of a high-iron particle (coal fly ash) before and after surface iron was removed by acid
washing and the effects of an inert particle (titanium), with or without iron added to the particle
surface, were evaluated. The effects of pretreating the rats with drugs to reduce iron-associated
ROS formation also were studied. Although coal ash caused considerable inflammation and
hyperactivity, acid washing to remove surface iron
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reduced the deleterious effects of the particle. However, compared to titanium alone, instillation
of a titanium particle coated with iron did not increase lung injury. Pretreatment with
allopurinol partially blocked lung inflammation, but desferrioxamine and an anti-neutrophil
antibody were less effective. The authors concluded that the results generally support the
hypothesis that ROS generation by iron on the surface of particles may exacerbate lung injury.
The inflammatory potential of 10 different metal-containing dusts of either natural or
anthropogenic origin was evaluated following intratracheal instillation in rats (Pritchard et al.,
1995). Measurements included (1) oxidized products of deoxyribose catalyzed by particulates,
(2) induction of a neutrophilic alveolitis after particulate instillation, (3) increments in airway
reactivity after particulate instillation, and (4) mortality after exposures to both dust and a
microbial agent. Except for titanium, in vitro generation of oxidized products of deoxyribose
increased with ionizable concentrations of all metals associated with the particles. After
intratracheal instillation of the dusts in rats, the neutrophil influx and lavage protein both
increased with ionizable concentrations of the same metals. Changes in airway reactivity
following instillation of the dusts also appeared to be associated with the ionizable
concentrations of these metals. Similarly, mortality after instillation of particles in mice
followed by exposure to aerosolized Streptococcus zooepidemicus reflected metal
concentrations. The authors concluded that in vitro measures of oxidant production and in vivo
indices of lung injury increased with increasing concentrations of the metals instilled
intratracheally.
Thus, it is clear that ROS produced through chemical reactions involving iron can initiate
lipid peroxidation, cell injury, and ultimately cell death. It may be possible that other transition
metals, by virtue of their ability to redox between valence states, also can generate ROS in the
presence of precursor oxidants and reducing agents. However, it has not been established in
inhalation studies that these reactions can occur in vivo.
11.3.9 Summary
Data from occupational studies and laboratory animal studies indicate that acute exposures
to high levels or chronic exposures to low levels (albeit high compared to ambient levels) of
metal particulate can have an effect on the respiratory tract. However, it is
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doubtful that the metals at concentrations present in the ambient atmosphere (1 to 14 //g/m3)
could have a significant acute effect in healthy individuals.
Acute and chronic inhalation exposures to arsenic, cadmium, copper, iron, and vanadium
are associated with respiratory effects, and, in the case of cadmium, renal effects. However, in
general, the levels used in the laboratory animal studies or experienced in occupational settings
are considerably higher (at least 10-fold and as much as 103- or 104-fold) than those found in the
ambient environment, and the results of these studies provide little insight into the morbidity and
mortality studies discussed in Chapter 12. This is not unexpected because of the patterns of
exposure and the total exposures, as well as differences in the populations exposed. Some of the
effects noted in the human occupational studies such as respiratory tract irritation, bronchitis,
impaired pulmonary function, cough, wheezing, are also observed in the epidemiological studies
discussed in Chapter 12 and may indicate a general effect of PM. However, these effects are
evident at exposures much greater than experienced in the ambient atmosphere. Nevertheless,
the toxicological studies of the metals do not appear to provide insight into the effects observed
in the epidemiological studies discussed in Chapter 12. While studies examining the potential
for the transition metals to cause lung injury have been conducted in vitro and in animals by
intratracheal instillation are interesting, these results thus far are of limited value.
11.4 ULTRAFINE PARTICLES
This section on ultrafine particles is designed to provide an overview of current concepts
concerning the potential pulmonary toxicity of this class of particulates. The occurrence of
ultrafine particles in the ambient environment as well as their sources are reviewed in Chapters 3
and 6. Studies assessing the comparative toxicity of particles of different sizes using
intratracheal instillation are reviewed in Section 11.9.1. Particles used in toxicological studies
are mainly in the fine and coarse mode size range. This section addresses the hypothesis that
ultrafine particles can cause acute lung injury and focuses on experimental studies in which
ultrafine particles generated as fumes were used. The ultrafine (nucleation mode) particle phase
has a median diameter of -20 nm (see Figure 3-13). Ultrafine particles with a diameter of 20
nm have an approximately 6 order of magnitude
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higher number concentration than a 2.5 //m diameter particle when inhaled at the same mass
concentration; particle surface area is also highly increased (Table 11-1).
At present, no toxicological studies with relevant ambient ultrafine particles have been
performed. Although ultrafine particles have been used in animal inhalation studies, the studies
did not focus on two potentially important aspects of ultrafine particles which are addressed in
this chapter; their presence in the exposure atmosphere as single particles rather than aggregates
and their low solubility. Single ultrafine particles occur regularly in the urban atmosphere at
high number concentrations (5 x 104 - 3 x 10s particles/cm3) but very low mass concentrations
(Brand et al., 1991; 1992; Castellani, 1993). These single ultrafine particles are not very stable
and eventually aggregate with larger particles but they are always freshly-generated by a number
of natural anthropogenic sources (e.g., gas to particle conversion; combustion processes;
incinerator emissions). Because results of studies with relevant ambient ultrafine particles at
relevant low mass concentrations (10 to 50 //g/m3) are not available in the literature, effects of
single ultrafine particles generated as polymer fumes are discussed in this section. Obviously,
polymer fume particles do not occur in the ambient atmosphere and they serve only as a
surrogate to indicate the toxic potential that some inhaled ultrafine particles may have. The
hypothesis that other ultrafine particles have this toxic potential as well needs still to be tested
but cannot be refuted at this time since studies with ultrafine copper oxide particles described in
this section also indicate their potential to cause acute effects. Human exposure to very fine acid
aerosols (~ 100 nm; 1,500 //g/m3) have also been conducted (Horvath et al., 1987). No
pulmonary function or symptom responses were observed suggesting that the soluble nature of
these particles or their tendency to either grow or aggregate may be responsible for the fact that
they did not induce responses similar to other (less soluble) ultrafine particles.
Inhalation studies in rats with aggregated ultrafine particles have shown that these particles
still required high concentrations (in the mg/m3 range) and repeated exposures to produce effects
in laboratory animals, although they were more active than larger-sized particles of the same
composition. These particles included ultrafine TiO2 aggregates (Ferin et al., 1992; Oberdorster
et al., 1992; Heinrich, 1994), aggregated carbon black particles (Heinrich, et al., 1995; Mauderly
et al., 1994a; Nikula et al., 1995), and diesel soot (White and Garg, 1981; Rudell et al., 1990).
Effects observed after subchronic or chronic exposure
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of rats included chronic pulmonary inflammation, pulmonary fibrosis, and induction of lung
tumors. No acute effects were observed, even at the highest exposure concentrations. Although
the studies with TiO2 and carbon black involved particles of ultrafine size (-20 nm), they were
inhaled as aggregates which are considerably larger than single 20 nm ultrafine particles. Thus,
these results may not fully reflect the toxicity of single 20 nm particles.
From these studies with aggregate ultrafine particles, it appeared that particle surface area
is an important parameter for expressing exposure-response and dose-response relationships of
inhaled highly insoluble particles. The significantly increased pulmonary inflammatory response
of aggregated ultrafine particles is presumably because of their highly increased surface area. If
the dose for particles of different sizes is expressed relative to their surface area, then responses
elicited by ultrafines would be comparable with those for larger-sized particles (Oberdorster et
al., 1992, 1994b). The finding that ultrafine particles can penetrate into the interstitium more
easily than larger-sized particles (Takenaka et al., 1986; Ferin et al., 1992) is also very
important. Transport across the epithelium appears to be facilitated if ultrafine aggregates
deaggregate upon deposition and are present as single particles.
As stated above, acute pulmonary effects were not observed after inhalation of aggregates
of ultrafine particles. In contrast, specific types of inhaled single ultrafine particles described
below can induce severe acute lung injury at low inhaled mass concentrations relative to
aggregated ultrafine particles (Oberdorster, 1995). Such model ultrafine particles can be
generated by heating of polytetrafluoroethylene (Teflon®; PTFE); the resulting condensation
aerosol consists of single ultrafine particles. More than 25 years ago it was recognized that the
toxicity of pyrolysis products of PTFE is associated with the particulate phase rather than with
gas phase constituents (Waritz and Kwon, 1968). It was demonstrated more recently that these
particles are of ultrafine size (Lee and Seidel, 1991a,b; Seidel et al., 1991). These particles form
upon heating of Teflon® to a critical temperature of -420 to 450 °C and have diameters from
<10 - 60 nm (median diameter of -26 nm) (Oberdorster et al., 1995a). The toxicity of PTFE
fumes has been recognized dating back to the 1950's, when exposures of rabbits, guinea pigs,
rats, mice, cats, and dogs resulted in acute mortality (Treon et al., 1955). Further studies in
experimental animals by several
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investigators (Scheel et al., 1968; Coleman et al., 1968; Griffith et al., 1973; Lee et al., 1976;
Alarie and Anderson, 1981) confirmed that these fumes are highly toxic to birds and mammals.
Extensive pulmonary epithelial and interstitial damage and alveolar flooding occurred after only
short-durations of exposure. Accidental exposures of humans to fumes generated from polymers
also demonstrated the high toxicity of these fumes for humans (Nuttall et al., 1964; Goldstein et
al., 1987; Dahlqvist et al., 1992). Associated effects include pulmonary edema, nausea and
headaches, together characterized by the term "polymer fume fever" in analogy to the
well-known symptoms of metal fume fever (Rose, 1992).
The toxicity of polymer fumes was initially thought to be associated with toxic gas phase
products, such as hydrogen fluoride (HF), carbonyl fluoride, and perfluoroisobutylene (PFIB).
However, detailed studies by Waritz and Kwon (1968) as well as more recent studies have
shown that the high toxicity is associated with the paniculate phase. For example, HF studies
showed that concentrations as high as 1300 ppm are needed to cause effects in the upper
respiratory tract of exposed rats; effects did not occur in the lung periphery where the fume
particles have been shown to be most effective (Stavert et al., 1991). Concentrations of HF in
fumes generated at the critical temperature are only ~ 10 ppm, and therefore, cannot be
responsible for the observed toxicity of the fumes (Oberdorster et al., 1995a). The more toxic
gas phase compounds, carbonyl fluoride and PFIB are generated only at temperatures
approaching 500°C when heating PTFE (Coleman et al., 1968; Waritz and Kwon, 1968).
Furthermore, rat inhalation studies with PFIB alone showed that lung pathology was detected
only when a high concentration of 90,000 //g/m3 was exceeded (Lehnert et al., 1993). Further
proof that the particles of polymer fumes represent the toxic entity is provided by studies in
which the particulate phase was removed by filters and subsequently the gas phase compounds
did not show toxicity in exposed rats (Waritz and Kwon, 1968; Warheit et al., 1990; Lee and
Seidel, 199 la).
It has also been suggested that highly toxic radicals on the surface of the polymer fume
particles may cause the acute effects. However, studies by Seidel et al. (1991) with fumes from
different polymers showed similar toxicities to the lung regardless as to whether significant
amounts of radicals could be detected on those particles or not. Although this still does not
exclude that some reactive toxic compounds may be attached to the particle surface,
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all of these studies provide strong evidence that the ultrafine particles are the cause of the PTFE
fume-associated, acute lung injury. It has also been shown that aging of the fumes leading to
particle aggregation diminishes their toxicity, indicating that the presence of ultrafine particles as
singlets is highly important for the toxicity of these particles (Lee and Seidel, 1991b; Warheit et
al., 1990).
To exclude the possibility that oxygen-derived radicals from the generation process may be
responsible for the observed pulmonary toxicity, PTFE particles were generated in a nitrogen
atmosphere (Waritz and Kwon, 1968) or in an argon gas atmosphere (Oberdorster et al., 1995b).
Results showed that the inhaled PTFE fumes generated in this way showed the same high
pulmonary toxicity in rats that was observed with PTFE fumes generated in air. The toxicity
consisted of severe hemorrhagic, pulmonary edema and influx of PMNs into the alveolar space
within 4 h after a 15-min exposure of healthy rats to an ultrafine particle mass concentration of
about 40 to 50 //g/m3; this was accompanied by high mortality (Oberdorster et al., 1995a;
Johnston et al., 1995). It was also determined by these investigators that a number concentration
of 1 x 10s PTFE particles/cm3 is equivalent to a mass concentration of ~ 10 //g/m3. Pulmonary
lavage data showed that up to 80% of lavageable cells consisted of PMNs. Acute mortality was
also observed in up to 50% of rats exposed to these concentrations of 5 x io5 particles/cm3.
Epithelial as well as endothelial cell damage occurred, resulting in both interstitial and alveolar
edema. The authors concluded that freshly-generated ultrafine PTFE particles inhaled as
singlets at low mass concentrations can cause severe acute lung injury and that ultrafine
particles, in general, penetrate readily through epithelial-endothelial barriers.
Additional results from studies with ultrafine PTFE particles directed at evaluating
mechanistic events in the lung by using in situ hybridization techniques on lung tissue showed
that the highly inflammatory reaction was characterized by significant increases in message for
the pro-inflammatory cytokine TNFa and the low molecular weight protein metallothionein
(Johnston et al., 1995). Furthermore, increases in abundance for messages encoding IL-la,
IL-lp, IL-6, TNFa and the antioxidants MnSOD and metallothionein were found in RNA
extracted from lung tissues. In addition to the increase in message of these pro-inflammatory
cytokines and antioxidants, abundance for message of inducible NOS was also increased,
whereas message for VEGF (vascular endothelial growth factor) was
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decreased in the acute phase (Johnston et al., 1995). The authors suggested that the acute lung
damage affecting epithelial and endothelial barrier functions may be due to the activities of
reactive oxygen species originating from activated inflammatory cells and reactive nitrogen
species produced via inducible NOS.
In another effort to evaluate acute effects and disposition of inhaled ultrafme particles
Stearns et al. (1994) exposed hamsters for 60 minutes to ultrafme CuO, Cu2O and Cu(OH)2
particles (11 nm diameter, og = 1.8; approximately 109 particles/cm3). A marked 4-fold increase
in pulmonary resistance was found which persisted for 24 hours. Immediately after exposure,
using electron spectroscopic imaging, copper oxide particles were found not only on and within
airway mucus and extracellular alveolar lining layers but also in airway and alveolar epithelial
cells, in the pulmonary interstitium and in alveolar macrophages. These particles were even
found in the alveolar capillaries and in pulmonary lymphatics. In addition, animals at 24 hours
post-exposure showed evidence of a pulmonary inflammatory response, including the
appearance of neutrophils and eosinophils.
Roth et al. (1994) demonstrated in human subjects that clearance of ultrafme particles is
delayed. These workers exposed three male subjects to ultrafme particles (18 nm CMD; 27 nm
MMD) of1U In-labeled indium oxide for two or three breathing cycles and measured
radioactivity present in the head, chest, and stomach immediately after inhalation and for 4 to 8
days at ensuing intervals. The clearance curves showed a fast clearance for particles deposited in
the thorax with a mean value of 7% and a slow clearance fraction with a mean value of 93%.
The half-life of the slow phase appeared to be on the order of 40 days, indicating greater
persistence of the ultrafme particles rather than the larger particles (>2 jim) in the lung.
Hatch et al. (1994) evaluated to what extent ultrafme particles (<100 nm) are present in
ambient air by determining their presence in alveolar macrophages of healthy people. Alveolar
macrophages isolated from lung lavage samples of 7 workers of an oil-fired power plant, 4
welders of the power plant and 3 university employees (no known occupational or
environmental exposures) were studied by electron energy loss spectroscopy and electron
spectroscopic imaging. Regardless of the occupation, ultrafme particles were observed in
phagolysosomes of macrophages of all volunteers, there was no correlation of ultrafme particle
quantity with occupation. Spectral analysis of the ultrafme particles revealed a
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variety of metals including cadmium, vanadium, titanium and iron. This study demonstrates the
presence of large numbers of ultrafine particles in alveolar macrophages of healthy people even
in the absence of specific occupational exposure. Whether all of these particles have been
inhaled as ultrafines or whether some of them dissolved in the macrophages from larger particles
to the ultrafine size is not known. However, since ultrafine particles occur in the ambient air
(Chapter 6) their presence in large numbers in alveolar macrophages of people demonstrates that
they are effectively deposited in the deep lung, although some of them may have been inhaled as
particles adsorbed to larger particles as suggested by the authors. The high deposition efficiency
of inhaled single ultrafine particles in the alveolar region (Chapter 10) contributes to the
plausibility of the suggestion by Hatch et al. (1994) that many of these particles were inhaled as
ultrafines.
In summary, certain freshly-generated ultrafine particles, when inhaled as singlets at very
low mass concentrations (<50 //g/m3), can be highly toxic to the lung. After inhalation and
deposition in the lung, ultrafine particles of low solubility can rapidly penetrate epithelial cell
barriers and penetrate to interstitial and endothelial sites (Stearns et al., 1994). Obviously,
ultrafine particles studied in experimental animals so far (PTFE-fume, copper oxides) are not
constituents of the ambient atmosphere and it is not clear how well these particles might serve as
surrogates for ambient ultrafines.
Mechanisms responsible for a potential high toxicity could include: (1) high pulmonary
deposition efficiencies of inhaled single ultrafine particles; (2) the large numbers per unit mass
of these particles; (3) their increased surface area available for reaction; (4) their rapid
penetration of epithelial layers and access of pulmonary interstitial sites; and (5) the presence of
radicals and perhaps acids on the particle surface depending on the process of generation of the
particles. Results of studies with model ultrafine particles indicate that particle number or total
particle surface area could be more important than mass concentration (see Table 11-1).
11.5 DIESEL EXHAUST EMISSIONS
Diesel engines emit both gas phase pollutants (hydrocarbons, oxides of nitrogen, and
carbon monoxide) and carbonaceous PM into the ambient atmosphere. The concentration of
diesel particulate in the ambient atmosphere although low is ubiquitous. The concentration of
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diesel particulate in the ambient atmosphere has been estimated to be about 1-6 //g/m3 in
Los Angeles (Health Effects Institute, 1995). A description of the diesel engine, its combustion
system, pollutant formation mechanisms and emission factors as well as the cancer and
noncancer health effects of diesel exhaust emissions have been recently reviewed elsewhere in
the Health Assessment Document for Diesel Emissions (U.S. Environmental Protection Agency,
1994) and in Diesel Exhaust: A Critical Analysis of Emissions, Exposure and Health Effects
(Health Effects Institute, 1995). The endpoints discussed in this section are those associated
with diesel paniculate and directly related to the epidemiological results discussed in Chapter 12.
Other components of diesel exhaust, such as sulfur dioxide (SO2), nitrogen dioxide (NO2),
formaldehyde, acrolein, and sulfuric acid may contribute to some of these potential health
effects. Endpoints not directly related to the epidemiological findings are not included in the
discussion but are presented elsewhere (International Agency for Research on Cancer, 1989;
Claxton, 1983; Lewtas, 1982; Ishinishi et al., 1986; Pepelko and Peirano, 1983; Pepelko et al.,
1980b,c; U.S. Environmental Protection Agency, 1994; Health Effects Institute, 1995).
Within the text, exposures are expressed in terms of the mass concentration of diesel
particles. Other major measured components in the studies are presented in the tables which
have additional details about the studies, including references. The Health Assessment
Document for Diesel Emissions (U.S. Environmental Protection Agency, 1994) that is in
preparation and the Diesel Exhaust Document (Health Effects Institute, 1995) should be
consulted for a complete evaluation of the health effects associated with diesel emissions.
11.5.1 Effects of Diesel Exhaust on Humans
It is difficult to study the health effects of diesel exhaust in the general population because
diesel emissions are diluted in the ambient air; hence, exposure is very low. Thus, populations
occupationally exposed to diesel exhaust are studied to determine the potential health effects in
humans. The occupations involving potential high exposure to diesel exhaust are miners, truck
drivers, transportation works, railroad workers, and heavy-equipment operators. All the
occupational studies considered in this section have a common problem—an inability to measure
accurately the actual exposure to diesel exhaust.
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The effects of short term exposure to diesel exhaust have been investigated primarily in
occupationally-exposed workers (Table 11-11). Symptoms of acute exposure to high levels of
diesel exhaust include mucous membrane, eye, and respiratory tract irritation (including chest
tightness and wheezing) and neuropsychological effects of headache, lightheadedness, nausea,
heartburn, vomiting, weakness, and numbness and tingling in the extremities. Diesel exhaust
odor can cause nausea, headache, and loss of appetite.
There have been a few experimental exposures of humans to diesel exhaust, but all were
single exposures. No significant changes in respiratory function were found in subjects exposed
for 1 (Battigelli 1965) or 3.7 (Ulfvarsson et al., 1987) hours to diesel exhaust at approximately
1,000 //g soot/m3 or less.
Rudell et al. (1990, 1994) exposed eight healthy subjects in an exposure chamber to diluted
exhaust from a diesel engine for one hour, with intermittent exercise. Dilution of the diesel
exhaust was controlled to provide a median NO2 level of approximately 1.6 ppm. Median
particle number was 4.3 x 106/cm3, and median levels of NO and CO were 3.7 and 27 ppm,
respectively (particle size and mass concentration were not provided). There were no effects on
spirometry or on closing volume using nitrogen washout. Five of eight subjects experienced
unpleasant smell, eye irritation, and nasal irritation during exposure. Bronchoalveolar lavage
was performed 18 hours after exposure and was compared with a control BAL performed 3
weeks prior to exposure. There was no control air exposure. Small but statistically significant
reductions were seen in BAL mast cells, AM phagocytosis of opsonized yeast particles, and
lymphocyte CD4/CD8 ratios. A small increase in recovery of PMNs was also observed. These
findings suggest that diesel exhaust may induce mild airway inflammation in the absence of
spirometric changes.
In underground miners, bus garage workers, dock workers, and locomotive repairmen
exposed to diesel exhaust, minimal and not statistically significant changes were reported in
respiratory symptoms and pulmonary function over the course of a workshift. In diesel bus
garage workers, there was an increased reporting of burning and watering of the eyes, cough,
labored breathing, chest tightness, and wheezing, but no reductions in pulmonary function
associated with exposure to diesel exhaust. In stevedores pulmonary function was adversely
affected over a workshift exposure to diesel exhaust but normalized after a few days without
exposure.
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TABLE 11-11. HUMAN STUDIES OF DIESEL EXHAUST EXPOSURE
Study
Description
Findings
Kahn et al. (1988)
El Batawi and
Noweir (1966)
Battigelli (1965)
Katz et al. (1960)
Hare and Springer
(1971)
Hare et al. (1974)
Linnell and Scott
(1962)
Battigelli (1965)
Reger (1979)
Ames et al. (1982)
Jorgensen and
Svensson (1970)
13 Cases of acute exposure,
Utah and Colorado coal
miners.
161 Workers, two diesel bus
garages.
Six subjects, eye exposure
chamber, three dilutions.
14 Persons monitoring
diesel exhaust in a train
tunnel.
Volunteer panelists who
evaluated general public's
response to odor of diesel
exhaust.
Odor panel under highly
controlled conditions
determined odor threshold
for diesel exhaust.
13 Volunteers exposed to
three dilutions of diesel
exhaust for 15 min to 1 h.
Five or more VC maneuvers by
each of 60 coal miners
exposed to diesel exhaust
at the beginning and end of
a work shift.
Pulmonary function of
60 diesel-exposed compared
with 90 non-diesel-exposed
coal miners over work
shift.
240 Iron ore miners matched
for diesel exposure,
smoking and age were given
bronchitis questionnaires
and spirometry pre- and
postwork shift.
Acute reversible sensory irritation,
headache; nervous system effects,
bronchoconstriction were reported at
unknown exposures.
Eye irritation (42%), headache (37%),
dizziness (30%), throat irritation (19%),
and cough and phlegm (11%) were reported in
this order of incidence by workers exposed
in the service and repair of diesel powered
buses.
Time to onset was inversely related and
severity of eye irritation was associated
with the level of exposure to diesel
exhaust.
Three occasions of minor eye and throat
irritation; no correlation established with
concentrations of diesel exhaust
components.
Slight odor intensity, 90% perceived, 60%
objected; slight to moderate odor
intensity, 95% perceived, 75% objected;
almost 75% objected; almost 95% objected.
In six panelists, the volume of air required
to dilute raw diesel exhaust to an odor
threshold ranged from a factor of 140 to 475.
No significant effects on pulmonary
resistance were observed as measured by
plethysmography.
FEVj, FVC, and PEFR were similar between
diesel and non-diesel-exposed miners.
Smokers had an increased number of
decrements over shift than nonsmokers.
Significant work shift decrements occurred
in miners in both groups who smoked; no
significant differences in ventilatory
function changes between miners exposed to
diesel exhaust and those not exposed.
Among underground (surrogate for diesel
exposure) miners, smokers and older age
groups, frequency of bronchitis was higher.
Pulmonary function was similar between
groups and subgroups except for differences
accountable to age.
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TABLE 11-11 (cont'd). HUMAN STUDIES OF DIESEL EXHAUST EXPOSURE
Study
Description
Findings
Gamble et al.
(1979)
Gamble et al.
(1987a)
Ulfvarson et al.
(1987)
Battigelli et al.
(1964)
Gamble et al.
(1987b)
200 Salt miners performed
before and after workshift
spirometry. Personal
environmental NO2 and
inhalable particle samples
were collected.
232 Workers in four diesel
bus garages were
administered acute
respiratory questionnaires
and before and after
workshift spirometry.
Compared to lead, acid
battery workers previously
found to be unaffected by
their exposures.
Workshift changes in
pulmonary function were
evaluated in crews of roll-
on/ roll-off ships and car
ferries and bus garage
staff. Pulmonary function
was evaluated in six
volunteers exposed to
diluted diesel exhaust, 2.1
ppm NO2, and 600 //g/m3
particulate matter.
210 Locomotive repairmen
exposed to diesel exhaust
for an average of 9.6 years
in railroad engine houses
were compared with 154
railroad yard workers of
comparable job status but
no exposure to diesel
exhaust.
283 Male diesel bus garage
workers from four garages
in two cities were examined
for impaired pulmonary
function (FVC, FEV1? and
flow rates). Study
population with a mean
tenure of 9 ± 10 years S.D.
was compared to a
nonexposed "blue collar"
population.
Smokers had greater but not significant
reductions in spirometry than ex- or
nonsmokers. NO2, but not particulate,
levels
significantly decreased FEV1, FEF25,
FEF50, and FEF75 over the workshift.
Prevalence of burning eyes, headache,
difficult or labored breathing, nausea,
and wheeze were higher in diesel bus workers
than in comparison population.
Pulmonary function was affected
during a workshift exposure to
diesel exhaust, but it normalized after a
few days with no exposure. Decrements
were greater with increasing intervals
between exposures. No effect on pulmonary
function was observed in the experimental
exposure study.
No significant differences in VC, FEVj,
peak flow, nitrogen washout, or diffusion
capacity nor in the prevalence of dyspnea,
cough, or sputum were found between the
diesel exhaust-exposed and nonexposed
groups.
Analyses within the study populations
population showed no association of
respiratory symptoms with tenure. Reduced
FEVj and FEF50 (but not FEF75) were associated
with increasing tenure. The study
population had a higher incidence of cough,
phlegm, and wheezing unrelated to tenure.
Pulmonary function was not affected in the
total cohort of diesel-exposed of diesel-
exposed but was reduced with 10 or more years
of tenure.
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TABLE 11-11 (cont'd). HUMAN STUDIES OF DIESEL EXHAUST EXPOSURE
Study
Description
Findings
Purdham et al.
(1987)
Reger et al.
(1982)
Ames et al. (1984)
Attfield (1978)
Attfield et al.
(1982)
Respiratory symptoms and
pulmonary function were
evaluated in 17 stevedores
exposed to both diesel and
gasoline exhausts in car
ferry operations; control
group was 11 on-site office
workers.
