-------
of a photochemical smog episode. The preceding does not mean, however, that
3
the acid concentrations cannot reach jin excess of 20 ug/m .
Studies that have measured strong acid aerosol acidity directly have shown
./> _o
that the highest H /SO. ratios will occur at the lowest S04 concentrations
(Pierson et al., 1980b; Keeler, 1987; and Morandi et al., 1983). These suggest
[ ™ 2
that the percentage of acid sulfate species is lower with higher SO^ since the
acid particles have more time to pass over areas with ammonia emissions.
Morandi et al. (1983) examined the local character of the distribution of
acid species for a regional smog episode in 1980 (Table 2-5). It can be seen
that the most acidic portion of this smog episode occurred at the beginning and
that with time the acidity decreased. In a follow-up study at Fairview Lake,
N.J. it was observed by Lioy et al.' (1987) that in the period from July 31
through August 3, 1984 the acid aerosol was composed primarily of apparent
NH.HSO
,.
During the last day of this period, however, the levels of
increased from approximately zero to 4 ug/m for 4 h in the afternoon. These
two types of phenomena must be examined more fully to identify the distribution
of possible situations when acidic species could be present in the atmospheric
environment. Such research would include identifying the physical-chemical
matrices necessary for the accumulation of acidic species (e.g., free radical
concentrations in summertime episodes or plume downwash in nocturnal
inversions). :
TABLE 2-5. ESTIMATED H2S04 (NH4)HS04 AND (NH4)2S04 CONCENTRATIONS BASED
ON TA-FPD AND QUARTZ FILTER MEASUREMENTS AT STERLING FOREST
Date
14 Aug
15 Aug
16 Aug
16 Aug
17 Aug
27 Aug
28 Aug
29 Aug
Time
1980
1980
1980
1980
1980
1980
1980
1980
12:00 -
24:00 -
24:00 -
12:00 -
24:00 -
09:15 -
09:15 -
09:15 -
24:00
12:00
12:00
24:00
12:00
21:15
21:15
16:05
1.2
1.6
0.0
0.0
0.0
5.2
5.4
1.3
H2S04*
±1.0
± 1.0
± 1.3
± 1.3
±1.0
|
NH4H(S04
12t
12
0
0
0
30
19
10
0.4
1.5
1.2
0.1
0
13.4
11.9
1.0
± 0.4
± 1.0
± 1.0
± 1.0
± 3.5
± 3.0
± 0.9
)*
4
11
32
8
-
70
43
8
(NH4)2S04
8.1 ±3.1
9.9 ±2.5
2.6 ±2.2
1.0 ± 1.0
2.9 ±1.0
-
10.5 ±1.5
11,0 ±4.1
*
84
77
68
92
90
—
38
82
tAs percent of total S042.
*umoles of S042 m3xlo"2.
Source: Morandi et al. (1983).
February 1988
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2.3 METEOROLOGY
Much has been written in the scientific literature about the development
of sulfate events (Hidy et al., 1978; Wolff et al., 1984; Samson, 1980;
Dutkiewicz et al., 1983; Lioy et al., 1980; Galvin et al., 1978; Whelpdale,
1978; Rahn and Lowenthal, 1984; Thurston and'Lioy, 1987). However, very few
studies have addressed the conditions conducive to the formation of local or
regional acid sulfate events. The data available on meteorological conditions
for acid events will be described for eight of the studies discussed in this
chapter, but these should not be considered inclusive, in fact, for the cases
reported the meteorological data are very limited. As stated previously, most
acid aerosol studies have been conducted during the summertime. Thus, the
nature of acidic aerosol events that can occur in different types of locales
and during the remaining three seasons must be identified in future chemical
characterization and human exposure studies.
In the Kelly et al. (1985) White Mountain, NY study aerosol acidity was
closely associated with S0~2 levels that resulted from the transport of
pollutant laden air masses from industrial regions (the air flow was from
southerly to westerly directions). The temporal pattern of acid events did not
vary with season, however, a seasonal variation of precursor S0? and NO and
the secondary products S0~2 and HN03 was detected. This variation was
attributed to seasonal variation in the oxidation process. Homogeneous
photochemical oxidation was reduced during the winter months due to decreased
temperatures and reduced insolation. Heterogeneous oxidation by H202 or 0- in
aqueous solution was also reduced due to the low concentration of the oxidants.
In the 1983-1984 Antigonish, Nova Scotia study by Smith-Palmer and
Wentzell (1986), acid events were associated with regional plumes that were
moved north and east by high pressure systems that passed over the center of
the eastern United States and central Canada. No local sources of acid or acid
precursors were noted in the analysis. Warm and hazy weather with air mass
trajectories over water for long distances characterized the acid events. Air
mass trajectories over water minimized the availability of NH3 from sources on
land. Acid aerosol events during the winter were of longer duration but had
lower acid levels than summer events. Winter events had high narrow peaks and
otherwise low near baseline acid levels.
February 1988 2-23 DRAFT—00 NOT QUOTE OR CITE
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Pollution events were associated with the transport of pollutants in
the Washington, D.C. to New York Ciiy corridor in the summer of 1980 study by
Morandi et al. (1983). South to southwesterly wind flows appeared to bring
regional plumes from the industrial regions of the eastern United States. In
the northeast these southwesterly wind flows typically occur during the summer
season. Events were associated with slow-moving high pressure systems that
accumulated secondary acid sulfate particles in the atmosphere. Decreased
visibility due to haze also characterized acid aerosol events.
The Glasgow, II study by Tanner et al. (1979) showed acid events associ-
ated with urban and power plant sources in the St. Louis vicinity. Events
occurred during daylight hours and1 were attributed to homogeneous photo-
chemical^ induced sulfuric acid formation. Conversely, ammonia levels were
higher during the nighttime.
The Lioy et al. (1980) analyses for 1977 found sulfate and acid levels
well correlated at High Point, NJ. High sulfate concentrations were associated
with westerly winds that carried precursor S02 from sources in the Ohio Valley
and western Pennsylvania and or the Washington, D.C. to Boston corridor.
These occurred with southerly to westerly flow on the backside of high pressure
systems that moved slowly across areas of major emissions of SO,,. High ozone
levels have also been recorded under these meteorological conditions. High
acid was detected in the denser portion of the hazy air mass.
From the year-long investigation in St. Louis (1977-1978) by Cobourn
(1979), the summer acid events occurred with haze, stagnation, high tempera-
ture, high humidity, and cloudless skies. Elevated surface levels were due to
long distance transport of hazy air masses associated with maritime tropical
systems. High acid levels during the afternoon hours were attributed to
enhanced photochemical gas phase reactions and vigorous mixing of pollutants in
the atmosphere.
Winter events occurred with slow moving wind trajectories from the north-
east, implicating emissions from the industrial northeastern United States.
Recent work by Ferris and Spengler (1985) implicated local plume emissions with
the occurrence of high acidic sulfate.
In the St. Louis, MO investigation by Huntzicker et al. (1984) in August,
1979, acid events occurred with a high pressure system characterized by light
surface winds from the southwest. In addition, high daytime temperatures and
absolute humidity are indicative of a maritime tropical air mass and could
February 1988 2-24 DRAFT-DO NOT QUOTE OR CITE
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also be deficient of ammonia. Two types of events were distinguished: one
occurring during the afternoon resulting from gas phase oxidation, and the
other early in the evening.
2.4 EMISSION DENSITIES AND DISTRIBUTION
2.4.1 Sulfur and Nitrogen Oxide Emission Densities
In the Eastern half of the United States, sulfur dioxide emissions are
highest in the area within the Ohio Valley from the Mississippi River through
Southwestern PA, see Figure 2-10. This core area is surrounded with rural
and urban centers that have significant S0£ emissions. In contrast, nitrogen
oxide emissions in the east are centered in the metropolitan corridor of New
York, New Jersey and Connecticut and the major urban areas such as Chicago and
Detroit, see Figure 2-11. The distribution of nitrogen oxide is more uniform
throughout the country than is that of sulfur dioxide.
In the western half of the nation, S02 emissions are centered in specific
areas related to large stationary sources such as smelters. The nitrogen
oxides emissions in the west are distributed much more broadly and the actual
emission densities are much lower in specific instances.
2.4.2 Sulfate Distribution
Many studies and monitoring programs have routinely provided data on the
sulfate ion, which is relatively easy to measure and is a major constituent in
the ambient aerosol. Acid sulfate species represent the principal component of
most acid aerosols. Thus while the animal toxicology and human clinical
studies of this document provide data that strongly suggest that the health
effects are related to the hydrogen ion rather than the sulfate ion, sulfate
levels should correlate to some degree with acid aerosol levels.
Unfortunately, presence of high sulfate does not necessarily indicate the
presence of a highly acidic component in the sulfate aerosol. Examination of
the extent to which sulfate can be distributed in the environment does give
some indication of the possible spatial extent of acid sulfate in the worst
possible case (i.e., little neutralization). The most extensive data base on
the regional nature of sulfate in the Eastern U.S. was acquired during the SURE
Project. Figure 2-12 shows the monthly average S0~2 concentrations and the
change over the course of a year of the magnitude and the spatial extent of
February 1988 2-25 DRAFT—DO NOT QUOTE OR CITE
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?\
ft _ 100-500
500-1000
>1000
Figure 2-10. Distribution of SO2 emissions in the SURE area for summer (metric tons/day).
Emissions are based on data representative of 1977.
Source: Mueller and Hidy (1983)..
February 1988
2-26
DRAFT—DO NOT QUOTE OR CITE
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<100
100-500
iill 500-1000
>1000
Figure 2-11. Distribution of NOX emissions in the SURE area for summer (metric tons/day)
Emissions are based on data representative of 1977.
Source: Mueller and Hidy (1983).
February 1988
2-27
DRAFT—DO NOT QUOTE OR CITE
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^£"k
vr^<
OCTOBER. 1978
804, /ig/m3
Figure 2-12. Monthly average distribution of 24-hour HIVOL particulate sulfate concentrations
in the eastern United States.
Source: Mueller and Hidy (1983).
February 1988 2-28
DRAFT—DO NOT 0! OR CITE
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such concentrations. The data also indicate that a significant portion of
the Eastern U.S. experiences average sulfate levels above 8 ug/m3.
The peak sulfate values recorded in SURE were in excess of 25 ug/m3 during
the summer with lower values during the winter. The higher concentrations
shifted to the southeast during the winter. In the Airborne Toxic Elements and
Organic Substances (ATEOS) study conducted at four sites in New Jersey during
1981-1983 mean values of approximately 10 ug/m3 were observed at each site
(Lioy and Daisey, 1986). Sulfate excursions were above 30 ug/m3 during the
summer, and above 20 |jg/m on a few occasions during the winter. The
Particulate Matter - Sulfur Oxides Criteria document (U.S. Environmental
Protection Agency, 1982a) states that on the West Coast the area around Los
Angeles has annual average sulfate values above 8 ug/m3. Hidy (1986) published
data indicating a peak concentration of S0~2 of 24.3 ug/m3 in Los Angeles in
1977.
f\
The regional relationship between SO^ and S02 present at the SURE
monitoring sites was examined using the ratio of sulfate sulfur to total
airborne sulfur (S0~2 and Sty. The results for each season are shown in
Figure 2-13. These findings indicate that the seasonal average of the
S04 /Total S ratio for summer was much higher than ratios for the winter.
During the winter, the ratios were substantially lower in the northern part of
the SURE study area than in the southern and the coastal sections. These
differences were consistent with the expectation of both greater rates of
S02 conversion to S04 and greater losses by dry deposition of S02 during the
summer months and in the south during winter months. During any of the seasons,
the maximum ratios usually occurred within 80 to 200 km of the major source
areas. These findings show that most of the conversion to S0~2 or S0? dry
deposition were associated with mesoscale meteorology even during regional
sulfate events. This latter point suggests that concentrations of the acidic
_o
portion of the S04 aerosol may be enhanced in areas downwind of urban or
stationary source plumes. The work of Gillani (see Section 2.2) was strongly
suggestive of the formation of sulfur aerosol in a variety of plume conditions.
2.5 HISTORIC ACID LEVELS
2.5.1 London Sulfuric Acid Data
A relationship between air pollution and mortality/morbidity was
recognized in England, especially after the severe London fog episode of
February 1988 2-29 DRAFT—DO NOT QUOTE OR CITE
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SUMMER
AUGUST, 1977
Figure 2-13. Geographical distribution ^>f the ratio of sulfate sulfur to total airborne sulfur
for different seasonal periods (in percent).
Source: Mueller and Hidy (1983).
February 1988
2-30
DRAFT—DO NOT QUOTE OR CITE
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December 5-8, 1952. Although suTfuric acid was considered one of the pollut-
ants possibly responsible for the increased mortality and morbidity (United
Kingdom Ministry of Health, 1954), routine air pollution monitoring conducted
by local authorities and other regulatory bodies did not have data for sulfuric
acid. Some inferential information was available to implicate acids, however,
from samples collected in London on five consecutive days in 1934 (Mader
et al.,. 1950). Seven to 9.5 h average sulfuric acid concentrations were
measured that ranged from 0 to 148 ug/m3.
Following the episode, the Air Pollution Research Unit at St. Bartholomew's
Hospital started an elaborate research program on air pollution (Cpmnrins and
Waller, 1967). Their daily measurement of British Smoke and S02 started in
January 1954. The concentrations of some other pollutants, including sulfuric
acid calculated from net aerosol acidity, were also measured during episodes
and, later, on a daily basis. In their ten years of air pollution measurements
(1954-1964), sulfuric acid measurements were reported for episodes starting in
the winter of 1957/1958. The highest daily and highest hourly apparent
sulfuric acid concentrations recorded were 347 pg/m3 and 678 ug/m3, respec-
tively, on days in December 1962. The daily measurement of sulfuric acid was
begun during April 1964 (Figure 2-14). It was noted that the sampling site at
the Medical College was in a commercial area, that the smoke came mainly from
domestic heating sources some distance from the site, and that much of the
sulfur dioxide came from central heating installations in commercial buildings
(Commins and Waller, 1967).
The analytical method for the aerosol acidity measurements was reported in
detail by Commins (1963). The total particulate matter from the sampled air
was collected by filtration, and the filters were immersed in a known excess of
0.01 N sodium tetraborate and titrated back to pH 7 with 0.01 N sulfuric acid.
This procedure allowed the sodium tetraborate to neutralize the acid before it
was neutralized by the insoluble base on the filter (interference). The
interferences by acidic gases, basic gases, and other particulate acids were
reported to be negligible. Although it was suggested that the predominant
acid in the air was sulfuric acid, it would be more appropriate to call the
measured index 'net strong acidity' since ammonium bisulfate could have been
present in significant amounts. The daily aerosol acidity values are plotted
February 1988 2-31 DRAFT-DO NOT QUOTE OR CITE
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in Figure 2-14 and averages, standard deviations, and maximums for years and
winter months (November 1 through February 29) are noted. Also, 9 a.m. hourly
total aerosol acidity data are available from 1965, though with no weekend data
and less completeness. It can be seen in Figure 2-14 that H concentration was
usually highest during the winter, probably due to increased heating fuel usage
and adverse meteorological conditions. A gradual decrease in acid concentra-
tion due to a Smoke Control Order can also be seen.
2.5.2 Los Angeles Data
In 1949 a study was conducted in Los Angeles, California to determine the
amount of free sulfuric acid in the atmosphere during periods of intense fog
and on clear days (Mader et al., 1950). The results for four separate 1-hour
3
sampling periods indicated a range in concentration from 0 to 157 ug/m . There
3
were two days with levels above 150 ug/m and each occurred on a day with high
relative humidity.
2.6 METHODOLOGY FOR STRONG ACID MEASUREMENT
Atmospheric strong acids consist principally of sulfuric and nitric acids
derived from the oxidation of sulfur dioxide and nitrogen oxides emitted from
stationary and for NO mobile combustion sources (National Research Council,
s\
1983). Some evidence suggests that hydrochloric acid may also be present in
the atmosphere (Rahn et al. , 1979) derived from primary, coal-fired utility
emissions or evolved due to interactions between sea salt and acidic sulfate
aerosols. These species are neutralized principally by atmospheric gaseous
ammonia (the latter mostly originated from surface biogenic and anthropogenic
sources) and soil-derived particulate matter to produce the observed composi-
tion of sulfate and nitrate aerosols and the levels of nitric acid found in the
atmosphere (Brosset et al., 1975; National Research Council, 1977).
Research efforts in progress on acid species are dependent on the develop-
ment and application in the last 10 to 20 years of techniques for rapid,
accurate, microscale determination of total strong acid and of individual
acidic species in atmospheric aerosol and gaseous samples. This section
details these technical developments, concentrating.largely on acidic aerosols;
February 1988 2-33 DRAFT—DO NOT QUOTE OR CITE
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although, a brief section is provided on nitric acid measurements. These
techniques consist mostly of filter-based schemes but with some continuous
and/or real-time approaches. Sampling/analysis protocols are recommended that
minimize analytical complications.
:
2.6.1 Methodologies for Strong Acids and Sulfuric Acids
Descriptions of methodologies for strong acids in aerosols are arranged
according to the measurement principle: filter collection and post^collection
extraction, derivatization and analysis, or real-time, in situ analysis—and
further segregated according to whether total aerosol strong acid content is
measured or individual species are determined.
2.6.1.1 Sulfuric Acid
2.6.1.1.1 Filter collection. Thermal volatilization schemes were popular for
several years for speciation of acidic sulfate compounds in aerosols. Filter
samples were heated and H2$04 collected by microdiffusion (Scaringelli and
Rehme, 1969; DuBois et al., 1969) or; determined directly by flame photometry
after volatilization from Teflon filters (Richards and Mudgett, 1974; Richards
et al., 1978). In one method, H2$04 was distinguished from other volatile
sulfates (e.g., NH4HS04 and (NH4)2S04), and nonvolatile sulfates (e.g.,
Na2S04) by heating in sequence at twb different temperatures (Leahy et al.,
1975). In another approach, 2-perimidinylammonium sulfate was formed from acid
sulfates and thermally decomposed to S02 for West-Gaeke analysis (Maddalone
et al., 1974).
These methodologies were stimulating attempts to analyze acidic sulfate
aerosols for individual species. However, due to serious recovery problems
(Leahy et al., 1975) and limited success in distinguishing the two major
aerosol species (NH4HS04 and (NH4)2$04) from each other (Thomas et al., 1976),
the methods have fallen into disfavor with three exceptions. One technique
uses a temperature-cycled diffusion denuder tube in connection with a real-time
flame photometric detector (FPD) to determine H2$04 in ambient aerosols (Tanner
et al., 1980; Allen et al., 1984). A related technique uses a series of
denuder tubes at varying temperatures to collect nitric acid, sulfuric acid
and bisulfate constituents separately for integrated analysis with several-
hour time resolution (Slanina et al.,;i981). Recently the heated denuder system
I
has been mated with a flame photometric detector to produce a computed-
I
controlled system for H2$04, ammonium acid sulfates and nonvolatile sulfate
February 1988 2-34 DRAFT—DO NOT QUOTE OR CITE
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with time resolution of 5 min to 1 h depending on requisite sensitivity
(Slanina et al., 1985). A photoionization detector has also been used for
the determination of H2SQ4 after preconcentration in a denuder and gas
chromatographic separation (Lindqvist, 1985). A related technique determines
nitric acid by denuder tube collection with subsequent decomposition to NO and
/x
determination by ozone-chemiluminescence (Klockow et al., 1982).
2.6.1.1.2 Extraction with pH measurement or H+ titration. Filter-collected
samples may be analyzed for net strong acid content by extraction into water or
dilute mineral acid. The extracted free acid content may be determined by
simple measurement of pH and, in the absence of weak acids, equated to the
amount of strong acid originally present in the sample. However, this determi-
nation can be in error because of the potential presence of buffering agents
such as weak carboxylic acids or hydrated forms of heavy metal ions; e.g.,
Fe(III) and Al(III) (Commins, 1963; Junge and Scheich, 1971).
Titration procedures for strong acid employing a logarithmic display of
data points (Gran titration) were originated by Junge and Scheich (1971)
perfected by Brosset and co-workers (Brosset and Perm, 1978; Askne and Brosset,
1972), and used widely by other groups (Stevens et al., 1978; and Liberti
et al., 1972). Coulometric generation of strong base for Gran titrations has
been used by several groups (Liberti et al., 1972; Krupa et'al., 1976; Tanner
et al., 1977). Dissolution of filter samples in 0.1 mM mineral acid followed
by Gran titration with correction for the blank (Tanner et al., 1977) allows
for titration of 1 jjmole levels of strong acid with precision and accuracy
better than ±10 percent (Stevens et al., 1978; Phillips et al., 1984).
The presence of partially dissociated weak acids, i.e., with pk s in the
range of the aqueous extract of aerosols can lead to overestimates of strong
acid contents (Lee and Brosset, 1978). The extent of this error source was
discussed by Keene and Galloway (1985) for precipitation samples in which
weak acids were preserved from microbial decomposition. Standard protocols
for aerosol collection and strong acid determination do not include preserva-
tion, which explains the absence of significant qualities of weak acids in
atmospheric aerosol samples (Ferek et al., 1983) and validates the use of Gran
titration approaches with continuous addition of titrant for strong acid
quantisation in those samples.
2.6.1.1.3 Specific extraction of atmospheric acids. Most of the effort in
specific extraction of. atmospheric acids has related to aerosol HpSO, analysis.
February 1988 2-35 DRAFT—DO NOT QUOTE OR CITE
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Benzaldehyde has been shown to be. specific for H2S04 in dried acidic aerosol
sulfate/nitrate samples with analysis for sulfate in aqueous back-extracts
(Leahy et al., 1975). Isopropanol (Barton and McAdie, 1971) quantitatively
extracts H?S04 from quartz filter media but also removes ammonium bisulfate
phases (Leahy et al., 1975). The behavior of isopropanol as an extractant Is
not well characterized for mixed nitrate/sulfate aerosols. In addition,
difficulties have been reported with quantitative removal and selectivity of
extraction using the benzaldehyde extraction technique (Appel et al., 1980;
Eatough et al., 1978). Since free H2S04 is not a common constituent of ambient
aerosols, use of specific extractant methodologies has decreased in recent
years in favor of generic strong acid; determinations.
2.6.1.1.4 Specific extraction with derivatization. A method has been proposed
for derivatization of collected H2S04 by dry diethylamine followed by reaction
with CS2 and cupric ion to form a colored complex for spectrophotometric deter-
mination (Huygen, 1975). This method suffers from a large ammonium bisulfate
interference. Likewise an approach in which filter-collected H2S04 is con-
verted to dimethyl sul fate by reaction with diazomethane, with subsequent
analysis by gas chromatography-flame photometric detection, does not specifi-
cally determine HpSO. in the presence of ammonium bisulfate and sulfate salts
(Penzhorn and Filby, 1976; Tanner and Fajer, 1981). A related method, by which
H2SO, and other aerosol strong acids fire converted to C-label led bis(diethyl-
ammonium) sulfate and analogs, is useful for determination of low levels of
strong acid in aerosols (Dzubay et al., 1979), but is also not specific for
H2S04. |
2.6.1.1.5 Continuous and/or real-time analysis. Sulfuric acid may be deter-
mined using a continuous flame photometric detector (FPD) although such measure-
ment is not real-time and represents an average concentration over a few-minute
period (Tanner et al., 1980; Allen et al., 1984; Slanina et al., 1985). The
technique uses a diffusion denuder tube for S02 removal attached to an FPD,
identical to the instrumentation for a continuous aerosol sulfur analyzer as
described by a few groups (Huntzicker et al., 1978; Cobourn et al., 1978; Camp
et al., 1982; Morandi et al., 1983). However, the temperature of the denuder
tube or a zone just upstream therefrom is cycled between room temperature and
about 120°C. At ambient temperatures sulfuric acid remains in the aerosol
phase, but at 120°C, it is volatilized and removed in the denuder tube. The
difference in response between ambient temperatures and 120° represents ambient
February 1988 2-36 DRAFT—DO NOT QUOTE OR CITE
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H2S04 levels. The minimum cycle time and hence time resolution for the tech-
nique is about 6-8 min. Sensitivity-enhanced FPD measurements using SFg-doped
Hp fuel gas are required for ambient measurements (D'Ottavio et al., 1981).