Differences in respiratory
symptoms and pulmonary
function were assessed in
823 coal miners from six
diesel equipped mines
compared to 823 matched
coal miners not exposed to
diesel exhaust.
Changes in respiratory
symptoms and function were
measured during a 5-year
period in 280 diesel-
exposed and 838 nonexposed
U.S. underground coal
miners.
Respiratory symptoms and
function were assessed in
2,659 miners from
21 underground metal mines
(1,709 miners) and nonmetal
mines (950 miners). Years
of diesel usage in the mines
were surrogate for exposure
to diesel exhaust.
Respiratory symptoms and
function were assessed in
630 potash miners from six
potash mines using a
questionnaire, chest
radiographs and
spirometry. A thorough
assessment of the
environment of each mine
was made concurrently.
No differences between the two groups for
respiratory symptoms. Stevedores had lower
baseline lung function consistent with an
obstructive ventilatory defect compared
with controls and those of Sydney, Nova
Scotia, residents. Caution in
interpretation is warranted due to small
sample size. No significant changes in lung
function over workshift nor difference
between two groups.
Underground miners in diesel-use mines
reported more symptoms of cough and phlegm
and had lower pulmonary function. Similar
trends were noted for surface workers at
diesel-use mines. Pattern was consistent
with small airway disease but factors other
than exposure to diesel exhaust thought to
be responsible.
No decrements in pulmonary function or
increased prevalence of respiratory
symptoms were found attributable to diesel
exhaust. In fact, 5-year incidences of
cough, phlegm, and dyspnea were greater in
miners without exposure to diesel exhaust
than in miners exposed to diesel exhaust.
Questionnaire found an association between
an increased prevalence of cough and
aldehyde exposure; this finding was not
substantiated by spirometry data. No
adverse symptoms or pulmonary function
decrements were related to exposure to NO2,
CO, CO2, dust, or quartz.
No obvious association indicative of diesel
exposure was found between health indices,
dust exposure, and pollutants. A higher
prevalence of cough and phlegm, but no
differences in FVC and FEVj, were found in
these diesel-exposed potash workers when
compared to predicted values from a logistic
model based on blue- collar staff working in
nondusty jobs.
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TABLE 11-11 (cont'd). HUMAN STUDIES OF DIESEL EXHAUST EXPOSURE
Study
Description
Findings
Gamble et al.
(1983)
Gamble and Jones
(1983)
Edling and Axelson
(1984)
Edling et al.
(1987)
Rudell et al.
(1989,1990,1994)
Respiratory morbidity was
assessed in 259 miners in
5 salt mines by respiratory
symptoms, radiographic
findings and spirometry.
Two mines used diesels
extensively, 2 had limited
use, one used no diesels in
1956,1957,1963, or 1963
through 1967. Several
working populations were
compared to the salt mine
cohort.
Same as above. Salt miners
were grouped into low,
intermediate and high
exposure categories based
on tenure in jobs with
diesel exposure.
Pilot study of 129 bus
company employees
classified into three
diesel exhaust exposure
categories clerks (0), bus
drivers (1), and bus garage
workers.
Cohort of 694 male bus
garage employees followed
from 1951 through 1983
were evaluated for
mortality
from cardiovascular
disease. Subcohorts
categorized by levels of
exposure were clerks (0),
bus drivers (1), and bus
garage employees (2).
Eight healthy non-smoking
subjects exposed for 60 min
in chamber to diesel
exhaust (3.7 ppm NO, 1.5 ppm
NO2, 27 ppm CO, 0.5 mg/m3
formaldehyde, particles
4.3 x 106/cm3). Exercise,
10 of each 20 min (75 W).
After adjustment for age and smoking, salt
miners showed no symptoms, increased
prevalence of cough, phlegm, dyspnea or air
obstruction (FEVj/FVC) compared to
aboveground coal miners, potash workers or
blue collar workers. FEVj, FVC, FEF50, and
FEF75 were uniformly lower for salt miners in
comparison to all the comparison
populations. No changes in pulmonary
function were associated with years of
exposure or cumulative exposure to
inhalable particles or NO2.
A statistically significant dose-related
association of phlegm and diesel exposure
was noted. Changes in pulmonary function
showed no association with diesel tenure.
Age- and smoking-adjusted rates of cough,
phlegm, and dyspnea were 145,169, and 93% of
an external comparison population.
Predicted pulmonary function indices showed
small but significant reductions; there was
no dose-response relationship.
The most heavily exposed group (bus garage
workers) had a fourfold increase in risk of
dying from cardiovascular disease, even
after correction for smoking and allowing
for 10 years of exposure and 15 years or more
of induction latency time.
No increased mortality from cardiovascular
disease was found among the members of these
five bus companies when compared with the
general population or grouped as sub-
cohorts with different levels of exposure.
Odor, eye and nasal irritation in 5/8
subjects. BAL findings small decrease in
mast cells, lymphocyte subsets and
macrophage phagocytosis, small increase in
PMNs.
11-108
-------
The chronic effects of exposure to diesel exhaust have been evaluated in humans in
epidemiologic studies of occupationally exposed workers. Most of the epidemiologic data
indicate the absence of an excess of chronic respiratory disease associated with exposure to
diesel exhaust. In a few of these studies, a higher prevalence of respiratory symptoms, primarily
cough, phlegm, or dyspnea was observed in the exposed workers. Reductions in several
pulmonary function parameters including FVC and FEVl3 and to a lesser extent forced
expiratory flow at 50 and 75% of vital capacity (FEF50 and FEF75), have also been reported.
Two studies (Reger et al., 1982; Purdham et al., 1987), each with methodological problems,
detected statistically significant decrements in pulmonary function when compared with matched
controls. These two studies coupled with other reported nonsignificant trends in respiratory
flow-volume measurements suggest that diesel exhaust exposure may impair pulmonary function
among occupational populations. A preliminary study of the association of cardiovascular
mortality and exposure to diesel exhaust found a risk ratio of 4.0. A more comprehensive study
by the same investigators, however, found no significant difference between the observed and
expected number of deaths due to cardiovascular disease.
The results of the epidemiologic studies addressing noncarcinogenic health effects
resulting from exposure to diesel exhaust must be interpreted cautiously because of a myriad of
methodological problems, including incomplete information on the extent of exposure to diesel
exhaust, the presence of confounding variables (smoking, occupational exposures to other toxic
substances), and the short duration and low intensity of exposure. These limitations restrict
definitive conclusions about diesel exhaust being the cause of any noncarcinogenic health
effects, observed or reported.
11.5.2 Effects of Diesel Exhaust on Laboratory Animals
In short-term and chronic exposure studies, toxic effects have been related to high
concentrations of diesel particulate matter. Data from short-term exposures indicate minimal
effects on pulmonary function, even though histological and cytological changes were observed
in the lungs (Table 11-12). Exposures for several months or longer to levels markedly above
environmental ambient concentrations resulted in accumulation of particles in the lungs,
increases in lung weight, increases in AMs and leukocytes, macrophage aggregation, hyperplasia
of alveolar epithelium, and thickening of the alveolar septa. Similar
11-109
-------
TABLE 11-12. SHORT-TERM EFFECTS OF DIESEL EXHAUST ON LABORATORY ANIMALS
Species/Sex
Rat, F-344, M;
Mouse, A/J;
Hamster, Syrian
Rat, F-344, M,
F; Mouse,
CD-1,M, F
Cat, Inbred, M
Rat, Sprague-
Dawley, M
Guinea Pig,
Hartley, M, F
Rat, F-344, M
Guinea Pig,
Hartley
M, F
Exposure
Period
20 h/day
7 days/week
10-13 weeks
7 h/day
5 days/week
19 weeks
20 h/day
7 days/week
4 weeks
20 h/day
7 days/week
4 weeks
20 h/day
7 days/week
4 weeks
20 h/day
5.5 days/week
4 weeks
20 h/day
7 days/week
8 weeks
Particles
(//g/m3)
1,500
0. 19 //m, MMD
210
1,000
4,400
6,400
6,400
6,800'
6,800'
6,000
6.8//m, MMD
6,300
CxT CO
Og-h/m3) (ppm)
2, 100,000 to 6.9
2,730,000
140,000 —
665,000 —
2,926,000 —
3,584,000 14.6
3,584,000 16.9
3,808,000 16.1'
3,808,000 16.7
2,640,000 —
7,056,000 17.4
NO2 SO2
(ppm) (ppm) Effects
0.49 — Increase in lung wt; increase in
thickness of alveolar walls; no
species difference
— — No effects on lung function; increase
— — in PMNs and proteases and AM
— — aggregation in both species
2. 1 2.1 Few effects on lung function; focal
pneumonitis or alveolitis
2. 49 2.10 Decreased body wt; arterial blood pH
2.76' 1.86' reduced; both vital and total lung
capacities increased
2.9 Exposure started when animals were
4 days old; increase in pulmonary
(<0.01 ppm O3)' flow; bradycardia
— — Macrophage aggregation; increase in
PMNs; Type 2 cell proliferation;
thickened alveolar walls
2.3 Increase in relative lung wt; AM
aggregation; hypertrophy of goblet
(<0.01 ppm O3)" cells; focal hyperplasia of alveolar
epithelium
References
Kaplan et al. (1982)
Mauderly et al. (1981)
Pepelkoetal. (1980d)
Pepelko(1982a)
Wiesteretal. (1980)
White and Garg (1981)
Weisteretal. (1980)
"Irradiated exhaust.
PMN = Polymorphonuclear leukocyte.
AM = Alveolar macrophage.
Source: quoted from U.S. Environmental Protection Agency (1994).
-------
histological changes, as well as reductions in growth rates and alterations in indices of
pulmonary function, have been observed in chronic exposure studies. Chronic studies have been
carried out using rats, mice, guinea pigs, hamsters, cats, and monkeys. Reduced resistance to
respiratory tract infections has been reported in mice exposed to diesel exhaust.
Reduced growth rates have been observed most often in studies with exposures of at least
2,000 //g/m3 diesel particulate matter which lasted for 16 h or more per day (Table 11-13).
No effects on growth or survival were noted at levels of 6,000 to 8,000 //g/m3 of PM when the
daily exposures were only 6 to 8 h/day.
Changes in pulmonary function have been noted in a number of different species
chronically exposed to diesel exhaust (Table 11-14). The lowest exposure levels that resulted in
impaired pulmonary function varied among the species tested but were in excess of 1,000 //g/m3.
Histological changes occurring in the respiratory tract tissue of animal exposed chronically
to high concentrations of diesel exhaust include alveolar histiocytosis, macrophage aggregation,
tissue inflammation, increases in polymorphonuclear leukocytes, hyperplasia of bronchiolar and
alveolar Type 2 cells, thickened alveolar septa, edema, fibrosis, and emphysema (Table 11-15).
Biochemical changes in the lung associated with these histopathological findings included
increases in lung DNA, total protein, and activities of alkaline and acid phosphatase, and
glucose-6-phosphate dehydrogenase; increased synthesis of collagen; and release of
inflammatory mediators such as leukotriene LTB and prostaglandin PGF2a. Some studies have
also suggested that there may be a threshold of exposure to diesel exhaust below which
pathologic changes do not occur. These no-effect levels were reported to be 2,000 //g/m3 for
cynomolgus monkeys, 110 to 350 //g/m3 for rats, and 250 //g/m3 PM for guinea pigs exposed for
7 to 20 h/day, 5 to 5.5 days/week for 104 to 130 weeks.
The pathological effects of diesel exhaust particulate matter appear to be strongly
dependent on the relative rates of pulmonary deposition and clearance (Table 11-16). At particle
concentrations of about 1,000 //g/m3 or above, pulmonary clearance becomes reduced, with
concomitant focal aggregations of particle-laden AMs. The principal mechanism of reduced
particle clearance appears to be the result of impaired AM function. This impairment seems to be
nonspecific and applies to insoluble particles deposited in the
11-111
-------
TABLE 11-13. EFFECTS OF CHRONIC EXPOSURES TO DIESEL EXHAUST
ON SURVIVAL AND GROWTH OF LABORATORY ANIMALS
Species/Sex
Rat, F-344, M, F;
Monkey,
cynomolgus, M
Rat, F344, M;
Guinea Pig,
Hartley, M
Hamster,
Chinese, M
Rat, Wistar, M
Rat, F-344, M, F;
Mouse CD-I
Rat, Wistar, F;
Mouse, MMRI, F
Rat, F-344
M, F
Rat0
F-344/Jcl.
Exposure
Period
7 h/day
5 days/week
104 weeks
20 h/day
5 days/week
106 weeks
8 h/day
7 days/week
26 weeks
6 h/day
5 days/week
87 weeks
7 h/day
5 days/week
130 weeks
19 h/day
5 days/week
104 weeks
16h/day
5 days/week
104 weeks
16 h/day
6 days/week
130 weeks
Particles
(//g/m3)
2,000
0.23-0.36 urn, MMD
250
750
1,500
0.19 urn, MMD
6,000
12,000
8,300
0.71 urn, MMD
350
3,500
7,000
0.25 urn, MMD
4,240
0.35 urn, MMD
700
2,200
6,600
110"
410"
1,080"
2,310"
3,720e
0.2-0.3 urn, MMD
CxT
(,ug-h/m3)
7,280,000
2,650,000
7,950,000
15,900,000
8,736,000
17,472,000
21,663,000
1,592,000
15,925,000
31,850,000
41,891,0000
5,824,000
18,304,000
54,912,000
1,373,000
5,117,000
13,478,000
28,829,000
46,426,000
CO
(ppm)
11.5
2.7'
4.4'
7.1'
—
—
50.0
2.9
16.5
29.7
12.5
—
—
32.0
1.23
2.12
3.96
7.10
12.9
N02
(ppm)
1.5
0.1"
0.27"
0.5"
—
—
4.0-6.0
0.05
0.34
0.68
1.5
—
—
—
0.08
0.26
0.70
1.41
3.00
S02
(ppm) Effects
0. 8 No effects on growth or survival
— Reduced body weight in rats at 1,500 //g/m3
—
—
— No effect on growth
—
— No effect on growth or mortality rates
— No effect on growth or mortality rates
—
—
1 . 1 Reduced body wts; increased mortality in
mice
— Growth reduced at 2,200 and 6,600 //g/m3
—
—
0.38 Concentration-dependent decrease in body
1.06 weight; earlier deaths in females exposed
2.42 to 3,720 //g/m3, stabilized by 15 mo
4.70
4.57
References
Lewis etal. (1989)
Schreck et al.
(1981)
Vinegar et al.
(1981a,b)
Karagianes
etal. (1981)
Mauderly et al.
(1984, 1987b)
Heinrich et al.
(1986a)
Brightwell et al.
(1986)
Research Committee
for HERP Studies
(1988)
"Estimated from graphically depicted mass concentration data.
'Estimated from graphically presented mass concentration data for NO2 (assuming 90% NO and 10% NO2).
°Data for tests with light-duty engine; similar results with heavy-duty engine.
"Light-duty engine.
'Heavy-duty engine.
Source: Quoted from U.S. Environmental Protection Agency (1994).
-------
TABLE 11-14. EFFECTS OF DIESEL EXHAUST ON
PULMONARY FUNCTION OF LABORATORY ANIMALS
Species/Sex
Rat, F-344
M, F
Monkey, M
Cynomolgus
Rat, F-344, M
Rat, Wistar, F
Hamster,
Chinese, M
Rat, F-344,
M, F
Hamster, Syrian
M, F
Rat, F-344;
Hamster Syrian
Rat, Wistar, F
Cat, inbred, M
Exposure
Period
7 h/day
5 days/week
104 weeks
7 h/day
5 days/week
104 weeks
20 h/day
5.5 days/week
87 weeks
7-8 h/day
5 days/week
104 weeks
8 h/day
7 days/week
26 weeks
7 h/day
5 days/week
130 weeks
19 h/day
5 days/week
120 weeks
16 h/day
5 days/week
104 weeks
19 h/day
5 days/week
140 weeks
8 h/day
7 days/week
124 weeks
Particles
(//g/m3)
2,000
0.23-0.36 urn MMD
2,000
0.23-0.36 urn, MMD
1,500
0.19 urn, MMD
3,900
0.1 urn, MMD
6,000
12,000
350
3,500
7,000
0.23-0.26 urn, MMD
4,240
0.35 urn, MMD
700
2,200
6,600
4,240
0.35 urn, MMD
6,000'
12,000"
CxT
(,ug-h/m3)
7,280,000
7,280,000
14,355,000
14,196,000-
16,224,000
8,736,000
17,472,000
1,593,000
15,925,000
31,850,000
48,336,000
5,824,000
18,304,000
54,912,000
56,392,000
41,664,000
83,328,000
CO
(ppm)
11.5
11.5
7.0
18.5
—
2.9
16.5
29.7
12.5
—
12.5
20.2
33.3
N02
(ppm)
1.5
1.5
0.5
1.2
—
0.05
0.34
0.68
1.5
—
1.5
2.7
4.4
S02
(ppm) Effects
0. 8 No effect on pulmonary function
0.8 Decreased expiratory flow; no effect on
vital or diffusing capabilities
— Increased functional residual capacity,
expiratory volume and flow
3.1 No effect on minute volume, compliance or
resistance
— Decrease in vital capacity, residual
— volume, and diffusing capacity; increase
in static deflation lung volume
— Diffusing capacity, lung compliance
— reduced at 3,500 and 7,000 ,ug/m3
1 . 1 Significant increase in airway
resistance
— Large number of pulmonary function
— changes consistent with obstructive and
— restrictive airway diseases at
6,600 /^g/m3 (no specific data provided)
1.1 Decrease in dynamic lung compliance;
increase in airway resistance
2. 1 Decrease in vital capacity, total lung
5.0 capacity, and diffusing capacity after
2 years; no effect on expiratory flow
References
Lewis et al. (1989)
Lewis et al. (1989)
Gross (1981)
Heinrich et al.
(1982)
Vinegar et al.
(1980, 1981a,b)
Mauderly et al.
(1988)
McClellan et al.
(1986)
Heinrich et al.
(1986a)
Brightwell et al.
(1986)
Heinrich et al.
(1986a)
Pepelko et al.
(1980e, 1981)
Moorman et al.
(1985)
"1 to 61 weeks exposure.
b62 to 124 weeks of exposure.
Source: Quoted from U.S. Environmental Protection Agency (1994).
-------
TABLE 11-15. HISTOPATHOLOGICAL EFFECTS OF DIESEL EXHAUST
IN THE LUNGS OF LABORATORY ANIMALS
Species/Sex
Rat, F-344, M
Mouse A/3, M;
Hamster,
Syrian, M
Monkey,
Cynomolgus, M
Rat, F-344, M,
F
Rat, Sprague-
Dawley, M;
Mouse, A/HEJ,
M
Hamster,
Chinese, M
Hamster,
Syrian, M, F
Rat, Wistar, M
Rat, F-344, F
Rat, F-344, M,
F; Mouse CD-I,
M, F
Exposure
Period
20 h/day
7 days/week
12-13 weeks
7 h/day
5 days/week
104 weeks
7 h/day
5 days/week
104 weeks
8 h/day
7 days/week
39 weeks
8 h/day
5 days/week
26 weeks
7-8 h/day
5 days/week
120 weeks
6 h/day
5 days/week
87 weeks
8 h/day
7 days/week
104 weeks
7 h/day
5 days/week
130 weeks
Particles
(//g/m3)
1,500
0.19 urn, MMD
2,000
0.23-0.36 urn, MMD
2,000
0.23-0.36 urn, MMD
6,000
6,000
12,000
3,900
0.1 urn, MMD
8,300
0.71 urn, MMD
4,900
350
3,500
7,000
0.23 urn, MMD
CxT
Og-h/m3)
2,520,000-
2,730,000
7,280,000
3,640,000
13,104,000
6,240,000
12,480,000
16,380,000-
18,720,000
21,663,000
28,538,000
1,592,000
15,925,000
31,850,000
CO NO2 SO2
(ppm) (ppm) (ppm) Effects
— — — Inflammatory changes; increase in lung
weight; increase in thickness of
alveolar walls
11.5 1.5 0.8 AM aggregation; no fibrosis,
inflammation or emphysema
11.5 1.5 0.8 Multifocal histiocytosis;
inflammatory changes; Type II cell
proliferation; fibrosis
— — — Increase in lung protein content and
collagen synthesis but a decrease in
overall lung protein synthesis in both
species; prolyl-hydroxylase activity
increased in rats in utero
— — — Inflammatory changes; AM accumulation;
— — — thickened alveolar lining; Type II cell
hyperplasia; edema; increase in
collagen
18.5 1.2 3.1 Inflammatory changes, 60% adenomatous
cell proliferation
50.0 4.0-6.0 — Inflammatory changes; AM aggregation;
aleovar cell hypertrophy; interstitial
fibrosis, emphysema (diagnostic metho-
dology not described)
7.0 1.8 13.1 Type II cell proliferation;
Inflammatory changes; bronchial
hyperplasia; fibrosis
2.9 0.05 — Alveolar and bronchiolar epithelial
16.5 0.34 — metaplasia in rats at 3,500 and 7,000
29.7 0.68 — //g/m3; fibrosis at 7,000 //g/m3 in rats
and mice; inflammatory changes
References
Kaplan et al.
(1982)
Lewis et al.
(1989)
Bhatnagar et al.
(1980)
Pepelko(1982a)
Bhatnagar et al.
(1980)
Pepelko(1982a)
Pepelko(1982b)
Heinrich et al.
(1982)
Karagianes et
al. (1981)
Iwai et al.
(1986)
Mauderly et al.
(1987a,b)
Henderson et al.
(1988)
-------
TABLE 11-15 (cont'd). HISTOPATHOLOGICAL EFFECTS OF DIESEL EXHAUST
IN THE LUNGS OF LABORATORY ANIMALS
Species/Sex
Rat, M, F,
F-344/Jcl.
Hamster,
Syrian, M, F
Mouse, NMRI, F
Rat, Wistar, F
Guinea Pig,
Hartley, M
Cat, inbred, M
Rat, Wistar, F
Exposure
Period
16 h/day
6 days/week
130 weeks
19 h/day
5 days/week
120 weeks
19 h/day
5 days/week
120 weeks
19 h/day
5 days/week
140 weeks
20 h/day
5.5
days/week
104 weeks
8 h/day
7 days/week
124 weeks
18 h/day
5 days/week
up to 24 mo
Particles
(//g/m3)
110'
410'
1,080'
2,310'
3,720"
4,240
4,240
4,240
250
750
1,500
6,000
6,000C
12,000"
840
2,500
7,000
CxT
Og-h/m3)
1,373,000
5,117,000
13,478,000
28,829,000
46,336,000
48,336,000
48,336,000
56,392,000
2,860,000
8,580,000
17,160,000
68,640,000
41,664,000
83,328,000
7,400,000
21,800,000
61,700,000
CO NO2 SO2
(ppm) (ppm) (ppm) Effects
1.23 0.08 0.38 Inflammatory changes; Type II cell
2.12 0.26 1.06 hyperplasia and lung tumors seen at
3.96 0.70 2.42 >400 ^g/m3; shortening and loss of cilia
7.10 1.41 4.70 in trachea and bronchi
12.9 3.00 4.57
12.5 1.5 1.1 Inflammatory changes; thickened
alveolar septa; bronchioalveolar
hyperplasia; emphysema (diagnostic
methodology not described)
12.5 1.5 1.1 Inflammatory changes; bronchio-
alevolar hyperplasia; alveolar lipo-
proteinosis; fibrosis
12.5 1.5 1.1 Thickened alveolar septa; AM
aggregation; inflammatory changes;
hyperplasia; lung tumors
— — — Minimal response at 250 and
— — — ultrastructural changes at 750 //g/m3;
— — — thickened alveolar membranes; cell
— — — proliferation; fibrosis at
6,000 A^g/m3; increase in PMN at 750
//g/m3 and 1,500 //g/m3
20.2 2.7 2.1 Inflammatory changes; AM aggregation;
33.2 4.4 5.0 bronchiolar epithelial metaplasia;
Type II cell hyperplasia; peri-
bronchiolar fibrosis
2.6 0.3 0.3 No effect on mortality. Reduced body
8.3 1.2 1.1 wt, bronchioalveolar hyperplasia, and
21.2 3.8 3.4 Inc. lung wt. at 2,500 and 7,000 ug/m3
Alveolar clearance rates reduced in all
groups at 3 mo.
BAL showed clear exposure-related
effects in all except lowest diesel
exposure group
References
Research
Committee for
HERP Studies
(1988)
Heinrich et al.
(1986a)
Heinrich et al.
(1986a)
Heinrich et al.
(1986a)
Barnhart et al.
(1981, 1982)
Vostal et al.
(1981)
Plopper et al.
(1983)
Hyde et al.
(1985)
Heinrich et al.
(1995)
-------
Species/Sex
TABLE 11-15 (cont'd). HISTOPATHOLOGICAL EFFECTS OF DIESEL EXHAUST
IN THE LUNGS OF LABORATORY ANIMALS
Exposure
Period
Particles
0/g/m3)
CxT
Qg-h/m3)
CO
(ppm)
NO2
(ppm)
S02
(ppm)
Effects
References
Rats, M, F
F-344/N
Mice
NMRI/C5L
F
16 h/day
5 day/week
up to 24 mo
18 h/day
5 days/week
up to 24 mo
2,500
6,500
10.3
26.9
0.73
3.78
4,500
39,000,000
14.2
2.3
Higher mortality in males. Nikula et al.
Reduced (1995)
body weight in males and females
at
6,500 ,ug/m3. Inc lung weight in
males and females at 2,500 and
6,500 //g/m3. Dose related
increases in AM hyperplasia,
alveolar epithelial
hyperplasia, chronic active
inflammation, septal fibrosis,
alveolar proteinosis
bronchioalveolar metaplasia,
focal fibrosis with alveolar
epithelial hyperplasia,
squamous metaplasia, and
squamous cysts
Reduced body weight, inc. lung Heinrich et al.
weight. (1995)
"Light-duty engine.
'Heavy-duty engine.
°1 to 61 weeks exposure.
d62 to 124 weeks of exposure.
AM = Alveolar macrophage.
PMN = Polymorphonuclear leukocyte.
Source: U.S. Environmental Protection Agency (1994).
-------
TABLE 11-16. EFFECTS OF EXPOSURE TO DIESEL EXHAUST ON THE PULMONARY
DEFENSE MECHANISMS OF LABORATORY ANIMALS
Species
Exposure
Period
Particles
(//g/m3)
CxT
G/g-h/m3)
CO NO2 SO2
(ppm) (ppm) (ppm) Effects
Reference
ALVEOLAR MACROPHAGE STATUS
Guinea Pig,
Hartley
Rat, F-344, M
Rat, F-344, M
Rat F-344/Crl,
M, F
Mouse, CD, M,F
Rat
Rat, F-344
M, F
20 h/day
5.5 days/week
8 weeks
7 h/day
5 days/week
104 weeks
20 h/day
5.5 days/week
26, 48, or
52 weeks
7 h/day
5 days/week
104 weeks
(rat),
78 weeks
(mouse)
7 h/day
5 day/week
12 weeks
7 h/day
5 days/week
18 weeks
<0.5 urn, MMD
250
1,500
0.19 urn, MMD
2,000
0.23-0.36 urn MMD
250'
750'
1,500"
0.19 urn, MMD
350
3,500
7,000
0.25 urn, MMD
200
1,000
4,500
0.25um, MMD
150
940
4,100
220,000
1,320,000
7,280,000
715,000-
8,580,000
1,274,000°
12,740,000°
25,480,000°
84,000
420,000
1,890,000
94,500
592,000
2,583,000
2.9 — — No significant changes in absolute numbers of AMs
7.5 — —
11.5 1.5 0.81 Little effect on viability, cell number, oxygen
consumption, membrane integrity, lyzomal enzyme
activity, or protein content of AMs; decreased
cell volume and ruffling of cell membrane and
depressed luminescence of AM
2.9 — — AM cell counts proportional to concentration of
4.8 — — DP at 750 and 1,500 //g/m3; AM increased in lungs in
7. 5 — — response to rate of DP mass entering lung rather
than toral DP burden in lung; increased PMNs were
proportional to inhaled concentrations and/or
duration of exposure; PMNs affiliated with
clusters of aggregated AM rather than DP
2.9 0.05 — Significant increases of AM in rats and mice
16.5 0.34 — exposed to 7,000 //g/m3 DP for 24 and 18 mo, respec-
29.7 0.68 — lively, but not at concentrations of 3,500 or
350 //g/m3 DP for the same exposure durations; PMNs
increased in a dose-dependent fashion in both
rats and mice exposed to 3,500 or 7,000 //g/m3 DP
and were greater in mice than rats
CLEARANCE
— — — Evidence of apparent speeding of tracheal
— — — clearance at the 4,500 //g/m3 level after 1 week of
— — — 99m Tc macroaggregated-albumin and reduced clear-
ance of tracer aerosol in each of the three
exposure levels at 12 weeks; indication of a lower
percentage of ciliated cells at the 1,000 and
4,500 //g/m3 levels
— — — Lung burdens of DP were concentration-related;
— — — clearance half-time of DP almost double in
— — — 4,100 lig/m3 group compared to 150 //g/m3 group
Chen et. al.