Acidic sulfates including sulfuric acid may also be differentiated using
humidograph techniques (Charlson et al., 1974) and recently developed
thermidograph variations (Larson et al., 1982; Rood et al., 1985). This latter
technique involves heating the aerosol-containing air stream progressively from
20°C to 380°C in 5 min cycles, rapidly cooling it to the dry bulb temperature
and measuring the light scattering at 65 to 70 percent RH with a nephelometer.
By comparing the results with the thermidograms of test aerosols, the frac-
tional acidity can be measured and approximate level of H2S04 determined.
The fractional acidity can also be determined using an impactor: attenu-
ated total reflectance (ATR), Fourier-transform infrared (FTIR), spectroscopic
technique (Cunningham and Johnson, 1976). Impactor samples are pressed into a
KBr matrix and the IR spectrum used to determine the relative acid and quali-
+ -2
tatively identify aerosols with molar H /SO^ ratios >1, the condition for the
presence of HpSO. in the aerosol samples.
2.6.1.2 Nitric Acid
2.6.1.2.1 Nitric acid sampling techniques. A summary of techniques presently
employed in nitric acid sampling is found in Table 2-6 (Stevens, 1986). All
are filter techniques that can include multiple hour or multiple day samples.
Research grade instrumental HNO^ samplers are available that use chemilumi-
nescence, tunable diode laser infrared spectroscopy, or Fourier transform
infrared spectroscopy as the operating principle.
Unlike the situation for acid sulfates, nitric acid technique intercom-
parisons were made in the Claremont, CA intercomparison study (Spicer et al.,
1982). This particular intercomparison did not include the annular denuder
system described in Table 2-6. A second intercomparison involving eighteen
instruments was conducted at Pomona College, CA during September, 1985 (Hering,
1986). The results from this particular experiment reported nitric acid
values that varied by a factor of two or more on all sampling days with the
differences increasing with loading. It appears that the technology for
nitric acid determinations still requires examination, including the develop-
ment of a reference standard.
February 1988 2-37 DRAFT—DO NOT QUOTE OR CITE
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2.6.2 Sampling Anomalies ,
Sampling anomalies have plagued the measurement technologies for atmo-
spheric strong acids present in the gas phase or as aerosols, justifying a
separate section on the nature of these artifact problems and suggested
sampling techniques to minimize their effects. These sampling problems
generally fall into two classes: (1) reversible or irreversible sorption
losses onto filter materials in integrative methodologies or onto sampling
lines in continuous and real-time techniques; (2) equilibrium-driven loss or
gain of species due to non-steady-state conditions in the sampled atmosphere
over the time period of the measurement. Both of these phenomena affect
sampling/analysis techniques for strong acids in the atmosphere and are
discussed below.
2.6.2.1 Sorption Losses. Studies of sorption losses on filters have centered
on three major areas related to measurement of strong acid content in atmos-
pheric samples. One area is the loss of strong acid in aerosol particles by
reaction with basic sites in the filter matrix used to collect the particles
(Appel et al., 1979). Filter matrices used for high-volume sampling include
glass fiber or cellulose. These media, particularly glass fiber filters of all
types, are unsuitable for collection of acidic aerosol particles for subsequent
extraction and titrimetry (Tanner et al., 1977; Appel et al., 1979; Coutant,
1977). This is true even if the glass fiber filters are pretreated with acid
as well as fired to high temperature, since subsequent rinsing exposes addi-
tional free basic sites in the glass, resulting in neutralization of the sample
(Tanner et al., 1977). High-purity quartz filters can be pretreated to remove
basic sites for high-volume sampling, hence, treated quartz and Teflon filter
media have generally replaced glass fiber or cellulose filters for sampling of
acid aerosols by high-volume and low-volume techniques, respectively.
The filter treatments described above also eliminate a positive source of
error in sulfate measurements - the artifact sulfate formed by base-catalyzed
oxidation of S02 (sorbed on the filter surface) to form sulfuric acid (Coutant,
1977; Pierson et al., 1976; Pierson et al., 1980a). The acid so formed is
neutralized on the filter surface, but the residual sulfate remains and is
measured using standard extraction/analysis techniques.
A third problem is the loss of strong acid contents by topochemical reac-
tions between co-collected basic and acidic particles on the filter surface.
This most frequently occurs as the result of coarse (>2.5 pm), alkaline, soil
February 1988 2-39 DRAFT—DO NOT QUOTE OR CITE
-------
derived particles interacting with fine (<2.5 pm), acidic sulfate particles
(Camp, 1980; Spicer et al., 1978; Tanner et a!., 1979). This problem can be
eliminated by sampling with a dichotomous sampler, by high-volume sampling with
a cyclone to remove coarse particles, or by sampling for shorter time dura-
tions. In connection with the latter solution, sampling in most ambient
environments for <3 h results in liow enough surface coverage to prevent
topochemical reactions, but this procedure does not prevent neutralization
during subsequent extraction procedures.
2.6.2.2 Equilibria-Driven Losses. Equilibria involving gas- and particulate-
phase species may lead to artifactual errors in sampling strong acids as well
as other species in the atmosphere under both steady-state and non-steady-state
conditions. Thermodynamic considerations suggest that aerosol sulfuric acid/
sulfate mixtures should be in dynamic equilibrium with atmospheric ammonia
(Lee and Brosset, 1979). Indeed, as noted initially, ammonia is believed to be
the principal neutralizing agent for sulfuric acid formed by heterogenous or
homogenous oxidation of SO^. However, the equilibrium level of NI-L for even
slightly acid sulfate is much below the usually observed ambient MH3 levels.
This suggests that a non-steady-state, mixing-limited situation normally exist
(Appel et al., 1979) or, alternatively, that mixed nitrate/sulfate salts are
usually present with their concomitantly much greater equilibrium NHg concen-
trations.
2.6.3 Recommended Protocols
2.6.3.1 Strong Acid Aerosols. The discussion above indicates that a recom-
mended method for analysis of strong acid in aerosols is collection on inert
filter media, ultrasonic extraction into weak acid (ca. 0.1 mM) and titration
with base using a Gran plot to determine the equivalency point. In some cases
a pH measurement of the extract can be sufficient. For sampling periods longer
than a few hours (depending on ambient levels), a virtual impactor-based
sampler that collects particles on Teflon filter media should be used. With
shorter term sampling for which highfvolume apparatus is required, acid-treated
I
quartz filters can be used, preferably ones with a cyclone pre-separator for
coarse particle removal. Automation of the titration procedure using coulo-
metric generation of hydroxide is a practical necessity when large numbers of
samples must be processed. Precision and accuracy approaching ±10 percent is
possible with careful-flow calibration and for sample sizes exceeding 0.5 ueq
(>25 ug as H2$04) (Phillips et al.j 1984).
February 1988 2--40 DRAFT—DO NOT QUOTE OR CITE
-------
2.6.3.2 Specific Determination of HpSO^. No method is fully satisfactory for
determining the low levels of H2S04 occasionally found in ambient aerosols.
Two approaches that may be used with reasonable success are the following.
Filter pack samples, collected on treated quartz filters that are then
thoroughly dried over desiccant, may be extracted into benzaldehyde, the
sulfate therein then back-extracted into water and determined by ion chroma-
tography or other soluble sulfate methodologies (Leahy et al., 1975; Tanner
et a!., 1977). Careful drying of the filter is required, as noted above, to
prevent significant interference from ammonium bisulfate (usually present in
excess of H2$04); in addition an impurity, benzoic acid, in the benzaldehyde
may be present in amounts sufficient to interfere with ion chromatography or
other sulfate determinations. Sulfuric acid may also be determined by flame
photometry using a temperature-eyeled diffusion denuder tube (Tanner et al.,
1980; Allen et al., 1984). Time resolution is limited by the minimum tempera-
ture cycle time of the denuder (5 to 10 min) and is quite adequate. However,
the limit of detection, only about 1 ug/m H2$04 even with sensitivity enhance-
ment through use of SFg -doped \\2 unless denuder concentration is used (Slanina
et al., 1985), is not adequate for many ambient applications. Direct denuder
tube collection of H2S04 in heated denuders is a viable alternative. The time
resolution is several hours if extraction and wet chemical analysis is used due
to the necessarily slow flow rate through denuder tubes.
2.6.4 Applications
The results from studies that have been conducted over about the past
twelve years on strong acid sulfate and sulfuric acid are reported in next
section. These studies have used a variety of quasi-continuous and integrated
sampling methods. Only the most recent studies have systematically used
approaches similar to those recommended in Section 2.6.3. The development of
the recommended techniques represent the advancements made by individual
investigators. No organized program exists to develop recommended techniques.
No program is currently in place that evaluates the relative uncertainties of
the methods employed in the individual studies. Major efforts to examine the
national exposure to acidic aerosol will require the development of a quality
assurance program and a program to examine which pre-collection devices will be
necessary to minimize alteration of the acid concentration actually present in
the atmosphere.
February 1988 2-41 DRAFT—DO NOT QUOTE OR CITE
-------
2.7 ATMOSPHERIC CONCENTRATION -
2.7.1 Atmospheric Acidic Sulfate Studies from 1974 to 1986
Results of field investigation^ of the surface concentration of acidic
sulfate species in the United States and Canada since 1974 are shown in
Table 2-7. A variety of sampling strategies and analytical methods were used,
and the individual sampling times ranged from 1 to 24 hours.
Most of the studies reported in Table 2-7 were conducted during the
i ~2
summer. This is the season when large scale regional ozone and S04 smog
episodes, which last at least three days, can or have occurred in the eastern
U.S. and Canada (Wolff and Lioy, 1980; Wolff et al., 1981). In addition,
photochemical smog episodes frequently occur in Los Angeles, CA (Hidy et al.,
1980) and Houston, TX (Beck and Tannahill, 1978). The magnitude of the winter-
time levels of acid sulfate species jwere derived from a more limited data base,
which is also described in Table 2-7. Spengler et al. (1988) reports daily
concentrations of H+ ion for a minimum of nine consecutive months in four
United States cities that show a seasonal pattern with lower concentrations in
the winter and higher levels in the summer months.
The ranges of SO^2, H+ (as H2S04) and/or H2S04 concentrations recorded in
these studies are shown in Table 2-8. It is apparent that a wide range of
•~O
SO. levels were encountered in acid aerosol studies with the peak concentra-
o
tion being 75 ug/m for an 8 h period in North America (Waldman et, al., 1987).
-2 3
At other times, each study recorded S04 decreases to as low as 0-2 ug/m .
The peak HpSO. value, measured with a flame photometric detector (FPD), was
41 ug/m3 (1 h average) in 1984 at! a site in St. Louis, MO (Ferris and
Spengler, 1985).
A H+ concentration (as equivalent H2S04) of 39 ug/m was observed in 1975
just northeast of St. Louis in Glasgow, IL (Tanner and Marlow, 1977). The
striking features of the Glasgow data were: (1) the H was measured in the
fine particle size range; (2) the measurements were 12 hour duration samples,
and (3) the visibility maps indicate the development of an urban plume from
St. Louis. A comparison of the {H*}/((H+} + {NH4+}) ratio on July 29, 1975
indicated that the aerosol in Glasgow, IL contained both NH4HS04 and H2S04<
A number of other studies also indicated the presence of both species
(Tanner and Marlow, 1977; Morandi et al., 1983; Huntzicker et al., 1984; Lioy
and Lippmann, 1986). Pierson et alj (1987) completed a study at both
February 1988 2-42 DRAFT—DO NOT QUOTE OR CITE
-------
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2-44
-------
TABLE 2-8. CONCENTRATION RANGES OF SO^2, H+ (as H2S04) AND H2S04
(in |jg/m3) MEASURED IN VARIOUS LOCATIONS IN NORTH AMERICAN
Sample
Duration
Study Hours
Glasgow, IL
1977
St. Louis, MO
1977 Summer
1978 Winter
Lennox, CA
Smokey Mountains
High Point, NJ
Brookhaven, NY
RTP, NC
Allegheny Mt, PA
Shenandoah
Valley, VA
Tuxedo, NY
Mendham, NJ
Houston, TX
New York City
St. Louis, MO
St. Louis, MO
Los Angeles, CA
Harriman, TN
Water town, MA
Fairview Lake,
NJ
Warren, MI
12
1
1
2-8
12
6
3
2,4
12
12
1-12
4,20
12
6
QC
QC
12
QC
QC
QC,4
24
Concentration
Range ng/m3)
so;2
7-48
5-60
3-24
1.2-18
6.2-17.4
3.0-36.6
1.0-23.7
3.6-19.8
1-32.5
2-40
1-41
1-37.3
2-32.4
3-25
<5-43
3-10
9-47
5-31
13-27
.4-36.7
H2S04
0-39
0-28
0-12
0-11
2.8-9.6
2.2-17.8
0.3-10.2
0-9.8
0-20
0-23
1-8.7
0-6.3
0-7.6
rim
0-7
0-34
0.6-3.2
0-18
0-14
0-12
.8-8.7
Reference
Tanner and Marlow (1977)
Cobourn (1979)
Cobourn and Husar (1982)
Appel et al. (1982)
Stevens et al. (1980)
Lioy et al. (1980)
Lioy et al. (1980)
Stevens et al . (1978)
Pierson et al. (1980b)
Stevens (1983)
Morandi et al. (1983)
Lioy and Lippmann (1986)
Stevens (1983)
Lioy et al . (1980)
Huntzicker et al. (1984)
Ferris and Spengler (1985)
John et al. (1985)
Spengler et al . (1986)
Spengler et alf (1986)
Lioy and Lippmann (1986)
Cadle (1985)
(continued on the following page)
February 1988
2-45
DRAFT—DO NOT QUOTE OR CITE
-------
TABLE.2-8. (continued)
Study
Whiteface Mt. ,
Sample
Duration
Hours
24
Concentration
Range ;(ug/m3)
S042 H2S04
0-58.9 0-14
Reference
Kelly et al. (1985)
NY
Nova Scotia
24
0-26
0-9
Smith-Palmer and Wentzell
(1986)
Toronto, Canada
Allegheny Mt. , PA
Laurel Mt. , PA
8,16
7,10
7,10
0-75
1.
2.
7-45.
2-55.
4
1
5
0-19.4
0.
0.
4-30.
5-42.
5
0
Waldman
Pierson
Pierson
et
et
et
al.
al.
al.
(1987)
(1987)
(1987)
Allegheny Mountain and Laurel Mountain in 1983 with observed peak H (as
apparent FLSO.) concentrations of 30i4 and 42.0 M9/m at the respective sites.
As stated previously, work by Morandi et al., (1983) included an attempt
to infer the distribution of acidic species from coincident instrumental FPD
measurements of H2S04 and filter analyses for H+. The results of that study
indicated there was no evidence of |the presence of any strong acids (pka <2)
other than NH4HS04 or H2S04- On the basis of this observation, and using
data from the FPD and filter samples, the SO^ associated with H2S04 and
NH-HSO. was inferred from the molar differences between the H and the
simultaneously measured H2S04 by the FPD (i.e., using equivalent average time
periods for the latter data). The results of the analysis showed:
1. The species H2S04, NH4HS04 and (NH4)2S04 can occur simulta-
neously in a present-day polluted atmosphere.
2. On occasion, S042 will be associated only with H2S04 and NH4
HS04.
3. During a period of sustained sulfate concentrations (2 to 3
days) the sulfates change in composition from acid to basic
species, (Table 2-5).
The latter observation was made during a large scale regional episode that
affected the northeastern U.S. at the end of August 1980.
February 1988
2-46
DRAFT—DO NOT QUOTED OR CITE
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The 1984 Fairview Lake, N.J. study reported by Lioy et al. (1987) was con-
ducted in a manner similar to Morandi et al. (1983). The species distribution
and concentration again showed that the occurrence of H2$04 is quite variable
and is usually limited in extent, while NHAHSOA was found over a series of days.
3
The approximate 1 h peak of H,,SOA was 12 ug/m .
The 1977-1978 St. Louis, MO study by Cobourn and Husar (1982) showed that
3
levels.of H2SOA in excess of 1 to 2.ug/m occurred sporadically, but most of
the time the occurrence of HgSO^ was rare. From July 15-18, 1977 St. Louis was
influenced by a highly stagnant southerly maritime tropical air mass. The
3
observed 1 h H0SO, was about 6 ug/m for much of July 17 and 18. In two 1 h
3
intervals, the levels exceeded 20 ug/m . In 1979, a short study (8 days) by
Huntzicker et al. (1984) also examined summertime H^SO, in St. Louis. The
period of increased acid occurred within a single day, and in this case was
determined to be associated with a local power plant, approximately 17 km away.
Winter measurements during the Cobourn and Husar (1982) study were made
in 1978. During the period, HpS04 was measured consistently in February and
March, but at lower peak levels than observed during the summertime.
For each of the other summertime studies, peaks of H2SOfl and/or H were
observed sporadically, and based upon the meteorological data, were associated
with the presence of a slow moving hazy summertime high pressure system. A
major acid sulfate event occurred over the period from August 1 through
August 12, 1977 (Lioy et al., 1980). The daily variation of the six hour
particulate sulfate, hydrogen ion samples, and the daily maximum ozone concen-
trations are shown in Figure 2-15. In the multi-site analyses of this period
the results of Lioy et al. (1980) for High Point, N.J. and Brookhaven, Long
Island, N.Y. showed peak excursions of H+ at High Point and Brookhaven
_o
(separated by 160 km) with the passage of SOA -laden air masses throughout the
northeastern U.S. On one day, August 4, 1977, both High Point and Brookhaven
were affected by air parcels that had passed over different geographical areas,
+ -2
and only the High Point site recorded high H and SO- .
New York City data for the same period were reported by Tanner et al.
(1981). They did not record any acidity during August 4 or on any other of the
fifteen sampling days. This suggested that after passing High Point, N.J.,
the flux of NH™ emanating from the metropolitan area neutralized the acid laden
+
air parcels. The values of H measured at Brookhaven, L.I., N.Y., were
consistently lower than the values measured at High Point, suggesting partial
February 1988 2-47 DRAFT—DO NOT QUOTE OR CITE
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150
6 ; 8
DAYS IN AUGUST. 1977
12
Figure 2-15. 6-hour 804 and H+, and 6-hour max. 03 samples collected during August, 1977 at
High Point, NJ.
Source: Lioy and Waldman (1988).
February 1988
2-48
DRAFT—DO NOT QUOTE OR CITE
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neutralization and/or fresh acid production over the New York metropolitan
area. Such changes in concentration suggested that complex relationships exist
among S02 emissions, oxidation rates and the availability of NH~.
Information on the regional nature of the acid in rural areas was also
documented by Lioy et al. (1980) in comparisons with Pierson et al. _(1980b)
for events occurring at Allegheny Mountain, PA during the same period. On
August 4, 1977 the levels of H+ (as H2$04) were 17.0 and 10.4 ug/m3 for the
periods 8 p.m. (August 3rd) to 8 a.m. (August 4th) and 8 a.m. to 8 p.m. (August
4th) respectively, which coincides with the peak observed at High Point, N.J.
(320 km east). Similar coincidence observations of H+ were found at both sites
for the period August 6 through August 10. An independent study in Research
Triangle Park, N.C. by Stevens et al. (1978) was conducted simultaneously with
another part of the Pierson et al. (1980b) study. On July 31, 1977, the last
day of the North Carolina study, the peak H+ concentrations observed by Stevens
et al. (1978) occurred simultaneously with an H+ event at Allegheny Mountain,
PA. The information from each comparison suggests that concentrations of acid
3
in excess of 5 ug/m occurred over extended periods for large segments of the
Northeast during the summer of 1977.
The later studies by Stevens et al. (1980), in the Great Smokey Mountains,
TN; by Stevens (1983) in the Shenandoah Valley, VA and by Lioy and Lippmann
(1986) in Mendham, NJ again show the presence of acidic species in other
nonurban areas within the Eastern U.S. Other results by Stevens (1983)
indicated the presence of acidic species in Houston, TX, and were supported by
semi-quantitative recent humidographic data from Waggoner et al. (1983).
In 1984 Spengler et al. (1986) initiated H2S04 studies at two of the
Harvard Six-Cities Health Study sites, Harriman, TN (coal burning area), and
Watertown, MA (suburb of Boston). Using the FPD system for HpS04 measurement
they classified acid events. Data from their study shows the H0SO» concentra-
q £4
tions and the duration of events with H^SO. >1 pg/m for at least two hours
(Table 2-9). This is a rather low threshold for classifying events, but the
study gives one of the few comparisons of acidity in two different environments.
Those that occurred in the coal burning area of Harriman, TN were of longer
duration and higher concentration than at Watertown, MA. In Watertown, MA, the
events were usually associated with regional transport conditions. In Harriman,
TN, the events were associated with regional and local HpSO. production. For
both of these sites, the total strong acidity was probably underestimated since
the ammonium bisulfate concentrations could not be measured by the FPD.
February 1988 2-49 DRAFT—DO NOT QUOTE OR CITE
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TABLE 2-9. ACID EVENTS (H2S04 £1 ug/m3 for S2 h)
Watertown, Massachusetts
(N = 72) j
Duration Concentration
(hr) (ug/m3)
Harriman, Tennessee
(N = 65)
Duration Concentration
(hr) (ug/m3)
MEAN
SD
75 percent
90 percent
MAX
7.2
5.2
8.0
17.7
24.0
2i.2
li.4
2.2
4'. 4
7.4
8.4
6.4
10.0
17.4
41.0
3.0
1.5
3.8
, 4.7
9.5
N = Number of samples.
Source: Spengler et al. (1986).
In another investigation by Harvard (Ferris and Spengler, 1985) a high
o
H2SO. concentration (41 ug/m ) was observed in St. Louis. In this case,
wintertime conditions were studied,land the results suggested an association
with power plant plumes.
A study by Appel et al., (1982) at Lennox in the Los Angeles basin was
conducted for the period July 10 to July 17, 1979. A four hour maximum of
11 ug/m3 of HpSO. was observed on July 16 apparently associated with the
daytime oxidation of local S02 emissions. Three other acid events were measured
during this interval, although consistently high levels of S04 were measured
throughout the sampling interval. !Recently, a study was conducted by John
et al. (1985) in Los Angeles in whij:h the apparent H2S04 was lower during this
week-long study. They used two sites, and the downwind location, east of LA,
recorded relatively high acid concentrations.
Cadle (1985) reported the results of acidity measurements (H ) at a
suburban site in Warren, MI from June 1981 through June 1982. The results were
consistent with the growing body of information on apparent H2SO^. The most
frequent excursions occurred during the summer with six 24 h samples exceeding
4 jjg/m3. However, the highest H^O, value occurred during the winter.
Two recent rural investigations, one in Whiteface Mt., NY (Kelly et al.
1985), and one in Nova Scotia, Canada (Smith-Palmer and Wentzell, 1986), focussed
on acidic sulfate aerosol. In each case, there was at least one period during
3
which the apparent H2S04 concentration exceeded 9 ug/m .
February 1988
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DRAFT—DO NOT QUOTE OR CITE
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To date, there have been a couple of studies in which the acid sulfate
species were measured at two or more sites located <45 km apart (Waldman et al.,
1987; Pierson et al., 1987). One study was conducted in Toronto, Canada during
the summer of 1986 and on July 25th, H (as H, SO-) was observed at all three
3
sites. The 8 h average peaks at each site were 8.3, 14.4, and 19.4 ug/m .
The other study, the 1983 Allegheny-Laurel Experiment, was conducted at sites
+ 3
36 km apart. Nine-hour average H (as H^SO.) concentrations of 30 and 42 |jg/m
were observed at these Pennsylvania sites on August 17, 1983 (Pierson et al.,
1987).
The preceding discussion was limited to the data presently available on
acid 'sulfate species. The studies were highly skewed to the summertime.
Although large segments of the population could be affected by these regional
acid events, seasonal profile of the types of situations where people could be
exposed to high concentrations of acid species are not available (e.g., downwind
of industrial and power plant plumes). The conditions conducive to high acid
exposure in the other seasons must be examined, as well as the spatial
distribution of acid sulfate (e.g., southeast and the mid-east during the
winter).
The studies of Pierson et al. (1980b), Lioy et al. (1980), and Stevens
et al. (1978) suggest that large areas of the northeast can be affected by acid
aerosol during the summer. Recent work by Thurston and Waldman (1987) also
suggest that these events can extend into Canada. Since the population
potentially affected would be large, well focused studies on regional exposure
to acid sulfate aerosol may be necessary.
2.7.2 Acid Sulfate Exposure and Events
The field studies described in the previous section measured a wide range
of acid sulfate concentrations in the atmosphere. Most of the H9SO. or H (as
3 6
HpSO,) values were below 5 ug/m , although events above 5 ug/m occurred at
least once over the course of each study. At present, there is no way to
define an acid event systematically as an episode, since, as previously noted,
periods of high acid sulfate do not necessarily coincide with periods of
-2
highest SO. concentrations; e.g., photochemical haze or smog. Therefore, the
definition of an acid sulfate episode would be quite arbitrary. In the context
of the following, a significant pollution excursion for acid sulfate will be
defined as an event in which the measurement of free sulfuric acid or H (as
February 1988 2-51 DRAFT—DO NOT QUOTE OR CITE
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HpSO.) reaches levels above 5 ug/m for at least 1 h. No relationship to
possible health effects is intended or implied in using the words significant,
episode, or event and in some cases the exposure may be overestimated, e.g.,
24 hrs, because the actual amount of time spent outdoors was not quantifiable
in each study.
With the preceding criteria, some of the studies listed in Table 2-7 were
selected for estimating the frequency of events, and the potential for exposure
o I
to acid sulfates as (ug/m )'h (Lioy and Waldman, 1988). It must be emphasized
that the exposure (concentration x time) calculation will only be applied for
determination of exposures that can occur during an event (annual average
calculations of exposure are inappropriate). Event exposure calculations may
be of some biological significance since it has been shown in a controlled human
study that exposures to 100 ug/m for more than one hour will yield enhanced
effects, not additive effects, on mucocilliary clearance (Spektor et al., 1988;
Schlesinger, 1988). For the purposes of the following discussion, however, the
exposure values (ug/m )«h should be interpreted as the maximum potential expo-
sure during an event, and not the biologically effective dose to an individual.
Because of the lack of a single approach to measuring acid sulfates, the
studies examined in Table 2-10 have been grouped by sampling duration. In the
case of studies with direct H7SO, measurements the total hydrogen ion exposure
+
will be underestimated, and in the case of studies with H measurements the
actual HpSO. exposure probably will be overestimated.
The exposure and event results shown in Tables 2-10 through 2-'-15 and are
divided into representative studies with sample collection times of 24 h, 12 h,
6 h 4 h, 1 h, and a combined sampling time (Lioy and Waldman, 1988). Unfor-
tunately, the locations for the studies with the twelve hour samples,
Table 2-11, and for the other sampling times, Table 2-12 through Table 2-15,
were different from those examined for the 24-h studies, Table 2-10. Thus the
results are not necessarily comparable specially. ;
For the 24 h studies, Table 2-10, the events lasted a maximum of 24 h,
which was the sample duration. This may be an underestimate of the length
of the episode since the portion of the next or preceding 24-h period may have
o
been above 5 ug/m and could not have been detected. The exposures for the 24-h
3 '
episodes ranged from 120 to 336 (jjg/m )^h. For the day of the study, however,
exposures were isolated instances of high acid sulfate.
February 1988 2-52 DRAFT—DO NOT QUOTE OR CITE
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TABLE 2-10. EPISODIC ACIDIC AEROSOL DATA AND ESTIMATES OF EXPOSURE FROM
SELECTED ACID SULFATE CLASSIFIED BY SAMPLING TIME. ONLY PERIODS WHERE
CONCENTRATIONS EXCEEDED 5 ug/m3 OF APPARENT H2S04 ARE USED AS EVENTS
24 HOUR DATA
Study
(Period)
White face Mt.*
(85 samples
collected
over 1 yr)
Nova Scotia**
(23 days)
Warren, MI***
(1 yr)
St Louis, MO****
(9 months)
Kingston, TN****
(9 months)
Date
1984
July
August
August
1983
September 6
1981
July
July
July
July
August
August
November
February
1985/1986
September
1985/1986
May 30
June 3
July 6
July 17
July 22
August 5
August 18
Peak
(ug/m3)
8.2
10.0
14.0
9.0
9.0
6.5
7.5
6.7
5.0
5.0
6.5
10.0
6.1
7.7
5.9
5.4
10.6
8.0
6.1
14.3
Mean
(ug/m3)
8.2
10.0
14.0
9.0
9.0
6.5
7.5
6.7
5.0
5.0
6.5
10.0
6.1
7.7
5.9
5.4
11.1
8.3
6.1
14.3
Exposure
(ug/m3)-h
197
240
336
216
216
156
180
160
120
120
156
240
146
184
141
135
509
384
146
343
*Kelly et al. (1985).
**Smith-Palmer and Wentzell (1986).
***Cadle (1985).
****Koutrakis et al. (1987).
The acid sulfate events for the 12-h samples reached 36-h in duration
and recorded peak exposures of 510 and 925 (ug/m3)'h. An interesting feature of
the 12-h studies was that each was conducted for a period of one month or less,
and each had at least one event with acidic sulfate exposure above
100 (ug/m >h. Obviously, the frequency of acid events can not be described
in this analysis, since longer studies would be required in each location.
February 1988
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TABLE 2-11. TWELVE HOUR ACID AEROSOL DATA AND ESTIMATES OF EXPOSURE
Study
Tuxedo, NY*
(31 days)
Glasgow, IL**
(8 days)
Smokey Mts***
(6 days)
Houston, TX****
(9 days)
*Morandi et al.
**Tanner et al.
***Stevens et al.
****Stevens (1983)
TABLE 2-12.
Study
High Point, NJ*
(11 days)
Date
1980
August 2
August 8
August 27
1975
July 22
July 26
July 28, 29
1978
September 20-21
September 21-22
September 24-26
1980
September 11
September 12
September 13
(1983).
(1977).
(1978).
•
SIX HOUR ACID
Date
1977
August 1
August 3
August 4-5
August 5-6
August 7-9
August 10
Peak
(ug/m3)
8.0
8.0
20.1
9.3
5.2
36.0
[
5.6
8.2
9.6
6.4
6.7
7.6
1
>
AEROSOL DATA
Peak
(pg/m3)
11.6
5.8
17.6
13.8
11.6
8.2
August 11-12 12.6
Mean
(ug/m3)
8.0
8.0
14.2
9.3
5.2
25.7
5.6
8.2
8.6
6.4
6.7
7.6
Duration
(h)
12
12
36
12
12
36
12
12 !
36
12
12
12
Exposure
(ug/m3)«h
97
97
511
112
62
925
68
98
308
76
81
91
AND ESTIMATES OF EXPOSURE
Mean
(|jg/m3)
11.6
5.8
9.0
10.1
7.4
6.5
8.3
Duration
(h)
6
6
24
30
36
18 i
24
Exposure
(|jg/m3)'h
69
35
215
304
264
118
198
Shenandoah Valley** 1980
(7 days)
August 29-
September
21.3
1
14.6
24 ,
350
*Lioy et al. (1980).
**Stevens (1983).
February 1988
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DRAFT-DO NOT QUOTE OR ,CITE
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TABLE 2-13. FOUR HOUR ACID AEROSOL DATA AND ESTIMATES OF EXPOSURE
Study
RTF, NC*
(3.5 days)
Lennox, CA**
(8 days)
Date
1977
July 31
1979
July 15
July 16
Peak
(|jg/m3)
12.3
8.1
10.9
Mean
(|jg/m3)
6.9
8.1
10.9
Duration Exposure
(h) (M9/m3)-h
4 27
2 16
(2h average)
4 42
*Stevens et al. (1978).
**Appel et al. (1982).
TABLE 2-14. ONE HOUR ACID AEROSOL DATA AND ESTIMATES OF EXPOSURE
Study
St. Louis, MO*
(61 days)
Date
1977
July 15
July 16-17
July 17
Peak
(pg/m3)
12.2
18.4
27.6
Mean
(ng/m3)
7.0
9.2
13.0
Duration
(h)
3
7
4
Exposure
(ng/m3)«h
21
64
52
(59 days)
St. Louis, MO**
(8 days)
1978
February 9-10 10.5 7.0 13
February 10 8.0 6.0 1
February 10 9.0 7.0 3
February 11 9.0 7.5 4
February 11 13.7 8.5 20
1984
August 4 7.4 7.4 1
August 5 9.8 9.8 1
August 6 7.4 7.4 1
August 7 12.3 12.3 1
August 8 8.3 8.3 1
91
6
21
30
170
7
10
7
12
8
Harriman, TN***
(7 days)
„
1984
August 13
August 14
August 15
August 16
August 17
August 18
August 19
8.0
10.0
18.0
9.0
7.0
14.0
6.0
6.0
6.5
8.5
6.3
5.8
8.0
5.2
7
13
16
4
5
11
2
42
85
136
25
29
88
10
(continued on the following page)
February 1988.
2-55
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TABLE 2--14. (continued)
Study
Watertown, MA***
(7 days)
Date
1984
August 9
August 10
August 12
Peak
(ug/m3)
14.0
14.0
11.0
Mean
(ug/m3)
7.0
7.5
7.0
Duration
(h)
6
12
8
Exposure
(ug/m3)'h
42
90
56
*Cobourn (1979).
**Cobourn and Husar (1982).
***Spengler et al. (1986).
TABLE 2-15. FOUR-, EIGHT- AND SIXTEEN-HOUR ACID AEROSOL DATA AND
ESTIMATES OF EXPOSURE
Study
Toronto
(6 weeks)
(Site 1)
(Site 1)
(Site 2)
(Site 3)
Date
1986
July 19
July 25
July 25
July 25
Peak
(ug/m3)
7.8
, 14.4
19.4
i 8.3
i
Mean
(ug/m3)
6.4
14.1
13.4
8.3
Duration
(h)
13.4
18.8
25.3
7.5
Exposure
(ug/m3)-h
86
264
338
62
Source: Waldman et al. (1987). ',
The 6 h analyses yielded information similar to the 12 h samples since
3
the two examples had calculated exposures above 100 (ug/m )*h during intervals
of sampling that encompassed less than two weeks. However, the intensity and
duration of the High Point, N.J. (Lioy et al., 1980) exposures were quite
different. In the period from August 5 through 12 there were almost continuous
exposures to acidic sulfate above 100 (ug/m )-h. On some of the days there
were 6 h periods when H+ (as H^SOL) was not above 5 pg/m , but these were the
exception rather than the rule.
The 4-h data are limited to two studies, (Table 2-13) Research Triangle
Park, N.C. (Stevens et al. 1978),! and Lennox, CA (Appel et al., 1982). There
3
were no acid exposures above 100 (jjg/m )*h in either case. General conclusions
on the absence of acid sulfate episodes in these instances can not be drawn,
since the duration of the programsi were less than two weeks.
The examples of 1-h sample studies, all of which made direct H2S04
measurements showed the duration of an acid episode ranging from 1 to 20 h.
February 1988
2-56
DRAFT—DO NOT QUOTE OR CITE
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In contrast to the locations examined previously, there were only two instances
3
during which exposures to H9SOA were above 100 (ug/m )-h and three above 80
3
(|jg/m )*h. In the case of St. Louis, this was puzzling, since the sampling
included an entire year, and there are major sources of SOp in the area (Husar
et al., 1978). The work, however, of Ellestad (1980) and the previously cited
work of Tanner and Marlow (1977) may explain part of this lack of frequent high
excursions in HUSO*. Even though St. Louis has major sources of SOp, the main
impact was probably at some distance downwind. During the 1975 Midwest
Interstate Sulfur Transformation and Transport (MISST) study at Glasgow, IL,
Ellestad (1980) measured particle light scattering downwind of the St. Louis
urban and power plant plumes and found aerosol production during the summer.
The Tanner and Marlow (1977) summertime H measurements indicated very high
o
exposures (>900 pg/m -h) at this same location. Thus the main acid impact from
the plume in this case was downwind. In the future, studies will require
careful consideration of where major plume impacts will occur, and their
potential for producing high acid concentrations and exposures.
In the Toronto, Canada study, Waldman et al. (1987) used a scheme which
involved collection of samples for a variety of time intervals, depending on
whether a sulfate episode was in progress-see Table 2-15 (Thurston and Waldman,
1987). The exposure analyses completed for the three sites across a metro-
politan area of 2.5 million people showed that there was one period, July 25th,
3
during which exposures at two of the three sites were above 100 ((jg/m )'h.
At the third site, the levels were much lower, probably because of local
neutralization. Thus, the potential for local differences in acid sulfate is
present and will have to be examined in the future to assess where maximum
exposures occur.
Research recently conducted at Camp Kiawa in Southern Ontario by Spengler
et al. (1988) considered exposure to acids on a 12-h basis for H and as 1-h
averages for HUSOA. For the same event described by Thurston and Waldman
3
(1987), a 1-h maximum of sulfuric acid of 50 |jg/m was measured at the camp.
The entire 36-h event had measured 12-h sequential H+ (as H9SO-,) of 120, 336,
3
and 150 (pg/m )*h. A delivered dose to the lung of 52 ug was calculated for
the peak 1-h acid concentration on July 25, 1986.
2.7.3 Atmospheric Nitric Acid Concentration
Ambient data on nitric acid in the atmosphere are available from Spicer
et al. (1982) for Claremont, CA, Figure 2-16. Another study conducted in
February 1988 2-57 DRAFT—DO NOT QUOTE OR CITE
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ou
'I
3 40
|
£ 30
ft
o
CM
LLN33N001
0 10
1
0
.'I' ' 1, 1
*DATA NOT REPORTED OR REMOVED FOR EXPERIMENTAL REASONS
—
—
—
—
;X%
1
•!•:•:
1
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:|:j:|:
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STUDY DAYS
Figure 2-16. Nitric acid measurements taken at Claremont, CA, August and September 1979.
Source: Spicer et al. (1982).
Los Angeles, California by Sickles (1986) measured levels of nitric: acid that
ranged from 0.2 to 32 jjg/m . By way of comparison, data collected in in the
i
Ohio Valley and in North Carolina are shown in Table 2-16 and Figure 2-17. The
results from these locations, which were obtained in a different time of the
year, indicate much higher concentration of HNO~ in California. Other data
i <3
taken by Spicer et al. (1978) during Ithe summer in St. Louis, MO showed maximum
concentrations in excess of 30 ug/m for 23 h and 200
for 1 h,
2.8 SUMMARY
The level of knowledge about the frequency, magnitude and duration of acid
sulfate particle events/episodes is insufficient. Efforts must be made to
gather more data, but these should be done in such a way that situations where
maximum human exposures may occur are the focus of the research. In addition,
February 1988
2-58
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TABLE 2-16. RESULTS OF COLUMBUS AMBIENT AIR SAMPLING
Date
10-17-79
10-18-79
10-19-79
10-20/22-79
10-22/23-79
10-23-79
10-24-79
10-25-79
10-26-79
10-27/28-79
10-29-79
10-30-79
10-31-79
11-2-79
11-19-79
11-28-79
12-4-79
12-11-79
12-18-79
1-3-80
1-8-80
1-16-80
1-21-80
1-28-80
2-11-80
2-19-80
2-25-80
3-3-80
3-10-80
3-17-80
3-24-80
3-31-80
4-9-80
4-14-80
4-21-80
4-28-80
5-12-80
5-21-80
5-28-80
6-3-80
6-9-80
6-14/15-80
6-23-80
6-30-80
7-7-80
7-8-80
Day Of
Week
W
Th
F
S-M
M-Tu
Tu
W
Th
F
S-S
M
Tu
W
F
M
W
Tu
Tu
Tu
Th
Tu
W
M
M
M
Tu
M
M
M
M
M
M
W
M
M
M
M
W
W
Tu
M
s-s
M
M
M
Tu
Total
Inorganic
Nitrates
(Mg/m3)
0.30
2.40
3.40
1.90
1.26
<0.50
3.43
3.37
2.10
4.66
7.83
5.39
2.28
3.11
2.32
2.11
3.29
1.92
2.81
2.57
3.89
1.68
5.92
7.86
4.97
3.89
4.59
2.66
1.06
4.32
2.14
3.06
9.54
1.43
2.80
5.03
4.20
9.26
7.78
3.54
1.57
4.66
6.79
2.03
3.99
4.24
(jjg/m3)
0.30
1.10
2.16
1.07
0.78
<0.50
3.10
2.36
0.60
3.00
3.15
2.04
0.54
2.22
0.65
1.53
2.28
0.78
2.51
1.20
3.41
0.54
5.15
6.43
3.21
1.61
3.92
0.36
0.47
3.30
0.68
1.15
9.17
0.29
0.96
3.62
2.72
1.48
2.09
0.90
0.82
1.55
2.32
0.70
1.44
1.98
HN03
<0.30
1.31
1.24
0.82
0.48
<0.50
0.33
1.01
1.50
1.66
4.67
3.35
1.74
0.90
1.67
0.59
1.02
1.14
0.30
1.38
0.48
1.14
0.77
1.43
1.76
2.28
0.67
2.31
0.59
1.02
1.46
1.91
0.38
1.14
1.85
1.41
1.48
7.78
5.69
2.64
0.75
3.10
4.46
1.33
2.54
2.27
SO^2
(ug/m3)
<0.30
1.01
14.02
0.87
0.60
2.52
3.31
0.56
0.78
3.80
0.76
4.49
2.57
2.75
1.84
0.53
1.08
0.72
3.65
0.84
3.05
15.27
3.90
4.40
7.15
1.09
6.18
2.01
0.47
0.51
5.63
0.33
2.27
<0.28
<0.32
1.58
3.64
12.41
2.94
3.36
0.88
6.52
12.32
1.12
3.76
3.72
HC1
(ug/m3)
_
-
-
-
_'
_
-
_
_
-
_
-
_
-
-
-
.
;
-
-
_
-
_
-
-
-
-
-
-
-
-
-
-
-
_
-
-
-
-
-
-
-
-
-
-
-
February 1988
(continued on the following page)
2-59 DRAFT—DO NOT QUOTE OR CITE
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TABLE 2-16. (continued)
Date
8-12-80
8-25-80
9-2-80
9-11-80
9-15-80
9-22-80
9-30-80
10-5-80
10-15-80
10-21-80
10-29-80
Day Of
Week
Tu
M
Tu
Th
M
M
Tu
M
W
Tu
W
Total
Inorganic
Nitrates
(ug/m3)
3.27
8.92
4.35
3.84
2.17
1.77
2.40
4.20
4.11
3.88
1.79
1
NOs
l(ug/m3)
' 1.06
• 5.24
3.66
2.20
1.58
0.96
1.43
3.19
2.38
2.52
1.42
HN03
(ug/m3)
2.43
3.67
0.68
1.64
0.60
0.81
0.97
1.01
1.73
1.35
0.37
S042
(ug/m3)
0.40
31.20
9.69
5.54
5.16
1.16
6.04
7.13
5.30
2.23
1.73
HC1
(pg/m3)
_
-
0.25
1.41
1.52
0.05
0.39
0.21
0.54
0.18
0.25
Source: Spicer (1986).
further data are required on the mechanisms of formation of HpSO,, and on
what factors can be used to predict acid sulfate episodes. The motivation for
conducting more studies is primarily the potential for an effect and the
establishment of the conditions for iexposure. The high exposures calculated
for some of the documented data were not for studies necessarily designed to
examine high as well as low human exposures. Most were basically designed to
investigate the characteristics of the atmosphere. Thus higher exposure
situations could be present in North America.
From the studies identified and discussed, it appears that two potential
exposure situations are possible. Those related to: (1) regional stagnation
and transport conditions, and (2) local plume impacts.
; o
Levels of apparent HpSO. in excess of 20 to 40 ng/m have been observed
for time durations ranging from 1 to 12 hours, and these were associated with
-2 3
atmospheric SO, levels in excess of 40 ug/m and with possible exposures
3
during episodes of >900 (ug/m )-h. Earlier London studies indicated that
2
HgSO, in excess of 100 ug/m can be present in the atmosphere, and exposures
>2,000 (ug/m )-h were possible.
It is apparent that the two types of outdoor conditions mentioned above
can lead to a number of possible situations for conducting epidemiological and
human exposure studies. The first would be studies conducted during major
summertime haze episodes, where large populations in the eastern U.S. could
February 1988
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DATE (1986)
Figure 2-17. Diurnal variation in nitrate concentration, Raleigh, NC, 1985.
Source: Stevens (1986).
February 1988
2-61
DRAFT—DO NOT QUOTE OR CITE
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be affected periodically by high acid sulfate levels. The exposure could be
manifested by high H^SO. and/or NH.HSO. accumulated over periods of one hour
or more throughout a day or sequence of days. Because these episodes occur
in the summer, large segments of jthe population will be participating in
outdoor activities in the rural and suburban areas. These individuals would
be most at risk during regional events, and would be the focus of opportunities
for epidemiological studies.
The second type of exposure would be confined to places downwind of a
power plant plume or urban plume during any season of the year. Obviously,
the greatest potential for population exposure would still be during the
summer; however, exposures could still occur during all of the other seasons.
The latter would be confounded by variable levels of outdoor activity, and
degree of penetration of the acid sulfate into the home. It should be noted
that the highest acid concentrations observed in the cited studies appear to
be associated with direct plume impacts. Therefore, these types of locations
warrant considerable attention in long-term health effect epidemiological
studies. In considering locations for investigations on exposures to acid
aerosols, locations outside the United States and Canada should be considered.
Space heating with open heat sources can lead to emissions of acid
aerosols indoors. This potential acid exposure situation should bo considered
for study.
At present there are a few studies that have included the measurement of
nitric acid vapor. As the use of samplers such as the annular denuder become
more common, the concentrations of the H in both the vapor phase and the
particulate phase will be more easily compared. Further research on the tech-
niques for nitric acid determinations is also necessary.
Most research on acid fog has been limited to rural and in mountainous
areas outside of California. A better data base on fog is necessary, especially
in terms of the potential for enhanced aerosol acidity after the fog evaporates.
2.8.1 Implications for Atmospheric Pollution Studies
Many of the technique limitations and the implications derived from
i
measurement of strong acids in atmospheric aerosols have already been
introduced in the preceding sections. A summary of these limitations and
implications is included below.
February 1988
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DRAFT—DO NOT QUOTE OR CITE
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1.
2.
3.
4.
5.
Most of the strong acid content of the atmospheric aerosol
derives from partially NH3-neutralized sulfuric acid aerosol.