(1980)
Castranova et al.
(1985)
Strom (1984)
Vostal et al.
(1982)
Henderson et al.
(1988)
Wolff and Gray
(1980)
Griffis et al.
(1983)
-------
oo
TABLE 11-16 (cont'd). EFFECTS OF EXPOSURE TO DIESEL EXHAUST ON THE PULMONARY
DEFENSE MECHANISMS OF LABORATORY ANIMALS
Species
Rat, F-344, M
Rat, Sprague-
Dawley
Rat, F-344,
M, F
Exposure
Period
7 h/day
5 days/week
26-104 weeks
4-6 h/day
7 days/week
0.1 to 14.3 weeks
7 h/day
5 days/week
130 weeks
Particles
C"g/m3)
2,000
0.23-0.36 urn
MMD
900
8,000
17,000
350
3,500
7,000
0.25 urn, MMD
CxT
(//g-h/m3)
1,820,000-
7,280,000
2,500-
10,210,000
1,593,000
15,925,000
31,850,000
CO NO2
(ppm) (ppm)
11.5 1.5
— 5.0
— 2.7
— 8.0
2.9 0.1
16.5 0.3
29.7 0.7
S02
(ppm) Effects Reference
0.8 No difference in clearance of 59Fe3O4 particles Lewis et al.
1 day after tracer aerosol administration; (1989)
120 days after exposure tracer aerosol
clearance was enhanced; Lung burden of DP
increased significantly between 12 to 24
months of exposure
0.2 Impairment of tracheal mucociliary clearance Battigelli et al.
0.6 in a concentration-response manner (1966)
1.0
— No changes in tracheal mucociliary clearance Wolff et al.
— after 6, 12, 18, 24, or 30 mo of exposure; (1987)
— increases in lung clearance half-times as
early as 6 mo at 7,000 //g/m3 level and 18 mo at
3,500 //g/m3 level; no changes seen at 350 //g/m3
level; after 24 mo of diesel exposure, long-
term clearance half-times were increased in
the 3,500 and 7,000 //g/m3 groups
MICROBIAL-INDUCED MORTALITY
Mice, CD-I, F — — — — — — No change in mortality in mice exposed
intratracheally to 100 ug of DP prior to
exposure to aerosolized Streptococcus sp.
Mice CD-I, F 7 h/day 2,000 280,000- 11.5 1.5 0.8 Mortality similar at each exposure duration
5 days/week 0.23-0.36 1,820,000 when challenged with Ao/PR/8/34 influenza
4, 12, or um MMD virus; in mice exposed for 3 and 6 mo, but not
26 weeks 1 mo, there were increases in the percentages
of mice having lung consolidation, higher
virus growth, depressed interferon levels and
a four-fold reduction in hemaglutin antibody
levels
Hatch et al.
(1985)
Hahon et al.
(1985)
-------
TABLE 11-16 (cont'd). EFFECTS OF EXPOSURE TO DIESEL EXHAUST ON THE PULMONARY
DEFENSE MECHANISMS OF LABORATORY ANIMALS
Exposure Particles
Species Period (//g/m3)
Mice, CR/CD-1, F 8 h/day 5,300 to 7,900
7 days/week
2 h up to
46 weeks
CxT
Og-h/m3)
11,000-
20,350,000
CO
(ppm)
19
to
22
NO2
(ppm)
1.8
to
3.6
SO2
(ppm)
0.9
to
2.8
Effects
Enhanced susceptibility to lethal effects of
S. pyogenes infections at all exposure
durations (2 and 6 h; 8, 15, 16, 307, and 321
days); inconclusive results with
S. typhimurium because of high mortality rates
in controls; no enhanced mortality when
challenged with A/PR8-3 influenza virus
Reference
Campbell et al.
(1980, 1981)
"Chronic exposure lasted 52 weeks.
""Chronic exposure lasted 48 weeks.
"Calculated for 104-week exposure.
DP = Diesel exhaust particles.
AM = Alveolar macrophage.
PMN = Polymorphonuclear leukocyte.
Source: Quoted from U.S. Environmental Protection Agency (1994).
-------
alveolar region. Other data suggest that the inability of particle-laden AMs to translocate to the
mucociliary escalator is correlated to the average composite particle volume per AM in the lung.
Data from rats indicate that when this particle volume exceeds a critical level, impairment
appears to be initiated. Such data for other laboratory species and humans, unfortunately, are
very limited.
There is a considerable body of evidence that the major noncancerous health hazards posed
by exposure to diesel exhaust are to the lung. These data also show that the exposures that cause
pulmonary injury are lower than those inducing detectable increases in lung tumors. These same
data further indicate that the inflammatory and proliferative changes in the lung play a key role
in the etiology of pulmonary tumors in exposed rats. A range of no adverse effect levels has
been estimated as 200-400 //g/m3 (Health Effects Institute, 1995).
11.5.3 Species Differences
The responses to inhaled diesel exhaust as well as other particulate differs markedly among
rodents. Data on the response to diesel exhaust for a number of species has been reviewed by
Mauderly (1994a). The data indicate that as with cancer, the non-cancer pulmonary effects of
diesel exhaust differ greatly in rats, mice and Syrian hamsters. Thus far, all animals show
epithelial proliferation with chronic high level exposure to diesel exhaust but the changes in the
respiratory bronchioles of cats differ from the changes in the alveolar ducts of rodents. Rats
appear to have a greater epithelial proliferative response to dusts than do mice. Guinea pigs
differ from other species in that the inflammatory response to dust is eosinophil-based rather
than neutrophil-based. Thus, it is unclear which of the animals used in inhalation studies is the
best model for predicting the responses of humans to dust exposure. Pepelko and Perrano
(1983) exposed 8 male cats to diluted DE (6000 //g/m3) for 5 days/week for 61 weeks, then to
12,000 //g/m3 for another 27 mo. At the end of the exposure, a restrictive respiratory function
impairment with nonuniform gas distribution was observed (Moorman et al., 1985). The
accompanying histopathology included peribronchiolar fibrosis and epithelial metaplasia in
terminal and respiratory bronchioles (Plopper et al., 1983). The epithelial changes lessened but
the fibrosis worsened during 6 mo after the exposure ended.
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The rat is the species for which most information about the noncancer effects of diesel
exhaust (Table 11-15) as well as other inhaled dusts has been obtained. The responses of rats
chronically exposed to carbon black or diesel particulate without the organic fraction, are
essentially identical to their responses to diesel exhaust (Mauderly, 1994b; Heinrich et al., 1995).
Heinrich et al. (1995) also demonstrated that the noncancer responses of rats to titanium dioxide
were also similar qualitatively and quantitatively. Muhle et al. (1991) reported that the
responses to chronically inhaled copying toner, a plastic dust pigmented with carbon black,
titanium dioxide and silica were also similar qualitatively to titanium dioxide and diesel exhaust.
Similar responses resulting from chronic exposure of rats to a range of other dusts including oil
shale dusts (Mauderly et al., 1994b), talc (National Toxicology Program, 1993), and coal dust
(Martin et al., 1977) have been described.
Few studies have examined the effects of exposure to diesel exhaust mixed with other
dusts. The response of rats chronically exposed to diesel exhaust soot and mineral dust was
studied by Mauderly et al. (1994b). Male and female F344 rats were exposed 7 hours/day
5 days/week for 30 mo to diesel exhaust, raw or retorted oil shale dust, or additive combinations
of diesel exhaust and shale dust. The diesel exhaust soot accumulated more rapidly in the lungs
than did the shale dust, due to differences in particle size, but the lung burdens of the two types
of dust were additive. The long-term effects on lung weight and density, and BALF
constituents, were greater than additive, the effects on respiratory function were approximately
additive, and the effects on particle clearance were less than additive. The noncancer health
effects of the combined exposures were more closely correlated with the total lung dust burden
than with the combined dust exposure concentrations.
Lewis et al. (1989) studied the effects of diesel exhaust and mineral dust in rats and
cynomolgus monkeys exposed to either diesel exhaust or coal dust at 2,000 //g respirable
particles/m3, or to a combination of 1,000 //g/m3 of each material. Lung burdens of the dusts
were approximately additive in rats but were not measured in the monkeys. Local
histopathological responses were similar and approximately additive for the two dusts in both
species.
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11.5.4 Effects of Mixtures Containing Diesel Exhaust
Mauderly (1993) reviewed the results of studies in which laboratory animals were exposed
to complex mixtures. In a study of diesel and coal dust, rats were exposed for 24 mo to
atmospheres containing diesel exhaust at 2000 //g/m3 coal dust at the same concentration, and a
combination of diesel exhaust and coal dust at 1000 //g/m3 each. Among the health end points
evaluated, the effects of diesel exhaust and coal dust were similar with coal dust being slightly
less toxic. No synergistic interactions between the exposure materials were noted. In another
study of diesel and shale oil dust, Mauderly et al. (1994b) exposed rats by inhalation for 7 h/day
5 days/week for up to 30 mo to raw or retorted oil shale dusts at 5,000 //g/m3, to diesel exhaust
at 3,500 //g/m3 or to additive combinations at total particulate concentrations of 8,500 //g/m3.
The three agents all accumulated progressively in the lungs and caused similar pneumoconiotic
responses. The magnitude of effects was more closely correlated to particle lung burdens than
to exposure concentrations. The effects of diesel exhaust and shale dusts generally were less
than additive for delay of particle clearance; additive for respiratory function impairment; and
greater than additive for lung collagen, airway fluid indicators of inflammation, and lung
tumors.
Mauderly (1989) discussed the susceptibility of the aging lung to inhaled pollutants.
Although the data is extremely limited in that only two particulate pollutants are discussed, it
appears that the aging lung might be more sensitive to particulate pollution. Rats were exposed
repeatedly for 6 mo to diluted, whole diesel exhaust at a concentration of 3,500 //g/m3. The
results indicated that rats exposed between 6 and 12 mo were more sensitive then rats born in the
chambers and exposed up to 6 mo of age. The results indicated that mice exposed as adults were
more susceptible than mice exposed at the onset of breeding age but while lung maturation was
still underway.
11.5.5 Particle Effect in Diesel Exhaust Studies
Diesel PM is composed of an insoluble carbon core with a surface coating of relatively
soluble organic constituents. Studies of diesel particle composition have shown that the
insoluble carbon core makes up about 80% of the particle mass and that the organic phase
11-122
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can be resolved into a more slowly dissolving component and a more quickly dissolving
component.
The relative contribution of the carbon core of the diesel particles versus organics adsorbed
to the surface of the particles to cancer induction and the uncertainty involved has been reviewed
(Health Effects Institute, 1995). The primary evidence for the importance of the adsorbed
organics is the presence of known carcinogens among these chemicals. These include poly cyclic
aromatics as well as nitroaromatics. Organic extracts of particles have also been shown to
induce tumors in a variety of injection, intratracheal instillation and skin painting studies, and
Grimmer et al. (1987) has, in fact, shown that the great majority of the carcinogenic potential
following intratracheal instillation resided in the fraction containing four- to seven-ring PAHs.
Evidence for the importance of the carbon core is provided by studies of Kawabata et al.
(1986), that showed induction of lung tumors following intratracheal instillation of CB that
contained no more than traces of organics and studies of Heinrich et al. (1995) that indicated that
exposure via inhalation to CB (Printex 90) particles induced lung tumors at concentrations
similar to those effective in diesel studies. Other particles of low solubility such as titanium
dioxide (Lee et al., 1986) have also been shown to induce lung tumors, although at much higher
concentrations than necessary for carbon particles or diesel exhaust. Pyrolyzed pitch, on the
other hand, essentially lacking a carbon core but having PAH concentrations at least three orders
of magnitude greater than diesel exhaust, was no more effective in tumor induction than was
diesel exhaust (Heinrich et al., 1986b). These studies suggest that the insoluble carbon core of
the particle is at least as important as the organic components and possibly more so for lung
tumor induction at high particle concentrations (>2,000 //g/m3).
Diesel soot and carbon black appear to elicit similar responses in animal inhalation studies
(Mauderly et al., 1994a; Heinrich et al., 1995; Nikula et al., 1995). Macrophage accumulation,
epithelial histopathology, and reduced clearance have been observed in rodents exposed to high
concentrations of chemically inert particles (Morrow, 1992), furthering the possibility that the
toxicity of diesel particles results from the carbon core rather than the associated organics.
However, the organic component of diesel particles consists of a large number of poly cyclic
aromatic hydrocarbons and heterocyclic compounds and their
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derivatives. A large number of specific compounds have been identified. These components of
diesel particles may also be responsible for the pulmonary toxicity of diesel particles. It is not
possible to separate the carbon core from the adsorbed organics in order to compare the toxicity.
As an approach to this question, a study has been performed in which rats were exposed to either
diesel exhaust or to carbon black, an inert analog of the carbon core of diesel particles. Rats
were exposed for 16 h/day, 5 days/week, for up to 24 mo to either 2,500 or 6,500 //g/m3 of either
particle (Nikula et al., 1995). Although the study is primarily concerned with the role of particle
associated organics in the carcinogenicity of diesel exhaust, non-neoplastic effects are also
mentioned. Both diesel exhaust and carbon black exposure resulted in macrophage hyperplasia,
epithelial hyperplasia, bronchiolar-alveolar metaplasia, and focal fibrosis. In general, the
number and intensity of the lesions seems to correspond to the exposure time and concentration
and that the morphological characteristics of the lesions were similar in the animals exposed to
diesel and to carbon black. The results suggest that the chronic noncancer effects of diesel
exhaust exposure are caused by the persistence of the insoluble carbon core of the particles,
rather than by the extractable organic layer. These studies have been reviewed (Health Effects
Institute, 1995) and the consensus is that particulate matter is primarily responsible for the rat
lung response to diesel exhaust.
11.5.6 Gasoline Engine Emissions
Mauderly (1994c) reviewed the toxicological and epidemiological evidence for health risks
from inhaled gasoline engine emissions. Although the data bank is more extensive for diesel
exhaust, animal studies have shown that heavy, chronic exposure to gasoline engine exhaust can
cause lung pathology and associated physiological effects.
In female beagle dogs exposed to gasoline engine exhaust for over 5 years (16 h/day,
7 days/week) there was little effect on respiratory function during the exposure. However,
subsequent tests revealed increases in lung volumes, dead space ventilation, and dynamic lung
compliance, and a decrease in alveolar-capillary gas exchange efficiency (Hyde et al., 1978).
There were also slight but distinct histopathological changes in the tracheobronchial and alveolar
regions.
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The effects of gasoline engine exhaust on the lungs of rodents were evaluated in a series of
studies in rats and Syrian golden hamsters exposed for up to 24 mo to two dilutions of gasoline
engine exhaust with particle concentrations of approximately 50 or 100 //g/m3 (Bellman et al.,
1983; Muhle et al., 1984; Heinrich et al., 1986a). While gasoline engine exhaust did not cause
any substantial histopathology or alterations of lavage fluid in either species, gasoline engine
exhaust in the higher concentration increased lung weight, retarded particle clearance, reduced
lung compliance, and increased acetylcholine sensitivity in rats. No significant changes in
function were found at either concentration in the hamster, or at the lower concentration in the
rat. In rats and hamsters exposed to gasoline engine exhaust and diesel engine exhaust (16
h/day, 5 days/week, for 24 mo), there were no significant changes in respiratory function
(Brightwell et al., 1989).
While the laboratory animal toxicological data base is limited there is some indication that
long term exposure to gasoline engine exhaust can produce effects on the respiratory tract. It is
unclear to what extent the other constituents of gasoline engine exhaust may have contributed to
the effects.
11.5.7 Summary
In summary, diesel particulate is a widespread pollutant that is present in low
concentrations in the ambient atmosphere (1 to 6 //g/m3 in Los Angeles). Data from
occupational studies and laboratory animal studies indicate that acute exposures to high levels or
chronic exposures to low levels (albeit high compared to ambient levels) of diesel particulate can
have an effect on the respiratory tract. However, it is doubtful that the diesel particulate at
concentrations present in the ambient atmosphere could have a significant effect.
Acute and chronic inhalation exposures to diesel particulate are associated with respiratory
effects. However, in general, the levels used in the laboratory animal studies or experienced in
occupational settings are considerably higher than those experienced in the ambient environment
and the results of these studies provide little insight into the morbidity and mortality studies
discussed in Chapter 12. This is not unexpected because of the patterns of exposure and the total
exposures, as well as differences in the populations exposed. Some of the effects noted in the
occupational studies such as respiratory tract irritation, bronchitis,
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impaired pulmonary function, cough, wheezing, are also observed in the epidemiological studies
discussed in Chapter 12. Although these responses were specific to diesel exhaust, the effects
appear to be due to the particles, per se. However, these effects are evident at exposures much
higher than those experienced in the ambient atmosphere. Accordingly, the toxicological studies
of specific diesel particulate do not appear to provide insight into the effects observed in the
epidemiological studies discussed in Chapter 12 which relate to PM in general.
11.6 SILICA
This section on silica particle toxicity is designed to give an overview of current concepts
regarding the pulmonary toxicity of these environmental pollutants as they relate to different
species, different polymorphs (crystalline vs. amorphous), and biological mechanisms of action.
No attempt has been made to review all of the relevant animal toxicity data, which is
voluminous. Silica is well established as a fibrogenic pollutant which causes lung tumors
following chronic exposures in rats. A review of the literature on the effects of silica can be
found elsewhere (U.S. Environmental Protection Agency, 1996).
The pulmonary response to inhaled silica has long been considered to be a major
occupational hazard, causing disability and deaths among workers in a variety of industries.
Some of the processes and work environments which are frequently associated with silica
exposure include mining, sandblasting of abrasive materials, quarrying and tunneling,
stonecutting, glass and pottery manufacturing, metal casting, boiler scaling, and vitreous
enameling (Ziskind et al., 1976).
11.6.1 Physical and Chemical Properties of Silica
Silica is one of the most common substances to which workers are exposed. Silica particle
emissions in the environment can arise from natural, industrial, and farming activities. There are
only limited data on ambient air concentrations of either crystalline or amorphous silica
particles, due in part, to the limits in accurately quantifying crystalline silica and to the inability,
under existing measurement methods, of separating the identity of crystalline silica from other
particulate matter. Davis et al., (1984) used radiographic
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diffraction to determine the inhalable composition and concentration of quartz in ambient
aerosols collected on dichotomous filters at 25 U.S. metropolitan areas. They reported the
average weight percentage of quartz in the coarse and fine particle mass to be 4.9 (+ 2.3) and 0.4
(+ 0.7), respectively. Combining the weight percentage data for the coarse fraction and 7 year
average annual arithmetic mean PM10 information available for 17 of the 25 areas, annual
average and high U.S. ambient quartz levels of 3 and 8 //g/m3, respectively, have been estimated
(U.S. Environmental Protection Agency, 1996). The actual fraction of quartz in PM10 samples
may be slightly lower than that which was estimated by Davis et al. (1984) in the coarse fraction
of dichotomous filters. However, these estimated U.S. levels are considered to be reasonable
upper bound estimates (U.S. Environmental Protection Agency, 1996). There are at least four
polymorphs or forms of crystalline silica dust. These include quartz, cristobalite, tridymite and
tripoli. Although identical chemically, they differ in their crystal parameters. The basic
structural units of the silica minerals are silicon tetrahedra, arranged in such a manner so that
each oxygen atom is common to two tetrahedra. However, there are considerable differences in
the arrangement of the silicon tetrahedra among the various crystalline forms of silica (Coyle,
1982). Naturally occurring rocks that contain amorphous forms of silica include diatomite or
diatomaceous earth, a hydrate form such as opal, and an unhydrated form, flint (Stokinger,
1981b). Silica is also a component of many naturally occurring silicate minerals in which
various cations and anions are substituted into a crystalline silica matrix. Examples of such
silicates are kaolin, talc, vermiculite, micas, bentonite, feldspar, asbestos, and Fuller's earth
(Silicosis and Silicate Disease Committee, 1988). Commonly encountered synthetic amorphous
silica, according to their method of preparation, are SiO2 gel (silica G), precipitated SiO2 (silica
P), and fumed SiO2 (silica F). The most outstanding characteristics of synthetic amorphous
silica compounds are their particle size and high specific surface area, which determine their
numerous applications (Stokinger, 1981b).
11.6.2 Health Effects of Silica
The causal relationship between inhalation of dust containing crystalline silica and
pulmonary inflammation and the consequent development of silica-induced pulmonary fibrosis
(i.e., silicosis) is well established (Spencer, 1977; Morgan et al., 1980; Bowden,
11-127
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1987). During the acute phase of exposure, a pulmonary inflammatory response develops and
may progress to alveolar proteinosis and a granulomatous-type pattern of disease in rats and
other rodent species. A pattern of nodular fibrosis occurs in chronically exposed animals and
humans (Ziskind, 1976; Spencer, 1977; Morgan et al., 1980; Bowden, 1987). Although there is
experimental evidence that quartz can also cause lung cancer, a clear correlation between
pulmonary fibrosis and neoplasia has been suggested but has not been definitively established.
Acute high occupational exposures can elicit a rapid onset of lung inflammation, leading to
serious, if not fatal, lung dysfunction.
The pulmonary pathological effects of inhaled crystalline silica are well established,
however, there is a paucity of information on the effects of inhaled amorphous forms of silica on
the respiratory tract. The limited toxicological information available suggests that the
respiratory tract effects following exposures to amorphous silicates may be reversible in the
absence of continuing exposures (Groth et al., 1981; Schepers, 1981; Goscicki et al., 1978;
Pratt, 1983). Thus, current evidence suggests that synthetic amorphous silica is not as severe a
hazard as the various polymorphs of crystalline silica.
Parameters which have been commonly used to assess the respiratory effects of silica
exposure in experimental animals include lung weight, development of pulmonary fibrosis, or
biomarkers for fibrosis, such as collagen content, cytotoxicity, pulmonary inflammation,
biochemical indices of homogenized lung samples or bronchoalveolar lavage samples, and
immunologic responses. Few studies have provided exposure dose-response data from which
definitive effect levels could be derived, thus necessitating comparisons among studies in which
experimental conditions may vary considerably. A review of the published laboratory animal
toxicology studies is available (U.S. Environmental Protection Agency, 1996).
11.6.3 Differences Between Chemical Forms of Silica
A few studies have been carried out to compare the effects of inhaled crystalline and
amorphous silica particulates (see Table 11-17). Pratt (1983) exposed guinea pigs for 21 to 24
mo to atmospheric suspensions of either cristobalite crystalline silica, amorphous diatomaceous
earth, or to amorphous volcanic glass. The index of lung pathogenicity was substantially higher
for the cristobalite-exposed animals compared to the other two polymorphs of amorphous silica
particles (Pratt, 1983). Hemenway et al. (1986) exposed
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TABLE 11-17. COMPARATIVE INHALATION TOXICITY STUDIES WITH DIFFERENT SILICA POLYMORPHS
to
VO
Particle
Cristobalite
Diatomaceous earth
(amorphous)
Volcanic glass
(amorphous)
Cristobalite
Alpha-quartz
Amorphous silica
(Zeofree 80)
Fumed silica
Precip. silica
Gel silica
Cristobalite
Alpha-quartz
(Mm-U-Sil)
Amorphous silica
(Zeofree 80)
Ludox
(Colloidal silica)
Species, Gender
Guinea pig (GP)
Same
Same
Male Fischer
344 rats
Same
Same
Male SD rats
Male Hartley GP
Male cynomolgus monkeys
Same
Same
Male SD rats
Same
Same
Same
Mass Concentration
151,000//g/m3
100,000 ^g/rn3
>151,000//g/m3
58,000 & 73,000 //g/m3
36,000 & 81, 000 //g/m3
30,000 Mg/m3
1 5,000 ,ug/m3
Same
Same
1 0,000 or 100,000 //g/m3
10,000, 50,000 or 100,000
//g/m3
10,000 or 1 00,000 ,ug/m3
10,000, 50,000 or 150,000
Exposure
Duration
7-8 h/d
5.5 d/wk
2 1-24 mo
6 h/d
8 days
5. 5-6 h/d
5 d/wk
up to 18 mo
Same
Same
6 h/d for 3 days
6 h/d for 3 days
6 h/d for 3 days
6 h/d for 2 or 4 wk
Observed Effect References
Total amount of silica Pratt et al. (1983)
accum. varied inversely
with the pulmonary tissue
damage. Cristobalite
produced the greatest
pulmonary effects.
Cristobalite produced the Hemenway et al. (1986)
most dramatic
inflammation and fibrotic
response. Amorph. silica-
transient inflamm. AQ
initial mild response but
progressive.
Monkeys developed greater Groth et al. (1981)
response to fumed silica
than rats or guinea pig.
Fumed silica produced
greater fibrotic and
pulmonary function
effects compared to gel or
ppt. silica
Exposures to Cristobalite Warheit et al. (1995)
or AQ produced persistent
and progressive pulmonary
inflammation and I
biomarkers of
cytotoxicity. Ludox and
amorphous silica elicited
transient pulmonary
inflammatory responses.
-------
rats for 8 days to aerosols of one of three silicon dioxide species, a-cristobalite, a-quartz, and
amorphous silica particulates. The greatest measure of lung injury was produced with
cristobalite, which caused substantial inflammation and fibrosis. Exposures to a-quartz
produced mild but progressive effects, while amorphous silica produced transient inflammation.
Warheit and coworkers carried out a number of short-term inhalation studies using cristobalite,
(a-quartz Min-U-Sil), Ludox colloidal silica, a form of precipitated amorphous silica, and
amorphous silica. Rats were exposed to silica aerosols for periods ranging from 3 days to 4
weeks and evaluated by bronchoalveolar lavage and cellular proliferation indices at several
postexposure time periods. Brief exposures to 2 different forms of crystalline silica particles at
100 //g/m3 produced persistent pulmonary inflammation characterized by neutrophil recruitment
and elevated biomarkers of cytotoxicity in BAL fluids. Progressive histopathologic lesions
previously were observed within 1 mo after a 3-day exposure (Warheit et al., 1991a). In
contrast, a 3-day exposure to amorphous silica, produced transient lung inflammation, and 2 or
4-week exposures to Ludox elicited pulmonary inflammation at 50,000 or 150,000 //g/m3 but not
at 10,000 //g/m3; most elevated biochemical effects were reversible. These results demonstrated
that the crystalline forms of silica dust were substantially more potent in producing pulmonary
toxicity compared to the amorphous or colloidal forms of silica (Warheit et al., 1991a, 1991b,
1995). In addition, the pulmonary effects of inhaled (a-quartz particles in rats were much more
potent than in the study reported by Hemenway and coworkers (1986).
11.6.4 Species Differences
The fibrogenic effects of crystalline silica exposure may vary depending on the species
used in experimental studies. Rats appear to be more sensitive to the development of
silica-induced lung injury and lung tumors in comparison to other rodent species such as mice
and hamsters (Saffioti, 1992; Saffioti et al., 1993; Uber and McReynolds, 1982). Warheit et al.,
(1994) reported that inhalation exposure to silica in complement-normal and
complement-deficient mice produced an acute pulmonary inflammatory response which was
mild and transient, compared to the pulmonary effects observed in rats wherein silica produced a
sustained and progressive pulmonary inflammatory response. In support of these results, mice
intratracheally injected with silica particles had a milder fibrogenic response
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when compared with rats (Hatch et al., 1984). It seems clear, however, that the silica-induced
response in mice depends upon the strain, as there appear to be low and high responding strains
of mice to silica (Callis et al., 1985; Hubbard, 1989).
Differences are not only apparent across and within rodent species, but also between
rodents and humans. Unlike the nodules observed in human radiographs, silicosis is manifested
in rat radiographs as a diffuse "haziness", described as a ground-glass appearance with some
peripheral striation (Kutzman, 1984). In a chronic study by Muhle et al. (1989), the principal
non-neoplastic finding in the silica-exposed rats, extensive subpleural and peribronchiolar
fibrosis, was described as being unlike the nodular fibrosis observed in human silicosis. Such
interspecies differences and the fact that most of the available laboratory studies only examined
one dose level may limit the utility of laboratory animal data for extrapolation of the silicosis
risk observed in higher exposure conditions of human occupational studies.
For additional information on the pathogenic development of silica-related lung disease in
humans and experimental animals, the reader is referred to a variety of informative reviews
(Ziskind et al., 1976; Spencer, 1977; Reiser and Last, 1986; Bowden, 1987; Crouch, 1990;
Goldstein and Fine, 1986; Warheit and Gavett, 1993).
11.7 BIOAEROSOLS
11.7.1 Types of Health Effects Associated with Bioaerosols
Exposure to biological aerosols can produce three general classes of health effects:
infections, hypersensitivity disease, and toxicoses. It is possible that these afflictions may make
people more susceptible to air pollutant effects.
11.7.1.1 Infections
Infections result when a living (micro)organism invades another organism, multiplies using
some component of the host as a nutrient source, and either directly (via digestion) or indirectly
(via release of toxins) causes disease. The number of individual living particles required to
cause disease depends on the virulence (ability to invade the host) of the organism, and on the
status of the host's immune system (Pennington, 1989). The organisms
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that most commonly cause infectious disease are viruses (e.g., influenza, measles, common
colds) and bacteria (e.g., Legionnaires' disease, tuberculosis). A few fungi can also cause
infections in healthy people (e.g., Histoplasma capsulatuni) or those with damaged immunity
(Q.g.,Aspergillusfumigatus) (Rippon, 1988).
Particle size is an important consideration for disease. Some agents can only cause
infection in the upper respiratory tract, and are best transmitted via large droplets (many
common colds). Others must reach the lower airway to cause infection, and large droplets that
impact in the upper airway are not usually part of the disease process (e.g., Mycobacterium
tuberculosis) (Burge, 1989). Infectious aerosols must remain alive and be able to invade and
replicate in the host in order to cause disease. Over time, infectious aerosols decay physically
(becoming less concentrated) and biologically (each remaining cell becoming less able to cause
disease). Airborne infectious diseases are generally caused by relatively resistant organisms that
are highly virulent (Cox, 1987).
11.7.1.2 Hypersensitivity Diseases
Hypersensitivity diseases are caused by exposure to allergens (a specific type of antigen)
and result from specific responses of the immune system (Pope et al., 1993). They are always
caused by two step processes. Initial exposures induce sensitization (i.e., cause the production of
circulating or fixed immune cells that recognize the agent), and subsequent exposures precipitate
symptoms (the agent reacts with the specific immune cell and releases mediators such as
histamine that result in overt symptoms). Thus the first exposure to a sensitizing agent does not
cause symptoms. The kinds of hypersensitivity diseases that are caused by bioaerosols include
asthma, allergic rhinitis and (rarely) allergic dermatitis (the "immediate" or IgE-mediated
diseases), and hypersensitivity pneumonitis (also called allergic alveolitis) which is mediated
primarily by the cellular immune system. Approximately 30% of the US population is affected
by IgE-mediated allergies. The incidence of hypersensitivity pneumonitis remains unknown.
Farmer's lung disease (a form of the disease) probably occurs in less than 3% of the farm
population.
Very little good data have been accumulated on the actual doses of an allergen (the agent
that stimulates the response) required for either sensitization or symptom development. For the
IgE-mediated diseases, relatively low level long-term exposure is considered to be
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important for sensitization and higher levels are needed to precipitate symptoms. For
hypersensitivity pneumonitis, intense short term exposures may result in sensitization, while
very low levels may induce symptoms.
Any allergen could probably cause either type of disease depending on the conditions of
exposure. Pollen and fungal allergens are well-known agents that precipitate hay fever and
asthma symptoms, while proteins released from dust mite fecal particles are apparently highly
effective sensitizers. Historically, the agents most commonly associated with hypersensitivity
pneumonitis are the thermophilic actinomycetes. In addition, fungal spores, bird droppings,
bacterial enzymes, and other agents have been reported to cause the disease.
Allergen-bearing particles that induce IgE-mediated disease range in size from <0.1 //m
(cat secretions) to 60 //m (some grass pollen). Apparently allergen-bearing particles must be <5
//m in order to cause hypersensitivity pneumonitis. In both diseases, there may be synergistic
effects between allergens and irritants (i.e., endotoxin, chemical air pollutants) with respect to
sensitization. Note that allergens are always water soluble, and must diffuse out of the allergen-
bearing particle before inducing their effect. It is likely, then, that the larger the particle, the
more slowly the allergen exposure, and hence the response, will occur.
11.7.1.3 Toxicoses
Microbial toxins are (essentially) chemicals that are produced by living organisms. The
microbial toxicoses are basically similar to the comparable diseases caused by non-biological
toxins. Microbial toxins are known that are mutagenic, teratogenic, tumorigenic, and cytotoxic.
In addition, some (like endotoxin) have adjuvant activity (i.e., they stimulate the immune
system).
Exposure/response relationships for biological toxins are poorly known with the possible
exception of endotoxin. Endotoxin clearly affects pulmonary function and at high levels may
cause serious disease (Burge, 1995). Organic dust toxic syndrome has been associated with
massive exposure to endotoxins (along with mycotoxins and other components of grain dust).
The incidence of the disease (the percent of the farm worker population with at least one attack)
ranges from 1% in Sweden to up to 44% in the United States (Do Pico, 1992). Grain dust also
causes a less acute disease with prolonged
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exposures at relatively low exposure levels. Whether a component of the grain itself or of
contaminating bacteria or fungi is actually the toxic agent remains unknown.
Mycotoxin-related lung disease remains poorly documented. There is some evidence that
exposure to Aspergillus flavus aerosols containing aflatoxin Bl is a risk for lung and esophageal
cancer in peanut handlers (Sorenson et al., 1984) and in farmers handling moldy corn (Baxter et
al., 1981). Exposure to trichothecene toxins contained in Stachybotrys atra has been blamed for
central nervous system symptoms, skin rashes, and pulmonary hemorrhages in specific cases,
although in all cases, exposure was inferred rather than measured (Croft et al., 1986).
Particle sizes required for disease related to biological toxin exposure depend on the nature
of the disease. Pulmonary effects of endotoxin probably require pulmonary deposition, while
systemic effects could be precipitated by larger particles impacting in the upper airway. The
fungal spores that have been blamed for mycotoxin-induced airway disease range from about 3
to 5 (j,m in diameter. The location of the mycotoxins in fungal spores is unknown. The toxins
may not be present on the surface of particles, and, in some cases, must be released from the
particle to be effective. Endotoxin is a part of the outer cell wall.
11.7.2 Ambient Bioaerosols
Ambient bioaerosols include fungal spores, pollen, bacteria, viruses, endotoxins, and
animal and plant debris. Bacteria, viruses and endotoxins are mainly found attached to aerosol
particles, while entities in the other categories are found as separate particles. Data for
characterizing ambient concentrations and size distributions of bioaerosols are sparse. Matthias-
Maser and Jaenicke (1994) found that bioaerosols constituted about 30% of the total number of
particles in samples collected on a clean day in Mainz, Germany. The proportion of particles
that were bioaerosols was higher in the fine size mode (as much as a third) and slightly lower in
the coarse size mode. In Brisbane, Australia, Glikson et al. (1995) found that fungal spores
dominate the bioaerosol count in the coarse fraction of PM10 and that the overall contribution of
bioaerosols to total PM10 particulate mass was on the order of 5 to 10%. However, the
cytoplasmic content of spores and pollen was often found to be adhered to particles emitted by
motor vehicles and particles of crustal origin.
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Fungal spores range in size from 1.5 jim to > 100 |im, although most are 2 to 4 jim MMAD.
They form the largest and most consistently present component of biological aerosols in ambient
air. Levels vary seasonally, usually being lowest when snow is on the ground. Fungal spores
often reach levels of 1000 to 10,000 spores/m3 during the summer months (Lacey and
Dutkiewicz, 1994; Madelin, 1994) and may be as high as 100,000/m3 near some anthropogenic
sources (agriculture activities, compost, etc.).
Asthma mortality has been associated with ambient levels of fungal spores, unadjusted OR
of 2.16 (95% CI = 1.31 to 3.56) per increment of 1000 spores/m3; controlling for time and pollen
counts reduced the RR to 1.2 (95% CI = 1.07 to 1.34) (Targonski et al., 1995). Asthma
mortality in Scotland shows a seasonal peak that follows the peak in ambient pollen levels
(MacKay et al., 1992). Exposure to fungal spores has also been identified as a possible
precipitating factor in respiratory arrest in asthmatics (O'Hollaren et al., 1991). Such exposure
can lead to allergic alveolitis (hypersensitivity pneumonitis) or pulmonary mycoses such as
coccidioidomycosis or histoplasmosis (Lacey and Dutkiewicz, 1994).
Bioaerosols can contribute to increased mortality and morbidity. Most commonly,
bioaerosols appear to exacerbate allergic rhinitis and asthma. Induction of hypersensitivity
generally requires exposure to concentrations that are substantially higher than in ambient air,
although subsequent antigenic responses require much lower concentrations. Association of
fungal and pollen spores with exacerbations of asthma or allergic rhinitis is well established
(Ayres, 1986) and fungal spore levels may be associated with asthma mortality (Targonski et al.,
1995). The incidence of many other diseases (e.g., cocci dioidomycosis) induced by fungal
spores is relatively low, although there is no doubt about the causal organisms (Lacey and
Dutkiewicz, 1994). The potential for fungal induced diseases is much higher in
immunocompromised patients and those with unusually high exposures, such as military
personnel.
In addition to fungal spores and pollen, other bioaerosol material can exacerbate asthma
and can also induce responses in nonasthmatics. For example, in grain workers who experience
symptoms, spirometry decrements, and airway hyperresponsiveness in response to breathing
grain dust, the severity of responses is associated with levels of endotoxin in the bioaerosol
rather than the total dust concentration (Schwartz et al., 1995). A classic series of studies (Anto
and Sunyer, 1990) proved that airborne dust from soybean husks was
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responsible for asthma epidemics and increased emergency room visits in Barcelona, Spain.
These studies indicate that airborne fragments of biological substances can produce severe health
effects.
Bacterial aerosol counts may range as high as 30,000 bacteria/m3 downwind of sewage
treatment facilities, composting areas, waterfalls from polluted rivers, or certain agricultural
activities. Typical levels in urban areas range from several hundred to several thousand
bacteria/m3 (Lighthart and Stetzenbach, 1994). Human pathogenic activity of such bacteria is
not well understood or characterized. Infective potential of aerosolized bacteria depends on size
(smaller are more effective), virulence, host immune status, and host species sensitivity (Salem
and Gardner, 1994). Aerosolized bacteria can cause bacterial infections of the lung including
tuberculosis and legionnaire's disease. The Legionella pneumophila bacterium is one of the few
infectious agents known to reside outside an infected host and is commonly found in water,
including lakes and streams. Levels of bioaerosols (fungi and bacteria) are generally higher in
urban than in rural areas (Lighthart and Stetzenbach, 1994).
Exposures to bioaerosols of the above types, while clearly capable of producing serious
health effects (especially at high concentrations often encountered in indoor environments)
appear unlikely to account for observed ambient (outdoor) PM effects on human mortality and
morbidity demonstrated by epidemiology studies reviewed in Chapter 12. This conclusion is
based on (1) bioaerosols generally represent only a very small percentage (< 5 to 10%) of
measured urban ambient PM mass; (2) they typically have even lower concentrations in ambient
air during winter months, when notable ambient PM effects have been demonstrated; and they
tend to be in the coarse fraction size range.
11.8 TOXICOLOGY OF OTHER PARTICULATE MATTER
11.8.1 Introduction
This section reviews the toxicology of other PM within the framework described in the
introduction to the chapter. The particle classes chosen for inclusion here are those which may
actually occur in ambient air or may be surrogates for these. For example, some of the particles
discussed are considered to be models of "nuisance" or "inert" dusts (i.e., those having low
intrinsic toxicity) and, as such, are likely to be representative of similar ambient
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PM. In many instances, there are only a few studies examining the response on specific
biological endpoints following inhalation exposure. In these cases, and where available,
intratracheal instillation studies have been used to compare the toxicity of different particle
types. While instillation may produce more severe pulmonary damage than would inhalation
(largely due to differences in delivered doses and dose rates), the relative toxicities of different
particles seem to be similar when given by either method (Driscoll et al., 1991). Thus,
intracheal instillation studies can be used for comparative potency purposes, but it is not possible
to quantitatively extrapolate the resulting exposure-response data to inhalation exposure-
responses. In a number of cases, particles with low intrinsic toxicity have been used in
instillation studies to delineate nonspecific particle effects from effects of known toxicants.
Some of these studies are discussed herein, as they offer the only database for such materials.
11.8.2 Mortality
Examples of studies in which effects on mortality were reported using particles >1 //m in
diameter are presented in Table 11-18; all of these studies involved repeated or chronic
exposures to high concentrations of various PM, some of which are considered to be of low
toxicity. While incomplete, the studies are of a variety of materials and indicate that essentially
no treatment-related mortality was induced in any of the studies.
Recent interest has been focused on the inherent toxicity of a smaller size class of particles,
namely the ultrafine particles which are discussed in Section 11.4. While the mass concentration
of ultrafine particles in ambient air may be low, their number concentration may be quite high,
as discussed previously.
11.8.3 Pulmonary Mechanical Function
Assessments of pulmonary mechanical function have generally been carried out with
particles having some inherent toxicity, as well as other studies examining effects of other
particles with low intrinsic toxicity (see Table 11-19). Wright et al. (1988) instilled rats
(Sprague-Dawley; F; 200g) with 10,000 //g iron oxide (0.1 //m GMD, og = 1.7) or silica
(quartz) (1.3 //m, og = 2.5). At 1 mo after exposure, they noted no changes in various indices of
pulmonary mechanics (total lung capacity [TLC];
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TABLE 11-18. EFFECTS OF PARTICIPATE MATTER (>1 ^m) ON MORTALITY
1
OJ
oo
Particle
Ti02
Toner
Coal dust
Petroleum coke
(micronized)
Petroleum coke
(micronized)
Volcanic ash
Ti02
Fly ash (coal)
California
road dust
Talc
Species, Gender,
Strain, Age, or
Body Weight
Rat, M/F, F-344,
8 weeks
Rat, M/F, F-344,
8 weeks
Rat, M, Wistar,
18 weeks
Rat, M, SD
Monkey, adult,
cynomologous
Rat, M/F, F-344,
3 mo
Rat, M/F, CD
Rat, M, Wistar,
3 mo
Rat, F-344
Rat, M/F, F-344
Exposure
Technique
Whole body
Whole body
Whole body
Whole body
Whole body
Whole body
Whole body
Whole body
Nose-only
Whole body
Mass Concentratic
C"g/m3)
5,000
16,000
6,600, 14,900
10,000, 30,000
10,000, 30,000
5,000, 50,000
10,000, 50,000,
250,000
270,000
300, 900
6,000, 18,000
Particle Characteristics
Size (//m); ag
l.l(MMAD); 1.5
4 (MMAD)
2.1 (MMAD); 2.7
3.1 (AED); 1.9
3.1 (AED); 1.9
Respirable (unspecified
size)
1. 5-1.7 (MMD)
47% < 3.75 //m
4 (MMAD); 2.2
2.7-3.2 (MMAD); 1.9
Exposure Duration
6 h/day, 5 days/week,
2 years
6 h/days, 5
days/week,
2 years
6 h/day, 5 days/week,
20 mo
6 h/day, 5 days/week,
2 years
6 h/day, 5 days/week,
2 years
6 h/day, 5 days/week,
2 years
6 h/day, 5 days/week,
2 years
6 h/day, 1 5 days
4 h/day, 4 days/week,
8 weeks
6 h/day, 5 days/week,
2 years
Observed Effect'
None
None
None
None
None
None
None
None
None
None
Reference
Muhle et al. (1991)
Muhle et al. (1991)
Karagianes et al.
(1981)
Klonneetal. (1987)
Klonneetal. (1987)
Wehneretal. (1983)
Lee et al. (1985)
Chauhanetal. (1987)
Kleinman et al.
(1995)
National Toxicology
Program (1993)
"Effect indicates "treatment related" mortality.
-------
TABLE 11-19. EFFECTS OF INHALED PM ON PULMONARY MECHANICAL FUNCTION
VO
Particle
Volcanic ash
Fly ash (coal)
(Illinois # 6)
Fly ash (coal)
(Montana
lignite)
Volcanic ash
Volcanic ash
Coal dust
Ti02
Species, Gender,
Strain, Age, or Body Exposure Mass Concentration
Weight Technique (//g/m3)
Rat, Whole body 9,400
Sprague-Dawley, 40
days
Guinea pig, Hartley, Nose-only 5,800
250-320 g
Guinea pig, Hartley, Nose-only 5,800
250-320 g
Rat, M/F, F-344, Whole body 5,000, 50,000
3 mo
Guinea pig, Hartley, Head 9,400
300-425 g
Rat, Wistar, Whole body 10,000
200-300 g,
conventional and
germ free
Rat, F, F-344, Whole body 5,000
8 weeks
Particle Characteristics
Size (//m); ag Exposure Duration
0.65 (MMAD); 1.78 2 h/days, 5 days
0.21 (MMAD);4.14 Ior2h
0.21 (MMAD); 4. 14 Ior2h
Respirable 6 h/day, 5 days/week,
24 mo
0.65 (MMAD); 1.78 2h
Geometric mean <5 //m 8 h/day, 120 days
— 6 h/day, 5 days/week,
24 mo
Observed Effect'
No changes (f, VT,
Vinsp, Vexp)
2h: iTLC, VC, DLCO
up to 96 h PE 1 h: no
effect
2h: iTLC, VC; no
change in DLCO
Tf for 50,000 //g/m3
by 8 mo; no change
for 5,000 //g/m3
No change in RQW,
-------
functional residual capacity [FRC]; nitrogen [N2] washout; FEV1; or peak expiratory flow
[PEF]) in animals exposed to iron oxide, but silica exposure resulted in changes in the N2
washout curve and decreased compliance. Begin et al. (1985) instilled into sheep (Male; 25 to
45 kg BW) 100,000 //g latex beads (0.1 //m) or asbestos fibers. The latex produced no change in
pulmonary function (TLC, residual volume [RV]; vital capacity [VC]; expiratory reserve volume
[ERV]; pulmonary compliance [Cpulm]; pulmonary resistance [Rpulm]; FRC), while the
asbestos produced a reduction in compliance, abnormalities in the N2 washout curve, and
changes in forced expiratory flow measurements.
There are a few studies of pulmonary function responses following inhalation exposures to
PM. Chen et al. (1990) evaluated pulmonary function of guinea pigs exposed to coal fly ash (5.8
Mg/m3, MMAD = 0.21 //m) produced during combustion of Illinois no. 6 coal (high sulfur) or
Montana lignite (low sulfur). Total lung capacity (TLC), vital capacity (VC), and diffusing
capacity for carbon monoxide (DLCO) were all significantly reduced below control values at 2h
and 8h postexposure in guinea pigs exposed to Illinois no. 6 ash. The DLCO was still 10% below
control values 96h postexposure. Guinea pigs exposed to the Montana lignite fly ash at
comparable concentration and particle size did not show alterations in diffusing capacity. The
authors suggested that the different effects could be due to sulfuric acid produced during
combustion of the two coals but neutralized by the high alkali content of the Montana lignite.
Wehner et al. (1983) exposed rats (F-344; M/F, 3mo) to 5,000 or 50,000 //g/m3 volcanic
ash (Mt. St. Helens) for 6 h/day, 5 days/week for up to 24 mo (Table 11-19). By 12 mo of
exposure, no changes in lung volume were noted. By 8 mo of exposure, there was an increase in
respiratory frequency in animals exposed at the higher concentration, but no change at the lower
concentration.
Heinrich et al. (1989b) exposed rats for 6 h/day, 5 days/week up to 24 mo to titanium
dioxide (TiO2) at 5,000 //g/m3 and silica at 1,000 //g/m3. Exposure to silica produced a
reduction in quasistatic lung compliance, tidal volume, (VT), inspiratory capacity (1C), VC, RV,
and TLC. Diffusion capacity for carbon monoxide (DLco) was also reduced, and the N2
washout curve was altered; these changes indicate a functionally restrictive lung, a finding often
noted in humans occupationally exposed to silicates. None of these variables were altered by
exposure to TiO2.
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Acidic sulfates have been associated with alterations in bronchial responsiveness, but there
are few studies with other particles which examined this response. Fedan et al. (1985) exposed
rats (F344, whole body) for 7 h/day, 5 days/week for 2 years to coal dust (size described as
respirable, but not specifically stated) at 2,000 //g/m3, and examined the pharmacological
response of isolated tracheal preparations to various agonists. The coal dust exposure increased
the maximal contractile response of the tracheal smooth muscle to acetylcholine (a
bronchoconstrictor), compared to air exposed control tissue, but did not alter the slope of the
acetylcholine concentration-response curve nor sensitivity (i.e., EC50). No change in response
to isoproterenol (a bronchodilator) was noted. Wiester et al. (1985) exposed guinea pigs for 2 h
to 9,400 //g/m3 of Mt. St. Helens volcanic ash (0.65 //m). No changes in pulmonary mechanics
measured during exposure (airway resistance, dynamic compliance, breathing frequency,
maximum inspiratory flow or expiratory minute volume) were noted. However, following
exposure, airway hyporesponsiveness to histamine challenge was observed.
It should be noted that, as with acidic sulfates, changes in pulmonary function may not be
the most sensitive marker of response to other PM. For example, inflammatory changes in
sheep following the instillation of latex particles (100,000 //g in 100 ml fluid) were not
associated with any changes in lung volumes, resistance, or compliance (Begin et al., 1985).
11.8.4 Pulmonary Morphology and Biochemistry
A considerable amount of the information concerning morphologic alterations from
inhaled particles has been obtained in studies of diesel exhaust, and this is discussed in this
chapter and reviewed elsewhere (U.S. Environmental Protection Agency, 1994; Health Effects
Institute, 1995). In addition, and as previously mentioned with acidic sulfate particles, markers
in lung BAL have been used to assess damage following PM exposure.
The ability of ambient particles to affect lung morphology was strongly suggested by
Bohm et al. (1989). They exposed rats (Wistar, F, 2.5 mo) for 6 mo to the ambient air of two
cities in Brazil, namely Sao Paulo and Cubatao. Although characterization of air pollution levels
was vague, pollution in the former appeared to be dominated by automobile exhaust gases, while
that in the latter by industrially derived paniculate matter. Rats exposed in Cubatao showed
various responses, such as mucus hypersecretion and epithelial
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hyperplasia, in both the upper and lower bronchial tree, while those exposed in Sao Paulo
showed effects generally limited to the upper bronchial tree. Particle concentrations (PM10) were
as high as 164 //g/m3 in Cubatao. Thus, high PM levels were suggested to be responsible for the
observed effects, although the contribution of other components of the pollutant mix could not
be discounted.
Some intratracheal instillation studies have compared morphological effects resulting from
exposure to different particles. Wright et al. (1988) instilled 10,000 //g iron oxide (Fe2O3;
0.1 //m GMD, og = 1.7) or 10,000 //g quartz (1.3 //m GMD, og = 2.5) into rats, and examined
the lungs 30 days following each exposure. The iron oxide did not produce any histological or
morphometric changes, while the quartz exposure resulted in aggregations of PMNs and AMs
around small airways, alveolar proteinosis, increased alveolar distances, airspace enlargement,
and increased thickness of respiratory bronchiolar walls.
Another example of an instillation study which may be used to compare effects from
different types of particles is that of Sanders et al. (1982), who instilled rats (F-344, female,
young adult) with 40,000 //g of either soil (sandy loam, 1.6 //m CMD), volcanic ash
(Mt. St. Helens, 0.5 to 1.5 //m CMD), or crystalline quartz (1.5 //m CMD). Mononuclear cell
infiltration was noted with both the soil and ash particles in regions of high particle aggregation.
There was also some Type 2 epithelial cell hyperplasia 7 to 37 days following ash or soil
instillation. However, the ash produced a fibrotic response to a greater extent than did the soil,
with indications from the former of a simple pneumoconiosis and moderate lipoproteinosis.
Some foci of particle-laden macrophages were noted in the mediastinal lymph nodes of soil
exposed animals, but the ash-exposed animals showed reactive lymphoid hyperplasia. Quartz
resulted in production of granulomas, deposition of collagen, widespread lipoproproteinosis, and
fibrosis in regional lymph nodes.
The comparative fibrogenic potential of a number of particle types was examined by
Schreider et al. (1985). Male Sprague-Dawley rats were exposed by intratracheal instillation to
5,000, 15,000, or 45,000 //g of Montmorillonite clay (0.84 //m CMD), quartz (1.1 //m), Mt. St.
Helens volcanic ash (1.2 //m), stack-collected coal fly ash (1.5 //m) or hopper-collected fly ash
(1.9 //m), or to 5,000 or 15,000 //g of a coal-oil ash mixture (3.9 //m). Lung histology was
assessed at 90 days post instillation. Neutrophils were noted in alveoli only with quartz (all
concentrations), stack ash (at high concentration), and
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volcanic ash (low and mid concentrations). Some fibrosis was produced by all of the particles,
although there were qualitative and quantitative differences among the different exposure
groups. The order of fibrosis potential, from greatest to least, was as follows: quartz > clay >
volcanic ash > hopper coal ash > stack coal ash > oil-coal ash mixture.
Begin et al. (1985) instilled 100,000 //g of 0.1 //m latex beads or asbestos fibers into the
lungs of sheep (25 to 45 kg) and examined lavage fluid at 1 to 60 days post instillation. The
latex produced only transient alveolitis and transient increases in the number of AMs and PMNs
in lavage beginning at day 1, whereas the asbestos-exposed animals had a persistent
inflammatory response and more severe damage. Callis et al. (1985) instilled silica or latex
particles (0.9 //m) into the lungs of mice. While the latter produced some increase in protein and
cell number in lavage, the response to the former was much greater. Finally, Lindenschmidt
et al. (1990) instilled rats with either of two inert dusts, (A12O3; 5.3 //m) and TiO2 (2.2 //m) at
1,000 or 5,000 //g/100g body weight and examined the lungs up to 63 days post instillation.
Both particle types produced similar increases in N-acetylglucosamine and total recovered cells
in lavage, while a minimal Type 2 cell hyperplasia noted with A12O3 was even less severe with
TiO2. However, when results were compared with those for instilled silica, any responses seen
with the inert particles decreased towards control level during the 2-mo study period, while
changes with silica progressed. This highlights the difference between the inert and fibrogenic
materials. Thus, the instillation studies suggest that there may be some nonspecific particle
effect, but clearly the chemical characteristics of the particle affects the ultimate biological
response. In any case, levels of particles with low intrinsic toxicity are not associated with major
nonspecific effects.