Regional levels of acid sulfate aerosols are predominantly
formed by secondary oxidation processes in the atmosphere, with
only a small fraction from primary emissions.
Techniques now exist that are in large part sufficiently
sensitive and selective for ambient measurements with adequate
time resolution for surface measurements. Improvements are
still needed for certain airborne applications.
No practical technique exists
bisulfate from ammonium sulfate
mixtures in ambient aerosols.
that distinguishes ammonium
in either internal or external
Local ammonia concentrations largely control the surface levels
of atmospheric strong acids to which populations are exposed.
Additional measurements of this important species are recom-
mended.
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3. DEPOSITION AND FATE OF INHALED ACID AEROSOLS IN THE RESPIRATORY TRACT
3.1 INTRODUCTION
This chapter first reviews the deposition of inhaled aerosols in the
respiratory tract for both humans and experimental animals. The special case
of hygroscopic aerosols is then addressed. Finally, an important factor
modifying the response to inhaled acids, namely neutralization by airway
surface fluid buffers or by endogenous ammonia, is assessed.
The respiratory tract is the major route of exposure to ambient acid
aerosols. In order to elicit any response, these aerosols must first deposit
on airway surfaces. The deposition of inhaled particles on the internal
surfaces of the airways defines the delivery rate to the initial contact
site(s) and, for materials that exert their action upon surface contact such
as irritants, is a major predicator of response. Deposition is controlled by
various physical mechanisms that are influenced by particle characteristics,
respiratory airflow patterns and rates, and respiratory tract anatomy. An
understanding of deposition is essential for interpretation of the results of
the animal toxicologic and human health effects studies discussed later.
Biological effects of aerosols are often related more to the quantitative
pattern of deposition within specific respiratory tract regions rather than to
total deposition. In regard to particle deposition, three main anatomic
regions can be considered: (1) the upper respiratory tract, which includes the
airways extending from the nose or mouth through the larynx; (2) the tracheo-
bronchial tree, which includes the conducting airways from the trachea through
the terminal bronchioles; and (3) the pulmonary or gas-exchange region, which
includes the respiratory bronchioles, alveolar ducts, alveolar sacs, and alve-
oli. Although there are numerous data on regional deposition of particles in
humans, many types of exposure protocols require use of experimental animals,
with the ultimate goal being extrapolation to humans. To apply results of
toxicologic studies adequately in risk assessment, it is essential to consider
differences in deposition patterns, since various animal species exposed to
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the same aerosol may not receive identical doses in comparable sections of the
respiratory tract.
3.2 PARTICLE DEPOSITION MECHANISMS AND PATTERNS
The deposition of inhaled particles in the respiratory tract occurs by
similar physical mechanisms in humans and experimental animals. There are five
significant mechanisms by which deposition may occur: impaction, sedimentation,
Brownian diffusion, interception, and electrostatic precipitation.
Impaction is the inertia! deposition of a particle onto an airway surface.
It occurs when the particle's momentum prevents it from changing course when
there is a change in the direction of bulk airflow. Impaction is the main
mechanism by which particles having aerodynamic diameters (Dae) >0.5 |jm deposit
in the upper respiratory tract and at or near tracheobronchial tree branching
points. The probability of impaction increases with increasing air velocity,
rate of breathing, particle density and size.
Sedimentation is deposition due to gravity. When the gravitational force
on an airborne particle is balanced by the total of forces due to air buoyancy
and air resistance, the particle will fall out of the air stream at a constant
rate, known as the terminal settling velocity. The probability of sedimenta-
tion is proportional to the particle's residence time in the airway and to
particle size and density, and decreases with increasing breathing rate.
Sedimentation is an important deposition mechanism for particles with diameters
(D ) >0.5 [im that penetrate to those-airways where air velocity is relatively
low, e.g. mid to small bronchi and bronchioles.
Submicrometer-sized particles, especially those with physical diameters
<0.2 urn, acquire a random motion due to their bombardment by surrounding air
molecules; this motion may then result in contact with the airway wall. The
displacement sustained by the particle is a function of a parameter known as
the diffusion coefficient, which is inversely related to particle cross-
sectional area. Brownian diffusion is a major deposition mechanism in airways
where bulk flow is low or absent, e.g., bronchioles and alveoli. However,
extremely small particles may deposit by diffusion in the upper respiratory
tract, trachea and larger bronchi.
Interception is a significant deposition mechanism for elongated parti-
cles, i.e., fibers, and occurs when the edge of the particle contacts the
airway wall. The probability of interception increases as airway .diameter
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decreases, and fibers that are long (e.g., 50 to 100 Mm) but thin (e.g.,
0.5 um) can penetrate into distal airways before depositing.
Some freshly generated particles can be electrically charged, and may
exhibit 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
and/or to space-charge effects, whereby repulsion of similarly charged parti-
cles results in increased migration towards the airway wall. The effect of
charge on deposition is inversely proportional to particle size and airflow
rate. Since most ambient particles become neutralized naturally due to air
ions, electrostatic deposition is generally a minor contributor to overall
particle collection by the respiratory tract; it may, however, be important in
laboratory studies.
Experimentally determined values for particle deposition within the human
respiratory tract as a function of the median size of the inhaled aerosol are
presented in the top panels of Figures 3-1 to 3-4. All values are expressed
as percentage deposition of the total amount of aerosol inhaled (i.e., deposi-
tion efficiency). The obvious variability is due to a number of factors, not
the least of which is the use of different experimental protocols in different
studies. Figure 3-1 shows the pattern for total respiratory tract deposition.
This is characterized by a minimum for particles with diameters of -0.3 to
0.5 Mm. As mentioned, particles with diameters >0.5 um are subject to impac-
tion and sedimentation, while the deposition of those <0.2 urn is diffusion
dominated. Particles with diameters between these values are minimally
influenced by all three mechanisms, and tend to have relatively prolonged
suspension times in air. They undergo minimal deposition after inhalation,
and most are, therefore, exhaled.
Studies of deposition in humans generally employ either oral or nasal
breathing, and the effect of breathing mode upon deposition is evident from
Figure 3-1. Inhalation via the nose results in greater total deposition than
does oral inhalation for particles with diameters >0.5 um; this is due to
enhanced collection in the nasal passages. On the other hand, there is little
apparent difference in total deposition between nasal or oral breathing for
particles with diameters between 0.02 to 0.5 um.
Figure 3-2 (top) shows the pattern of deposition in the human upper
respiratory tract. Again, it is evident that nasal inhalation results in
enhanced deposition. The greater the deposition in the head, the less is the
February 1988 3-3 DRAFT-DO NOT QUOTE OR CITE
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100
80
O HUMAN (ORAL)
® HUMAN (NASAL)
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Figure 3-1. Deposition efficiency (percentage deposition of amount inhaled)
in humans and experimental animals for total respiratory tract.
Source: Schlesinger (1987).
February 1988
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RAFT—DO NOT QUOTE OR CITE
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IUU
80
60
40
20
I
0)
a
Z °
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o
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10
Figure 3-3. Deposition efficiency (percentage deposition of amount inhaled)
in humans and experimental animals for tracheobronchia! region.
Source: Schlesinger (1987).
February 1988
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60
40
20
OJ
a
•^m Q
O
H
I
g 60
40
20
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i
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I
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PARTICLE DIAMETER, Mm
Figure 3-4. Deposition efficiency (percentage deposition of amount inhaled)
in humans and experimental animals for pulmonary region.
Source: Schlesinger (1987)
February 1988
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DRAFT—DO NOT QUOTE OR CITE
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amount available for removal in the lungs. Thus, the extent of collection in
the upper respiratory tract affects deposition in more distal regions.
Figure 3-3 (top) depicts deposition in the tracheobronchial tree. In this
region, the relationship between deposition and particle size is not as well
defined as in other regions; fractional tracheobronchial deposition is rela-
tively constant over a wide particle size range.
Deposition in the human pulmonary region is shown in Figure 3-4 (top).
With oral inhalation, deposition increases with particle size, after a minimum
at ~0,5 urn. With nasal breathing, on the other hand, deposition tends to
decrease with increasing particle size. The removal of particles in more
proximal airways determines the shape of the pulmonary curve. For example,
increased upper respiratory and tracheobronchial deposition would be associated
With a reduction of pulmonary deposition; thus, nasal breathing results in less
pulmonary penetration of larger particles, and a lesser fraction of deposition
for entering aerosol than does oral inhalation. Thus, in the latter case, the
peak for pulmonary deposition shifts upwards to a larger sized particle, and is
more pronounced. On the other hand, with nasal breathing, there is a relatively
constant pulmonary deposition over a wider range of sizes.
Since much information concerning responses to inhaled acids is collected
using experimental animals, the comparative regional particle deposition in
these animals must be considered to help interpret, from a dosimetric view-
point, the implications of animal toxicological results to humans. The bottom
panels of figures 3-1 to 3-4 show deposition in commonly used experimental
animals. 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
relatively 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 \m. Inter-
species differences in regional deposition efficiencies occur due to anatomical
and physiological factors. In most experimental animal species, deposition in
the upper respiratory tract nears 100 percent for particles >2 urn, indicating
greater efficiency than that seen in humans. In the tracheobronchial tree,
there is a relatively constant, but lower, deposition efficiency for particles
of 0.1 to 5.0 urn in all species compared to humans. Finally, in the pulmonary
region, deposition efficiency peaks at a lower particle size (~1 pm) in the
experimental animals than in humans (2 to 4 urn).
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In evaluating studies with aerosols in terms of interspecies extrapola-
tion, it is not adequate to express the amount of deposition merely as a
percentage of the total inhaled. Since overall respiratory tract deposition
for the same size particle may be quite similar in humans and many experimental
animals, it follows that deposition efficiency is independent of body size
(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 initial mass deposition. If the total amount of deposition is
normalized to body weight, smaller animals would receive greater initial
particle burdens per unit weight per unit exposure time than would larger ones.
3.3 HYGROSCOPIC AEROSOLS
Most deposition studies tended to focus on insoluble and stable test
aerosols whose properties do not change during inhalation. Ambient aerosols,
however, usually contain deliquescent or hygroscopic particles that may grow
while in transit in the humid respiratory airways. Such particles will deposit
according to their hydrated, rather than their initial, size (Blanchard and
Willeke, 1984; Cavender et al., 1977). In general, the larger the initial
particle size, the less is the absolute growth and growth rate; in any case,
the deposition pattern of a specific hygroscopic aerosol can usually be related
to its growth characteristics. A comprehensive review of those factors affect-
ing the deposition of hygroscopic aerosols has been provided by Morrow (1986).
Because of dynamic changes in particle size, it is likely that deposition
of an acid particle may not be predictable from data on nonhygroscopic aerosols
inhaled at the same size. For example, a 1 pm (Dae) particle of H2$04 may grow
to nearly 3 pro (D ) while in the nasal passages, increasing total respiratory
36
tract deposition by a factor of 2 or more over that expected for the original
1 urn particle; this is due to an increase in both upper respiratory tract and
tracheobronchial deposition. Concomitantly, there would be a decrease in
pulmonary deposition. However, actual differences in deposition may vary,
depending upon the initial size of the acid droplet. For example, the rela-
tionship between total respiratory tract deposition and inhaled particle size
for humans (Figure 3-1) suggests that hygroscopic .particles inhaled at <0.5 urn
would actually show a decrease in total deposition if they grow no larger than
0.5 urn, and will only begin to show an increase in deposition if the final
diameter reached is >1 urn. On the other hand, 0.3 to 0.5 urn hygroscopic
February 1988 3-9 DRAFT—DO NOT QUOTE OR CITE
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particles may show substantial changes in their deposition probability.
Particles >5 urn may minimally grow in one respiratory cycle, and may not show
an increase in deposition at all compared to similarly sized nonhygroscopic
particles (Perron et al., 1987). Analytical deposition models developed
specifically for hygroscopic sulfate particles (Martonen and Patel, 1981a,b)
also indicate that total respiratory tract deposition efficiencies for such
particles in humans should be greater than those for nonhygroscopic particles
if the sulfate originates from particles having diameters larger than 0.1 to
0.3 urn. But even if the total deposition of hygroscopic and nonhygroscopic
particles of the same initial size is the same, regional deposition may differ
(Martonen et al., 1985).
The deposition of acid sulfate aerosols has been examined in experimental
animals. Dahl and Griffith (1983) assessed the deposition of H2SCL aerosols in
guinea pigs and rats. Upper respiratory tract and lung, as well as total
respiratory tract, deposition of aerosols ranging in size from 0.4 to 1.2 urn
(MMAD) was found to increase with increasing initial droplet size. Although
the lung deposition of 0.5 urn acid .particles was similar to that for 0.5 urn
nonhygroscopic particles, 1 urn H2$(K particles deposited much more effectively
than did 1 urn nonhygroscopic particles. On the other hand, Dahl et al. (1983)
examined the deposition of similarly sized hLSO- aerosols in dogs, and found
the deposition pattern at two relative humidities (20 percent and 80 percent)
to be similar to that of nonhygroscopic aerosols having the same size. The
interindividual variability of deposition in these animals was greater than the
differences due to relative humidity, It was suggested that hygroscopicity was
not a dominate determinant of deposition site in this larger mammal. Thus, the
relative effect of hygroscopicity on ultimate deposition pattern is not resolved,
since results using ideal models and those from actual experiments may not
agree; in addition, the extent of the effect on deposition may depend upon the
animal species.
3.4 NEUTRALIZATION BY AIRWAY SECRETIONS AND ABSORBED AMMONIA •
Two important chemical defenses against inhaled acid include endogenous
ammonia and airway surface liquid buffers. Acids .may react with ammonia to
produce ammonium salts or may be buffered by airway secretions. The capacity
to buffer or neutralize inhaled acid may thus be an important factor in the
eventual toxicity to the organism.
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3.4.1 Airway Surface Liquid Buffering
The acid-base equilibrium of airway surface fluids may be altered by
buffer content, secretion rate, and presence of inflammation and may differ
according to the region of the lung from which the airway secretions are
obtained (Lopez-Vidriero et al., 1977). Reported values of sputum pH range
from 5 to 8. Changes in pH of airway secretions alter the properties of the
mucus macromolecules and hence the viscosity of the mucus gel layer. Secretion
of sulfated mucins (sulfomucins) may be partially responsible for alterations
in pH.
Gatto (1981) measured the pH of the mucus gel surface layer in rats using
a surface pH probe inserted through a tracheal "window." The pH averaged
7.52. Cholinergic stimulation caused a decrease to 7.46, presumably due to
increased secretion of acidic glycoproteins and sialic acid in the mucus.
The effect of alterations of pH on ciliary motility and on the morphology
of the airway mucosa was examined by Holma et al. (1977). These authors
reported that previous studies of cilia from invertebrates, fundamentally
similar to human cilia, show that not only the pH but also the ionic composi-
tion of the medium influence ciliary motility. Ciliostasis occurs in mammalian
respiratory tract cilia at pH's ranging from 5.2 to 6.4. Human bronchial pH
was measured with a surface pH electrode inserted via a bronchoscope. This
yielded i_n situ measurements of mucus pH (Guerrin et al., 1971). Normal values
ranged from 6.5 to 7.5 with a mean of approximately 6.9. These investigators
also showed that hypercapnia (respiratory acidosis) was associated with a
reduction in mucus pH. Inflammation and infection was associated with
considerably more acidic mucus pH's (5.2 to 6.2). Tracheal pH measured in
rabbits averaged about 6.6, slightly more acidic than in the humans.
Bodem and co-workers (1983) measured endobronchial pH using a flexible pH
probe passed through a bronchoscope and wedging it in a peripheral bronchus.
Measurements made in normals and 18 patients revealed a mean pH of 6.6 (range
6.44 to 6.74). The presence of pneumonia in the patients was associated with
a slightly lower (6.48) pH. The average endobronchial pH in a group of five
dogs was 7.1.
Mucus is converted from a gel to a sol at a pH of about 7.5. Holma et al.
(1977) indicate that the mucus is secreted in an alkaline form (and thus as a
gel) and is subsequently acidified by carbonic acid formed by C02 dissolved in
the mucus layer. It .was suggested that acidification of the gel layer by
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inhaled acids or acid forming gases: (SO,,, C02) would cause increased mucous
viscosity and hence increased clearance, provided the pH is not reduced suf-
ficiently to reduce ciliary motility^
Ciliary motility of isolated bovine trachea! strips was studied. Normal
ciliary activity was observed in the pH range of 6.7 to 9.7. H2S04 was used
for acidification and complete cilipstasis was observed at pH 4.9, Further-
more, at acid pH, epithelial cells "loosened from each other and from the
basement membrane". Since normal motility is maintained to pH 6.7 (in cows),
Holma et al. (1977) concluded it was unlikely that ambient levels of SO,, would
cause sufficient acidification of the mucus layer to alter ciliary motility.
Ciliostasis was typically preceded by intracellular edema.
In a more recent study, Holma (1985) examined the buffer capacity and
pH-dependent rheological characteristics of human sputum. The pH of sputum
is in equilibrium with respiratory CO,,; the normal sputum pH of about 7.4 is
established by the buffering system of the sputum. Sputum equilibrated with
5 percent C02 at 37°C and 100 percent RH was titrated with H2$04 to pH 3.
Although buffer capacity was variable depending on the sputum sample, depres-
sion of sputum pH from 7.25 to 6.5 required the addition of approximately
6 umol of H per ml of sputum. Sputum from asthmatics had a lower initial pH
(6.8; range 6.3 to 7.4) and reduced buffering capacity. Sputum viscosity was
minimal at a pH of 7.5 and was increased as the sputum was acidified. Recent
work by Holma (Holma, 1988) demonstrates a minimal value for mucus viscosity at
a pH of 7.0. Viscosity increased with acidification or alkalinization of the
mucus. Since the capacity of mucus to buffer H+ is reduced in asthmatics, this
provides another reason to be concerned with acid aerosol exposure of this
sensitive group. I
Assuming a tracheobronchial mucus volume of 2.1 ml, between 8 and 16 umol
of H if evenly distributed throughout the airways would be required to depress
the pH to 6.5. Since 1 ug H is obtained from 49 ug of H2SO., between 390 and
780 ug of H2SO. would be needed to cause this depression of pH. Assuming
exposure duration of 30 min, ventilation of 20 L/min and 50 percent deposi-
tion of 100 ug/m3 H2SO^ (1M), 0.6 umol of H+ would be deposited in the lung
(50 percent x 100 ug/m x (600 L -r '1,000 L/m3) = 30 ug = .3 umol H2S04 or
0.6 ug of H ). However, if deposition was localized to airways with a small
volume of mucus, less acid would be required to cause reductions in pH.
Fine et al. (1987) hypothesized that buffered acid aerosols (with a
greater "hydrogen ion pool") would cause more bronchoconstriction than
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unbuffered acid aerosols of the same pH. Since the 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 pH. If a change
in pH is the primary mechanism that triggers bronchoconstriction following
inhalation of acid aerosol, then it follows that buffered acids would be more
potent bronchoconstrictive agents. The subjects were 8 nonsmoking clinically
mild asthmatics whose medications included theophylline and p-sympathomimetic
bronchodilators. Their asthma was stable throughout the study and,there were
no significant deviations in baseline SR .
aw
Subjects were first administered unbuffered HC1 and H2S04 aerosols of pro-
gressively increasing acidity (pH's were 7, 5, 4, 3, 2). The osmolarity of the
aerosolized solutions was about 300 mOsm (i.e., isoosmolar). Only one subject
experienced a demonstrable increase (120 percent) in SR at pH = 2 with HC1;
the mean increase was 28 percent for HC1 at pH = 2 and 15 percent for H2S04 at
pH = 2. With buffered acid aerosols at pH = 2 all subjects (except one with
H2S04) experienced at least a 50 percent increase in SR (the mean change is
not reported since the test was terminated at different levels of titratable
acidity for each subject depending on his or her response). Most subjects
experienced cough during the acid aerosol challenges.
These studies demonstrate that the acidity of inhaled aerosols is related
to their potential to stimulate cough and bronchoconstriction. More specifi-
cally, these responses are related to the total available hydrogen ion
(titratable acidity), not just the. pH. Since airway surface fluids are capable
of buffering small amounts of hydrogen,ion, the minimal response to unbuffered
acids is presumably related to a transient change in airway surface pH. These
observations suggest the possibility that persistent effects of acid aerosols
(reported in other studies) may be related to persistence of changes in pH of
airway surface fluids.
Since most acid fogs are likely to have a low osmolarity, Balmes and
colleagues (Balmes et al., 1988a; Balmes et al., 1988b) investigated the
hypothesis that increased acidity could potentiate the known effects of
hypoosmolar aerosols to cause bronchoconstriction (Sheppard et al., 1983) in
subjects with asthma. Subjects were administered increasing quantities of five
different aerosols (5.2 to 6.3(jm): hyposmolar saline (HS), HS + HpS04,
HS + HN03, HS + H2S04 + HNOg, and issomolar H2S04. All acid solutions were
adjusted to pH 2. Response to the aerosols was assessed by giving subjects a
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series of increasing aerosol concentrations. The amount of aerosol required to
increase airway resistance by 100 percent was determined by making a series of
SR measurements after each dose of aerosol.
aw
The three acid hypoosmolar aerosols caused a 100 percent increase in SRgw
at a lower aerosol concentration than did the hypoosmolar saline. There were
no differences in responses related to acid composition of the aerosol.
Isoomolar H2$04 aerosol did not cause a 100 percent increase in SRaw even at
the highest dose, estimated to be 43.5 mg/m .
The results of this study support one of the conclusions of Fine et al.
(1987), namely that the H+, not SO^ o|r NOg anion, is the stimulus for broncho-
constriction. However, this study also demonstrates that H is a more potent
stimulus to bronchoconstriction when;administered as a hypoosmolar aerosol.
Nevertheless, as the authors point out, both the water content and the acid
content of the aerosols were much higher than would be seen even in the worst
case acid fog situation.
Potential risk groups sensitive to acid deposition would include individ-
uals with "acid-saturated" mucus (i.e. low initial pH), individuals whose
mucus has a low buffering capacity, or those with an incompletely developed
mucociliary system (i.e. infants).
3.4.2 Ammonia Neutralization of Inhaled Acid
Ammonia is present in the expired air of man and animals. Kupprat et al.
(1976) reported in man expired volumes of 2 pi at rest and 6 pi during exercise,
approximately equivalent to 0.2 ppm or 138 pg/m • Robin et al. (1959) reported
o i
levels of 0.38 ppm or 262 pg/m in dogs given intravenous NH^HCOg solution.
Larson and co-workers (1977) presented the hypothesis that expired ammonia
from the respiratory tract could neutralize a significant portion of inhaled
acid aerosol. They used a variety of sampling techniques to determine the
source(s) of the respiratory ammonia in a group of 16 subjects. When gas was
sampled from the mouth, the median NH3 concentration ranged from 130 to
210 pg/m3. Samples taken from the nose or directly from an endotracheal tube
had a median concentration of 21 to 29 pg/m3. It was suggested that the mouth
i
was a major source of expired ammonia, possibly from the bacterial decom-
position of salivary urea. One microgram of NH3 can convert 5.8 pg of H2$04 to
ammonium bisulfate or 2.9 pg of sulfuric acid aerosol to ammonium sulfate. It
was determined that with the range i of respiratory ammonia levels (up to
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3
520 ug/m ) a maximum of 1,500 ug HLSO. could be neutralized to (NHOpSO.. The
extent to which respiratory ammonia can neutralize sulfuric acid aerosol
depends not only upon the production of respiratory ammonia but also upon the
inspiratory flow rate and the time within the airways that elapses prior to
impaction or sedimentation of the aerosol.
c Larson et al. (1979a) extended their observations in a group of 10 subjects
and observed a higher mean value for ammonia concentration sampled at the mouth
3
of 690 ppb or 475 ug/m . These results are comparable to the mean value of
3
790 ppb (544 ug/m ) reported by Hunt and Williams (1977). The increase in
ammonia levels reported by Larson et al. (1979a) in their second report was
apparently due to an improvement in the sampling method.