The effects of inhaled PM on pulmonary morphology are outlined in Table 11-20. Most of
the studies used fly ash and volcanic ash; TiO2 has also been used to assess effects of a
"nuisance" (low intrinsic toxicity) type of particle. However, with the exception of the study of
road dust by Kleinman et al. (1995), exposure concentrations ranged from very high to
extremely high and likely caused overload with long-term exposures. Responses, when they did
occur, were quite similar for the various particles, characterized by focal aggregates of
particle-laden macrophages with evidence of an inflammatory response; the intensity of both
effects was related to exposure duration and concentration. On the other
11-143
-------
TABLE 11-20. EFFECTS OF PARTICIPATE MATTER ON RESPIRATORY TRACT MORPHOLOGY
Particle
Coal dust
(micronized
bituminous)
Petroleum coke
(micronized
raw)
Fly ash (coal)
Volcanic ash
(Mt. St.
Helens)
Ti02
Species, Gender,
Strain, Age or Exposure Mass
Body Weight Technique Concentration
C"g/m3)
Rat, M, Whole body 6,600, 14,900
Wistar, 1 8 weeks
Rat, M/F, S-D; Whole body 10,000, 30,000
Monkey,
cynomologous
(mature)
Rat, M/F, Whole body 36,000
F-344, 10-13 mo
Rat, M/F, Whole body 5,000, 50,000
F-344, 3 mo
Rat, F, Whole body 5,000
F-344, 8 weeks
Particle
Characteristics
exposure Duration
Size (//m); ag
2. 1 (MMAD); 2.7 6 h/day, 5 days/week,
20 mo
3.1 (AED); 1.9 6 h/day, 5 days/week,
2 years
3.6 (MMAD); 2 7 h/day for 3 days on
week 1,
5 days/week next
3 weeks,
2 days in week 5
Respirable 6 h/day, 5 days/week,
(no size given) up to 24 mo
6 h/day, 5 days/week,
up to 24 mo
Observed Effect
Accumulation of aggregates of
particles in
AMs immed. after exposure; alveolar
histocytosis, interstitial fibrosis
and emphysema, indication of simple
pneumoconiosis; no lesions in upper
respiratory tract.
Rat: chronic pulmonary inflammation
at 3, 6, 12, and 18 mo observation times
at both cone; focal fibrosis;
sclerosis; squamous alveolar
metaplasia. Monkey: accumulation of
particle-laden AMs; no inflammation
No exposure-related histopathology in
large or small airways; but increased
cell division; slight increase in
number of hypertrophic Type 2 cells by
2 weeks; small areas of thickened
alveolar walls and some perivenous
inflammatory cell infiltration; by 4
weeks, aggregation of AMs with
particles and greater alveolar wall
thickening and inflammation; some
resolution by 42 weeks in pathology.
At 5,000 //g/m3: small aggregations of
particle-laden AMs at 4 mo and some
thickening of alveolar septa.
Aggregates of dust deposits at 8 mo,
and some peribronchiolar lymphoid
hyperplasia which increased by 12 mo.
Enlargement of mediastinal nodes by 12
mo.
At 50,000 //g/m3: more severe lesions;
low to moderate AM accumulation by 4 mo
which increased by 8 mo and stabilized
by 12 mo. Prominent peribronchial and
mediastinal node reaction by 4 mo,
which increased by 8 mo and stabilized
by 12 mo; alveolar proteinosis by 8 mo.
No fibrosis; no bronchiolar
hyperplasia; no accumulation of AMs in
lung tissue.
Reference
Karagianes et al.
(1981)
Klonne et al.
(1987)
Shami et al.
(1984)
Wehner et al.
(1983)
Heinrich et al.
(1989b)
-------
TABLE 11-20 (cont'd). EFFECTS OF PARTICIPATE MATTER ON RESPIRATORY TRACT MORPHOLOGY
Particle
Fly ash (coal)
Ti02
Volcanic ash
California road
dust
TiO2
Fly ash
(fluidized bed
coal
combustion)
Fly ash (coal)
Fly ash
(fluidized bed
coal
combustion)
Fly ash
(pulverized
coal
combustion)
Species, Gender,
Strain, Age or Exposure Mass
Body Weight Technique Concentration
0/g/m3)
Mice, M, Nose-only 200,000
C57BL/6,
12 weeks
Guinea pig, F, Whole body 23,000
Dunkin-Hartley,
300-350 g
Rat, Whole body 9,400
Sprague-Dawley,
40 days
Rat, F-344 Nose-only 900
Rat, M/F, Whole body 10,000, 50,000,
CD 250,000
Rat, M/F, F-344, Whole body 142,000
12-16 weeks
Hamster, golden, Whole body 2,000,
8 weeks 1,000, 2,000
20,000
Rat, M/F, F-344, Whole body 36,000
12 weeks
Rat, M/F, Whole body 37,000
F-344, 12 weeks
Particle
Characteristics
Exposure Duration Observed Effect
Size (//m); ag
1.6-1.7 (MMAD); 100 min Increased no. of AMs; no other
1.4-1.5 lesions evident by light microscopy.
95% < 1.98 (MMAD) 20 h/day, 14 days At 1 day PE: dust laden cells in
bronchial lymph nodes and BALT; some
thickening of alveolar septa in areas
of high dust cone.; some degenerative
changes in AMs; no PMNs. At 6 d PE:
increased number of dust laden AMs.
0.65 (MMAD); 1.78 2 h/day, 5 days Slight peribronchial and perivascular
mononuclear cell infiltration.
4 (MMAD); 2.2 4 h/day, 4 days/week, T Alveolar septal wall thickness;
8 weeks i Alveolar diameter
1.5-1.7 (MMAD) 6 h/day, 5 days/week, At 10,000 //g/m3: slight alveolar
2 years epithelial
hyperplasia. At 50,000 //g/m3: marked
alveolar epithelial hyperplasia;
bronchioarization of alveoli adjacent
to terminal bronchioles; alveolar
proteinosis.
At 250,000 lig/m3: increased alveolar
hyperplasia and bronchioarization;
deposition of collagen fibers.
3 (MMAD); 2.6 6 h No pathology, except accumulation of
particles.
2.3-2.4 (MMAD); 20 h/day, 7 days/week, Accumulation of particle-laden AMs in
1.5 6 mo proximal alveoli in
concentration/duration dependent
fashion; T PMNs at 20,000 |ig/m3 in
peripheral alveoli.
3.6 (MMAD); 2.0 7 h/day, 5 days/week, Slight enlargement of lung associated lymph
4 weeks nodes due to increased no. of lymphoid cells
(persistent up to 48 weeks PE); small cluster
of particle laden AMs in alveoli.
2.7 (MMAD); 2. 1 7 h/day, 5 days/week, Moderate enlargement of lung
4 weeks associated lymph nodes due to hyperplasia
and cell accumulation (persistent up to
48 weeks PE); small granulomas in lungs.
Reference
Fisher and
Wilson
(1980)
Baskerville
etal.
(1988)
Raub et al.
(1985)
Kleinman
etal.
(1995)
Lee et al.
(1985)
Hackett
(1983)
Negishi
(1994)
Bice et al.
(1987)
Bice et al.
(1987)
-------
TABLE 11-20 (cont'd). EFFECTS OF PARTICIPATE MATTER ON PULMONARY MORPHOLOGY
Particle
Carbon black
Carbon black
Fly ash (coal)
Shale dust (raw
or spent)
Coal dust
Species, Gender,
Strain, Age or Exposure Mass Concentration •
Body Weight Technique (//g/m3)
Rat, M, Whole body 10,000
F-344,
14-15 weeks
Rat, F, Wistar 6,000
6 weeks
Rat, M, Whole body 270,000
Wistar, 160- 175 g
Monkey, Whole body 10,000, 30,000
cynomolgus, M/F,
2-4. 5 kg
Rat, M/F, F344,
90-95 g
Monkey Whole body 2,000
cynomolgus, M
Rat, M/F, F-344
Mice, M/F CD-I
Particle Characteristics
Size (//m); ag Exposure Duration
2.0/0. 12 7 h/day, 5 days/week,
(MMAD) 12 weeks
(bimodal distr.
with 70% in
smaller mode) 2. 5/2. 3
n/s 1 8 h/day, 5 days/week,
10 mo
47% <3.75 fj.m 6 h/day, 15 days
3.9-4.5; 6 h/day, 5 days/week,
(1.8-2.2) 2 years
8.6 fj,m (MMAD) 7-h/day, 5 days/week,
up to 2 years
Observed Effect
Mild hyperplasia of Type 2 cells;
particle laden AMs in distal
terminal bronchioles and proximal
alveolar ducts.
Moderate to severe hyperplasia in
bronchioalveolar region; some
inflammation; alveolar
lipoproteinosis
Mild infiltration of mononuclear
cells and mild pneumonitis 45 days
PE; numerous particle-laden AMs
outside alveoli up to 105 days PE;
T lung weight by 30 days PE.
Concentration-related accumulation
of AMs; subacute bronchiolotis and
alveolitis
Concentration-related
proliferative bronchiolitis and
alveolitis, chronic inflammation
with spent shale; no
lymph node inflammation;
accumulation of AMs
Type II cell hyperplasia and
pulmonary lipodosis in rats;
increased phagocytosis. Mild
obstructive airway disease in
monkeys.
Reference
Wolff etal.
(1990)
Nolle et al.
(1994)
Chauhan et al.
(1987)
MacFarland et
al. (1982)
Lewis et al.
(1989)
Key to abbreviations:
NS: Not specified
PE: Post-exposure
AM: Alveolar macrophage
PMNs: Polymorphonuclear leukocytes
-------
hand, the Kleinman et al. (1995) study at relatively low particle concentrations showed a more
diffuse pattern of morphological change and no inflammatory loci.
There is some evidence for interspecies differences in response to comparable exposure
atmospheres (Klonne et al., 1987). In the study of Shami et al. (1984), increased proliferation of
large and small airway epithelial cells occurred in the absence of overt histopathology following
exposure to fly ash. The authors suggested that this may indicate some potential for the
interaction of fly ash with carcinogens.
Clark et al. (1990) exposed dogs (mongrel, 15 to 20 kg) for 5 min to wood smoke (from fir
plywood sawdust and kerosene; no specified particle size or exposure concentration) via an
endotracheal tube. The lungs were examined for increased extravascular water around the
pulmonary arteries, which was found to occur with smoke exposure but not in air sham controls.
This response was suggested to be due to increased microvascular permeability without any
increase in capillary pressure. A decrease in lung compliance was also noted with smoke
exposure.
Table 11-21 outlines studies in which lavage fluid was analyzed following inhalation
exposure to PM. As with morphology, most exposure concentrations were very high, but
effects, when they occurred, indicated inflammation.
As mentioned earlier, eicosanoids are potent mediators of various biological functions, and
alterations in arachidonic acid metabolism, which may be involved in lung pathology, can be
assessed in lavage fluid. Exposure to coal dust (25,000 //g/m3) produced decreases in
prostaglandin E2, and increases in thromboxane A2 and leukotriene B4, perhaps suggesting
smooth muscle constriction, vasoconstriction and increased chemotactic activity of macrophages
(Kuhnetal., 1990).
Table 11-22 outlines studies examining lung biochemistry following particle inhalation,
mostly to fly ash. In some cases, effects on the xenobiotic metabolizing system of the lungs
were examined. For example, van Bree et al. (1990) exposed rats to coal fly ash (10,000,
30,000, 100,000 //g/m3) and examined cytosolic antioxidant enzymes and the microsomal P-450
linked mixed function oxidase system involved in lung metabolic defense against reactive
oxygen species and xenobiotic compounds. They noted both exposure-related increases and
decreases in different components of this system, which they ascribed to differential effects of
organic and trace metal components of the ash. Srivastava et al. (1985)
11-147
-------
TABLE 11-21. EFFECTS OF PARTICIPATE MATTER ON MARKERS IN LAVAGE FLUID
oo
Particle
Carbon black
Volcanic ash
Ti02
Ti02
Coal dust
California
road dust
Ti02
Fe203
Carbon black
Carbonyl
iron
Carbon
black
Ti02
Coal dust
Species,
Gender, Strain,
Age or Body
Weight
Mouse, F,
Swiss, 20-23
days
Mouse, F,
CD-I, 4-8 weeks
Rat, M, F-344
180-200 g
Rat, HAN
Rat, HAN
Rat, F-344
Rat, M/F, F-344,
8 weeks
Rat, M,
Long-Evans,
225-250 g
Rat, M,
F-344,
14-15 weeks
Rat, M
CrliCDBR,
8 weeks
Mouse, F,
Swiss
20-23 g
Guinea pig, M/F,
400 g
Rat, F, F-344,
180 g
Exposure
Technique
Nose-only
Whole body
Whole body
Whole body
Whole body
Nose-only
Whole body
Nose-only
Whole body
Nose-only
Nose-only
Whole body
Whole body
Mass Concentration
(//g/m3)
10,000
9,400
50,000
50,000
10,000, 50,000
300, 900
5,000
18,000-24,000
10,000
100,000
10,000
24,000
25,000
Particle Characteristics
Size (//m); ag
2.45 (MMAD); 2.54
0.65 (MMAD); 1.8
1 (MMAD); 2.6
4 (MMAD); 2.2
1.1 (MMAD); 1.6
1.45- 1.7 (MMAD);
2.9-3
2.0/0.12
(MMAD)
(bimodal distr.
with 70% in
smaller mode); 2.5/2.3
3.6 (MMAD); 1.7
2.4 (MMD); 2.75
85% < 2 ij,m
4-5
Exposure Duration
4 h/day, 4 days
2h
6 h/day, 5 days
8 h/day, 5 days/week
(up to 15 weeks)
8 h/day, 5 days/week
(up to 1 5 weeks)
4 h/day, 4 days/week,
8 weeks
6 h/day, 5 days/week,
24 mo
2h
7 h/day, 5 days/week,
12 weeks
6 h; 6 h/day, 3 days
4h
8 h/day, 5 days/week,
3 weeks
16 h/day, 7 days/week,
2 weeks
Observed Effect
No change in total cell no. or
differential counts; no change in
albumin
levels.
Increase in PMNs.
No change in: AMs, PMNs, lymphocytes;
LDH; protein; to 63 days PE.
Slight increase in PMNs at 15 weeks.
Increased PMNs (persistent).
T Albumin at 900 //g/m3; no change in
total cells or differential counts
No change in total cell no. in lavage
but T AMs and J PMNs some time points; no
change in LDH, protein,
6-glucuronidase
in lavage.
No change total cell no. or
differential counts.
T PMNs in lavage; T acid
proteinase in lavage.
No change in total cell no,
protein, or LDH.
No change in total cell no. or
differential count at 20 h PE.
No change in LDH, AP, AG, Cathepsin D at
4-24 h PE.
T TxAj, LTB4, protein; I PGE2 at 1 day PE;
TxAj, and LTB4 change persistent for
2 weeks.
Reference
Jakab (1992, 1993)
Grose et al.
(1985)
Driscoll et al.
(1991)
Brown et al.
(1992)
Brown et al.
(1992)
Kleinman et al.
(1995)
Muhle et al.
(1991)
Lehnert and Morrow
(1985)
Wolff etal.
(1990)
Warheit et al.
(1991a)
Jakab and Hemenway
(1993)
Kuhn et al. (1990)
Sjostrand and
Rylander (1984)
-------
TABLE 11-21 (cont'd). EFFECTS OF PARTICIPATE MATTER ON MARKERS IN LAVAGE FLUID
Species, Gender, Particle
Strain, Age or Exposure Mass Characteristics
Particle Body Weight Technique Concentration
Og/m3) size (//m); ag
TiO2 Guinea pig, M/F, Whole body 24,000 Most between 0.5-2 (GMD)
400 g
Exposure Duration Observed Effect
8 h/day, 5
days/week,
3 week
No change PMNs; T no. AMs,
eosinophils by 16 weeks
PE.
Reference
Fogelmark et al. (1983)
Key to abbreviations:
LDH: lactate dehydrogenase
AP: acid phosphatase
AG: N-acetyl-6-d-glucosaminidase
TxA^ thromboxane A2
LTB4: Leukotrine B4
PGE2: Prostaglandin E2
AM: alveolar macrophage
PE: post-exposure
PMN: polymorphonuclear leukocyte
T: increase
I: decrease
VO
-------
TABLE 11-22. EFFECTS OF PARTICIPATE MATTER ON LUNG BIOCHEMISTRY
Particle
Fly ash
(coal)
Carbon black
Fly ash
(fluidized bed
coal)
Carbonyl iron
Fly ash
(fluidized bed
coal
combustion)
Fly ash
(coal)
Fly ash
(coal)
Species,
Gender, Strain,
Age or Body
Weight
Rat, M,
Wistar, 5 weeks
Rat, M,
F-344, 200-250 g
Rat, M/F,
F-344
Rat, M,
CrliCDBR,
8 weeks
Rat, M/F,
F-344,
10-13 weeks
Rat, M,
Wistar,
160-175 g
Rat, M,
Wistar,
160-170 g
Particle
Exposure Mass Concentration Characteristics
1 echmque (//g/nr*)
Size (//m); ag
Whole body 10,000, 30,000, 80-95% mass was
100,000 <42 /an (AED)
Whole body 6,000 0.22 (MMAD)
Whole body 142,000 3 (MMAD); 2.6
Nose-only 100,000 3.6 (MMAD); 2.6
Whole body 36,000 3.6 (MMAD); 2
Whole body 270,000 47% < 3.75 /an
Whole body 270,000 47% <3.75 /an
Exposure Duration
6 h/day, 5
days/week,
4 weeks
20 h/day, 1-14 days
6h
6 h/day, 3 days
7 h/day, 3 days
week 1; 5 days/week
week 2-4; 2 days
week 5
6 h/day, 1 5 days
6 h/day, 1 5 days
Observed Effect
T Cytosolic GSHPX, protein at 30,000
100,000; T G6PDH at 100,000; T lung
microsomal protein, i microsomal BROD
at 30,000/100,000; no change
microsomal P-450 content; induction
of EROD activity at all cone, (all in
lung tissue).
No change in synthesis of lung total
DNA; no change in DNA synthesis of Type
2 cells.
T Labeling of Type 2 cells;
T incorporation of thymidine in AM DNA,
persisting 4 days PE; T labeling airway
epithelial cells,
persistent up to 4 days PE.
No effect on labeling index of lung
parenchymal or airway cells.
T Labeling index of large airway basal
cells and bronchiolar Clara cells at
2 weeks, resolved by 2 weeks PE;
T labeling index of Type 2 cells
by 4 weeks, resolved by 2 weeks PE.
T P-450 content; T activity of aryl
hydrocarbon hydro xylase, glutathione
S-transferase, 8-amino levulinic acid
synthetase; inhibition of
hemeoxygenase.
T Total lung phospholipids;
T phosphatidylcholine up to 45 days PE.
Reference
van Bree et
al. (1990)
Wright (1986)
Hackett
(1983)
Warheit et
al. (1991a)
Shami et al.
(1984)
Chauhan et
al. (1989)
Chauhan and
Misra(1991)
Key to abbreviations:
GSHPX = glutathione peroxidase
G6PDH = glucose 6 phosphate dehydrogenase
BROD = benzoxyresorufin 0-dearylase
EROD = NADPH-mediated ethoxyresorufin 0-deethylase
T: increase
I: decrease
PE = post exposure
AM = alveolar macrophage
-------
also found that the effects of fly ash were likely due to chemicals adsorbed onto, or that were
part of, the fly ash particle, rather than to some nonspecific particle effect. This was because the
activity of the lung mixed function oxidase system was induced in rats by instillation of coal fly
ash (<0.5 //m), but not by instillation of glass beads.
There is some evidence that fly ash exposure can initiate cell division and DNA synthesis
in the lungs (Hackett, 1983; Shami et al., 1984), but exposure levels were very high
(>30,000
11.8.5 Pulmonary Defenses
11.8.5.1 Clearance Function
Mucocttiary Transport
Grose et al. (1985) exposed (whole-body) rats (Sprague-Dawley CD, M, 60 to 70 days) to
volcanic ash from Mt. St. Helens (0.65 //m, og=1.8) at 9,400 //g/m3 for 2 h. At 24 h post
exposure, a depression in ciliary beat frequency in excised tracheas was noted. Whether this
would contribute to any change in mucociliary transport function in the intact animal is
unknown.
Pulmonary Region Clearance and Alveolar Macrophage Function
A number of studies have examined particle retention following exposure to high
concentrations of inhaled particles, some of which have low intrinsic toxicity. Such exposures
resulted in a phenomenon known as overload, in which the effectiveness of lung clearance
mechanisms is significantly reduced. This response, which is nonspecific to a wide range of
particles, is discussed in detail in Chapter 10.
While there are no studies of effects of exposure to nonacidic sulfate particles on alveolar
region clearance, there have been several studies examining AM function following inhalation
exposures (Table 1 1-23) or with in vitro exposure. High exposure concentrations of various
particles can depress the phagocytic activity of AMs following inhalation.
To examine the effects of different fly ashes, Garrett et al. (1981b) incubated rabbit AMs
with < 1,000 //g of either conventional coal combustion fly ash or fluidized bed combustion fly
ash at >3 and <3 //m, for 20 h. While all exposures caused reductions in cell viability and cell
ATP levels, conventional coal fly ash <3//m produced the greatest
11-151
-------
TABLE 11-23. EFFECTS OF PARTICIPATE MATTER ON ALVEOLAR MACROPHAGE FUNCTION
1
l^ft
to
Particle
Carbon black
Volcanic ash
Ti02
Fly ash
(coal)
Ti02
Coal dust
California
road dust
Iron oxide
(Fe203)
Carbonyl
iron
Carbon black
Ti02
Species, Gender,
Strain, Age, or
Body Weight
Mouse, F,
Swiss, 20-23 g
Mouse, F,
CD-I, 4-8 weeks
Rat, M, F-344
180-200 g
Mouse, F,
BALB/C; C57BL;
6-8 weeks
Rat, HAN
Rat, HAN
Rat, F-344
Rat, M,
Long-Evans,
225-250 g
Rat, M,
CrliCDBR,
8 weeks
Mouse, F,
Swiss, 20-23 g
Guinea pig, M/F
400g
Exposure
Technique
Nose-only
Whole body
Whole body
Whole body
Whole body
Whole body
Nose-only
Nose-only
Nose-only
Nose only
Whole body
(/jg/m3)
10,000
9,400
50,000
535
(fine particle
fraction
< 2. 1 /mi)
50,000
10,000, 50,000
300, 900
18,000-24,000
100,000
10,000
24,000
Particle Characteristics
Size (/mi); ag
2.45 (MMAD); 2.54
0.65 (MMAD); 1.8
1 (MMAD); 2.6
32 %< 2.1 /mi
(bywt)
"respirable fraction"
"respirable fraction"
4 (MMAD)
1.45-1.7 (MMAD); 2.9-3
3.6 (MMAD); 1.7
2.4 (MMD); 2.75
Most between
0.5-2(GMD)
Exposure Duration Observed Effect"
4 h/day, 4 days No change in F -mediated AM
phagocytic activity up to
40 days PE.
2 h No change in viability of
recovered cells; no effect
on AM phagocytosis at 0 or
24 h PE.
6 h/day, 5 days No change in spontaneous/
stimulated release of IL- 1
by AMs up to 63 days PE.
148 days i AM phagocytic activity by
21 days of exposure.
8 h/day, 5 days/week No change in chemotactic
activity of AM.
8 h/day, 5 days/week Decreased AM chemotactic
activity.
4 h/day, 4 days/week, i Production of superoxide
8 weeks at high concentration; no
change in Fc receptor
mediated phagocytic
activity.
2 h No change in AM adherence;
T phagocytic activity of AM
(Fc-mediated) up to 20 days
PE.
6 h; 6 h/day, 3 days No change in AM chemotactic
activity; cell viability ;
slight T AM phagocytic
activity for single exp.
4 h No change in F -receptor
mediated AM phagocytic
activity.
8 h/d, 5 days/week, No change in AM phagocytic
3 weeks activity.
Reference
Jakab (1992, 1993);
Jakab and Hemenway
(1993)
Grose et al. (1985)
Driscoll et al. (1991)
Zarkower et al. (1982)
Brown et al. (1992)
Brown et al. (1992)
Kleinman et al. (1995)
Lehnert and Morrow
(1985)
Warheitetal. (199 la)
Jakab and Hemenway
(1993)
Fogelmark et al.
(1983)
-------
effect. These results suggest toxicity somewhat dependent on size, as observed previously with
other endpoints.
There is little available data on complex mixtures of other PM. Pick et al. (1984) exposed
rabbits (NZW, 1.5 to 2 kg) for 0.2 to 2 h to the pyrolysis products derived from Douglas fir
wood (exposure concentrations and particle size were not stated). They noted an increase in the
total number of cells recovered by lavage immediately postexposure, and the magnitude of this
increase was related to the exposure duration. The ratio of AMs, PMNs and lymphocytes was
constant at all exposure durations except for the longest, in which case lymphocyte numbers
increased. A depression in the uptake and intracellular killing of Pseudomonas aeruginosa was
found in AMs obtained from the smoke-exposed animals compared to cells from air controls.
Furthermore, cells from the smoke-exposed animals were smaller, and had reduced surface
adherence.
To examine for a nonspecific particle effect on phagocytosis, Finch et al. (1987) exposed
bovine AMs in vitro to TiO2 (1.57 //m MMD, og=2.3) or to glass beads (2.1 //m, og=1.8), the
former at 2.3 or 5 //g/ml, and the latter at 5 or 8.4 //g/ml. Neither exposure altered phagocytic
activity, but TiO2 did produce some decrease in cell viability.
Macrophages may contact particles via chemotactic-directed movement. Constituents of
lung fluid having high chemotactic activity are components of complement, and particles which
activate complement tend to show greater chemoattractant activity for macrophage accumulation
at sites of particle deposition (Warheit et al., 1988). For example, in an in vitro study,
iron-coated asbestos and carbonyl iron particles activated chemotactic activity in rat serum and
concentrated rat lavage proteins, while volcanic ash did not. When the rats were exposed by
inhalation to 10,000 to 20,000 //g/m3 of these particles, only the volcanic ash failed to produce
an increased number of macrophages on the first alveolar duct bifurcations, the primary
deposition site for these particles and fibers. Complement proteins on alveolar surfaces are
likely to be derived primarily from normal transudation of serum components from the
pulmonary vasculature (Warheit et al., 1986). The generation of chemotactic factors at particle
deposition sites may facilitate clearance for some particle types, but not for others, such as silica
(Warheit et al., 1988, 1991a).
In a somewhat related study, Hill et al. (1982) examined the interaction with complement
of coal combustion fly ash particles (2 to 3 //m MMAD) from different sites,
11-153
-------
using serum from dogs. In addition to releasing peptides that are chemotactic for macrophages
and other inflammatory cells, fly ash also induced release of lysosomal enzymes and increased
vascular permeability, all processes involved in inflammation. While the authors noted that
some fly ash samples activated complement, while others did not, they were not able to
determine which component on or in the ash was responsible for this action. A possibility was
suggested to be some metals, such as Mn, which are potent activators of the complement cascade
(Lewetal., 1975).
Thoren (1992) examined the metabolic activity of AMs by measuring heat exchange rates
after exposing cell monolayers to TiO2 or manganese dioxide (MnO2) at
0.6 - 4 x 106 particles/ml. The former affected metabolism only at the highest concentration
used, while the latter caused changes at lower concentrations as well.
The response of AMs to PM is influenced by both physical and chemical characteristics of
the particles with which they come into contact. Shanbhag et al. (1994) exposed a macrophage
cell line (P388D1) to particles of two different composition (TiO2 or latex) at comparable sizes,
0.15 and 0.45 //m for the former, and 0.11 and 0.49 for the latter. They also used pure titanium
at 1.76 //m for comparison to latex at 1.61 //m. Titanium dioxide decreased cellular
proliferation, depending upon both size and concentration. Similar sizes and concentrations of
latex produced lesser responses. In addition, cells incubated with latex released factors, into the
medium, which produced fibroblast proliferation to a greater extent than did cells incubated with
TiO2 of a similar size and concentration.
11.8.5.2 Resistance to Infectious Disease
Susceptibility of mice to challenge with several infectious agents has been used to assess
effects of various inhaled particles on microbial defense of the lungs (Table 11-24). The study
of Jakab (1993) is of particular interest because the infectious agents used were selected based
upon differences in the antimicrobial defense mechanism most effective in eliminating each
organism. Thus, Staphylococcus aureus defense depends primarily upon the integrity of AMs,
while that for Proteus mirabilis involves both AMs and PMNs. Listeria monocytogenes
defenses involve specific acquired immunity, namely the integrity of the lymphokine-mediated
components of the cell- mediated immune response (e.g., AMs and lymphocytes). A number of
host defenses play a role in defense against influenza, including
11-154
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TABLE 11-24. EFFECTS OF PARTICIPATE MATTER ON MICROBIAL INFECTIVITY
Particle
Carbon black
Carbon black
Ti02
Coal dust
Volcanic ash
Ti02
Ti02
Species, Gender,
Strain, Age, or
Body Weight
Mouse, F,
Swiss, 20-23 g
Mouse, F, Swiss,
20-23 g
Guinea pig, F,
Dunkin-Hartley
300-350 g
Mouse, F, Swiss
CD-I, 20-24 g
Mouse, F, CD-I,
4-8 weeks
Mouse,
Harlan-Olac,
8 weeks
Mouse,
Harlan-Olac,
8 weeks
Particle
Exposure Mass Characteristics
1 echnique Concentration Exposure Duration Observed Etlect
Og/m3) size ^m). Og
Nose-only 4,700-6,100 2.45 (MMAD); 2.54 4h/day, 4 days No effect on susceptibility to
infection
from S. aureus administered 1 day PE;
no effect on intrapulmonary killing
of
bacteria by AM.
Nose-only 10,000 2.4 (MMAD); 2.75 4h/day, 4 days No change in no. of S. aureus or P.
mirabilis recovered in lung after
bacterial challenge or on
intrapulmonary killing of bacteria
administered 1 d PE; no effect on
proliferation of L. monocytogenes;
no effect on proliferation or
elimination of influenza A virus; no
change in albumin level in lavage 4 h
after bacterial challenge; no change
in PMN in lavage 4 h after challenge.
Whole body 23,000 95% < 1.98 ,um (MMAD) 20 h/day, 14 days No change in susceptibility to
Legionella pneumophila administered
1-6 days PE but AM with heavy particle
burden did not ingest bacteria.
Whole body 2,000 80% <10//m; 50% <5 //m 7 h/day, 5 days/week, No change in susceptibility to
6 mo influenza virus administered after
1, 3 and 6 mo exposure; decrease in
interferon level in lung at 3 mo; no
change in inflammatory response to
virus.
Whole body 9,400 0.65 (MMAD); 1.8 2h No change in susceptibility to
bacteria (Streptococcus) or virus
administered 0 or 24 h PE; no change
in lymphocyte response to mitogens.
Whole body 2,000,20,000 95%<1.98 /rni(UDS) 20 h/day, 2 or 4 weeks i Clearance of P. haemolytica
administered after exposure in
proportion to exposure duration at
20,000 //g/m3 only.
Whole body 20,000 95% <1.98 urn (UDS) 20 h/day, 10 days J Clearance of P. haemolytica,
persistent up to 10 days PE.
Reference
Jakab (1992)
Jakab (1993)
Baskerville
et al. (1988)
Hahon et al.
(1985)
Grose et al.
(1985)
Gilmour et al.
(1989a)
Gilmour et al.
(1989a)
-------
TABLE 11-24 (cont'd). EFFECTS OF PARTICIPATE MATTER ON MICROBIAL INFECTIVITY
Species, Gender, Particle
Strain, Age, or Exposure Mass Characteristics
Particle Body Weight Technique Concentration
Og/m3) size (>m); ag
TiO2 Mouse, Harlan- Whole body 20,000 95% <1.98 //m
Olac, 8 weeks (UDS)
Key to abbreviations :
i : decrease
PE: post-exposure
Exposure Duration Observed Effect
20 h/day, 7 days i Response to bacterial
antigens of
mediastinal lymph node
lymphocytes from mice
inoculated with P. haemolytica
after exposure.
Reference
Gilmour et al.
(1989b)
-------
specific cytotoxic lymphocytes. However, repeated exposure to 10,000 //g/m3 carbon black did
not alter any of these antimicrobial defense systems.
Particles of low intrinsic toxicity may impair mechanisms involved in the clearance of
bacteria, perhaps increasing their persistence and resulting in increased infectivity. To examine
this possibility, a study was aimed at determining whether animals (guinea pigs) in which
phagocytic activity was impaired by exposure to a high concentration (23,000 //g/m3) of an
"inert" dust (TiO2) were more susceptible to bacterial infection, in this case due to Legionella
pneumophila (Baskerville et al., 1988). While those AMs having heavy burdens of TiO2
particles did not phagocytize the bacteria, there was no increase in infectivity in particle-exposed
compared to air-exposed control animals; this was suggested to be due to the recruitment of
monocytes into the lungs of the TiO2-exposed animals, and these cells were able to phagocytize
the bacteria.
The studies presented in Table 11-24 indicate that particles inhaled even at high
concentrations did not reduce resistance to microbial infections. However, some changes were
noted in an instillation study. Hatch et al. (1985) examined various particles administered by
intratracheal instillation for their ability to alter infectivity in mice subsequently exposed to a
bacterium (Streptococcus sp). The specific particle types and their sizes (VMD) were as
follows: conventional coal combustion fly ash from various sources (0.5 //m); various samples
of fluidized bed combustion coal fly ash (0.4 to 1.3 //m); various samples of oil combustion fly
ash (0.8-1.3//m); volcanic ash (1.4 and 2.3//m); latex (0.5 and 5 //m); and urban air particles
(0.4 //m) from Dusseldorf, Germany, Washington, DC, and St. Louis, MO. The instillation dose
was 100 //g particles/mouse. An increase in infectivity was found with all oil fly ash samples,
some of the combustion and fluidized bed coal fly ash samples, ambient air particles from
Dusseldorf and Washington, latex, and also from carbon and ferric oxide particles of unstated
size. Exposure to volcanic ash, St. Louis ambient particles, and other coal fly ash samples did
not have an effect. It was postulated that the activity of the fly ash reflected either the speculated
presence of metals or the ability of the ash to alter the pH of airway fluid. In a corollary to the
above study, rabbit AMs were incubated for 20 h with the various particles and cell viability
assessed. Viability was reduced by all oil fly ash samples, coal fly ash, ambient particles from
all three sites,
11-157
-------
volcanic ash and latex. These results did not totally correlate with the response following
in vivo exposures.
To examine effects of particles on nonimmunological antiviral defense, Hahon et al.
(1983) exposed monolayers of mammalian cells (rhesus monkey kidney cell line) to coal
combustion fly ash (2.5 //m) at 500 to 5,000 //g/10 ml medium and assessed effects on
interferon. Induction of interferon due to infection with influenza and parainfluenza virus was
reduced when the cells were pretreated with the fly ash. This was suggested to be due to either
the matrix itself, or to some surface component which was not extractable with either polar or
nonpolar solvents.
One study examined the effect of two larger particles on infectivity. Grose et al. (1985)
instilled (42 //g/animal) mice (CD-I, F, 4 to 8 weeks) with two sizes of volcanic ash from Mt.
St. Helens, namely coarse mode (12.1 //m MMAD, og=2.3) and fine mode (2.2 //m MMAD,
og=1.9), followed by challenge with bacteria (Streptococcus sp.) immediately or 24 h
postexposure. No particle size related difference was noted in susceptibility to bacterial
infection, with both sizes producing a similar increase in infection following bacterial challenge
at 24 h, but not immediately, after pollutant exposure. However, inhalation exposure to 9,400
3 volcanic ash (0.65 //m) for 2 h produced no change in infectivity (Table 1 1-24).
11.8.5.3 Iniiminologic Defense
The few studies on effects of inhaled particles on respiratory tract immune function are
shown in Table 1 1-25. Particles may affect some aspects of immune defense and not others.
For example, fly ash did not produce any change in the cellular immune response, namely
delayed hypersensitivity, but did depress the ability of macrophages to enhance T-cell
mitogenesis (Zarkower et al., 1982).
11.8.6 Systemic Effects
A few studies have examined systemic effects of inhaled particles. One assessed the ability
of particles to affect systemic immune responses (Eskew et al., 1982). Mice (F, BALB/C) were
continuously exposed for various times to coal combustion fly ash (32% by wt <2.1 //m), and
the antigenic response of spleen cells to protein derivatives after
11-158
-------
TABLE 11-25. EFFECTS OF PARTICIPATE MATTER ON RESPIRATORY TRACT IMMUNE FUNCTION
Species, Gender,
Strain, Age, or Exposure
Particle Body Weight Technique
Fly ash Rat, M/F, F-344, Whole body
(fluidized bed 12 weeks
coal
combustion)
Fly ash Rat, M/F, Whole body
(pulverized F-344, 12 weeks
coal
combustion)
Fly ash (coal) Mouse, F BALB/C; Whole body
C57BL 6-8 weeks
Key to abbreviations :
AM: macrophage
PE: post-exposure
IL = interleukin
T : increase
i : decrease
Mass
Concentration
C"g/m3)
36,000
37,000
760
(fine particle
fraction, <2. 1
//m)
2,200
(fine particle
fraction, <2. 1
//m)
Particle Characteristics
Exposure Duration Observed Effect
Size (,um); ag
3.6 (MMAD); 2.0 7 h/day, 5 days/week, No effect on humoral immune
4 weeks function.
2.7 (MMAD); 2. 1 7 h/day, 5 days/week, i Antibody response at 48 weeks
4 weeks PE.
32% < 2. 1 /*im 28 days (continuous) i Ability of AMs to stimulate
(by wt) PHA-induced T-lymphocyte
mitogenesis.
160 days (continuous) No change in ability of animals
sensitized with BCG during
exposure to respond to purified
protein derivative challenge
(delayed hypersensitivity
cellular immune response).
Reference
Bice et al.
(1987)
Bice et al.
(1987)
Zarkower et al.
(1982)
-------
sensitization with BCG (delayed hypersensitivity reaction) was examined, as was the mitogenic
response of spleen cells to concanavalin A or lipopolysaccharide (LPS). Exposure for 1 to
8 weeks to 1,150 //g/m3 reduced the mitogenic response of spleen cells after 3 weeks of
exposure, but not after 5 or 8 weeks and only for concanavalin A. Exposure for 5 mo to 2,220
Mg/m3 increased thymidine incorporation into spleen cells from BCG-sensitized mice. Finally,
exposure for 5 weeks to 871 //g/m3 reduced the number of antibody plaque forming cells in the
spleen and the hemagglutinin titer. These results suggest that fly ash has little effect on the
cellular immune response, but depresses the humoral response. The implications of the increase
in thymidine incorporation into the spleen of BCG-sensitized mice was not clear, but may
indicate an increase in resistance to infection.
In another study of systemic immunity, Mentnech et al. (1984) exposed rats (F344, M,
whole body) to 2,000 //g/m3 coal dust (40% <7//m) for 7 h/day, 5 days/week for 12 or 24 mo.
The number of antibody-producing cells in the spleen 4 days after immunization with sheep red
blood cells was used as a test of effects on humoral immunity, while the proliferative response of
splenic T-lymphocytes to the mitogens concanavalin A and phytohemagglutin was used to assess
cellular immunity. No changes were found.
11.8.7 Toxicological Interactions of Other Particulate Matter
Mixtures
11.8.7.1 Laboratory Animal Toxicology Studies of Particulate Matter Mixtures
Toxicological interactions with PM may be antagonistic, additive, or synergistic
(Mauderly, 1993). The presence and nature of any interaction seems to depend upon the
concentration of pollutants in the mixture, the exposure duration, and the endpoint being
examined, and it is not possible to predict a priori from the presence of certain pollutants
whether there will be any interaction.
Mechanisms responsible for the various forms of interaction are generally not known. The
greatest hazard in terms of potential health effects from pollutant interaction is the possibility of
synergism, especially if effects occur at all with mixtures which do not occur at all when the
individual constituents are inhaled. Various broad mechanisms may underly synergism. One is
physical, the result of adsorption or absorption of one material on a particle and subsequent
transport to more sensitive sites, or sites where this material would not normally deposit in toxic
amounts. This may explain the interaction found in studies of
11-160
-------
mixtures of carbon black and formaldehyde, or carbon black and acrolein (Jakab, 1992, 1993),
especially since formaldehye has been shown to be absorbed onto particles (Rothenberg et al.,
1989).
Somewhat related to this hypothesis is the possibility of reactions on particle surfaces,
forming some secondary products which may be more lexicologically active than the primary
material and which is then carried to some sensitive site. This may explain the results of the
Jakab and Hemenway (1993) study, wherein mice were exposed to carbon black either prior to
or after exposure to O3, and then to both materials simultaneously. Simultaneous exposure
produced evidence of interaction, while exposure to carbon black either before or after O3 did
not produce responses which were different from that due to exposure to O3 alone. The authors'
suggested that this was due to a reaction of O3 on the surface of the carbon black particles in the
presence of adsorbed water, producing surface bound, highly lexicologically active reactive
oxygen species. Production of these species would not occur when the exposures were
sequential.
Another mechanism may involve a pollutant-induced change in the local
microenvironment of the lung, enhancing the effects of the co-inhalant. Thus, the observed
synergism in rats between O3 and acidic sulfates was suggested to be due to a shift in the local
microenvironmental pH of the lung following deposition of acid, enhancing the effects of O3 by
producing a change in the reactivity or residence time of reactants, such as radicals, involved in
O3-induced tissue injury (Last et al., 1984). This hypothesis was examined in a series of studies
(Last et al., 1983, 1984, 1986; Last and Cross, 1978; Warren and Last, 1987; Warren et al.,
1986) in which rats were exposed to various sulfur oxide aerosols [H2SO4, (NH4)2SO4, Na2SO4]
with and without oxidant gases (O3 or NO2), and various biochemical endpoints examined.
Acidic sulfate aerosols alone did not produce any response at concentrations that caused a
response in conjunction with O3 or NO2. Further evidence that the synergism was due to FT was
the finding that neither Na2SO4 nor NaCl was synergistic with O3 (Last et al., 1986). But if this
was the only explanation for acid/O3 interaction, then the effects of ozone should be consistently
enhanced by the presence of acid in an exposure atmosphere regardless of endpoint examined.
However, in the study of Schlesinger et al. (1992b), in which rabbits were exposed for 3 h to
combinations of 0.1, 0.3, and 0.6 ppm O3 with 50, 75, and 125 //g/m3 H2SO4 (0.3 //m),
antagonism was noted
11-161
-------
when evaluating stimulated production of superoxide anion by AMs harvested by lavage
immediately after exposure to 0.1 or 0.3 ppm ozone in combination with 75 or 125 //g/m3
H2SO4, and also for AM phagocytic activity at all of the ozone/acid combinations; there was no
change in cell viability compared to air control.
The database for binary mixtures containing PM other than acid sulfates is quite sparse.
But as with acidic sulfates, interaction depends upon pollutant combinations, exposure regimen
and biological endpoints (see Table 11-26). Some interaction was noted following exposure of
mice to mixtures of 9,400 //g/m3 volcanic ash and 2.5 ppm SO2 (Grose et al., 1985), in that
synergism was suggested in terms of immune cell activity and numbers but no interaction was
found with overall bacterial infectivity. On the other hand, exposure of mice to various
concentrations of carbon black and formaldehyde (HCHO) produced no evidence of interaction
in terms of bacterial infectivity but possible synergism in terms of macrophage phagocytic
activity (Jakab, 1992).
The infectivity study of Jakab (1993), in which mice were exposed to acrolein and carbon
black (Table 11-26), is of interest because, as mentioned earlier, the microbial agents were
selected on the basis of the defense mechanisms they elicited. The results indicated that while
particle or acrolein exposure alone did not alter infectivity from any of the microbes, exposure to
the mixture did, and also suggested differential effects on different aspects of antimicrobial
defense. For example, the increase in intracellular killing of P. mirabilis was ascribed to the
increase in PMN levels after bacterial challenge. The reduced effectiveness for L.
monocytogenes and influenza virus were somewhat more persistent, which led the authors to
suggest that the particle/gas mixture had a greater impact upon acquired immune defenses than
on innate defense mediated by AMs and PMNs, this being the major defense against S. aureus
and P. mirabilis.
Another complex mixture examined was a combination of gaseous sulfur (IV), particulate
sulfur (IV) and paniculate sulfur (VI). A series of studies involved exposures (whole body) of
Beagle dogs (M, 34 mo old) for 22.5 h/day, 7 days/week for up to 290 days to such an
atmosphere, in which respirable sulfur IV (0.6 //m MMAD, og=2) was maintained at a
concentration of 300 Mg/m3 (Heyder et al., 1992; Maier et al., 1992; Kreyling et al., 1992;
Schulz et al., 1992; Takenaka et al., 1992). Various biological endpoints were examined, and
responses included reductions in nonspecific defense
11-162
-------
TABLE 11-26. TOXICOLOGIC INTERACTIONS TO MIXTURES CONTAINING NON-ACID AEROSOL PARTICLES
Co-pollutant
Chemical //g/m3 ppm
S02 2,500 —
SO2 2,500 —
S02 2,500 —
SO2 2,500 —
HCHO 1,000; 2.4-
3
HCHO — 4.1-
5
SO2 2,500 —
HCHO — 2.4-
3
Particle
Chemical ,ug/rn3 (//m) . AP^U1"
Exposure Regime Conditions
Volcanic 9,400 2h Whole body
ash (0.65 //m,
MMAD,
ag=1.8)
Volcanic 9,400 2 h Whole body
ash (0.65 //m,
MMAD,
ag=1.8)
Volcanic 9,400 2h Whole body
ash (0.65 //m,
MMAD,
ag=1.8)
Volcanic 9,400 2 h/day, 5 days Whole body
ash (0.65 fj.m,
MMAD,
ag=1.8)
C black 1,000; 4h Nose-only
2,400-6,80
0
(2.45 //m,
MMAD,
ag=2.54)
C black 4,800- 4h Nose-only
13,200
Volcanic 9,400 2 h Whole body
ash (0.65 fj.m,
MMAD,
ag=1.8)
C black 2,400-6,80 4h Nose-only
0
(2.45 f^m,
MMAD,
ag=2.54)
Species, Gender
Strain, Age or
Body Weight
Mouse, F,
CD-I,
4-8 weeks
Rat, M,
Sprague-Dawley,
60-70 days
Rat, M,
Sprague-Dawley,
60-70 days
Rat, M,
Sprague-Dawley,
60-70 days
Mouse, F,
Swiss, 20-23 g
Mouse, F,
Swiss, 20-23 g
Rat, M,
Sprague-Dawley,
60-70 days
Mouse, F,
Swiss, 20-23 g
Endpoints
Infectivity to Group C
Streptococcus or virus
given 0 or 24 h after
exposure
Lavaged cell nos. at 0 or
24hPE
AM phagocytosis at
0 or 24 h PE
Splenic lymphocyte
response to mitogen
(phytohemogglutinin)
Infectivity of S. aureus
administered prior to
pollutant; differential
counts in lavage
Infectivity of S. aureus
administered prior to
pollutant; differential
counts in lavage
Tracheal ciliary beat
frequency at 0, 24, 72 h
PE
Infectivity of S. aureus
administered prior to
pollutant; differential
counts in lavage
Response to
Mixture
No change in
susceptibility
to infection
T PMN;
T lymphocytes;
I AM (no change
in total cell
no.)
I phagocytic
activity
Decrease
None
None
Decrease
None
Interaction
None
Possible at 0 h:
effect greater
than either
pollutant
alone; similar to
SO2 alone at 24 h
Possible at 0 hr:
effect greater
than either
pollutant alone;
at 24 h: similar
to SO2 alone
Possible
synergism:
no effect
with either
pollutant alone
None
None
None: same as
ash alone
None
Reference
Grose et al.
(1985)
Grose et al.
(1985)
Grose et al.
(1985)
Grose et al.
(1985)
Jakab
(1992)
Jakab
(1992)
Grose et al.
(1985)
Jakab
(1992)
-------
TABLE 11-26 (cont'd). TOXICOLOGIC INTERACTIONS TO MIXTURES
CONTAINING NON-ACID AEROSOL PARTICLES
Co-pollutant
Chemical //g/m3 ppm
HCHO — 1
HCHO — 4.1-5
HCHO — 1.8-2.8
5
HCHO — 5
Acrolein — 2.5
Particle
Chemical //g/m3 (//m) Exposure
Exposure Regime Conditions
C black 1,000; and 4h Nose-only
2,400-6,800
(2.45//mMMAD,
ag = 2.54)
C black 4,800-13,200 4h Nose-only
(2.45 Aim,
MMAD,
ag=2.54)
C black 4,700-6,100; 4h/day, 4 days Nose-only
10,000
C black 10,000 4h/day, 4 days Nose-only
C black 10,000 4h/day, 4 days Nose-only
(2.4 //m,
MMAD'
a=2.75)
Species, Gender
Strain, Age or
Body Weight Endpoints
Mouse, F, Infectivity of
Swiss, 20-23 g S. aureus
administered prior
to
pollutant;
differential
counts in lavage
Mouse, F, Infectivity of
Swiss, 20-23 g S. aureus
administered prior
to
pollutant;
differential
counts in lavage
Mouse, F, Infectivity of
Swiss, 20-23 g S. aureus
administered 1 day
after last
pollutant
exposure;
differential
counts in lavage
Mouse, F, Fc-receptor
Swiss, mediated
20-23 g M0 phagocytosis up
to 40 days PE
Mouse, F, Infectivity to
Swiss, 20-23 g S. aureus,
P. mirabilis,
L. monocytogenes;
influenza A virus
administered 1 day
PE
Response to
Mixture
None
None
None
i Phagocytic
activity from
day 25 PE, return
to normal by day 40
PE
i Elimination of
virus; i killing of
L. monocytogenes;
i killing of
S. aureus;
T killing of
P. mirabilis
T PMN count
4 h after
P. mirabilis
challenge;
No change total
cell no. by lavage
after S. aureus
Interaction
None
None
None
Possible
synergism: no
3-day effect of
C black or HCHO
alone
Possible
synergism: no
effect of either
alone
Possible: no
effect of C black
Possible:
greater than
either alone
None
Reference
Jakab (1992)
Jakab (1992)
Jakab (1992)
Jakab (1992)
Jakab (1993)
-------
TABLE 11-26 (cont'd). TOXICOLOGIC INTERACTIONS TO MIXTURES
CONTAINING NON-ACID AEROSOL PARTICLES
Co-pollutant
Chemical //g/m3 ppm
S02 2,700 —
Particle
Chemical /^g/m3 (//m) Exposure
Regime
Volcanic 9,400 2 h/day, 5 days
ash (0.65,
MMAD,
ag=1.78)
Species,
Gender
Exposure Strain, Age or Endpoints
Conditions Body Weight
Whole body Rat, Pulmonary
Sprague-Dawley mechanics
(40 days)
Response to
Mixture Interaction
Reduced tidal None: effect due
volume and peak to SO2
expiratory flow;
no effect on
breathing
frequency
Reference
Raub et al.
(1985)
-------
capabilities of AMs such as phagocytosis and production of reactive oxygen species; increases in
protein and p-N-acetylglucosaminidase in lavage fluid; increased rate of clearance of test
particles from lungs to blood (suggesting a change in the permeability of the epithelium); minor
changes in pulmonary function; and some histopathological effects, such as hyperplasia of
respiratory epithelium of the posterior nasal passages and a slight (but not statistically
significant) decrease in the volume density of alveolar septa. The exact role played by specific
components of this mixture could not be determined because responses to individual components
were not examined.
11.8.7.2 Human Studies of Particulate Matter Mixtures Other Than Acid Aerosols
Few studies have examined the effects of particles other than acid aerosols, despite the fact
that ambient particulate matter consists of a mixture of soluble and insoluble material of varying
chemical composition. Human safety considerations limit experimental exposures to particles
considered to be essentially inert and non-carcinogenic. As reviewed in the 1982 Criteria
Document (U.S. Environmental Protection Agency, 1982), Andersen et al. (1979) examined
effects on healthy subjects of exposure to Xerox toner at concentrations ranging from 2,000 to
25,000 //g/m3. These concentrations are not relevant to outdoor environmental exposures.
Nevertheless, the studies were remarkable for the virtual absence of symptomatic or lung
functional responses.
Utell et al. (1980) exposed healthy young subjects with acute influenza to a NaNO3 aerosol
(0.5 //m) or NaCl (control), and observed significant reductions in specific airway conductance
in response to the NaNO3 aerosol, but not to NaCl aerosol, for up to 1 week following the acute
illness. These studies suggested that individuals with acute viral illness may experience
bronchoconstriction from particulate nitrate pollutants that do not have effects on healthy
subjects. However, the concentration of particles in these experiments was ~7,000 //g/m3, more
than 100 times greater than peak ambient concentrations.
Three more recent studies have attempted to examine effects of exposure to carbon black
particles, either alone or in combination with other pollutants (see Table 11-27). First, Kulle et
al. (1986) exposed 20 healthy nonsmokers (10 males and 10 females) to air, 0.99 ppm SO2, 517
Mg/m3 activated carbon aerosol (MMAD =1.5 //m, GSD = 1.5), and SO2 + activated carbon for
four hours in an environmental chamber. Two 15-minute
11-166
-------
TABLE 11-27. CONTROLLED HUMAN EXPOSURE STUDIES OF
PARTICULATE MATTER MIXTURES OTHER THAN ACID AEROSOLS
Ref.
Green et
al. (1989)
Kulle et
al. (1986)
Yang and
Yang
(1994)
Subjects
24 healthy
18to35yrs
20 healthy
20 to 35 yrs
30 healthy
25 asthmatic
23 to 48 yrs
MMAD2 GSD3 Temp RH
Exposures1 (/^m) (/^m) Duration Exercise (°C) (%)
Air; activated 1.4 1.8 2h 15 of each 22 65
carbon 510 //g/m3; 30 min.,
HCHO 3.01 ppm; 57 L/min
carbon 510 //g/m3
+ HCHO 3.01 ppm
Air; activated 1.5 1.5 4h 15 minx 2, 35 22 60
carbon 517 //g/m3; L/min
SO2 0.99 ppm;
carbon 517 //g/m3
+ SO2 0.99 ppm.
Mouthpiece: 30 min At rest
Bagged polluted
air,
TSP = 202 //g/m3
Symptoms
Increased
cough with
carbon +
HCHO
No symptoms
related to
carbon
exposure
Lung Function
No direct effects
of carbon.
Additive effects
of carbon + HCHO on
FVC, FEV3, peak
flow; decrements
less than 5%.
No direct or
additive effects
of carbon exposure
Healthy subjects:
no change
Asthmatics: iFEVj
=7%
Other Effects
Increased
airway
responsiveness
in asthmatics
reported; no
allowance for
change in
airway caliber
Comments
No control
exposure
-------
exercise periods (VE = 35 L/min) were included in the exposure. The exposure days were
separated by one week and were bracketed by control air exposures on the day prior to and the
day following the experimental exposure. Measurements included respiratory symptoms,
spirometry, lung volumes, and airway responsiveness to methacholine. The carbon aerosol
exposure resulted in no significant effects on symptoms or lung function, and exposure to carbon
+ SO2 did not enhance the very small effects on lung function seen with SO2 alone. Results of
methacholine challenge testing were not provided.