Larson et al. (1979b) also reported measurements of expired ammonia in the
3 3
dog. Ammonia concentration at the mouth was 130 ug/m but was only 41 ug/m
when measured in the trachea. This again suggested the importance of the oral
cavity as a source of ammonia.
Barrow and Steinhagen (1980) found an average expired NH- level of 78 ppb
3
in nose-breathing rats, or 54 ug/m . This is only slightly higher than results
3
for nose breathing humans, ~25 ug/m . Trachea! cannulated rats had NH- levels
3
of 286 ppb or about 197 ug/m . Thus, these results suggest that the nose is a
sink for NH, in the rat.
Vollmuth and Schlesinger (1984) measured expired ammonia levels in a
3
group of 5 rabbits. They noted an average expired level of 185 ug/m . When
the rabbits underwent an oral cleansing and tooth brushing regimen prior to
3
measurement, the NH, levels decreased to 126 ug/m , indicating a significant
oral source of ammonia. Fasting, with oral hygiene, caused a further
reduction in expired ammonia to 68 ug/m . It was concluded that fasting
probably further reduced the oral sources of ammonia and was not associated
with reduced amino acid metabolism. Using the model of Larson et al. (1982)
it was estimated that about 14 percent of inspired 0.3 urn hygroscopic sulfuric
3
acid aerosol would be neutralized with a NH- level of 185 ug/m and an oral
cavity residence time of 200 msec.
3
Larson et al. (1982) measured expired ammonia levels of 31 ug/m (45 ppb)
3
and 57 ug/m (82 ppb) from dogs breathing through the nose or mouth
3
respectively. Ammonia concentration in the trachea averaged 28 ug/m (40 ppb).
They calculated the concentration of NH- that would be in equilibrium
with blood NH* of 38 ug/m3.
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In addition, NFL levels were measured at the trachea for air drawn
3
unidirectional through either the nose or mouth. Similar levels of ~83 ug/m
were seen regardless of whether the air entered via the nose or mouth.
Neutralization of inhaled acid aerospl was linearly related to the concentra-
tion of NH« at the level of the larynx; approximately 60 percent of inhaled
0.5 urn sulfuric acid aerosol was neutralized with laryngeal ammonia levels of
3
~135 ug/m and a flow rate of 0.1 L/s. The authors made estimates of
o
neutralization of 100 ug/m H^SO- in humans using a model based on this study.
They estimated that, with oral levels of ammonia, particles less than 0.2 urn
would be fully neutralized by ammonia prior to entering the trachea; only about
30 percent of 0.5 urn particles would! be neutralized under similar conditions.
Larson et al.'s estimates indicate a slightly less efficient neutralization of
inhaled acid than the model of Cocks and McElroy (1984).
There appears to be considerable variability in expired ammonia levels
from one species to another. The mode of breathing or the location from which
ammonia is sampled is also the source of considerable variation. It is
important to establish whether these differences are true species differences
or methodological differences.
The probability of endogenous ammonia causing neutralization of inspired
acid aerosols has been an issue in a number of investigations. Some of the
factors implicated in neutralization of acid aerosols have been discussed by
Larson et al. (1978). The likelihood of neutralization of acid aerosols
depends upon
1. particle size — small particles are subject to more rapid
neutralization than large particles with the same acid
concentration
2. concentration of ammonia in the airways
3. concentration of acid in the aerosol - this is partially depen-
dent on hygroscopic growth of the aerosol in the airways !
4. residence time of the aerosol in the airways.
It appears that ammonia concentrations are not uniform throughout the respira-
tory tract, and thus neutralization is also dependent on the avenue of inhala-
tion of acid aerosols; oral inhalation offers the greatest potential for
neutralization by ammonia.
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Loscutoff et al. (1978) exposed dogs to various levels of sulfuric acid
3
aerosol. With 1 or 3.5 mg/m HpSO they reported that all expired sulfate
was in the form of an ammonium salt. Such measurements, of course, provide no
indication of the fate of HpSO- that is deposited within the lung.
Utell et al. (1986) discussed the effects of oral ammonia in a recent
3
symposium presentation. They exposed asthmatics to 350 pg/m . sulfuric acid
3 3
aerosol via mouthpiece under conditions of low (69 pg/m ) or high (340 |jg/m )
expired ammonia levels. Exposure lasted 10 min while subjects performed light
exercise. The reduction in FEV-, Q was significantly greater if the subjects
were exposed when the oral ammonia levels were lower. The higher oral ammonia
level has the potential (i.e., if the reaction goes to completion and uses up
all the ammonia) to convert over 900 pg of H,,S04 to (NH^SO., while the lower
ammonia concentration could convert only about 190 |jg. These data strongly
support the hypothesis that oral or respiratory ammonia may play an important
role in the airway toxicity of sulfuric acid aerosol. However, recent studies
by Avol et al. (1986) suggest that further investigation of the ammonia neutra-
lization hypothesis is needed.
Cocks and McElroy (1984) have recently presented a model analysis of
neutralization of sulfuric acid aerosols in human airways. The acidity of the
particles is a function of dilution by particle growth and neutralization by
absorbed ammonia. With acid concentrations of 0.14 M, droplet growth does
not occur and neutralization is determined principally by ammonia absorption.
At higher acid concentrations,, droplet growth dilution is a major factor in
determination of pH (See Table 3-1).
Table 3-1 presents selected results of the model analysis of Cocks and
McElroy (1984). Data are presented for 5.0 (acid fog) and 0.5 pm (acid
3
aerosol) particles at both 500 (oral) and 50 (nasal) (jg/m ammonia, at times of
0.1 and 1.0 s, and for two different acid concentrations.
For 0.5 |jro particles with HLSO. concentration of 3M, aerosol mass concen-
3 3
tration of 100 |jg/m and ammonia of 500 pg/m, neutralization is complete in
3
0.3 s. With NH~ levels of only 50 (jg/m , neutralization requires 3 s. With an
acid concentration of 0.14M, where no particle growth occurs, neutralization
proceeds more rapidly. The authors concluded that, even with nasal levels of
ammonia, substantial neutralization of droplets less than 0.5 pm would occur.
With droplets in the "acid fog" size range and with low pH, neutralization is
slowed considerably, especially with low respiratory ammonia levels. However,
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TABLE 3-1. MODEL ESTIMATES OF NEUTRALIZATION OF 0.5 AND 5.0 urn PARTICLES
BY "ORAL" AND "NASAL" LEVELS OF AMMONIA
(Adapted from Cocks and McElroy, 1984)
H2S04
3.3M
0.14M
Aerosol
mass NH3
ug/m3 ng/rn3
1,000 500
(oral)
50
(nasal)
100 500
50
1,000 500
100 500
50
MMAD
|jm
5.0
0.5
5.0
0.5
5.0
0.5
5.0
0.5
5.0
1.0
5.0
1.0
5.0
1.0
% Neutral
O.ls
0.6
99
0.1
6.9
0.6
90.2
0.06
9.0
11.7
100
12
100
1.2
27
ized in
1.0s
7.7
99
0.8
14.2
7.9
99.9
0.79
81.3
81.9
100
I 100
11.7
100
the typically dilute solutions in acid fog droplets lend themselves to rapid
neutralization such that the reaction of 5 urn particles with oral levels of
ammonia would be complete in less tha;n 1.0 s with aerosol mass concentration
as high as 100 ug/m3.
Larson (1988) recently presented a model analysis which considered both
airway deposition and ammonia neutralization. This analysis indicates that
virtually no acid fog particles will successfully traverse the nasal airway
whether ammonia is present or not. During mouth breathing, acid fog particles
could reach the larynx and trachea but they are largely neutralized by oral
ammonia. Using calculations from this model, the effect of ammonia in
decreasing acid deposition of small (and more concentrated) aerosols; was much
less than for the large particles.
February 1988
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3.5 CONCLUSIONS
The respiratory tract is a target for inhaled particles, as well as a
portal of entry by which other organs may be affected. When aerosols are
inhaled by humans or experimental animals, different fractions of the inhaled
materials deposit by a variety of mechanisms in various locations in the
respiratory tract. Particle size distribution and other particle properties,
respiratory tract anatomy, and airflow patterns all influence deposition.
Impaction, gravitational settling, and diffusion dominate the deposition
of particles in the respiratory tract, with electrostatic attraction and
interception being of relatively minor importance. Oiffusivity and the inter-
ception potential of a particle depend on its geometrical size, whereas the
probability of settling and impaction depend on its aerodynamic diameter.
Gravitational settling accounts for deposition in the tracheobronchial and
pulmonary regions, while impaction contributes to deposition in the upper
respiratory tract and tracheobronchial regions. Diffusion primarily affects
respiratory tract deposition of particles with diameters smaller than 0.2 [im.
Hygroscopicity is a major particle characteristic which affects deposition.
Hygroscopic particles change in size once inhaled, and may have different
patterns of deposition when compared to nonhygroscopic particles at the same
size; the difference is a function of the initial particle size and composition.
Some portion of inhaled acids will be transformed into the ammonium salts
as the acid enters the respiratory tract. Acid that is deposited in the
airways prior to reaction with ammonia will be buffered by airway surface
fluids. The extent to which these two processes will influence the ultimate
fate of the acid will depend upon a number of factors. Larger particles in the
"acid fog" size range (5 pm) will be slower to be neutralized but more likely
to impact upon the airway walls. Smaller particles (~0.5 pm) are subject to
more rapid chemical transformation by ammonia.
The total capacity to buffer or "neutralize" acid is substantial. How-
ever, regional capacities vary considerably. For example, the surface liquid
buffering capacity of the non-ciliated airways and alveoli is probably quite
low. Furthermore, alveolar ammonia levels are lower than in the oral cavity.
It is therefore likely that the physiologic effects of inhaled acid aerosols
are due to either accumulation of acids at specific sites that overwhelms the
neutralization/buffer capacity or to accumulation in lung regions that have a
low neutralization/buffer capacity.
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3.6 REFERENCES
Avol, E. L.; Linn, W. S.; Hackney, J. D. (1986) Acute respiratory effects of
ambient acid fog episodes: final report. NIEHS grant no. ES03291-02;
September.
Balmes, J. R.; Fine, J. M.; Gordon, T.; Sheppard, D. (1988a) Potential broncho-
constrictor stimuli in acid fog.jIn: International symposium on the health
effects of acid aerosols: addressing obstacles in an emerging data base;
October 1987; Research Triangle Park, NC. EHP Environ. Health Perspect.:
in press.
Balmes, J. R.; Fine, J. M.; Christian, D.; Gordon, T.; Sheppard, D. (1988b)
Acidity potentiates bronchoconstriction induced by hypoosmolar aerosols.
[Manuscript submitted].
Barrow, C. S.; Steinhagen, W. H. (1980) NH3 concentrations in the expired air
of the rat: importance to inhalation toxicology. Toxicol. Appl., Pharmacol.
53: 116-121. ;
Blanchard, J. D.; Willeke, K. (1984) Total deposition of ultrafine sodium
chloride particles in human lungs. J. Appl. Physiol. 57: 1850-1856.
Bodem, C. R.; Lampton, L. M.; Miller, D. P.; Tarka, E. F.; Everett, D. (1983)
Endobronchial pH. Am. Rev. Respir. Dis. 127: 39-41.
Brain, J. D.; Mensah, G. A. (1983) Comparative toxicology of the respiratory
tract. Am. Rev. Respir. Dis. 128(suppl.): S87-S90.
Cavender, F. L.; Steinhagen, W. H.; McLaurin, D. A., Ill; Cockrell, B. Y.
(1977) Species difference in sulfuric acid mist inhalation. Am. Rev.
Respir. Dis. 115(suppl.): 204.
Cocks, A. T.; McElroy, W. J. (1984) Modeling studies of the concurrent growth
and neutralization of sulfuric acid aerosols under conditions in the human
airways. Environ. Res. 35: 79-96.
Dahl, A. R.; Griffith, W. C. (1983) Deposition of sulfuric acid mist in the
respiratory tracts of guinea pigs and rats. J. Toxicol. Environ. Health
12: 371-383.
Dahl, A. R.; Snipes, M. B.; Muggenburg, B. A.; Young, T. C. (1983) Deposition
of sulfuric acid mists in the respiratory tract of beagle dogs. J.
Toxicol. Environ. Health 11: 141-149.
Ferron, G. A.; Kreyling, W. G.; Haider, B. (1987) Influence of the growth of
salt aerosol particles on the deposition in the lung. Ann. Occup. Hyg.: in
press.
Fine, J. M.; Gordon, T.; Thompson, Jr E.; Sheppard, D. (1987) The role of
titratable acidity in acid aerosol-induced bronchoconstriction, Am. Rev.
Respir. Dis. 135: 826-830.
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Gatto, L. A. (1981) pH of mucus in rat trachea. J. Appl. Physiol. 50: 1224-1226.
Guerrin, F.; Voisin, C. ; Macquet, V.; Robin, H. ; Lequien, P. (1971) Apport
de la pH metric bronchique ui situ [Measurement of pH in the bronchi
in situ]. In: Ulmer, W. T., ed. Chronic inflammation of the bronchi:
proceedings of the Societas Europaea Physiologiae Clinicae Respiratoriae
and Gesellschaft fuer Lungen- und Atmungsforschung; December 1969; Bochum,
Federal Republic of Germany. Basel, Switzerland: S. Karger; pp. 372-383.
(Herzog, H., ed. Progress in respiration research: v. 6).
Holma, B. (1985) Influence of buffer capacity and pH-dependent rheological
properties of respiratory mucus on health effects due to acidic pollution.
Sci. Total Environ. 41: 101-123. .
Holma, B. (1988) Effects of inhaled acids on airway mucus and its consequences
for health. In: International symposium on the health effects of acid
aerosols: addressing obstacles in an emerging data base; October 1987;
Research Triangle Park, NC. EHP Environ. Health Perspect.: in press.
Holma, B.; Lindegren, M.; Andersen, J. M. (1977) pH effects on ciliomotility
and morphology of respiratory mucosa. Arch. Environ. Health 32: 216-226.
Hunt, R. D.; Williams, D. T. (1977) Spectroscopic measurements of ammonia in
normal human breath. Am. Lab. (Fairfield, Conn.) 9: 10-22.
Kupprat, I.; Johnson, R. E. ; Hertig, B. A. (1976) Ammonia: a normal constituent
of expired air during rest and exercise. Fed. Proc. Fed. Am. Soc. Exp.
Biol. 35: 478.
Larson, T. V. (1988) The influence of chemical and physical forms of ambient
air acids on airway doses. In: International symposium on the health
effects of acid aerosols: addressing obstacles in an emerging data base;
October 1987; Research Triangle Park, NC. EHP Environ. Health Perspect.:
in press.
Larson, T. V.; Covert, D. S. ; Frank, R.; Charlson, R. J. (1977) Ammonia in the
human airways: neutralization of inspired acid sulfate aerosols. Science
(Washington, DC) 197: 161-163.
Larson, T. V.; Covert, D. S.; Frank, R.' (1978) Respiratory NH3: a possible
defense against inhaled acid sulfate compounds. In: Folinsbee, L. J. ;
Wagner, J. A.; Borgia, J. F.; Drinkwater, B. L.; Gliner, J. F. ; Bedi, J.
F. , eds. Environmental Stress: individual human adaptations, proceedings
of a symposium; August 1977; Santa Barbara, CA. New York, NY: Academic
Press; pp. 91-99.
Larson, T. V. ; Covert, D. S. ; Frank, R. (1979a) A method for continuous mea-
surement of ammonia in respiratory airways. J. Appl. Physiol.: Respir.
Environ. Exercise Physiol. 46: 603-607.
Larson, T. V.; Frank, R.; Covert, D. S.; Holub, D.; Morgan, M. (1979b) Measure-
ments of respiratory ammonia and the chemical neutralization of inhaled
sulfuric acid aerosol in anesthetized dogs. Am. Rev. Respir. Dis.
119(suppl.): 226.
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Larson, T. V.; Frank, R. ; Covert, D. S. ; Holub, D. ; Morgan M S (1982)
^^t^L^^^-telj
M v • MV' »ds- ResPirat<>ry defense mechanisms (in two parts)- part I
New York, NY: Marcel Dekker, Inc.; pp. 289, 326. pari,s;. part 1.
F' G'; Kl"lland> B. W. (1978) Neutralization^
"
*o™ \' *•''• r?telf M' (1981a) Model1n9 the dose distribution of H9SO.
~- ^^ tracheobronch1al t~e. Am. Ind. Hyg. Assoc. J.4
453-460.
H> +'• a^ ComPutat^» of ammonium blsulfate aerosol
conducting airways. J. Toxicol. Environ. Health 8- 1001-1014
'
international symposium organized
"iety; Septei '
hygroscopic
/is, D. M.; Bromberg, P. A.; Forkner, C. E. , Jr • Tyler J M
129: 270-27119 6XCretl0n by mamma^'an lung. Science (Washington, *DC)
TA/' B- (19817? Biological disposition of airborne particles- basic
ip es and application to vehicle emissions. In- AirPollution tho
automobile and public health. Washington, DC: National Academy Press.* in
!ghDand^r2oknchoconstricti^ A''' Bet.hel' *' A' (1983) Mechanism of
Respir. Dis. 127:"Si-694.^ lndllced by dlstll1ed water aerosol. Am. Rev
Utell M J.; Morrow, P. E.; Bauer, M. A.; Hyde, R W • Schrek R M
Modifiers of responses to sulfuric acioI aerosols \'n asthmati s
Aerosols: formation and reactivity. London: Pergamon Press
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DRAFT—DO NOT QUOTE OR CITE
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Vollmuth, T. A.; Schlesinger, R. B. (1984) Measurement of respiratory tract
.ammonia in the rabbit and implications to sulfuric acid inhalation
studies. Fundam. Appl. Toxicol. 4: 455-464.
February 1988 3-23 DRAFT—DO NOT QUOTE OR CITE
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-------
4. TOXICOLOGICAL STUDIES OF ACID AEROSOLS
4.1 INTRODUCTION
The goal of toxicologic studies is the estimation of risk to humans.
Often, this is done empirically with the use of animal models. These serve to
identify the nature of responses to toxicant exposure and the range of doses
over which such responses occur, and to provide information on mechanisms of
potential human toxicity and the pathogenesis of disease. Although studies
with experimental animals allow planning of future human studies and are, thus,
often done prior to initiating testing with humans, they are also needed for
protocols which cannot be used with humans at all, e.g., chronic or repeated
exposures which may result in delayed and/or nonreversible changes; such
studies serve to assess how the duration, and other conditions, of exposure
affect response. In addition, the use of destructive endpoints, such as patho-
logic assessment, requires animal models even with acute exposure protocols.
This chapter reviews and evaluates the toxicology of acid aerosols in
experimental animals. Almost all of the available data have been derived from
studies using acid sulfates, i.e., ammonium sulfate ((NH.)2SO.), ammonium
bisulfate (NH4HS04), and sulfuric acid (H2S04). The bulk of the studies
included involve exposure via inhalation; the effects of acids administered by
other routes have been discussed only when they help to assess the mechanisms
underlying responses to inhaled aerosols.
Although acid aerosols may be constituents of ambient atmospheres, they
are usually not the only pollutants present. Thus, the toxicologic effects of
pollutant mixtures are of concern in assessing the relative biological signifi-
cance of ambient acid aerosols. In this section, only studies in which a
specific acid is a primary component of the pollutant mix are discussed; those
in which the only acid present is formed secondarily due to chemical reaction
in the exposure atmosphere have not been included. .
It will be evident from this survey of the data base that there is a great
deal of variation, both qualitatively and quantitatively, in observed responses
to inhaled acids. One major reason involves response differences between
February 1988 4-1 DRAFT—DO NOT QUOTE OR CITE
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species, or between strains of the same species, due to inherent sensitivity
differences, or differences in age, health status, aerosol deposition patterns,
and respiratory tract NH~ levels. But even within the same species or strain,
variability may be quite large among various studies; this is likely due to
the lack of standardization in exposure protocols. A number of experimental
variables may impact upon the observed results. Differences in median acid
particle size as well as in size distribution affect the extent of aerosol
penetration into the respiratory tract, with resultant differences in the
mechanism or degree of toxic action at the site of initial contact and, per-
haps, the extent of neutralization by respiratory tract NH~. Hygroscopic
growth is also dependent upon the initial size of the acid droplets. Relative
humidity of the exposure atmosphere is another important factor affecting the
size of the inhaled acid particle and, therefore, the extent and rate of
subsequent particle growth. In addition, the nominal acidity of a droplet may
be altered by hydration after inhalation, or in the exposure system itself.
Other reasons for variability may involve the lack of adequate characterization
of the exposure atmosphere at the animal's breathing zone, the failure to
validate that the exposure system is dosing the animals as expected, or even
differences in the manner in which data are analyzed.
A single major confounding factor in assessing acid aerosol toxicology, and
a likely explanation for at least some of the wide variations in response even
within one species, is neutralization °Y both endogenous or exogenous NH~
(Chapter 3). The former may be affectfed by factors such as the time between the
last feeding and acid exposure and the normal bacterial flora of the respiratory
tract, while a major factor influencing exogenous levels is the particular mode
of exposure. For example, a greater potential for neutralization exists with
whole body chamber exposures, due to the possible release of NH, from excrement.
In any case, the result of neutralization would be delivery to the animals of
less strong acid than anticipated; but without knowing the extent of conversion
to less acidic, or neutral, products, the exact composition of the resultant
exposure atmosphere is not certain. Thus, in many studies, the actual relation
between sulfuric acid levels as measured in the generation or exposure atmos-
phere and dose to target site is difficult to evaluate. Mode of exposure may
also impact upon relative regional deposition and rate of hygroscopic growth.
Thus, multiple factors are involved in determining the responses observed in any
study, and these factors may interact with each other, accounting for the
variations in response to inhaled acid aerosols seen in the current data base.
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4.2 MORTALITY
The maximal toxic response is death, and a number of studies have examined
the acute lethality of acid aerosols, mainly H^SO.. As will be evident with
other toxicologic endpoints, large interspecies differences occur. Treon
et al. (1950) ranked species in terms of their sensitivity, based upon expo-
sures (chamber) of various duration (15 min to 7 h/d for 5d) to 87 to
3
1,610 mg/m H^SO. aerosols consisting of particles with diameters mostly <2 urn;
the ranking, in order of decreasing sensitivity, was as follows: guinea pig,
mouse, rat, rabbit.
Within a particular species of experimental animal, the HLSO. concentra-
tion required for lethality may be dependent upon animal age and exposure
aerosol particle size. In terms of the former, Amdur et al. (1952) determined
the t^SO. (1 |jm, MMD) concentration to produce 50 percent mortality (LC,-0) for
an 8-hr exposure (chamber) in guinea pigs to be 18 mg/m for 1 to 2 mo old
o
animals, and 50 mg/m for 18 mo old animals. The effect of particle size on
lethal concentration is shown in Table 4-1. Although the actual LC™ may
differ at similar sizes in different studies, the data show that in any one
study, smaller particles are less effective than are larger ones.
TABLE 4-1. EFFECT OF H2S04 PARTICLE SIZE ON MORTALITY
Particle Size
(unO
0.8 (MMD)
2.7 (MMD)
0.4 (MMAD)
0.8 (MMAD)
LC50a
(mg/m3)
60
27
>109
30.3
References
Pattle et al.