Second, a separate report from the same laboratory (Green et al., 1989) examined potential
interactions between formaldehyde (HCHO) and carbon exposure. Twenty-four healthy
nonsmokers without airway hyperresponsiveness were exposed for two hours to air, 3 ppm
HCHO, 510 //g/m3 activated carbon aerosol (MMAD = 1.4 //m, GSD = 1.8) and HCHO +
carbon. Exposures incorporated exercise (VE = 57 L/min) for 15 of each 30 minutes. The
exposures were separated by one week. Measurements included symptoms, spirometry, lung
volumes, and serial measurements of peak flow. There were no significant effects on symptoms
or decrements in lung function with exposure to carbon alone. The combination of carbon and
HCHO increased cough at 20 and 80 minutes of exposure when compared to either pollutant
alone. There were also small (less than 5%) but statistically significant decrements in FVC,
FEV3, and peak flow with carbon + HCHO, compared with either pollutant alone. The authors
speculated that the enhancement of cough with carbon + HCHO resulted from increased delivery
of HCHO adsorbed to carbon.
Finally, the studies by Anderson et al. (1992), summarized previously, were designed to
test the hypothesis that inert particles in ambient air may become coated with acid, thereby
delivering increased concentrations of acid sulfates to "sensitive" areas of the respiratory tract.
Carbon black particles (MMAD ~ 1 //m, GSD ~2 //m) were coated with H2SO4 using fuming
H2SO4. Electron microscopy findings suggested successful coating of the particles. Fifteen
healthy and 15 asthmatic subjects were exposed for 1 h to acid-coated carbon, with a total
suspended particulate concentration of 358 //g/m3 for asthmatic subjects and 505 //g/m3 for
healthy subjects. On separate occasions, subjects were also exposed to carbon black alone
(-200 //g/m3, estimated as the difference between total suspended particulate and non-carbon
particulate concentrations), H2SO4 alone (~ 100 //g/m3), and air.
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No adverse effects of particle exposure on lung function or airway responsiveness were observed
for either study group.
Clinical studies of single particulate pollutants or simple mixtures may not be
representative of effects that occur in response to complex ambient mixtures. In an attempt to
examine effects of an ambient air pollution atmosphere under controlled laboratory conditions,
Yang and Yang (1994) exposed 25 asthmatic and 30 healthy subjects to polluted air collected in
a motor vehicle tunnel in Taiwan. This compressed air sample contained 202 //g/m3 particles as
well as 0.488 ppm NO2, 0.112 ppm SO2, and 3.4 ppm carbon monoxide (CO). The chemical and
size characteristics of the particles were not provided. Mouthpiece exposure to polluted air was
performed at rest for 30 min, and lung function and methacholine responsiveness were assessed
after exposure. Small but significant decrements in FEVj and FVC were observed in asthmatic,
but not healthy subjects when compared with baseline measurements. However, no control
exposure to air was performed, which seriously limits interpretation of these results. The small
decrements in lung function could have resulted from exposure conditions other than the
pollutants, such as humidity or temperature of the inhaled air, which were not specified.
Thus, few studies have examined effects of particles other than acid aerosols on lung
function, although available data suggest inert particles in the respirable range have little or no
acute effects at levels well above ambient concentrations. Other than the studies of Rudell et al.
on diesel exhaust discussed in Section 11.5.1, no studies have examined effects on mucociliary
clearance, epithelial inflammation, or host defense functions of the distal respiratory tract in
humans.
11.9 PHYSICOCHEMICAL AND HOST FACTORS INFLUENCING PARTICULA
MATTER TOXICITY
11.9.1 Physicochemical Factors Affecting Particulate Matter
Toxicity
The physicochemical factors modulating biological responses to PM are not always clear.
However, the available toxicological database does allow for some speculation as to factors
which may influence biological responses to diverse types of PM. For example, the toxic
potency of inorganic particles may be related to certain physicochemical characteristics.
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While the bulk chemical makeup of a particle would clearly influence its toxicity, responses may
also be driven by chemical species adsorbed onto the particle surface, even for those particles
considered to have low intrinsic toxicity. Furthermore, certain physical properties of particles,
such as size or surface area, and of aerosols, such as number concentration, may be factors in
determining reponses to PM. This section provides an overview of current hypotheses
concerning particle characteristics which may relate to toxicity.
Particle Acidity: It should be clear from discussions in Section 11.2 that the deposition of
acidic particles in the respiratory tract can result in various biological effects. The bulk of the
toxicologic database on acidic PM involves sulfate particles, primarily H2SO4 and the available
evidence indicates that the observed responses to these are likely due to the FT, rather than to the
SO4. Thus, effects observed for this pollutant likely apply to any acidic particle having a
similar deposition pattern in the respiratory tract, although the specific chemical composition of
different acids may be a factor mediating the quantitative response (Fine et al., 1987a). In terms
of FT, the irritant potency of an acid aerosol may be related more to the total available FT
concentration (i.e., titratable acidity in lung fluids following deposition) rather than to the free
FT concentration as measured by pH (Fine et al., 1987b). In any case, the response to acidic
particles appears to be due to a direct irritant action and/or the subsequent release of humoral
mediators.
Acidic particles exert their action throughout the respiratory tract, with the response and
location of effect dependent upon particle size and mass concentration. They have been shown
to alter bronchial responsiveness, mucociliary transport, clearance from the pulmonary region,
regulation of internal cellular pH, production of cytokines and reactive oxygen species,
pulmonary mechanical function, and airway morphology.
Particles do not have to be pure acid droplets to elicit health effects. The acid may be
associated with another particle type. For example, in the study of Chen et al. (1990), guinea
pigs were exposed to two different fly ashes, one derived from a low sulfur coal and one from a
high sulfur coal (Table 11-19). Levels of acidic sulfates associated with the fly ash were found
to be proportional to the coal sulfur content, and greater effects on pulmonary functional
endpoints were noted for the high sulfur fly ash than for the low sulfur fly ash.
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Particle Surface Coatings: The presence of surface coatings may make certain particles
more toxic than expected based solely upon particle core composition. This was noted in studies
of acid-coated metal oxides (Section 11.2.3) and is discussed in greater detail in Section 11.3.8.
Certain surface metals may be especially important in this regard, and because trace metal
species vary geographically, this may account to some extent for particles in different areas
having different toxic potentials.
Particle Size: Studies which have examined PM-induced mortality seem to suggest some
inherent potential toxicity of inhaled ultrafine particles (Section 11.4), and other endpoints
appear to show this as well. This is especially important when considering particles which may
have low inherent toxicity at one size, yet greater potency at another. However, the mechanism
which underlies a size-related difference in toxicity is not known at this time.
To compare toxic potency of particles of different sizes, intratracheal instillation has often
been used. This technique allows the delivery of equivalent doses of different materials and
avoids differences in deposition which would occur if particles of different sizes were inhaled.
While this approach may highlight inherent similarities and differences in responses to particles
of various sizes, in reality, there would be greater deposition of singlet ultrafine particles (in the
size range used in the toxicology studies described) in the lungs, especially within the alveolar
region, than for the larger fine or coarse mode particles.
The release of proinflammatory mediators may be involved in lung disease, and their levels
may be increased with exposure to ultrafine particles. For example, Driscoll and Maurer (1991)
compared effects of instilled fine (0.3 //m) or ultrafine (0.02 //m) TiO2, in rat (F344) lungs.
Concentrations were 10,000 //g particles/kg BW. Lavage was performed up to 28 days
post-exposure, and pathology was assessed at this 28-day time point. While both size modes
produced an increase in the number of AMs and PMNs in lavage, the increase was greater and
more persistent with the ultrafine particles. The release of another monokine, tumor necrosis
factor (TNF), by AMs was stimulated with both sizes, but again the response was greater and
more persistent for the ultrafmes. A similar response was noted for fibronectin produced by
AMs. Finally, fine particle exposure resulted in a minimally increased prominence of
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particle-laden macrophages associated with alveolar ducts, while ultrafine particle exposures
produced somewhat of a greater prominence of macrophages, some necrosis of macrophages and
slight interstitial inflammation associated with the alveolar duct region. In addition, increased
collagen occurred only with ultrafine particle exposure.
Oberdorster et al. (1992) instilled rats with 500 //g TiO2 in either fine (0.25 //m) or
ultrafine (0.02 //m) sizes, and performed lavage 24 h later. Various indicators of acute
inflammation were altered with the ultrafine particles; this included an increase in the number of
total cells recovered, a decrease in percentage of AMs and increase in percentage of PMNs, and
an increase in protein. On the other hand, instillation of the fine particles did not cause
statistically significant effects. Thus, the ultrafine particles had greater pulmonary inflammatory
potency than did the larger size particles of this material. The investigators attributed enhanced
toxicity to greater interaction of the ultrafine particles, with their large surface area, with
alveolar and interstitial macrophages, resulting in enhanced release of inflammatory mediators.
They suggested that ultrafine particles of materials of low in vivo solubility appear to enter the
interstitium more readily than do larger size particles of the same material, which accounted for
the increased contact with macrophages in this compartment of the lung. In support of these
results, Driscoll and Maurer (1991) noted that the pulmonary retention of ultrafine TiO2 particles
instilled into rat lungs was greater than for the same mass of fine mode TiO2 particles.
Not all ultrafine particles will enter the interstitium to the same extent, and this may
influence toxicity. For example, both TiO2 (-20 nm) and carbon black (-20 nm) elicit an
inflammatory response, yet much less of the latter appears to enter the interstitium after exposure
(Oberdorster et al., 1992). Since different particles may induce chemotactic factors to different
extents, it is possible that less chemotoxis with TiO2 results in less contact with and phagocytosis
by macrophages, a longer residence time at the area of initial deposition, and a resultant greater
translocation into the interstitium. Similarly, Brown et al. (1992; Table 11-23) noted following
inhalation exposure of rats to TiO2 or coal mine dust that the former did not affect macrophage
chemotaxis, while the latter reduced it; the coal dust also produced a greater inflammatory
response than did the TiO2. This is consistent with less interaction of coal dust with AMs and
greater movement into the interstitium.
The above studies appear to support the concept of some inherent toxicity of ultrafine
particles compared to larger ones. Both particle size and the resultant surface area of a unit
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mass of particles likely influences toxic potential. Surface area is important because, as noted
above, adsorption of certain chemical species on particles may enhance their toxicity, and this
could be an even greater factor for ultrafine particles with their larger surface area per unit mass.
Other studies have compared effects following exposures to larger than ultrafine particle
sizes, and the results ranged from none detectable to some particle size-related differences.
Raub et al. (1985) instilled into rats coarse mode (12.2 //m) and fine mode (2.2 //m) volcanic ash
at two dose levels, 50,000 or 300 //g particles/animal. The coarse mode produced a change in
end expiratory volume, but no changes in other pulmonary function endpoints (i.e., frequency,
VT, peak inspiratory and expiratory flows, VC, RV, TLC). When lungs were examined 6 mo
after instillation, animals exposed to the low dose of either size fraction showed no changes in
lung weight or hydroxyproline content compared to control, while those exposed to the high
concentration of coarse mode ash showed increased lung weight. In terms of histopathology,
both size modes produced some focal alveolitis. Thus, there were essentially no differences in
responses between the two size modes, especially at the low exposure dose. In a similar study,
Grose et al. (1985) instilled mice with 42 //g/animal of volcanic ash in the same two size
fractions as above, coarse and fine, 24 h prior to challenge with bacteria (Streptococcus sp.). A
small, but similar, increase in susceptibility to infection was noted with both particle sizes.
Shanbhag et al. (1994) exposed a mouse macrophage cell line (P388D1) to particles of two
different composition (TiO2 or latex) at comparable sizes, 0.15 and 0.45 //m for the former, and
0.11 and 0.49 for the latter. They also used pure titanium at 1.76 //m for comparison to latex at
1.61 //m. In order to examine effects of particle surface area, the cells were exposed to a
constant surface area of particles, expressed in terms of mm2 per unit number of cells. This was
obtained based upon particle size and density and, therefore, the weight percentage was greater
for larger particles than for smaller ones for the same surface area. Furthermore, because of
particle density differences, the weight percentage for similarly sized particles of different
materials to obtain the same surface area also differed. The authors noted that at a constant total
particle surface area to cell ratio, the 0.15 and 0.45 //m particles were likely to be less
inflammatory than were the 1.76 //m particles, in that the smaller particles produced lower
elicited levels of interleukin-1 and less cell
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proliferation. These results indicate that the larger particles had greater toxicity than the smaller
ones in this experimental system. Thus, the exact relationship between particle size and toxicity
is not resolved. It may differ for different size modes and may also depend on the specific
experimental system used.
Particle Number Concentration: The number concentration of particles within an aerosol
will increase as the size of the constituent particles decrease. Thus, for a given mass
concentration of a material, there would be greater particle numbers in an ultrafine aerosol than
in a fine aerosol. As previously discussed (Section 11.2.3), studies have shown various
biological responses, such as reductions in lung volumes and diffusion capacity, alterations in
biochemical markers, and changes in lung tissue morphology, in guinea pigs following exposure
to ultrafine ZnO having a surface layer of H2SO4. These responses were much greater than were
found following exposure to H2SO4 aerosols in pure droplet form yet having a similar mass
concentration.
A possible contribution to this differential response is that the number concentration of
particles in the exposure atmospheres were different, resulting in different numbers of particles
deposited at target sites. At an equal total sulfate mass concentration, H2SO4 existed on many
more particles when layered on the ZnO carrier particles than when dissolved into aqueous
droplets (i.e., pure acid aerosol); this was because the particle size distribution of the former
aerosol was smaller than that of the latter. Therefore, it is possible that the greater the number of
particles containing H2SO4, the greater will be the number of cells affected after these particles
deposit in the lungs, and the more severe will be the overall biological response. While
differences in particle size distributions between the coated and pure acid particles may have
influenced the results to some extent, a recent study (Chen et al., 1995) confirmed that the
number of particles in the exposure atmosphere, not just total mass concentration, is an
important factor in biological responses following acidic sulfate particle inhalation when
aerosols having the same size distribution were compared.
11.9.2 Host Factors Affecting Participate Matter Toxicity
Not only do the differences in particle chemistry and morphology influence responses to
inhalation of particulate matter, but also various factors related to host susceptibility. One
obvious example is the differences associated with species susceptibility as well as differences
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in dosimetry related to animal mass and lung structure and geometry. Host health status,
specifically the presence of pulmonary inflammation or bacterial or viral infection or nutritional
status also may markedly alter responses to PM. The presence of chronic pulmonary disease is
also a factor in both animals and humans. Age of the animal, especially very young or very old,
can influence susceptibility.
Host Health Status: Epidemiological studies suggest there may be subsegments of the
population that are especially susceptible to effects from inhaled particles (see Chapter 12). One
particular group may be those having lungs compromised by respiratory disease. However, most
toxicology studies have used healthy adult animals, and there are very few data to allow
examination of the effects of different disease states upon the biological response to PM.
A number of studies have examined the effects of lung disease on deposition and/or clearance of
inhaled aerosols, and these are discussed in Chapter 10. Alterations in deposition sites and
clearance rates/pathways due to concurrent disease may impact upon dose delivered from
inhaled particles, and thus influence ultimate toxicity.
Some work has been performed with sulfate and nitrate aerosols using models of
compromised hosts. Rats and guinea pigs with elastase-induced emphysema were examined to
assess whether repeated exposures (6 h/day, 5 days/week, 20 days) to (NH4)2SO4 (1,000 //g/m3,
0.4 (j,m MMAD) or NH4NO3 (1,000 //g/m3, 0.6 //m MMAD) would alter pulmonary function
compared to saline-treated controls (Loscutoff et al., 1985). Similarly, dogs having lungs
impaired by exposure to NO2 were treated with H2SO4 (889 //g/m3, 0.5 //m, 21 h/day, 620 days)
(Lewis et al., 1973). Results of both of these studies indicated that the specific induced disease
state did not enhance the effect of acidic sulfate aerosols in altering pulmonary function; in
some cases, there were actually fewer functional changes in the diseased lungs than in the
unimpaired animals. It is possible, however, that other types of disease states could result in
enhanced response to inhaled acidic aerosols; as mentioned, asthma is a likely one, but there are
no data to evaluate whether effects are enhanced in animal models of human asthma.
Few studies have examined effects of other particles in health compromised host models.
Mauderly et al. (1990) exposed young rats having elastase-induced emphysema to whole diesel
exhaust (3,500 //g soot/m3) for 24 mo (7 h/day, 5 days/week). Various endpoints were examined
after exposure, including pulmonary function (e.g., respiratory
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pattern, lung compliance, DLco), biochemical components of BAL (e.g., enzymes, protein,
collagen), and histopathology and morphometry. There was no evidence that the diseased lungs
were more susceptible to the diesel exhaust than were normal lungs. In fact, in some cases, there
seemed to be a reduced effect of the diesel exhaust in the emphysematous lungs. But this could
be due to a reduced lung burden in the diseased lungs, resulting from differences in deposition
and/or clearance compared to normal lungs.
Rats having elastase-induced emphysema were exposed to 9,400 //g/m3 (0.65 //m) Mt. St.
Helens volcanic ash for 2 h/day for 5 days (Raub et al., 1985; Table 11-19), with and without
2,700 //g/m3 SO2. Effects on pulmonary mechanics were similar to those noted in normal
animals exposed to the same atmospheres.
Raabe et al. (1994) exposed rats with elastase-induced emphysema to two particle
atmospheres, a California-type aerosol and a London-type aerosol. The former consisted of 1.1
to 1.5 //m (MMAD; og = 1.7 to 2.4) particles of graphitic carbon, natural clay, NH4HSO4,
(NH4)2SO4, NH4NO3, and trace amounts of metals (PbSO4, VOSO4, MnSO4, and NiSO4). The
latter consisted of 0.8 to 0.9 //m particles (og = 1.7 to 1.8) of NH4HSO4, (NH4)2SO4, coal fly ash,
and lamp black carbon. The elastase treated rats showed increased lung DNA and RNA, a
general marker for repair of cell damage. Exposure for 3 days (23 h/day) to the London aerosol
produced a further increase not seen in exposed normal rats. A 30-day exposure to the
California aerosol enhanced small airway lesions in the elastase-treated animals. These
preliminary results suggest that the California aerosol and the London aerosol both caused
significant responses in animals with elastase-induced emphysema, but clarification of these
responses must await a more comprehensive treatment of these data.
Thus, the available toxicological database indicates only limited evidence of enhanced
susceptibility to PM of "compromised" hosts. However, these studies were restricted to
emphysema models and it is not known whether other simulated pulmonary diseases would
enhance susceptibility to PM in laboratory animals.
Species Differences: The effects of asbestos-free talc at 6,000 or 18,000 //g/m3 (2.7-3.2
//m) were studied in male and female F344 rats and B6C3F1 mice exposed 6 hours/day 5
days/week for 24 mo (National Toxicology Program, 1993). In rats and mice exposed to the
higher concentration for 24 mo the specific talc lung burdens (mg/g lung)
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were nearly identical. Rats had a greater increase than mice in lung weight as well as greater
elevations of neutrophils, enzymes and protein in BALF. The histopathology of rats, including
accumulations of talc-filled macrophages, inflammation, epithelial hyperplasia and squamous
metaplasia, and focal fibrosis was identical to that described for other dusts. The histopathology
differed in that the epithelial hyperplasia and metaplasia, and focal fibrosis observed in rats was
absent in mice. These findings illustrate that differences between the responses of rats and mice
persist across a wide range of different types of inhaled dusts.
There are a few reports comparing the responses of other species to chronic dust inhalation
(Mauderly, 1994a). Alarie et al. (1973, 1975) studied the response of cynomolgus monkeys and
guinea pigs chronically exposed to coal combustion fly ash in combination with H2SO4. In the
study (Alarie et al., 1973), monkeys and guinea pigs were exposed 23+ hours/day 7 days/week
for either 52 weeks (guinea pigs) or 78 weeks (monkeys) to approximately 500 //g ash/m3
(MMAD «2.6//m) in combination with 0.1 to 5.0 ppm sulfur dioxide. Although particles
accumulated in the lungs in both species (including bronchial and alveolar deposition) and
caused slight inflammation, type II cell proliferation was observed in guinea pigs but not
monkeys. In the second study (Alarie et al., 1975), guinea pigs and monkeys were exposed 23+
hours/day 7 days/week for 18 mo to approximately 500 //g ash/m3 (MMAD -4-5//m) in
combination with 100 or 1,000 //g sulfuric acid mist/m3. The effects attributed to fly ash were
similar to those described in the first study. Comparison between guinea pigs and monkeys in
this series of studies is complicated because the concentrations of co-pollutants and fly ash were
not always equivalent and the deposition pattern of the 2.6-5.3 //m fly ash particles is
undoubtedly different in monkeys than in guinea pigs.
Comparison of Human and Laboratory Animal Response: There are limited data
allowing direct comparisons of responses of humans and laboratory animals to ambient
particulate matter constituents. Chronic occupational exposures to high concentrations of
mineral dusts cause pneumoconioses in human lungs, consisting primarily of fibrotic responses
with many features similar to those observed in animals. Exposure to silica and dusts with high
quartz content causes granulomatous lesions in both human and animal lungs. Merchant et al.
(1986) provided a comprehensive review of the pulmonary responses to coal dust in coal
workers. The focal collections of dust (macules) and the progressive focal
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fibrosis have many 1989). features similar to the responses of rats (Martin et al., 1977; Lewis
et al., Although little information is available on the effects of coal dust in other animals,
Heppleston (1954) reported dust accumulations and responses in the lungs of rabbits and ponies
that were similar to the responses seen in humans. Emphysema, a common feature of
pneumoconiosis even in nonsmoking coal workers (Green et al., 1992) is not a prevalent finding
in other species and is usually found only in association with large scars in rats (Mauderly et al.,
1988). Other features including the epithelial hyperplasia of rodents and squamous metaplasia
of rats are not seen in coal workers' pneumoconiosis.
There are obviously similarities and differences between animals and humans and among
animals in their responses to chronic dust inhalation. It is not yet clear which, if any, animal
species is a good model for predicting noncancer pulmonary responses of humans to chronic
dust exposure. The most common bioassay species, rats and mice, clearly differ in their
responses, but it is not clear which best represents humans.
Age of Animals: There is limited information on the effects of inhaled particles as a
function of changes occurring with age in laboratory animals Mauderly (1989). Mauderly et al.
(1987c) exposed rats for 6 mo to diluted, whole diesel exhaust containing 3500 //g/m3 (MMAD
«0.25//m) soot particles. Effects in rats conceived and born in the exposure chambers and
exposed up to 6 mo of age were compared to those of rats exposed between 6 and 12 mo of age.
Soot accumulated in similar amounts in the lungs of both the young and adult groups, but soot-
laden macrophages formed more intraalveolar aggregates in the adults. Tissue responses
adjacent to the aggregated macrophages were greater in the adults than in the young rats. Lung
weight and the cellularity of pulmonary lymph nodes increased and particle clearance was
delayed in the older group, but not in the younger group. Exposure throughout the period of
lung development did not cause differences between the lung morphology or respiratory function
of exposed and sham-exposed young rats after they reached adulthood (6 mo of age). These
results indicate that rats with developing lungs may be less susceptible than adults to the effects
of diesel exhaust.
Mauderly (1989) indicates that there is insufficient information on the influence of age on
the effects of inhaled particles. It is therefore inappropriate to draw conclusions regarding age-
related susceptibility at the present time.
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11.10 POTENTIAL PATHOPHYSIOLOGICAL MECHANISMS FOR THE EFFECT
CONCENTRATIONS OF PARTICULATE POLLUTION
11.10.1 Physiological Mechanisms
The pathophysiologic mechanisms by which low level ambient particle concentrations may
increase morbidity and mortality are not clear. Potential mechanisms might be posited through
examining hypotheses considering the pathological mechanisms by which inhaled particles
might alter normal physiological, immunological, and biochemical processes in the lung.
In the healthy person, air is drawn into the respiratory tract through a branching airway
network. Although the large airways of the tracheobronchial region continuously branch into
narrower airways the increase in total cross sectional area makes resistance to airflow low. The
inspired air ultimately enters the alveolar or gas exchange region of the lung where the area
available for the diffusion of gases is large and the distances for diffusion across the respiratory
membrane are minimal.
In the healthy person, the pulmonary circulation is a low resistance system requiring only
about 1/5 of the pressure required to pump blood through the high resistance systemic circuit.
Any changes in the pulmonary vasculature that increase the resistance to blood flow through the
lungs will impose an additional work load on the right ventricle which, if severe enough in a
compromised individual, could result in right heart failure.
In considering the potential mechanisms by which increases in ambient PM might affect
morbidity and mortality, it is important to consider the physiological characteristics of the
population most affected. In general, the population most susceptible to elevations in ambient
PM is older (see chapter 12) and may have preexisting respiratory disease. As the healthy older
population (Folkow and Svanborg, 1993; Dice, 1993; Lakatta, 1993) ages, cardiorespiratory
function, including lung volumes, FEVl3 and cardiac output reserve (Kenney, 1989) decline.
Many of the decrements in physiological function associated with the aging process also may be
associated with pathological changes caused by disease or other environmental stressors
impacting a person over their lifespan.
There is little information on the extent to which an elderly population might be more
susceptible to the effects of particulate pollution in the ambient environment (Cooper et al.,
1991). The elderly might be expected to be more susceptible to parti culate pollution because
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of numerous changes in the body's protective mechanisms. While young and healthy animals
might be more adaptable, older animals and those with chronic illness have a more limited
ability to adapt to environmental stressors.
11.10.2 Physiological-Particle Interaction
Particles inhaled into the respiratory tract deposit at a variety of sites depending on their
size, shape, and the pulmonary ventilation characteristics of the organism. Once deposited, the
particles may be cleared by from the lung, sequestered in the lymphatics, metabolized or
otherwise transformed by mechanisms described in Chapter 10.
If the particle mass inhaled into the lung is so excessive that the normal pulmonary
clearance mechanisms are overwhelmed, or if repeated insult from toxic particles has somehow
reduced the ability of normal mechanisms to clear particles, then particles, their degradation
products, and metabolic products associated with the clearance process may accumulate and
present an additional stress to the organism. This stress may affect the entire organism and not
just the respiratory tract. While a young healthy organism may tolerate or adapt to the
consequences of an excessive particle load, an older organism or one with chronic respiratory
disease or one rendered more susceptible by other stressors (dietary, crowding, thermal, etc.)
may become sicker or may die. Thus, it is possible that death of an organism may be the result
of an accumulation of lifetime stressors (or, the response to these stressors) that is exacerbated
by the addition of an incremental particle load on the system.
Cardiorespiratory system function may be compromised and become less efficient in older
people or as a result of disease. Inhaled particles could, conceivably, further compromise the
functional status in such individuals. Because a small increase in environmental particle
concentrations would not be lethal to most subjects, the terminal event(s) must presumably result
from a triggering or exacerbating of a lethal failing of a critical function, such as ventilation, gas
exchange, pulmonary circulation, lung fluid balance, or cardiovascular function in subjects
already approaching the limits of tolerance due to preexisting conditions.
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11.10.3 Pathophysiologic Mechanisms
It is conceivable that inhaled particles, their reaction products, or the physiological
response to deposited particles may further impair ventilation in the chronically ill individual.
Inhaled particles may induce further bronchoconstriction and increase resistance to air flow by
activating airways smooth muscle, as in asthmatics. Inhaled particles may also influence various
airway secretions that could add to and thicken the mucous blanket leading to mucus plugging or
decreased mucociliary clearance. Increases in airways resistance would increase the work of
breathing and, in turn, the increased effort would require a greater proportion of the inhaled
oxygen for the respiratory muscles and increase the potential risk of respiratory failure.
Inhaled particles or their pathophysiological reaction products could also act at the alveolar
capillary membrane. At this site, inhaled particles could decrease the diffusing capacity of the
lungs by increasing diffusion distances across the respiratory membrane (by increasing the
thickness of the respiratory membrane) and causing abnormal ventilation-perfusion ratios in
parts of the lung by altering ventilation distribution.
Inhaled particles, especially ultrafine particles could also act at the level of the pulmonary
vasculature. Inhaled particles or the pathophysiological reaction to inhaled particles could elicit
changes in pulmonary vascular resistance that could further alter ventilation perfusion
abnormalities in people with respiratory disease. Particles could also cause alteration of the
distribution of ventilation by causing changes in airway resistance. Diseases such as emphysema
destroy alveolar walls as well as the pulmonary capillaries they contain. This causes a
progressive increases in pulmonary vascular resistance and elevates pulmonary blood pressure.
The generalized systemic hypoxia could result in further pulmonary hypertension and interstitial
edema that would impose an increased workload on the heart.
Potential mechanisms which might be evoked to explain the phenomenon of particle
related mortality have been considered by Utell and Frampton (1995). Mechanisms which could
conceivably account for the particle-related mortality include: (1) "premature" death, that is the
hastening of death for individuals already near death (i.e., hastening of an already certain death
by hours or days); (2) increased susceptibility to infectious disease; and (3) exacerbation of
chronic underlying cardiac or pulmonary disease.
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Particulate pollution could contribute to daily mortality rates by affecting those at greatest
risk of dying; those individuals for whom death is already imminent. Elevated concentrations of
particulate matter, which might be only a minor irritant to healthy people, could be the "last
straw" that tips over the precariously balanced physiology of a dying patient. In developing this
possibility, Utell and Frampton (1995) have compared the effect associated with particulate
matter with that associated with temperature deviations. Time-series analyses have shown
relationships between temperature changes, regardless of the direction change, and increasing
mortality of a magnitude similar to that described for air pollution (Kunst et al., 1993). While
there are a few deaths that can be attributed to hyperthermia and hypothermia, the excess
mortality due to moderate temperature deviations is associated primarily with the chronically
and terminally ill. It is this excess mortality that is likely caused by further stress on over-
burdened compensatory mechanisms.
However, if particulate air pollution simply represents a physiological stress similar to
thermal stress, and the excess mortality is occurring among individuals who would have died
within days or weeks, one would expect to see a "harvesting effect". That is, following the
increase in mortality associated with an increase in particulate pollution mortality should fall
below baseline, because some of those at risk will have already died. Although Kunst et al.
(1993) have reported such an effect with temperature-related mortality, it has not been evident in
epidemiology studies of ambient particulate exposure. It is possible however, that epidemiologic
studies may not be sensitive enough to detect a harvesting effect because the overall changes in
mortality are small. However, even in the 1952 London Fog episode, there was no decline in
mortality following the peak in excess deaths; instead, increased mortality appeared to remain
somewhat elevated in the days after pollution levels had returned to baseline (Logan, 1953).
Other studies suggest that the effect of particles on mortality cannot be explained solely by
death-bed effects. In longitudinal studies, Dockery et al. (1993) and Pope et al. (1995) found a
strong association between particulate air pollution and mortality in U.S. cities after adjusting for
cigarette smoking and other risk factors. Moreover, mortality and respiratory illness in the Utah
Valley have been linked with particulate exposure associated with a steel mill. These findings
indicate an effect on annual mortality rates that cannot be explained by hastening death for
individuals already near death.
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Particle exposure could increase susceptibility to infection with bacteria or respiratory
viruses, leading to an increased incidence of, and death from, pneumonia in susceptible members
of the population. Potential mechanisms could include effects on mucociliary clearance,
alveolar macrophage function, adherence of microorganisms to epithelia, and other specific or
nonspecific effects on the immune response. However, pneumonia rarely results in death within
24 h of onset; serious infections of the lower respiratory tract generally take days or weeks to
evolve. This would potentially contribute to morbidity effects from PM that are lagged by
several days or weeks (Chapter 12). If pollutant exposure increased susceptibility to infectious
disease, it should be possible to detect differences in the incidence of such diseases in
communities with low vs. high particulate concentrations. It might be expected that emergency
room visits and hospitalizations for pneumonia caused by the relevant agent should be
measurably higher on days with elevated ambient particle concentrations. Examples of this are
evident in data from several cities (see Chapter 12). Laboratory animal studies indicate that PM
exposure can impair host defenses. Exposure to acidic aerosols has been linked with alterations
in mucociliary clearance and macrophage function. However, bacterial infectivity studies with
exposure to non-acidic aerosols and other particulate species have not been shown
experimentally to cause increased infection.
What chronic disease processes are most likely to be affected by inhaled particulate
matter? To explain the daily mortality statistics, there must be common conditions that
contribute significantly to overall mortality from respiratory causes. The most likely candidates
are the chronic airways diseases, particularly chronic obstructive pulmonary disease (COPD).
COPD is the fourth leading cause of death in the US, and is the most common cause of non-
malignant respiratory deaths, accounting for more than 84,000 deaths in 1989 (U.S. Bureau of
the Census, 1992). This group of diseases encompasses both emphysema and chronic bronchitis,
however, information on death certificates does not allow differentiation between these
diagnoses. The pathophysiology includes chronic inflammation of the distal airways as well as
destruction of the lung parenchyma. There is loss of supportive elastic tissue, so that the airways
collapse more easily during expiration, obstructing flow. Processes that enhance airway
inflammation or edema, increase smooth muscle contraction in the conducting airways, or slow
mucociliary clearance could adversely affect gas exchange and host defense. Moreover, the
uneven ventilation-perfusion matching
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characteristics of this disease, with dependence on fewer functioning airways and alveoli for gas
exchange, means inhaled particles may be directed to the few functioning lung units in higher
concentration than in normal lungs (Bates, 1992)
Asthma is a common chronic respiratory disease that may be exacerbated by air pollution.
Mortality from asthma (about 3% of all respiratory deaths) has been rising in the last 15 years
(Gergen and Weiss, 1992), and air pollution has been implicated as a potential causative factor.
Atmospheric particle levels have been linked with increased hospital admissions for asthma,
worsening of symptoms, decrements in lung function, and increased medication use. The
incidence of asthma is higher among children and young adults. Although asthma deaths are
rare below the age of 35, asthma is the leading cause of non-infectious respiratory mortality
below the age of 55. Nevertheless, approximately 70% of all asthma-related deaths occur after
age 55 (National Center for Health Statistics, 1993). Death due to asthma may contribute to
overall PM-related mortality but it is doubtful that asthma is a leading cause.
Particulate pollutants have been associated with increases in cardiovascular mortality both
in the major air pollution episodes and in the more recent time-series analysis. Bates (1992) has
postulated three ways in which pollutants could affect cardiovascular mortality statistics. These
include: acute airways disease misdiagnosed as pulmonary edema; increased lung permeability,
leading to pulmonary edema in people with underlying heart disease and increased left atrial
pressure; and, acute bronchiolitis or pneumonia induced by air pollutants precipitating
congestive heart failure in those with pre-existing heart disease. Moreover, the pathophysiology
of many lung diseases is closely intertwined with cardiac function. Many individuals with
COPD also have cardiovascular disease caused by: smoking; aging; or pulmonary hypertension
accompanying COPD. Terminal events in patients with end-stage COPD are often cardiac, and
may therefore be misclassified as cardiovascular deaths. Hypoxemia associated with abnormal
gas exchange can precipitate cardiac arrhythmias and sudden death.
In comparison to healthy people, individuals with respiratory disease have greater
deposition of inhaled aerosols in the fine (PM25) mode. The deposition of particles in the lungs
of a COPD patient may be as much as three-fold greater than in a healthy adult. Thus, the
potential for greater target tissue dose in susceptible patients is present. The lungs of
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individuals with chronic lung diseases, such as asthma, bronchitis, emphysema, etc. are often in
a chronic state of inflammation. In addition to the fact that particles can induce an inflammatory
response in the respiratory region, the influence of particles on generation of proinflammatory
cytokines may be enhanced by the prior existence of inflammation. Phagocytosis by alveolar
macrophages is down-regulated both by inflammation and the increased levels of ingested
particles. Therefore, people with lung disease not only have greater particle deposition, but the
conditions that exist in their lungs prior to exposure are conducive to amplification of the effects
of particles and depression of their clearance.
11.11 SUMMARY AND CONCLUSIONS
11.11.1 Acid Aerosols
The results of human studies indicate that healthy subjects do not experience decrements in
lung function following single exposures to H2SO4 at levels up to 2,000 //g/m3 for 1 h, even with
exercise and use of acidic gargles to minimize neutralization by oral ammonia. Mild lower
respiratory symptoms (cough, irritation, dyspnea) occur at exposure concentrations in the mg/m3
range. Acid aerosols alter mucociliary clearance in healthy subjects, with effects dependent on
exposure concentration and the region of the lung being studied.
Asthmatic subjects appear to be more sensitive than healthy subjects to the effects of acid
aerosols on lung function, but the effective concentration differs widely among studies.
Adolescent asthmatics may be more sensitive than adults, and may experience small decrements
in lung function in response to H2SO4 at exposure levels only slightly above peak ambient levels.
Although the reasons for the inconsistency among studies remain largely unclear, subject
selection and acid neutralization by NH3 may be important factors. Even in studies reporting an
overall absence of effects on lung function, occasional asthmatic subjects appear to demonstrate
clinically important effects. Two studies from different laboratories have suggested that
responsiveness to acid aerosols may correlate with degree of baseline airway
hyperresponsiveness. There is a need to identify determinants of responsiveness to H2SO4
exposure in asthmatic subjects. In very limited studies, elderly and individuals with
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chronic obstructive pulmonary disease do not appear to be particularly susceptible to the effects
of acid aerosols on lung function.
Two recent studies have examined the effects of exposure to both H2SO4 and ozone on
lung function in healthy and asthmatic subjects. In contrast with previous studies, both studies
found evidence that 100 //g/m3 H2SO4 may potentiate the response to ozone.
Human studies of particles other than acid aerosols provide insufficient data to draw
conclusions regarding health effects. However, available data suggest that inhalation of inert
particles in the respirable range, including three studies of carbon particles, have little or no
effect on symptoms or lung function in healthy subjects at levels above peak ambient
concentrations.
The bulk of the laboratory animal toxicologic data base on PM involves sulfur oxide
particles, primarily H2SO4, and the available evidence indicates that the observed responses to
these are likely due to H+ rather than to SO4 .
Acidic sulfates exert their action throughout the respiratory tract, with the response and
location of effect dependent upon particle size and mass and number concentration. At very
high concentrations that are not environmentally realistic, mortality will occur following acute
exposure, due primarily to laryngospasm or bronchoconstriction; larger particles are more
effective in this regard than are smaller ones. Extensive pulmonary damage, including edema,
hemorrhage, epithelial desquamation, and atelectasis can also cause mortality, but even in the
most sensitive animal species, concentrations causing mortality are quite high, at least a
thousand-fold greater than current ambient levels.
Both acute and chronic exposure to H2SO4 at levels well below lethal ones will produce
functional changes in the respiratory tract. The pathological significance of some of these are
greater than for others. Acute exposure will alter pulmonary function, largely due to
bronchoconstrictive action. However, attempts to produce changes in airway resistance in
healthy animals at levels below 1,000 //g/m3 have been largely unsuccessful, except when the
guinea pig has been used. The lowest effective level of H2SO4 producing a small transient
change in airway resistance in the guinea pig is 100 //g/m3 (1-h exposure). In general, the
smaller size droplets (submicron) were more effective in altering pulmonary function, especially
at low concentrations. Very low concentrations (< 100 //g/m3) of acid-coated ultrafine particles
are associated with lung function and diffusion decrements, as well as
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airway hyperresponsiveness. Yet even in the guinea pig, there are inconsistencies in the type of
response exhibited towards acid aerosols. Chronic exposure to H2SO4 is also associated with
alterations in pulmonary function (e.g., changes in the distribution of ventilation and in
respiratory rate in monkeys). But, in these cases, the effective concentrations are >500 //g/m3.
Hyperresponsive airways have been induced with repeated exposures to 250 //g/m3 H2SO4 in
rabbits, and have been suggested to occur following single exposures at 75 //g/m3.
Severe morphologic alterations in the respiratory tract will occur at high (» 1,000 //g/m3)
acid levels. At low (> 100 //g/m3) levels and with chronic exposure, the main response seems to
be hypertrophy and/or hyperplasia of mucus secretory cells in the epithelium; these alterations
may extend to the small bronchi and bronchioles, where secretory cells are normally rare or
absent.
The lungs have an array of defense mechanisms to detoxify and physically remove inhaled
material, and available evidence indicates that certain of these defenses may be altered by
exposure to H2SO4 levels <1,000 //g/m3. Defenses such as resistance to bacterial infection may
be altered even by acute exposure to concentrations of H2SO4 around 1,000 //g/m3. However,
the bronchial mucociliary clearance system is very sensitive to inhaled acids; fairly low levels of
H2SO4 produce alterations in mucociliary transport rates in healthy animals. The lowest level
shown to have such an effect, 100 //g/m3 with repeated exposures, is well below that which
results in other physiological changes in most experimental animals. Furthermore, exposures to
somewhat higher levels that also alter clearance have been associated with various morphometric
changes in the bronchial tree indicative of mucus hypersecretion.
Limited data also suggest that exposure to acid aerosols may affect the functioning of
AMs. The lowest level examined in this regard to date is 500 //g/m3 H2SO4. Alveolar region
particle clearance is affected by repeated H2SO4 exposures to as low as 125 //g/m3 (Schlesinger
etal., 1992a).
The assessment of the toxicology of acid aerosols requires some examination of potential
interactions with other air pollutants. Such interactions may be antagonistic, additive, or
synergistic. Evidence for interactive effects may depend upon the sequence of exposure as well
as on the endpoint examined. Low levels of H2SO4 (100 //g/m3) have been
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shown to react synergistically with O3 in simultaneous exposures using biochemical endpoints
(Warren and Last, 1987). In this case, the H2SO4 enhanced the damage due to the O3. The most
realistic exposures are to multicomponent atmospheres, but the results of these are often
difficult to assess due to chemical interactions of components and a resultant lack of precise
control over the composition of the exposure environment.
11.11.2 Metals
Data from occupational studies and laboratory animal studies indicate that acute exposures
to high levels or chronic exposures to low levels (albeit high compared to ambient levels) of
metal particulate can have an effect on the respiratory tract. However, it is doubtful that the
metals at concentrations present in the ambient atmosphere (1 to 14 //g/m3) could have a
significant acute effect in healthy individuals.
The toxicity data on inhalation exposures to arsenic are limited in humans and laboratory
animals. Acute data are largely lacking for this route of exposure. In humans, inhalation
exposure data, primarily limited to long-term occupational exposure of smelter workers, indicate
that chronic exposure leads to lung cancer. In laboratory animals, intratracheal administration of
arsenic compounds in the lungs have not indicated tumor development in rats and mice, but
insufficient exposure duration may have been used in these studies. However, respiratory tract
tumors occurred in hamsters exposed to intratracheal doses of arsenic when a charcoal carbon
carrier dust was used to increase arsenic retention in the lungs.
Chronic inhalation exposure to arsenic has also been shown to cause both skin changes
(such as hyperpigmentation and hyperkeratosis) and peripheral nerve damage in workers;
however, the available inhalation studies in laboratory animals have not evaluated these
endpoints. The laboratory animal inhalation data are limited and thus do not allow a thorough
comparison of the toxicological and carcinogenic potential of arsenic with the human data.
Species differences in dosimetry, absorption, clearance, and elimination of arsenic (i.e., strong
affinity to rat hemoglobin) exist between rats and other animal species, including humans, which
complicate comparisons of quantitative toxicity.
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The kidney is clearly the primary target of chronic inhalation exposure to cadmium in the
human; toxicity is dependent on cumulative exposure. Tubular proteinuria occurs after kidney
levels of cadmium accumulate to a certain level, estimated at 200 jig/g kidney weight.
The respiratory system is also a target of inhaled cadmium in humans and animals. Intense
irritation occurs following high-level exposure in humans and more mild effects on pulmonary
function (dyspnea, decreased forced vital capacity) occur following chronic low-level exposure.
These effects and their mechanism have been investigated to a greater degree in laboratory
animals, although spirometry has not been conducted in animals. The observed effects
(increased lung weight, inhibition of macrophages and edema) are consistent with the irritation
observed in human studies. In humans, symptoms reverse with cessation or lessening of
exposure; laboratory animal studies have reported no progression or slight reversal with
continued exposure.
Rat studies show that several forms of cadmium (cadmium chloride, cadmium oxide dust
or fume, cadmium sulfide, or cadmium sulfate) can cause lung cancer. There is some evidence
that lung cancer has been observed in humans following high occupational exposure, although
confounding exposures were present. Because animal cancer studies only examined the lung,
they did not address the suggestive evidence of cadmium-related prostate cancer found in several
occupational studies.
Although both human and laboratory animal data are limited, both data bases support the
respiratory system as a major target of inhaled copper and copper compounds, including copper
sulfate and copper chloride. In humans, the data are limited primarily to subjective reporting of
respiratory symptoms following acute and chronic inhalation exposures to copper fumes or dust
supported with radiographic evidence of pulmonary involvement. The human data do not
include pulmonary function tests or histopathology of the respiratory tract. In laboratory animal
studies, supporting evidence exists for the involvement of the respiratory system after copper
inhalation exposure. Respiratory tract abnormalities in mice repeatedly exposed to copper
sulfate aerosols, and decreased tracheal cilia beating frequency in singly exposed hamsters have
been reported. Respiratory effects, although minor, have also been observed in rabbits; these
included a slight increase in amount of lamellated cytoplasmic inclusions in alveolar
macrophages, and a slight increase in volume density of alveolar Type 2 cells. Although
respiratory effects were observed in both human and
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laboratory animal studies, direct comparisons are not possible since different parameters were
examined in the different species for which limited data exist. Immunological effects have been
investigated in only one animal study. In the one study addressing the issue, immunotoxic
effects observed included: decreased survival time after simultaneous S. zooepidemicus aerosol
challenge, and decreased bactericidal activity after simultaneous K. pneumonia aerosol exposure.
There is limited information on iron toxicity, with human data primarily from chronic
occupational exposures. Both human and laboratory animal data, mostly qualitative information,
do demonstrate that the respiratory system is the primary target organ for iron oxides following
inhalation exposure. However, the differences in toxicity (if any) for different particle sizes or
valence states of iron have not been well studied. In humans, respiratory effects (coughing,
siderosis) have been reported in workers chronically exposed to iron dust. In laboratory animals,
hyperplasia and alveolar fibrosis have been reported after inhalation or intratracheal
administration of iron oxide. The lack of information on the histopathological changes in the
lungs of exposed workers precludes direct comparison with animal data. Brief exposure to
relatively high concentrations of large iron oxide particles in humans have not been associated
with adverse responses. The available human and laboratory animal studies are limited and do
not provide conclusive evidence regarding the respiratory carcinogenicity of iron oxide.
Human and laboratory animal data confirm the respiratory tract as the primary target of
inhaled vanadium compounds. Laboratory animal data suggest that vanadium compounds
damage alveolar macrophages, and that toxicity is related to compound solubility and valence.
Because of the difficulty in obtaining clinical signs of respiratory distress in laboratory animals,
most reported animal data consisted of histological findings (increased leukocytes and lung
weights, perivascular edema, alveolar proteinosis, and capillary congestion). Human
occupational case studies and epidemiological studies generally emphasize clinical symptoms of
respiratory distress, including wheezing, chest pain, bronchitis, rhinitis, productive cough, and
fatigue including the possibility of vanadium induced asthma. No human data were found
describing histopathology following oral or inhalation exposure.
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No major differences in the pharmacokinetics of zinc in humans and laboratory animals
were evident. Both human and laboratory animal data demonstrate that the respiratory system is
the primary target organ for zinc following inhalation exposure; the toxic compounds most
studied are zinc chloride and zinc oxide. In humans, the development of metal fume fever,
characterized by respiratory symptoms and pulmonary dysfunction, was observed in workers and
experimental subjects during acute exposures to zinc oxide. An immunological component is
believed to be responsible for these respiratory responses. Quantitative data on chronic
exposures in humans are not available. Inflammation with altered macrophage function,
morphological changes in the lungs, and impaired pulmonary function (decreased compliance,
total lung capacity, decreased diffusing capacity) were observed in guinea pigs. Rats also
showed altered macrophage function in the lungs. At subchronic durations, histopathological
changes in the lungs (increased macrophages) were observed in rats, mice, and guinea pigs
exposed to zinc chloride. It is clear that zinc can produce inflammatory response in both human
and animal species. Alveologenic carcinomas have been observed in mice exposed to zinc
chloride for 20 weeks; however, human studies have shown no evidence of increased tumor
incidences at exposure levels found in occupational settings. Zinc compounds are soluble in
lung fluids and do not appear to accumulate in the respiratory tract.
Studies examining the potential for the transition metals to cause lung injury by the
generation of ROS have been conducted in vitro and in animals by intratracheal instillation.
While these studies are interesting, the results thus far are of limited value.
11.11.3 Ultrafme Particles
There are only limited data available from human studies or laboratory animal studies on
ultrafine aerosols. They are present in the ambient environment as singlet particles but represent
an extremely small portion of the mass. However, ultrafine particles are present in high numbers
and have a high collective surface area. There are in vitro studies that show ultrafine particles
have the capacity to cause injury to cells of the respiratory tract. High levels of ultrafine
particles, as metal or polymer "fume", are associated with toxic respiratory responses in humans
and other mammals. Such exposures are associated with cough, dyspnea, pulmonary edema, and
acute inflammation. Presence of ultrafine particles,
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especially the metals Cd, V, Ti, Fe, in human alveolar macrophages indicates widespread
exposure to ultrafmes as single particles in ambient air. At concentrations less than 50 //g/m3,
freshly generated insoluble ultrafine particles can be severely toxic to the lung. There are also
studies on a number of ultrafine particles (diesel, carbon black, acidic aerosols) where the
particles are not present in the exposure atmosphere as singlet particles. Insufficient information
is available at the present time to determine whether ambient ultrafine particles may play a role
in PM-induced mortality.
11.11.4 Diesel Emissions
Acute toxic effects caused by exposure to diesel exhaust are mainly attributable to the
gaseous components (i.e., mortality from carbon monoxide intoxication and lung injury from
respiratory irritants). When the exhaust is diluted to limit the concentrations of these gases,
acute effects are not seen.
The focus of the long-term (> 1 year) animal inhalation studies of diesel engine emissions
studies has been on the respiratory tract effects in the alveolar region. Effects in the upper
respiratory tract and in other organs were not found consistently in chronic animal exposures.
Several of these studies are derived from research programs on the toxicology of diesel
emissions that consisted of large-scale chronic exposures, which are represented by multiple
published accounts of results from various aspects of the overall research program. The
respiratory system response has been well characterized in terms of histopathology,
biochemistry, cytology, pulmonary function, and respiratory tract clearance. The pathogenic
sequence following the inhalation of diesel exhaust as determined histopathologically and
biochemically begins with the phagocytosis of diesel particles by AMs. These activated
macrophages release chemotactic factors that attract neutrophils and additional AMs. As the
lung burden of diesel particles increases, there is an aggregation of particle-laden AMs in alveoli
adjacent to terminal bronchioles, increases in the number of Type 2 cells lining particle-laden
alveoli, and the presence of particles within alveolar and peribronchial interstitial tissues and
associated lymph nodes. The PMNs and macrophages release mediators of inflammation and
oxygen radicals and particle-laden macrophages are functionally altered resulting in decreased
viability and impaired phagocytosis and clearance of particles. There is a substantial body of
evidence for an impairment of particulate
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clearance from the bronchioalveolar region of rats following exposure to diesel exhaust. The
latter series of events may result in the presence of pulmonary inflammatory, fibrotic, or
emphysematous lesions. The noncancer toxicity of diesel emissions is considered to be due to
the particle rather than the gas phase, since the long-term effects seen with whole diesel are not
found or are found to a much lesser extent in animals exposed to similar dilutions of diesel
exhaust filtered to remove most of the particles. Chronic studies in rodents have demonstrated
pulmonary effects at 200 to 700 //g/m3 (expressed as equivalent continuous exposure to adjust
for protocol differences). A range of no adverse effect levels has been estimated as from 200 to
400 Mg/m3.
Several epidemiologic studies have evaluated the effects of chronic exposure to diesel
exhaust on occupationally exposed workers. None of these studies are useful for a quantitative
evaluation of noncancer toxicity because of inadequate exposure characterization, either because
exposures were not well defined or because the possible confounding effects of concurrent
exposures could not be evaluated.
11.11.5 Silica
Emissions of silica into the environment can arise from natural, industrial, and farming
activities. There are only limited data on ambient air concentrations of amorphous or crystalline
silica, principally because existing measurement methods are not well suited for distinguishing
silica from other particulate matter. Using available data on the quartz fraction of coarse dust
(Davis et al., 1984) and average annual arithmetic mean PM10 measurements for 17 U.S.
metropolitan areas, annual average and high U.S. ambient quartz levels of 3 and 8 //g/m3,
respectively, have been estimated (U.S. Environmental Protection Agency, 1996). Davis et al.
(1984) found that most of the quartz was in the fraction between 2.5 to 15 //m MMAD.
Silica can occur in two chemical forms, amorphous and crystalline. Crystalline forms
include quartz, which is the most prevalent; cristobalite, tridymite, and a few other rare forms.
Freshly fractured crystalline silica is more lexicologically reactive than aged forms of crystalline
silica. Amorphous silica is less well studied but is considered less potent than crystalline silica.
Occupational studies show that chronic exposure to crystalline silica causes inflammation of the
lung which can progress to fibrosis and silicosis, a human fibrotic
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disease, which can lead to early mortality. Some occupational studies also show a concurrent
incidence of lung cancer. The role, if any, of silica-induced lung inflammation, fibrosis, and
silicosis in the development of lung cancer is postulated but not adequately demonstrated.
Crystalline silica interaction with DNA has been shown under in vitro conditions. Chronic
exposure studies in rats also show a similar pattern of lung inflammation, fibrosis, and lung
cancer. The International Agency for Research on Cancer (1987) classified crystalline silica as a
"possible" human carcinogen owing to a sufficient level of evidence in animal studies, but with
inadequate evidence in human studies. The health statistics of the U.S. do not reveal a general
population increase in the incidence of these silica-related disease, although there is an increase
within segments of the occupational work force.
These effective occupational exposures are greater and the particle sizes smaller than those
likely to be experienced by the general public, including susceptible populations. Information
gaps still exist for the exposure-response relationship for levels of exposure within the general
population.
11.11.6 Bioaerosols
Ambient bioaerosols include fungal spores, pollen, bacteria, viruses, endotoxins, and plant
and animal debris. Such biological aerosols can produce three general classes of health effects:
infections, hypersensitivity reactions, and toxicoses. Bioaerosols present in the ambient
environment have the potential to cause disease in humans under certain conditions. However, it
is improbable that bioaerosols, at the concentrations present in the ambient environment, could
account for the observed effects of particulate matter on human mortality and morbidity reported
in PM epidemiological studies. Moreover, bioaerosols generally represent a rather small fraction
of the measured urban ambient PM mass and are typically present even at lower concentrations
during the winter months when notable ambient PM effects have been demonstrated.
Bioaerosols also tend to be in the coarse fraction of PM.
11.11.7 "Other Particulate Matter"
Toxicologic studies of other particulate matter species besides acid aerosols, metals,
ultrafine particles, diesel emissions, silica, and bioaerosols were discussed in this chapter.
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These studies included exposure to fly ash, volcanic ash, coal dust, carbon black, TiO2, and
miscellaneous other particles, either alone or in mixtures.
A number of studies of the effects of "Other PM" examined effects of up to 50,000 //g/m3
of respirable particles with inherently low toxicity on mortality and found no effects. Some mild
pulmonary function effects of 5,000 to 10,000 //g/m3 of similar particles were observed in rats
and guinea pigs. Lung morphology studies revealed focal inflammatory responses, some
epithelial hyperplasia, and fibrotic responses to exposure generally >5,000 //g/m3. Changes in
macrophage clearance after exposure to >10,000 //g/m3 were equivocal (no infectivity effects).
In studies of mixtures of particles and other pollutants, effects were variable depending on the
toxicity of the associated pollutant. In humans, associated particles may increase responses to
formaldehyde but not to acid aerosol. None of the "other" particles mentioned above are present
in ambient air in more than trace quantities. The relevance of any of these studies to ambient
particulate standard setting is extremely limited.
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