Pattle et al.
Wolff et al.
Wolff et al.
(1956)
(1956)
(1979)
(1979)
aBased upon 8-hr exposures (chamber) of guinea pigs.
Various environmental factors may confound the response to HLSO.. For
example, Pattle et al. (1956) noted an increase in HLSO. lethality in guinea
pigs when exposure was performed at a cold temperature (0°C), compared to room
temperature. This effect was ascribed to the direct action of cold on the
constrictive response, i.e., an added stress. On the other hand, temperature
differences may also have affected the hydration of the acid particles, which
may have altered deposition patterns.
February 1988 4-3 DRAFT—DO NOT QUOTE OR CITE
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Fairly high concentrations of HJSO. are required for lethality,, even in a
species as sensitive as the guinea pig. Amdur et al. (1952) found the LCrt for
3
8-hr exposures in 1 to 2 mo old guinea pigs to be 8 mg/m (1 urn, MMD). Thomas
et al. (1958) found no deaths in guinea pigs exposed (in chambers) continuously
(24 hr/d) for 18 to 140 days to 4 mg/m3 (0.59 to 4.28 urn, MMAD); exposures to
o .
26.5 mg/m (0.59 pro) for 18 to 45 days also resulted in no mortality. Finally,
Schwartz et al. (1979) reported an LP5Q of 100 mg/m H2S04 (0.3 to 0.4 pm,
MMAD; erg, ~1.5) for continuous, 7 d exposures (chamber). i
The cause of death due to acute,;high level HpSO. exposure is laryngeal or
bronchial spasm. As the concentration is reduced, more deep pulmonary damage
occurs prior to death. Lesions commonly seen are focal atelectasis, hemor-
rhage, congestion, pulmonary and pertvascular edema, and epithelial desquama-
tion of bronchioles; hyperinflation is also often evident (Amdur, 1971; Wolff
et al., 1979; Cavender et al., 1977b; Pattle and Cullumbine, 1956). Since
death appears to be due largely to an irritant response, differences in the
deposition pattern of smaller and larger acid droplets may account for the
observed particle size dependence of lethal concentration; larger particles
would deposit to a greater extent in the upper bronchial tree, within which the
bulk of irritant receptors are located.
A major concern in toxicologic assessment is the relative role of concen-
tration^) and exposure duration(T) in producing a response. Unfortunately,
there are few data available to allow analysis of C x T relationships for acid
exposure. Amdur et al. (1952) did examine this in guinea pigs, and found
3 ,
that exposure for 72 h to 8 mg/m H2SQ4 did not increase mortality percentages
over those observed due to 8-h exposures to the same concentration. Thus,
lethality appeared to depend on concentration rather than on the duration of
exposure. On the other hand, the extent of any histological damage appeared to
be related to cumulative exposure (Amdur et al., 1952).
There are few data to allow assessment of relative LC™ for acid aerosols
t)U
other than H2S04. However, Pattle et al. (1956) noted that if sufficient
ammonium carbonate was added into the chamber in which guinea pigs were exposed
to H2SO. to give excess NH~, protection was afforded to acid levels that, in
the absence of NFL, would have produced 50 percent mortality. This infers that
HpSO. is more acutely toxic than its neutralization products, i.e., NHLHSO.
and/or (NH»)2SO.. Pepelko et al. (1^80) exposed rats (chamber) for 8 h/d for
3 days to (NH4)2S04 at 1,000 to 2,000 mg/m3 (2 to 3 |jm, MMAD); no mortality
February 1988 4-4 DRAFT—DO NOT QUOTE OR CITE
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resulted. On the other hand, 40 percent and 17 percent mortality was observed
in guinea pigs exposed once for 8 h to 800 to 900 or 600 to 700 mg/m ,
respectively, of similarly sized-particles; no mortality was observed at levels
o
<600 mg/m . Death was ascribed to airway constriction. As with H?SO., guinea
pigs are more sensitive to the lethal effects of
The embryotoxic potential of H2$04 has been examined in three species.
Hoffman and Campbell (1977) exposed chick embryos continuously, from the 1st
through the 14th day of development, to HpSO^ at 6.06 mg/m (0.2 to 0.3 urn,
MMAD). There was no effect on survival rate nor on organ/body weight ratios,
but embryonic weight was slightly, but significantly, reduced, as was serum
lactic dehydrogenase activity. This latter was suggested to reflect a delay in
normal development. In another study, Murray et al. (1979) exposed pregnant
mice and rabbits daily for 7 h, during the major period of organogenesis, to
2
up to 20 mg/m H2S04. There was no evidence of any teratogenic effect, at
least based upon histological examination.
4.3 PULMONARY FUNCTION
The earliest studies examining the toxicology of inhaled acid aerosols at
sublethal levels used changes in pulmonary function as indices of response. A
survey of the data base is presented in Table 4-2.
One of the major exposure parameters that affects response is particle
size. In terms of altering pulmonary mechanics, specifically pulmonary resis-
tance in guinea pigs, studies by Amdur (1974) and Amdur et al. (1978a,b) have
found the irritant potency of H2S04, (NH4)2$04, or NH4HS04 to increase with
decreasing particle size, i.e., the degree of response per unit mass of S04~ at
any specific exposure concentration increased as particle size decreased, at
least within the range of 1 to 0.1 nm. 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
concentrations above the lethal threshold, large particles are more effective
in eliciting response, while at sublethal levels, smaller particles are more
effective. There is, however, some indication that even with pulmonary func-
tion as the endpoint, a greater response may be obtained with large particles
at high concentrations. Thus, Amdur (1958) found that in a series of 1 hr
exposures to ~2 to ~40 mg/m H2$04 at sizes of 0.8 or 2.5 urn, the latter size
resulted in a greater response only at the highest exposure concentration used.
February 1988 4-5 DRAFT—DO NOT QUOTE OR CITE
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Pulmonary functional responses to H^SO, suggest a major site of action to
be the conducting airways, as evidenced by exposure induced alterations in
resistance and compliance. However, some data also suggest that high exposure
levels may affect more distal lung regions. Changes in pulmonary diffusing
capacity (DL ), which could indicate damage to the gas-exchange region of the
co -
lungs, were noted in dogs exposed at 0.889 mg/m (Lewis et al., 1973); they
3
were not found in guinea pigs exposed at 0.1 mg/m (Alarie et al., 1973). How-
ever, deep lung effects of HpSO^ are also evident from studies of morphologic
and lung defense endpoints, discussed in subsequent sections.
The particle size of the acid aerosol appears to affect the temporal
pattern of response. For example, Amdur (1958) observed that changes in
pulmonary resistance in guinea pigs following art acute exposure to 0.8 urn H^SO.
began immediately, while a delay in the onset of response was observed when
2.5 urn particles were used. In a subsequent study also with guinea pigs (Amdur
et al., 1978a), resistance was found to return to control levels by 1/2 hr
after exposure to 0.1 mg/m HpSO* when the particle size was 1 urn, but exposure
to the same mass concentration of 0.3 urn particles resulted in the maintenance
o
of elevated resistance through this same time. Thus, the response to 0.1 mg/m
at 1 [jm was slight and rapidly reversible, while that with 0.3 urn 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 dose
o
related, and at exposure concentrations >0.1 mg/m with either 1 or 0.3 urn
particles, resistance remained elevated at the 1/2 h post-exposure measurement
time.
Although the studies by Amdur and colleagues appear to provide a reason-
able picture of the relative effects of acid particle size and exposure concen-
tration on the bronchoconstricive response of guinea pigs at sublethal exposure
levels, there is some conflict between these results and reports by others.
Whereas the former work supports a concentration dependence for respiratory
mechanics alterations, i.e., animals in each exposure group responded uniformly
and the degree of response was related to the exposure concentration, others
(Wolff et al., 1979; Silbaugh et al., 1981b) have found that individual guinea
pigs exposed to HpSO, will show an "all-or-none" constrictive response, i.e.,
in atmospheres above a threshold concentration, some animals will manifest
major changes in pulmonary mechanics ("responders"), while others will not be
affected at all ("nonresponders"). As the exposure concentration is increased
February 1988 4-9 DRAFT—DO NOT QUOTE OR CITE
-------
further, the percentage of the population that is affected, i.e., the ratip of
responders to nonresponders, will increase, producing an apparent dose-response
relationship. However, the magnitude of the change in pulmonary function is
similar for all responders regardless of exposure concentration. Sensitivity
to this all-or-none response may be related to an animal's airway caliber prior
to HpSO- exposure, since responders: had higher pre-exposure values for
resistance, and lower values for compliance, than did nonresponders. In any
case, the threshold concentration for the all-or-none response is fairly high
(>10 mg/m3 H0SO,); in the study of Silbaugh et al. (1981b), deaths of some
3
responders occurred at >24.3 mg/m .
Reasons for the discrepancy with the studies of Amdur and colleagues are
not known; they may involve differences in guinea pig strains, ages, health
status, or other exposure conditions., In any case, the dyspneic response of
the guinea pig responders is similar to asthma attacks in humans, in both its
rapidity of onset and in the characteristic obstructive pulmonary function
changes with which it is associated.
Another approach to evaluate the acute pulmonary functional response to
HySQ, in guinea pigs involves co-inhalation of C02 (Wong and Alarie, 1982;
Matijak-Schaper et al., 1983; Schaper et al., 1984). This procedure assesses
the response to irritants by measuring the decrease in tidal volume (Vj) which
is routinely increased above normal by adding 10 percent CCL, to the exposure
atmosphere. Although the exact mechanism underlying a reduction in C02
response is not known (e.g., it may be due to changes in resistance or compli-
ance) the assumption is that the change in ventilatory response afte?.r irritant
exposure is due to direct stimulation of irritant receptors. An exposure
concentration dependent decrease in response to CO,, has been found following
1-hr exposures (head-only) to H2$04 (~1 (jm, MMD) at levels >40.1 mg/m3 (Wong
and Alarie, 1982). Subsequently, Schaper et al, (1984) exposed guinea pigs
(head-only) for 0.5 h to H^S04 at 1.8 to 54.9 mg/m3 (0.6 Mm, AED, ag ~ 2.9).
At concentrations >10 mg/m , the level of response (i.e., the maximum decrease
in ventilatory response to C09) increased as a function of exposure concen-
3
tration. However, below 10 mg/m , there was no relation between exposure
concentration and response; in these cases, the effect was transient, with a
decrease in COp response occurring at the onset .of acid exposure, but
subsequently fading.
February 1988 4-10 DRAFT—DO NOT QUOTE OR CITE
-------
The results of the studies with C0? 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 a concentration-response rela-
o
tionship observed at HpSO. concentrations <10 mg/m 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 differ-
ences of the experimental techniques and/or animal strains used.
The relative potency of various sulfates to alter resistance or compliance
in guinea pigs with acute exposure was examined by Amdur et al. (1978b). They
found that the percentage increase in resistance per unit mass of SO/" (at
equivalent particle sizes) was greater for HpSO, than for either (NHLKSO, or
NH4HS04. However, NH4HS04 was found to be less potent than was (NH4)2S04< The
greater irritancy of (NH4)2S04 compared to NH4HS04 is unexpected, since the
former is less acidic. This particular ranking was not found in pulmonary
function studies in humans (Utell et al., 1982) nor in mucociliary transport
studies in rabbits (Schlesinger, 1984). Using an acidic NO salt, i.e.,
f\
NH.NO,,, Loscutoff et al. (1985) found no changes in pulmonary mechanics in rats
3
or guinea pigs exposed to 1 mg/m (0.6 urn) for 6 h/d, 5 d/wk for up to 20 d;
(NH4)2$04 was more potent in this regard.
The specific mechanism underlying acid induced pulmonary functional
changes is not known, but irritant receptor stimulation may occur due to direct
contact by deposited particles or due to 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) incubated guinea pig lung fragments with various salts,
including (NH4)2S04, NH4N03, NH4C1, NaCl, and Na2$04. The first three resulted
in histamine release in proportion to their concentration ((NIOpSO. was the
most effective), while no histamine release was found with the latter two.
Since S0»~ itself appeared not to be involved in the response (no effect was
^ +
seen with Na2S04) and NH4 was apparently needed for sulfate-mediated histamine
release, this mechanism would not seem to explain the bronchoconstrictive
effects due to H2S04 exposure. However, in whole animal studies, similar
pulmonary function responses were found in guinea pigs exposed to histamine or
H2S04 (Popa et al., 1974; Silbaugh et al., 1981b), and H2S04 exposure resulted
in degranulation of mast cells (Cavender et al., 1977a). Whether histamine is
February 1988 4-11 DRAFT—DO NOT QUOTE OR CITE
-------
involved in other species of animals is not certain. Interspecies differences
in response to histamine do exist; perhaps this is one factor accounting for
interspecies response differences to HLSO..
Evidence for a direct response to H2$04 in altering pulmonary function is
found using the C02 coinhalation procedure. Schaper and Alarie (1985) noted
that the responses to histamine and H^SO. differed in both their magnitude and
temporal relationship, suggesting direct action of the inhaled acid. •
There are few data to allow an interspecies comparison of acid aerosol
induced pulmonary function response, but examination of the available evidence
(Table 4-2) suggests that guinea pigs are more sensitive than the other species
examined. An exception is the study by Loscutoff et al. (1985), in which rats
were more affected by exposure to (NH^pSO^ than were guinea pigs; this was not
supported by the (NH4)2$04 mortality study of Pepelko et al. (1980). The
reason for this discrepancy is unknown.
The results of pulmonary function studies indicate that HgSO^ is a
bronchoactive agent that will alter luhg 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. But although changes in resistance and compliance are markers
of exposure, the health significance of these in normal individuals is unknown.
On the other hand, all subgroups of an exposed population may not have equal
sensitivity to inhaled pollutants. In fact, some may be especially sensitive.
For example, in humans increased hospital admissions in summer for acute respi-
ratory disease, including asthmatic attacks, may be related to ozone, sulfate
and temperature (Bates and Sizto, 1986). These investigators speculate that
the On and sulfate may be surrogates for other pollutants; it has been
suggested that one possibility for the latter is H^SO, (Lippmann, 1985). Some
lung diseases, the most notable of which is asthma, involve a change in airway
"responsiveness", i.e., an alteration in the degree of reaction to exogenous
(or endogenous) bronchoactive agents, resulting in increased airway resistance
at levels of these agents which do not affect 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.
The ability of H^SO. aerosols to alter airway responsiveness has been
assessed in two studies. Silbaugh et al. (1981a) exposed guinea pigs (chamber,
February 1988 4-12 DRAFT—DO NOT QUOTE OR CITE
-------
80 percent RH) for 1 hr to 4 to 40 mg/m3 H2$04 (1.01-Mm, MMAD, ag = 1.3-1.7)
and examined the subsequent response to inhaled histamine. Some of the animals
showed an increase in pulmonary resistance and a decrease in compliance at
3
H2S04 concentrations xL9 mg/m and without histamine challenge; only the
animals showing this constrictive response during acid exposure also had major
increases in histamine sensitivity, suggesting that airway constriction
may have been a prerequisite for the development of hyperresponsivity. In
another study, Gearhart and Schlesinger (1986) exposed rabbits (nose-only,
80 percent RH) to 0.25 mg/m3 H2$04 (0.3 urn, MMAD; ag = 1.6) for 1 h/d, 5 d/wk,
and assessed airway responsiveness after 4, 8, and 12 mo of exposure, using
acetylcholine administered intravenously. Hyperresponsivity 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. Unlike the
previous results in guinea pigs, there was no change in baseline resistance
(i.e., measured prior to bronchoprovocation challenge) at any time during the
acid exposures. Thus, repeated exposures to HpSO, resulted in the production
of hyperresponsive airways in previously normal animals; this may then
"sensitize" the airways to further acid exposure, or to exposure to other
airborne materials.
The mechanism that underlies sulfuric acid-induced airway hyperrespon-
siveness is not clear. Neither is its relation to airway disease. Although
hyperresponsivity is associated with specific diseases, its pathogenetic
significance is not understood. Human asthmatics and, to some extent, chronic
bronchitics typically have hyperresponsive airways (Ramsdell et al., 1982;
Ramsdale et al., 1985; Simonsson, 1965), but it is not known whether this state
is a predisposing factor in clinical disease, or merely a reflection of other
changes in the airways that precede it. At this point, circumstantial
evidence supports the hypothesis that an increase in airway responsivity may be
a risk factor in development of obstructive airway disease (Fish and Menkes,
1984). More work is clearly needed to resolve this issue.
From the previous discussion, it is possible that one particular group
of individuals that may have altered response to pollutants are those with
respiratory disease. Unfortunately, there are very few data to allow examina-
tion of the effects of different disease states in experimental animals upon
response to acid aerosols. Rats and guinea pigs with elastase-induced pulmonary
emphysema were examined to assess whether repeated exposures (6 h/d, 5 d/wk,
February 1988 4-13 DRAFT—DO NOT QUOTE OR CITE
-------
20 d) to (NH4)2S04 (1 mg/m3, 0.4 urn MMAD) or NH4N03 (1 mg/m3, 0.6 pm MMAD)
would alter pulmonary function compared to saline-treated controls (Loscutoff
et al., 1985). Similarly, dogs having lungs impaired by exposure to N02 were
treated with H2$04 (0.889 mg/m3, 21 h/d, 620 d) (Lewis et al., 1973). Both of
these studies indicated that the specific disease states induced did not enhance
the effect of acid aerosols in altering pulmonary function; in some cases, there
were actually fewer functional changes in the diseased lungs thail in the
unimpaired animals. It is, however, possible that other types of disease states
could result in enhanced response to inhaled acid aerosols; as mentioned, asthma
is a likely one.
4.4 RESPIRATORY TRACT MORPHOLOGY AND BIOCHEMISTRY
Morphologic damage associated with exposure to lethal levels of acid
aerosols has been previously discussed. Of greater concern, perhaps, are those
changes associated with sublethal exposures. A survey of these, as determined
microscopically, is provided in Table 4-3. ;
Single or multiple exposures to H2$04 at fairly high levels (»1 mg/m ) is
associated with a number of characteristic responses, e.g., alveolitis,
bronchial and/or bronchiolar epithelial desquamation, and edema. However, the
sensitivity of morphologic endpoints to these exposure levels is dependent upon
the animal species. Comparative sensitivity of the rat, mouse, rhesus monkey
and guinea pig was examined by Schwartz et al. (1977) using mass concentrations
of H2S04 >30 mg/m3 at comparable particle sizes. Both the rat and the monkey
were quite resistant, while the guinea pig and mouse were the more sensitive
species. The nature of lesions in the latter two were similar, but differed in
location; this is, 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 rats (Schlesinger, 1985), which could
account for the laryngeal and upper trachea! location of the lesions seen in
the former. 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).
As mentioned previously, the severity of lung histologic damage appears to
depend upon total dose, rather than concentration alone. For example, guinea
February 1988
4-14
DRAFT—DO NOT QUOTE OR C.ITE
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pigs exposed to 8 mg/m3 H9SO. for 72 hr (C x T = 576 (mg/m )-h showed more
3
extensive tissue damage than did those exposed at 20 mg/m for 8 h (C x T = 160
(mg/m3)-h. There was no mortality at the first condition, but 50 percent at
the second (Amdur et al., 1952).
With mortality and pulmonary mechanics as endpoints, the particle size of
the acid droplet plays a role in relative toxicity. There are conflicting data
in this regard with morphologic alteration, although the reasons for this are
unclear. Thomas et al. (1958) exposed guinea pigs for 5 mo to >1 mg/m HgSO^
at three sizes, 0.59, 0.93, and 4.28 urn (MMAD). At nonlethal levels, the
midsize particle appeared to be the most effective in producing a morphologic
response. More recently, however, Cavender et al. (1977b) exposed guinea pigs
to 20 mg/m3 HUSO, for 7 to 28 d at three particle sizes, 0.53, 0.99, and
1.66 urn (MMD). There was no apparent size-related difference in response.
Similarly, Alarie et al. (1975) noted no size dependence (<1 urn to 5 urn) for
o
the histopathologic effect of >1 mg/m H^O- exposures in monkeys.
Repeated or chronic exposures to HpSO. at concentrations <1 mg/m produce
a response characterized by hypertrophy and hyperplasia of epithelial secretory
3
cells. In morphometric studies of rabbits exposed to 0.25 to 0.5 mg/m ^SO^
(0.3 urn) f°r 1 n/d, increases in the relative number or density of secretory
cells have been found to extend to the bronchiolar level (Schlesinger et al.,
1983; Gearhart and Schlesinger, 1988), where these cells are normally rare or
absent. The changes began within 4 wk of exposures, and persisted for up to
3 months following the end of exposure. Persistently increased secretory cell
number in peripheral airways is significant, since an excess of mucus in this
region, a likely consequence of this increase (Jeffery and Reid, 1977), is
associated with chronic bronchitis (Hogg et al., 1968; Matsuba and Thurlbeck,
1973).
A shift in the relative number of smaller airways in rabbits was found
after 4 mo of exposure to 0.25 mg/m3 (0.3'urn) for 1 hr/d, 5 d/wk (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., 1978); in these cases, the size change is ascribed
to inflammation. It is, therefore, of interest that the response seen in the
acid-exposed rabbits was not accompanied by inflammation. In any event, size
change seems to be an early change relevant to clinical small airways disease.
Damage to the respiratory tract following exposure to acid aerosols may be
determined by methods other than direct microscopic observation. Analysis of
February 1988 4-19 DRAFT—DO NOT QUOTE OR CITE
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bronchopulmonary lavage fluid obtained from exposed animals can also provide
valuable information. For example, levels of cytoplasmic enzymes, such as
lactic dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G-6PD), are
markers of cytotoxicity; an increase in lavageable protein suggests Increased
permeability of the alveolocapillary barrier; levels of membrane enzymes, such
as alkaline phosphatase, are markers of disrupted membranes; the presence of
fibrin degradation products (FDP) provide evidence of general damage; and
sialic acid, a component of mucoglycoprotein, may be an indicator of mucus
secretory activity. A lack of alteration in lavage indices suggests that there
was no major injury to the lungs.
Henderson et al. (1980b) exposed rats (chamber) for 6 h to H^O^ (0.7 pm,
HMAD) at 1.5, 9.5, and 98.2 mg/m3 and found FDP in blood serum after,exposure
at all concentrations. No FDP was found in the lavage fluid, but since the
washing procedure did not include the upper respiratory tract (i.e., anterior
to and including the larynx), the investigators concluded that the FDP observed
in the serum was an indicator of upper airway injury. An exposure concentra-
tion dependent increase in sialic acid content of the lavage fluid was also
observed; this was ascribed to increased secretory activity in the tracheo-
bronchial tree. •,
Wolff et al. (1986) exposed both rats and guinea pigs for 6 h to H2S04
(0.8 to 1 Mm, MMAD), at levels of 1.1 to 96 mg/m3 for the former and 1.2 to
27 mg/m3 for the latter. No changes in LDH, lavageable protein nor sialic acid
content of lavage fluid was found in the rat. However, some of the guinea pigs
exhibited bronchoconstriction after exposure to 27 mg/m , and only these
animals showed increased levels of lavageable protein, sialic acid and LDH. No
change in lavageable protein was found in the lungs of rats exposed for 3 d
(23.5 h/d) to 1 mg/m3 (0.4 to 0.5 urn, MMAD) H2$04 (Warren and Last, 1987), nor
for 2 d (23.5 h/d) to 5 mg/m3 (0.5 (jmjMMAD) (NH4)2$04 (Warren et al.., 1986).
The hydroxyproline content of the lungs may provide an index of collagen
deposition or degradation. No change in total lung synthesis or content of
hydroxyproline was found in rat lungs after exposure for 7 d (23.5 h/d) to
4.84 mg/m3 (0.5 pm, MMAD) (NH4)£S04, nor due to a 7 d exposure to 1 mg/m
(0.5 Mm) H2S04 (Last et al., 1986). ;
A series of studies by Last and colleagues assessed the synthesis of
collagen by minces prepared from rat lungs after iji vivo acid sulfate expo-
sure; this is a possible indicator of the potential for pollutants to produce
fibrosis. Exposure for 7 d (23.5 h/d) to H2$04 at 0.04, 0.1, 0.5, and
February 1988 4-20 DRAFT—DO NOT QUOTE OR CITE
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3
1 mg/m (0.4 to 0.5 urn, MMAD) resulted in no increase in collagen synthesis
rate (Warren and Last, 1987). No effect on collagen synthesis by rat lung
q
minces was found due to 7 d exposures to (NI-L^SO. at 5 mg/m (0.8 to 1 |jm,
MMAD) (Last et al., 1983).
Another parameter of damage and/or inflammation is change in lung DNA, RNA
or total lung protein. No significant changes in any of these were found in
•a
rats after exposure to 1 mg/m" H2$04 (<1 |jm) for 3 d (Last and Cross, 1978),
nor in tissue protein content in rats exposed for up to 9 d to a similar
concentration of HpSO. (Warren and Last, 1987).
The data base concerning morphological alterations shows that acid
sulfates are both upper airway and deep lung irritants. But the specific
pathogenesis of acid-induced lesions is not known. As with pulmonary mechan-
ics, both a direct irritant effect of deposited acid droplets on the epithelium
and/or indirect effects, perhaps mediated by humoral factors such as histamine,
may be involved. Similar lesions have been produced in guinea pig lungs by
exposure to either histamine or HpSO. (Cavender et al., 1977a); however, the
former appears to initiate the lesions, and once they are so initiated, further
acid exposure produces necrosis more rapidly than does further histamine
exposure. In addition, some lesions may be secondary to reflex bronchocon-
striction, 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 (Brownstein, 1980).
The mechanism underlying secretory cell hyperplasia at low H^SO. exposure
levels is also unknown; it may involve an acid-induced increase in division of
existing cells, or transition from a different cell type. Other irritants
(e.g., tobacco smoke and SOp) have been shown to result in the conversion of
one epithelial cell type into another, e.g., serous cell to goblet cell, or
Clara cell to goblet cell (Reid et al. , 1983; Phipps, 1981; Reid and Jones,
1979).
4.5 RESPIRATORY TRACT DEFENSES
The response to air pollutants often depend upon interaction with an array
of nonspecific and specific respiratory tract defenses. The former consist of
nonselective mechanisms protecting against a wide variety of inhaled materials;
the latter require immunologic stimulation for activation. Although these
February 1988 4-21 DRAFT—DO NOT QUOTE OR CITE
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systems may function independently, they are linked; for example, response to
an immunologic insult may enhance subsequent response to non^-antigenie materi-
als as well. 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, depression or over-activity
of these systems may be involved in the pathogenesis of lung disease.
Studies of altered lung defenses due to inhaled acid aerosols have concen-
trated on examination of conducting and respiratory region clearance function;
there are only a few studies of effects upon immunologic competence.
4.5.1 Clearance Function
Clearance, a major nonspecific defense mechanism, is the physical removal
of material that deposits on airway surfaces. The mechanisms involved are
regionally distinct. In the conducting (i.e., tracheobronchial) airways,
clearance occurs via the mucociliary system, whereby a mucus "blanket" overly-
ing the ciliated epithelium is moved by the coordinated beating of the cilia
towards the oropharynx. The mucus cover is actually bilayered, at least in the
central airways. It consists of a lower hypophase (spl) overlying the
epithelium and bathing the cilia, and an upper epiphase (gel) resting on top of
the cilia.
In the respiratory (i.e., alveolated) 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. These cells rest
freely within the fluid lining of the alveolar epithelium where they move by
ameboid motion. Via phagocytic ingestion of deposited particles, macrophages
help prevent penetration through the alveolar epithelium and subsequent
trans!ocation to other sites. These cells contain proteolytic enzymes, allow-
ing digestion of a wide variety of organic materials, and they also kill
bacteria through peroxide-producing oxidative mechanisms. In addition,
macrophages are involved in the induction and expression of immune reactions.
Thus, the macrophage provides a link between the lung's nonspecific and
specific defense systems. Macrophages may be cleared from the respiratory
region along a number of pathways, but the primary one is via the mucociliary
system after these cells reach the distal terminus of the mucus blanket
(Bowden, 1984).
February 1988 4-22 DRAFT—DO NOT QUOTE OR CITE
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4.5.1.1 Conducting Airways - Mucocillary Clearance. The assessment of effects
upon miicociliary clearance due to inhaled acid aerosols often involved examina-
tion solely of mucus transport rates in the trachea, since this is a readily
accessible airway and trachea! mucociliary clearance measurements are more
straightforward to perform than are those aimed at assessing clearance from the
entire tracheobronchial tree. Table 4-4 outlines reported studies of acid
aerosol effects upon trachea! mucociliary clearance; all of the available data
are for sulfate compounds.
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 size of the aerosol used precluded significant tracheal
deposition. This is supported by noting that Wolff et al. (1981) found
tracheal transport rates in dogs to be depressed only when using 0.9 urn H2$04,
while no effect was seen with a 0.3 urn aerosol at an equivalent mass concen-
tration. In any case, the use of tracheal clearance rate as a sole toxicologic
endpoint may be misleading, inasmuch as other studies (Schlesinger et al.,
1978, 1979) have demonstrated changes in bronchial clearance that were not
associated with any change in tracheal transport.
The results of studies assessing the effects of acid aerosols upon
bronchial mucociliary clearance are outlined in Table 4-5. Observed responses
to HUSO, indicate that the direction of clearance change, i.e., slowing or
speeding, following acute exposure is dependent upon both exposure concentra-
tion (C) and exposure time (T) (Schlesinger, 1988); stimulation of clearance
occurs at low CxT values, and retardation at higher levels. However, the
actual value needed to produce an observed acceleration may be dependent upon
the region within the bronchial tree from which clearance is being measured, in
relation to the region that is most affected by the deposited acid (Leikauf
et al., 1984). Thus, in effect, low H^SO, exposure concentrations, i.e., ~0.1
3
to 0.3 mg/m for 1 hr, accelerate clearance from the large proximal airways,
where little deposit, while slowing clearance from the distal ciliated airways,
where there is greater acid deposition. At higher exposure concentrations,
q
i.e., > ~0.75 mg/m for 1 hr, mucociliary clearance from both proximal and
distal conducting airways is depressed.
Comparison of responses to H2S04 suggest that, there are possible inter-
species differences in sensitivity of mucociliary clearance to inhaled acid
aerosols (Wolff et al., 1986). As an example, the speeding of tracheal trans-
3
port in the rat with ~100 mg/m HpSO. seems anomalous since, in other species,
February 1988 4-23 DRAFT—DO NOT QUOTE OR CITE
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levels >1 mg/m produce mucociliary depression. The reasons for this observa-
tion are not known. The rat is less susceptible to the lethal effects of
Hr,S04, and it does not have strong bronchoconstrictive reflex responses
following H2S(K exposures. These characteristics, together with the lack of
effect of H2S04 on bronchial clearance at fairly high exposure levels
(3.6 mg/m3 for 4 hr), suggest that the mucociliary system of the rat may also
differ in sensitivity from most of the other species studied. Although the
lack of response of tracheal transport in the guinea pig at HpSO. levels
3 3
>1 mg/m is also surprising, its response at 1 mg/m is also different from
that of the rat and more in line with other species (Wolff, 1986), As with all
studies, however, it should be borne in mind that differences in experimental
variables, such as aerosol particle size, may contribute to some extent to
apparent response differences between species.
The relative irritant potency of acid sulfate aerosols, in terms of
altering mucociliary clearance, is likely related to their degree of acidity.
Schlesinger (1984) exposed rabbits for 1 h to submicrometer aerosols of NH4HS04,
(NH4)2S04 and Na2S04. Exposure to -0.6 to 1.7 mg/m3 NH4HS04 produced a signif-
icant depression of clearance rate only at the highest level. No significant
effects were observed with the other sulfate compounds at levels up to
~2 mg/m3. When these results are compared to those from a study using H2$04
(Schlesinger et a!., 1984), the ranking of irritant potency is found to be
H2S04 > NH4HS04 > (NH4)2S04, Na2S04; this strongly suggests a relation between
the hydrogen ion (H+) concentration (total acidity) and the extent of bronchial
mucociliary clearance alteration. In another study, Schlesinger et al. (1978)
found bronchial clearance to be altered in donkeys exposed to H9SO- for 1 hr at
q 3
levels above -0.2 mg/m , while exposures to (NH4)2S04 at up to 3 mg/m produced
no response.
The mechanism by which deposited acid aerosol may alter clearance is not
certain. The effective functioning of mucociliary transport depends upon
optimal beating of the cilia and the presence of mucus having appropriate
physicochemical properties. Both ciliary beating and mucus viscosity may be
affected by the deposition of acid (Holma, 1985). Normally, tracheobronchial
mucus has a pH of -6.5 to 8.2 (Kwart et al., 1963; Guerrin et al., 1971; Gatto,
1981; Holma et al., 1977). In vitro studies have shown that, at alkaline pH,
mucus is more fluid than at acid pH; the inflection point occurs at a pH between
7.5 to 7.6 (Breuninger, 1964). A small increase in viscosity which may occur
due to deposited acid could "stiffen" the mucus blanket, perhaps promoting the
February 1988 4-26 DRAFT—DO NOT QUOTE OR CITE
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clearance mechanism and, thus, increasing its efficiency (Holma et al., 1977).
Such a scenario may occur at low HgSO^ 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; differential alterations in rheological properties of the sol or gel
layers may have different effects upon the system (Puchelle and Zahm, 1984).
Higher exposure concentrations of H^SO., in addition to altering mucus
viscosity, may also affect ciliary beating. Schiff et al. (1979) and Grose
et al. (1980) found that 2- to 3-h in vivo exposures of hamsters to ~0.9 to
3
1 mg/m H^SO. resulted in a depression of ciliary beating frequency in trachea!
explants prepared after exposure. J.n vitro studies indicate that complete
ciliostasis will occur if the pH is low enough (Holma et al., 1977); however,
regional ciliostasis, presumably with a change in clearance function, may occur
at pH values above this critical level. Thus, a H -induced depression of
ciliary beating, due to a direct impact upon the cilia and/or to a change in
mucus viscosity, could account for the observed retardation of clearance
observed at high concentrations of HpSO* (or NH.HSO.) with acute exposures.
There is some evidence, however, that the response to H2SO. may not be
entirely due to the free H . Schiff et al. (1979) exposed hamster trachea!
rings jji vitro to H^SO. in medium for 3 h and examined ciliary beat frequency
and cytology; the pH of the medium was ~5. There was no effect upon beat
frequency when the tissue was examined within 1 h after exposure, although
morphological damage was evident at this time; at 24 h after exposure, beat
frequency was depressed. They then exposed tracheal explants for 3 h to the
same medium as above, but with the pH adjusted to 5 using hydrochloric acid
(HC1). Exposure under this condition resulted in a reduction in beat
frequency, but no change in cell morphology. When these latter explants were
transferred to fresh culture medium, the cilia resumed beating at their normal
frequency. According to the investigators, these results indicated that medium
at pH 5 itself produced no lasting morphological effects, and that acidity
alone (at least as measured by pH) was not responsible for the observed morpho-
logical and functional effects produced by the H?SO.. Fine et al. (1987) have
+
suggested that response is due to total H concentration rather than pH.
Another (or an additional) mechanism by which deposited acid may affect
mucociliary clearance .is via alteration in the rate and/or amount of mucus
secretion. A mild, irritant induced increase in the quantity of mucus, to
February 1988 4-27 DRAFT—DO NOT QUOTE OR CITE
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which the mucociliary system adapts by speeding transport, is consistent with
the initial increase in bronchial clearance rates observed following acute
exposures to low concentrations of H2$04. Direct evidence for hypersecretion
is limited. In a study that examined secretory rate, Last and Cross (1978)
showed that exposure of rats for 23.5 h/d for 3 days to submicrometer H2S04 at
~1 mg/m3 did not affect the secretion of mucus glycoprotein from trachea!
explants prepared after exposure; however, the effect on secretion from smaller
conducting airways was not examined. On other hand, Henderson et al. (1978),
using analysis of lavage fluid to detect responses in the lungs of rats exposed
to 1, 10, or 100 mg/m3 H2SO. for 6 h, showed a dose related increase in sialic
acid content, which the authors suggested to indicate increased mucus secre-
tion. Although mild irritation may increase clearance rate, at some point,
oversecretion due to higher exposure concentrations will likely result in an
overloading of the clearance system, and a retardation in transport rate
(Wolff, 1986; Albert et al., 1973). This likely occurs with repeated or
o
chronic exposures, even to lower (0.1-0.25 mg/m ) acid concentrations.
The airways actively transport ions, and the interaction between trans-
epithelial ion transport and consequent fluid movement is important in the
maintenance of the mucus lining. A change in ion transport due to deposited
acid particles may, for example, alter the depth and/or composition of the sol
layer (Nathanson and Nadel, 1984), perhaps affecting clearance rate.; Although
no data are available regarding acid sulfates, Stutts et al. (1981) found that
ammonium nitrate (NH.NO-) altered sodium and chloride transport across canine
T" ««5 _1_ «•
trachea! epithelium. The response was ascribed to NH^ rather than to N03 ,
since sodium nitrate (NaN03) had no effect; mucociliary transport was not
examined.
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 impair-
ment 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 pathology.
Short-term exposures to acid aerosols may lead to persistent clearance
changes. Schlesinger et al. (1978) demonstrated that weekly 1-h exposures of
O
donkeys to submicrometer H2S04 at 0.2 to 1 mg/m produced a transient slowing
of bronchial clearance in 3 of 4 animals. However, two of the four (including
one that did not respond after any individual test) developed persistently
February 1988 4-28 DRAFT—DO NOT QUOTE OR GITE
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slowed clearance after about 6 of the exposures; this slowing persisted for two
months after all acid exposures had ceased.
The development of persistent alterations after a relatively small number
of 1-h weekly exposures emphasizes that, in order to evaluate fully the impact
ambient acid aerosols might have upon the inception and progression of respira-
tory disease, it is essential to consider the effects of intermittent expo-
sures, especially at low exposure concentrations. Thus, as a follow-up to the
above study, Schlesinger et al. (1979) exposed the two donkeys that had shown
only transient responses, as well as two previously unexposed animals, to
0.1 mg/m3 H^SO. for 1 h/d, 5 d/week for 6 months. Within the first few weeks
of exposure, all four animals developed erratic clearance rates. The two
previously unexposed animals developed persistently slowed bronchial clearance
during the second three months of exposure, and during four months of follow-up
clearance measurements, while the two previously exposed animals adapted to the
new exposures in the sense that their clearance times fell consistently within
the normal range during the last few months of acid exposure. However, after
the end of the exposure series, their clearance rates were significantly faster
than prior to any acid exposures, and remained so for the entire follow-up
period (Lippmann et al., 1982).
Schlesinger et al. (1983) exposed rabbits to 0.25 to 0.5 mg/m H2S04
(0.3 urn, MMAD) for 1 h/d, 5 d/wk for 4 weeks, during which time bronchial
mucociliary clearance was monitored. Clearance was accelerated on specific
individual days during the course of the acid exposures, especially at
0.5 mg/m . In addition, clearance was significantly faster, compared to
preexposure levels, during a 2-week follow-up period after acid exposures had
ceased.
The longest-term exposure at relatively low H2$04 levels for examination
of effects on bronchial clearance was the study of Gearhart and Schlesinger
(1988). Rabbits were exposed to 0.25 mg/m3 H2S04 for 1 h/d, 5 d/wk for up to
52 wk, and some animals were also provided a three month follow-up period.
Clearance was slower during the first month of exposure and this slowing was
maintained, and became progressive, throughout the rest of the exposure period.
After cessation of exposure, clearance became still slower (a phenomenon seen
in the donkey study, above), and did not return to normal by the end of the
follow-up period. No significant change in clearance was observed in sham
control animals. Differences in the direction of clearance change between
this study and that of Schlesinger et al. (1983) were due to differences in
February 1988 4-29 DRAFT—DO NOT QUOTE OR CITE
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exposure protocol. In both studies, however, histologic analysis 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 associated with a shift in the chemistry of mucus
towards a greater content of acidic glycoproteins; this would tend to make
mucus more viscous.
4.5.1.2 Respiratory Region
a. Antimicrobial Activity
The development of an infectious disease requires both the presence of
the appropriate pathogen and host vulnerability. The alveolar macrophage
represents the main defense against pathogenic organisms depositing in the
respiratory region of the lungs. The ability of acid aerosols to modify
resistance to infection could result from a decreased ability to clear
microbes, and a resultant increase in their residence time, due to alterations
in normal macrophage function. To test this possibility, the rodent bacterial
infectivity model has been used (Gardner and Graham, 1977). In this technique,
mice are challenged with a bacterial aerosol after exposure to the pollutant
of interest; mortality rate and 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. Studies
that have used the infectivity model to assess effects of acid aerosols are
outlined in Table 4-6. It is evident that these aerosols are apparently not
very effective in enhancing susceptibility to bacterial-mediated respiratory
disease. The only study that demonstrated any response was that of Coffin
(1972), and increased mortality occurred only at an extremely high exposure
level that likely resulted in extensive morphological damage.
In a related type of study, Fairchild et al. (1975b) examined the
clearance rate of viable bacteria from the lungs of mice, using a colony count
assay involving culturing ground lung tissue. They found that exposures
(chamber) to 1.5 mg/m3 of submicrometer (0.6 pm, CMD) H2$04 for 1.5 h/d for 4
days prior to, or for 4 h after, exposure to a bacterial aerosol produced no
alteration in the physical removal of this aerosol from the lungs. Since the
bulk of microbial clearance was likely due to macrophage activity, these
results are another, a.lbeit indirect, indication that H2$04 exposures at modest
levels produce no measurable effect on bacterial infectivity.
February 1988 4-30 DRAFT—DO NOT QUOTE OR CITE
-------
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4-31
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Macrophages are also involved in antiviral defense, but there are no data
directly examining effects of acid on viral infectivity. In a study that
examined this indirectly, macrophages harvested from mice exposed to submicro-
meter hLSO. at very high levels (125 to 154 mg/m3) for 10 to 14 days showed
decreased interferon titers in the culture media (Schwartz et al., 1979); this
suggests impaired resistance to viral infection.
b. Respiratory Region Clearance
There are only a few studies that examined the ability of acid aerosols
to alter clearance of nonviable particles from the respiratory region. Rats
exposed (nose-only) to 3.6 mg/m3 H2S04 (1 ym, MMAD) for 4 h showed a signif-
icant delay in clearance when the relative humidity of the exposure atmosphere
was low (39%); no change in clearance was found when humidity was raised to
85% (Phalen et al., 1980). On the other hand, acceleration of clearance was
seen in rabbits exposed for 1 h to H£S04 at 1 mg/m3 (80% RH; 0.3 urn, MMAD;
erg = 1.6) (Naumann and Schlesinger, 1986).
Some studies involving repeated exposures to acid aerosols have been
o
reported. In one, rabbits were exposed (nose-only) to 0.25 mg/m (0.3 urn,
MMAD; erg = 1.7) H2S04 for 1 h/d> 5 d/wk, and 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 d after each
tracer exposure) was found to be accelerated during the first test, and this
acceleration was maintained throughout the acid exposure period. In another
study (Schlesinger and Gearhart, 1987), rabbits were exposed (nose-only) 2 h/d
for 14 days to 0.5 mg/m3 HLSO. (0,3 urn MMAD); retardation of respiratory region
clearance of tracer particles administered on the first day of exposure was
found. Schlesinger (1988) exposed rabbits to H2S04 (0,3 (jm, MMAD) at
0.25-1 mg/m3 for 1-4 hr/d for 14 d. The results of this and the other two
studies suggest a graded response which is dependent upon both exposure concen-^
tration and time; low values of CxT accelerate respiratory region clearance and
high levels retard it, such as is seen with mucociliary transport following
acute H2S04 exposure (Schlesinger, 1988) and with respiratory region clearance
after repeated exposures to other inhaled pollutants (Ferin and ILeach, 1977;
Driscoll et al., 1986).
The mechanisms responsible for the altered respiratory region clearance
patterns seen in the above studies| are not known. Observed clearance is the
net consequence of a number of underlying responses; these likely include
February 1988 4-32 DRAFT—DO NOT QUOTE OR CITE
-------
inflammation, epithelial lesions, release of specific mediators, and/or altered
functioning of alveolar macrophages. The effects of acid aerosols on lung
tissue have been previously discussed. There are only a few studies examining
the response of macrophages, or the induction of inflammation following acid
aerosol exposures.
In order to perform their role in clearance adequately, macrophages must
be competent in a number of functions, e.g., phagocytosis, mobility, and
attachment to a surface (Gardner, 1984). Alterations in any one, or combina-
tion, of these individual factors could perhaps result in altered clearance.
Naumann and Schlesinger (1986) noted a reduction in surface adherence and an
enhancement of phagocytosis in macrophages obtained by lavage from rabbits
3
following a 1-h exposure (oral tube) to 1 mg/m (0.3 pm, MMAD; ag = 1.6)
H2$04. The acid exposure produced no change in the viability or numbers of
recoverable macrophages. This is not surprising, since Coffin (1972) found no
o
change in the number of recoverable macrophages from mice exposed to 300 mg/m
H2S04 for 3 h.
In the only study with repeated H9SOA exposures, macrophages were
£. 1 • -
recovered by lavage from rabbits inhaling (nose-only) 0.5 mg/m H2S04 (0.3 urn,
MMAD) for 2 h/d for up to 13 days (Schlesinger, 1987). Macrophage counts were
increased after 2 of the daily exposures, but returned to control levels
thereafter. Neutrophil counts remained at control levels throughout the study,
indicating there to be no inflammatory response. Random mobility of macro-
phages was decreased after 6 and 13 of the exposures. The number of phago-
cytically active macrophages and the level of such activity was increased after
2 exposures, but phagocytosis became depressed by the end of the exposure
series. Although such studies demonstrate that HpS04 can alter macrophage
function, they have not as yet been able to provide a complete understanding of
the cellular mechanisms that may underlie the changes in respiratory region
clearance observed with exposure to acid aerosols.
The relative potency of the acid sulfate aerosols in terms of altering
respiratory region clearance was examined by Schlesinger (1988). Rabbits were
exposed for 2 h/d for 14 d to 2 mg/m3 (NH4)2S04 and to 0.5-2 mg/m3 NH4HS04-
None of these exposures altered the clearance of tracer particles from the
respiratory region measured during the exposure period. This contrasts with
the retardation of clearance observed using similar exposures to 0.5 mg/m
H2S04 (Schlesinger and Gearhart, 1987), suggesting that the response was likely
due to H . However, the H associated with the H2S04 appeared to be more
"potent" than that associated with NH4HS04.
February 1988 4-33 DRAFT—DO NOT QUOTE OR CITE
-------
The role of relative acidity in altering macrophages has not been examined
in any detail. Aranyi et al. (1983) found no change in total or differential
counts of free cells lavaged from mice exposed (chamber) to submicrometer
(NH4)2S04 at 1 mg/m3 for 3 h/day for 20 days. Changes with H2$04 were
discussed above.
4.5.2 Immunologic Defense
Little is known about the effects of acid aerosols on humoral (antibody)
or cell-mediated immunity. Since numerous antigens may be present in inhaled
air, the possibility exists that air pollutants may enhance immunologic reac-
tion and, thus, produce a more severe response and one with greater pulmonary
pathogenic potential. Pinto et al. (1979) found that mice that inhaled H2$04
(chamber; neither mass concentration nor particle size was specified) for
30 min daily and were then exposed weekly to a particulate antigen (sheep red
blood cells) exhibited higher serum and bronchial lavage antibody titers than
did animals exposed to the antigen alone. Other sulfate compound aerosols may
also have this effect. Although none have been directly examined, S02 appears
to have an adjuvant effect on antibody production (Matsumura, 1970). Pinto et
al. (1979) also noted that the combination of acid with antigen produced a
histopathologic response, characterized by mononuclear cell infiltration around
the bronchi and blood vessels, while exposure to acid or antigen alone did not.
Thus, the apparent adjuvant activity of H2$04 may have been a factor promoting
lung inflammation.
Osebold et al. (1980) exposed mice (chamber) to 1 mg/m H2S04 (0.04 [tm,
CMD; erg = 1.86) to determine whether this enhanced the sensitization to an
inhaled antigen (ovalbumin). The exposure regime involved intermittent 4 d
exposures, with up to 16 total days of exposure; no increase in senssitization
compared to controls was found. Kitabatake et al. (1979) exposed guinea pigs
(head-only) to 1.91 mg/m3 (<1 urn, MMAD) at 30-min intervals, twice per week,
for 4 weeks, followed by up to 10 additional paired treatments with the H2S04
for 30 min each, then exposure to aerosolized albumin for another 30 min. The
breathing pattern of the animals was monitored for production of dyspnea,
i.e., an "asthmatic attack." Enhanced sensitization was found after ~4 of the
albumin exposures. A subsequent challenge with ace.tylcholine suggested hyper-
responsive airways.
February 1988 4-34 DRAFT—DO NOT QUOTE OR CITE
-------
Acid aerosols may mediate the production of lung tumors. Godleski et al.
(1984) examined the effect of inhaled (NH4)2S04 on benzo[a]pyrene (BaP)-induced
carcinogenesis in hamster lung. Animals were exposed (chamber; 39 percent RH)
to -0.2 mg/m3 (NH4)2$04 (0.3 urn, MMD; ag = 2.02), with or without instilled
BaP, for 6 hr/d, 5 d/wk, for 15 wk; they were observed for an additional 2 yr.
Exposure to (NhL^SCK resulted in a significant reduction in tumor incidence
during the first 6 mo of observation but, by 2 yr, there were no differences
between those groups receiving BaP alone or BaP plus (NhL^SO^ These results
indicated some interaction between BaP and sulfate, but not one that provided
long-term protection against tumor development; they contrast with studies
showing that S04~ (administered by routes other than inhalation) did enhance
the development of tumors induced by other carcinogens (Blunck and Crowther,
1975; DeBaun et al., 1970; Cohen and Bryan, 1978). These latter likely
involved different metabolic and/or chemical reaction pathways; thus, it is
possible that inhaled acid sulfates could enhance carcinogenesis resulting from
materials other than BaP.
4.6 EFFECTS OF MIXTURES CONTAINING ACID AEROSOLS
Most of the toxicological data concerning effects of acid aerosols are
derived from exposures using single compounds. Although these data are essen-
tial, it is also important to study responses that result from inhalation of
typical combinations of materials, since general population exposures do
involve mixtures. Toxicological interaction provides a basis whereby low
concentrations of ambient pollutants may be damaging in combination. Thus, the
lack of any toxic effect following exposure to an individual pollutant should
always be interpreted with caution, since mixtures often behave differently
than expected from the same pollutants acting separately. In this regard, the
effects of acid aerosols may be influenced by various co-pollutants. Table 4-7
presents a survey of studies examining various endpoints following exposures to
mixed atmospheres containing acid aerosols. Most of the studies listed
involved inhalation of atmospheres containing only two pollutants. Investiga-
tions using more complex atmospheres are discussed separately.
The occurrence or extent of any toxicological interaction involving acid
aerosols depends on the endpoint being examined, as well as on the co-inhalant.
For example, in most studies that employed acid with 03, the response was due
February 1988 4-35 DRAFT—DO NOT QUOTE OR CITE
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solely to the latter rather than to the former. The major exceptions are the
studies of Last and colleagues (see Table 4-7), in which 03 and H2$04 were
synergistic in altering lung protein content and collagen synthesis, and that
of Osebold et al. (1980), in which the inclusion of H2$04 potentiated the
response to inhaled antigen seen with 03 alone. This latter study suggests
that inhalation of pollutant mixtures containing acid aerosols may increase
the number of sensitized individuals, or augment a reaction in those already
sensitized. These studies are highly suggestive that H2S04 acts by increasing
the effective dose of 03 delivered to its target site(s) in the lungs.
Although most interaction studies involve simultaneous exposure to more
than one pollutant, exposure to one substance may alter the response to another
subsequently inhaled. Thus, the order of exposure to inhaled materials may be
important in eliciting a toxic interaction. For example, using sequential
exposures (chamber), Gardner et al. (1977) found an additive increase in
infectivity when mice were exposed to 0.1 ppm 03 for 3 h immediately before
exposure to 0.9 mg/m3 (0.2 pm, VMD) H2S04- for 2 h; no difference from control
was found when the H2$04 was administered prior to the 03- On the other hand,
Silbaugh and Mauderly (1986), using bronchoconstriction as the endpoint,, found
that a 2 h exposure (chamber, 65 to 72 percent RH) of guinea pigs to 0.8 ppm
03 did not alter the response to a subsequent 1-hr exposure to 12 mg/m
(0.63 urn, MMAD) H2S04. Grose et al. (1980) exposed hamsters (chamber) to
0.1 ppm 03 for 3 h followed by 1.09 mg/m3 (0.3 pm, VMD) H2S04 for 2 h. A
reduction in ciliary activity in isolated tracheal cultures was oJDserved, but
the magnitude of the change was significantly less than that found with
exposure to the H2$04 alone; QS alone produced no change at all. ;
Another factor which may influence the interaction between acid aerosols
and other inhaled materials is the particle size of the former. Using pulmo-
nary resistance in guinea pigs as the endpoint, Amdur (1957) found a synergis-
tic response following a 1-h inhalation (head-only) of 82 ppm :S02 with
19 mg/m3 of 0.8 urn (MMD) H2S04; on the other hand, no synergism was seen when
inhalation involved a 2.5 urn acid;droplet. Last et al. (1986) observed a
synergistic response on biochemical indices in rat lung with exposure (chamber,
80 percent RH) to H2$04 (1 mg/m3) and 03 (0.6 ppm) when the droplet size was
0.5 urn (MMAD), while no potentiation of 03 response was seen with a droplet
size of 0.03 urn. Apparently, in this case, the aerosol that had greater
February 1988 4-40 DRAFT-DO NOT QUOTE OR CITE
-------
deposition in the terminal-respiratory bronchiolar region (the major site of 0-
deposition) was most interactive with 0-.
The pollutant atmosphere in most environments is a complex mix of more
than two materials. A few studies have attempted to examine the effects of
multicomponent atmospheres containing acid particles. Mannix et al. (1982)
examined the effects of a 4 h exposure (chamber) of rats to a S09-sulfate mix,
3
consisting of S02 (5 ppm) plus 1.5 mg/m (0.5 urn, MMAD, ag = 1.6) of an aerosol
containing (NH4)2$04 and Fe2(S04)3. No change in particle clearance from the
tracheobronchial tree or respiratory region was found. Aranyi et al. (1983)
exposed mice (chamber; 48 to 54 percent RH; 5 h/d, 5 d/wk for 103 d) to
mixtures of 03 (0.1 ppm), S02 (5 ppm) and (NH4)2$04 (1.04 mg/m3; 0.39 urn MMAD;
ag 2.42), and noted enhanced bactericidal activity of macrophages, compared to
03 alone. This same exposure regime also resulted in a greater (compared to 03
alone) degree of iji vitro cytostasis to tumor target cells cocultured with
peritoneal macrophages obtained from exposed mice. The investigators suggested
that these results indicated possible macrophage activation by the complex
atmosphere.
Hyde et al. (1978) exposed dogs (in chambers) for 16 hr/d for 68 mo to
o
pollutant mixtures as follows: H2SO. (0.09 mg/m , <0.5 urn) + S02 (0.4 ppm);
H2S04 (0.09 mg/m3) + S02 (0.46 ppm) + auto exhaust; H2$04 (0.11 mg/m3) + S02
(0.4 ppm) + irradiated auto exhaust (which results in production of oxidants);
nonirradiated auto exhaust; or irradiated auto exhaust. The animals were
examined for morphological damage 32 to 36 mo after exposures ended. Although
there was no evidence of any interaction between auto exhaust and sulfur
oxides, most groups showed enlargements of air spaces in proximal acini and
hyperplasia of bronchiolar cells. Pulmonary function changes were also
observed in these animals (Stara et al., 1980). Unfortunately, the individual
component(s) of the mixtures causing these effects could not be determined.
Kleinman et al. (1985a,b) exposed rats (nose-only) for 4 h to atmospheres
consisting of various combinations of 03 (0.6 ppm), N02 (2.5 ppm), S02 (5 ppm)
and aerosol. The latter consisted of 1 mg/m (0.2 pm, MMAD) of either
(NH4)2S04 or H2S04, laced with iron and manganese sulfates. The metallic salts
act as catalysts for the conversion of sulfur (IV) into sulfur (VI), and the
incorporation of gases into the aerosol droplets. The respiratory region was
examined for morphological effects. A confounding factor in these studies was
the production of nitric acid in atmospheres that contained 03 and N02, and
February 1988 4-41 DRAFT—DO NOT QUOTE OR CITE
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nitrate in those that contained 03 and (NH4)2$04 but not NO^ Nevertheless, a
significant enhancement of tissue damage was produced by exposure to atmo-
spheres containing H2S04 (or HN03) compared to those containing (NH4)2S04. In
addition, there was a suggestion that the former atmospheres resulted in a
greater area of the lung becoming involved in lesions, which were characterized
by a thickening of alveolar walls, cellular infiltration in the interstitium
and an increase in free cells within alveolar spaces. Exercise seemed to
potentiate the histological response to the complex mixture containing H2$04
(Kleinman et a!., 1988).
Mautz et al. (1985) examined the effects of complex mixtures upon pulmo-
nary mechanics in exercising dogs. Exposures (nose-only) were for 200 min to
atmospheres consisting of 03 (0.45 to 0.7 ppm), S02 (4.8 to 5.2 ppm), H2S04
(0.8 to 1.2 mg/m3, 0.2 pm MMAD), and catalytic salts (iron and manganese
sulfates). A greater increase in resistance and decrease in compliance was
found with the complex atmospheres containing the sulfate compounds than with
0- alone. Although this was ascribed to the presence of the H2S04, synergism
could not be definitively concluded since the mixture was not tested without
°3-
Most of the toxicologic data base for H2$04 consists of studies aimed at
assessing the effects of exposure to submicrometer aerosols such as would be
formed secondarily in the atmosphere from S02. Recently, the response to
sulfuric acid coating the surface of metallic oxide particles was examined by
Amdur and Chen (1988); this was intended to simulate primary emissions from
coal combustion processes. Guinea pigs were exposed for 3 hr/day for 5 days
to ultrafine (0.05 urn CMD, erg = 2) aerosols of zinc oxide (ZnO), which
contained a surface coating of H2S04- Levels as low as 0.20-0.30 mg/m as
equivalent H2S04 delivered in this manner resulted in significant reductions in
total lung volume, vital capacity, and CO diffusing capacity. The effects
appeared to be cumulative, in that their severity increased with increasing
days of exposure. These exposures also resulted in an increase in the protein
content of pulmonary lavage fluid (an index of lung damage) as well as an
increase in neutrophils (and index of inflammation). The investigators found
that much higher exposure levels of pure H2$04 aerosol were needed to produce
comparable results. This suggests that the physical state of the associated
acid in pollutant mixtures is an important determinant of response. e
February 1988 4-42 DRAFT-DO NOT QUOTE OR CITE
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It is apparent from this survey of the data base that toxicologic interac-
tions with acid aerosols may be antagonistic, additive, or synergistic. The
latter poses the greatest threat in terms of potential health effects.
There are various mechanisms by which synergism may occur. One is physi-
cal, the result of adsorption of one material onto the acid particle and
subsequent transport to more sensitive sites, or sites where this material
normally would not deposit in concentrated amounts. The acid particles, thus,
essentially act as carriers. A second mechanism involves dissolution and
reaction within an acid droplet, forming some secondary product(s) that may be
more toxicologically active than the primary materials.
A third mechanism may involve an acid induced change in the local micro-
environment of the lung, enhancing the effects of the co-inhalant. This was
proposed by Last and colleagues based upon 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 sulfate aerosols (H,,S04, (NH^SO^, Na,,S04)
with and without oxidant gases (0, or NO,,), and various biochemical endpoints
examined. Acidic sulfate aerosols alone did not produce any response at levels
that caused a response in conjunction with 03 or NO,,. The investigators sug-
gested that the deposition of the acid aerosol produced a shift in local pH
within the alveolar milieu; this shift then resulted in a change in the
reactivity or residence time of reactants (e.g., radicals) involved in oxidant-
induced pulmonary effects. Further evidence that the toxic interaction was
due to acidity was the finding that neither Na,,S04 nor NaCl was synergistic
with 03 (Last et al., 1986).
4.8 SUMMARY AND CONCLUSIONS
The bulk of the toxicologic data base on acid aerosols involves sulfate
compound particles, primarily submicrometer H-SO-. There are no data for larger
HpSO. droplets that would be constituents of acid fogs, and few data for other,
nonsulfur constituents of such fogs or other acidic atmospheres, e.g., nitrogen
compounds such as HNO~. However, the available evidence indicates that the
+ =
observed responses to acid sulfates are likely due to H rather than to SO. .
Thus, HpSO. may be considered to be a "model" acidic irritant and the observed
effects seen for this pollutant likely apply, at least qualitatively, to other
acid aerosols having .similar deposition patterns in the respiratory tract.
However, it has been suggested that the irritant potency of an acid may be
February 1988 4-43 DRAFT—DO NOT QUOTE OR CITE
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related more to its total H+ concentration, i.e., titratable acidity, rather
than to its free H+ concentration as measured by pH (Fine et al., 1987). This
implies that the specific chemical composition of different acids may be a
factor mediating the quantitative response. In any case, the toxicity of
H2SO. is likely due to the direct .-irritant action of deposited acid droplets
and/or to the subsequent release of humoral mediators such as histamine.
A survey of the data base for H2$04 toxicology shows what often appear to
be contradictory or, at the least, variable results. There are a number of
possible explanations for these. A major one involves response differences
between animal species (or strains) due to intrinsic sensitivity differences,
or differences in age, aerosol deposition pattern, and respiratory tract NH3
levels. Various experimental variables (e.g., relative humidity), mode of
exposure, aerosol particle size, exogenous NH3 levels, also differ in different
studies. But in spite of such differences, a number of generalizations regard-
ing the toxicology of HpSO. may be made, based upon relative consistencies in
similar studies.
The available evidence indicates that H2S04 exerts its action throughout
the respiratory tract, with the type and magnitude of response dependent upon
particle size, mass concentration, and, for most endpoints, exposure duration.
At very high concentrations (>15 mg/m ), mortality will occur following acute
exposure, due primarily to laryngeal or bronchoconstriction; larger particles
are more effective in this regard than are smaller ones. Somewhat lower
exposure levels will also result in death, but this is due to extensive
pulmonary damage, including edema, hemorrhage, epithelial desquamation, and
atelectasis. But even in the most sensitive species, LDQ levels are quite high
(>8 mg/m )
Both acute and chronic exposure to H2$04 at levels well below lethal ones
will produce functional changes in the respiratory tract. The pathological
significance for some of these is 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 mg/m3 have been largely unsuccessful, except in the guinea pig. The
lowest effective level of HpSO, producing bronchoconstriction to date in the
guinea pig is 0.1 mg/m3 (1 h exposure). In general,, the smaller-size droplets
were more effective in altering pulmonary function, especially at low concen-
trations. Yet even in this species, there are inconsistencies in the type of
[ :
February 1988 4-44 DRAFT—DO NOT QUOTE OR CITE
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response exhibited towards acid aerosols. Some studies show an exposure-
concentration response beginning at 0.1 mg/m , while others show an all-or-npne
response beginning only at concentrations much higher than this, and no
response at lower levels. Chronic exposure to HpSO- 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
3
effective concentrations are >0.5 mg/m .
The relationship between the above changes in pulmonary function and
disease is unclear. But the development of hyperresponsive airways in healthy
animals due to acid aerosols, at levels below those producing any change in
lung functional indices without bronchoconstrictor challenge, does have impli-
cations for the pathogenesis of airway disease due to nonspecific irritant
exposure. Hyperresponsive airways have been induced in rabbits with repeated
3
exposures to 0.25 mg/m >LSO • the effects on responsivity of long-term
exposure to lower levels are not known.
Severe morphologic alterations in the respiratory tract will occur at high
acid levels. At low 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. This likely results in an
increase in secretory rate and mucus volume in such airways, which is a possi-
ble factor in the pathogenesis of obstructive lung disease.
The lungs have an array of defense mechanisms to detoxify and physically
remove inhaled material, and available evidence indicates that certain of these
3
defenses may be altered by exposure to HLSO. at levels <1 mg/m . Defenses such
as resistance to bacterial infection are not altered even by acute exposure to
3
concentrations as high as 150 mg/m . However, the bronchial mucociliary
clearance system is very sensitive to inhaled acids; much lower levels of
3
HpSO. (<1 mg/m ) produce alterations in mucociliary transport rates in healthy
animals. The lowest level shown to have such an effect, 0.1 mg/m with repeated
exposures in the donkey, is well below concentrations that result in other
physiological changes in most experimental animals. Furthermore, exposures to
somewhat higher concentrations that also alter clearance have been associated
with various morphometric changes in the bronchial, tree indicative of mucus
hypersecretion.
February 1988 4-45 DRAFT—DO NOT QUOTE OR CITE
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Limited data also suggest that exposure to acid aerosols may affect the
functioning of alveolar macrophages; the lowest level examined in this regard
is 0.5 mg/m3 HpSO.. Although the: pathogenic implications of such effects are
not certain, they likely play some role in altering removal of material from
the respiratory region. Respiratory region particle clearance is affected by
3 !
repeated H2SO- exposures to as low as 0.25 mg/m .
Effective clearance mechanisms are critical in reducing the residence time
of inhaled, deposited materials, and alterations in clearance^ especially due
to chronic acid aerosol exposure, may be associated with lung disease.
Mucociliary efficiency influences the development of acute infectious disease
(Proctor, 1979; Niederman et al., 1983), and there is accumulating evidence
that dysfunction of bronchial clearance plays a role in the pathogenesis of
chronic bronchitis (Albert et al., 1973; Schlesinger et al., 1983) and may be
an early indication of disease in otherwise asymptomatic individuals (Mossberg
and Camner, 1980; Goodman et al., 1978).
The role of acid aerosols, specifically H2$04, in the development of
chronic bronchitis is supported by a comparison of results from studies of
sufamicrometer HpSO, mist and cigarette-smoke exposures (Lippmann et al., 1982);
the latter are known to be involved in the etiology of human chronic bronchi-
tis. The effects of both agents on bronchial mucociliary clearance patterns
were found to be essentially the same following either single or intermittent
exposures in experimental animals and humans.
The pathogenic implications of alterations in clearance from the respira-
tory region are more speculative than those for mucociliary clearance, but
clearance rates are reduced in humans with chronic obstructive lung disease and
in cigarette smokers (Bohning et al., 1982; Cohen et al., 1979).; This suggests
some relation between altered defense and chronic lung disease development in
these latter individuals; the results of toxicologic assessments suggest the
former precedes the latter. <
The assessment of the toxicology of acid aerosols requires some examina-
tion of potential interactions with other air pollutants. Although such
interactions may be antagonistic,!additive, or synergistic, the exact mechanism
by which they occur is not well defined, and evidence for them may depend upon
the sequence of exposure as well as on the endpoint examined. Low levels of
hLSO, (0.04 mg/m3) have been shown to react synergistically with 0- in
24 . " •
simultaneous exposures, using biochemical endpoints. In this case, the HgSO^
February 1988 4-46 DRAFT—DO NOT QUOTE OR CITE
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enhanced the damage due to the O,. This is common in studies with 0,, while
HpSO, toxic effects themselves may be more directly manifest with other, less
potent, co-inhalants. There is some evidence that sulfuric acid existing as a
sulfate coating on other particles may be more potent than the acid existing
as a sulfate droplet. The most realistic exposures are to multicomponent
atmospheres, but the results of these are often difficult to assess due to
chemical interactions between the components and a resultant lack of precise
control over the ultimate composition of the exposure environment.
In conclusion, the acute effects of acid (i.e. HpSO.) inhalation involve,
at high levels, bronchoconstriction and, at lower levels, alterations in the
rate of clearance from the tracheobronchial tree and pulmonary region. The
toxicologic data base also allows for speculation that the potential does exist
for the production of chronic lung disease due to long-term inhalation of acid
aerosol, i.e., H^SO,. The diseases most likely to be associated with such
exposures are asthma and chronic bronchitis. The greatest potential health
threat due to pollutant interactions likely involves 0^, since synergism has
been found with combinations of peak ambient levels of 0- (0.2 ppm) and hLSCL
O *^ £~ '
(0.04 mg/m ); in this case, the associated disease is speculated to be
pulmonary fibrosis. However, the lowest level of acid capable of eliciting
responses (alone or in combination with other pollutants) is currently not
known.
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5. CONTROLLED HUMAN EXPOSURE STUDIES OF ACID AEROSOLS
5.1 INTRODUCTION
The effects of inhaled acid aerosols were studied initially because of
interest in occupational exposures. These early studies, conducted in the
1950/s, have been followed by an-extensive series of investigations, most of
which have been completed since 1977. The impetus for the more recent studies
appears to have been the concern over production of sulfates by automotive
catalytic converters. The sparse data on environmental levels of airborne
acidity have hindered the design of human exposure studies. The majority of
studies have been conducted using sulfuric acid aerosol and its salts, although
the effects of nitrates and hydrochloric acid aerosols have also been examined.
A broad range of concentrations of these aerosols have been studied ranging
3 3
from 10 ug/m to more than 1,000 ug/m . The "dose" of inhaled aerosol has been
varied by using exposures of different durations (from 10 minutes up to
4 hours) or by increasing the ventilatory exchange by incorporating exercise.
In addition to these rather straightforward considerations, the delivered
"dose" is also affected by the upper airway path traversed by the aerosol and
the size of the particles as well as their potential for hygroscopic growth
in'the respiratory tract, as discussed in Chapter 3~. '
The studies reported in this section have been conducted on both normal
and asthmatic subjects; the latter group represents a potentially "susceptible"
population. Aerosols have been inhaled either directly through a mouthpiece or
facemask or during unencumbered breathing in an environmental chamber. Several
different types of measurements have been made following exposure. In most
cases, some measures of lung function such as spirometry or plethysmography
have been made. In addition, the effects of acid aerosols on airway reactivity
and on mucociliary clearance have been studied rather extensively.. Another
area of investigation has been the influence of aerosol acidity and the poten-
tial for neutralization of acid by ammonia or by airway surface fluid buffers.
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The first investigation into- the effects of acid aerosols on human lung
function was conducted by Amdur and co-workers in 1952 (Amdur et al., 1953).
Using a group of 15 subjects, they studied the retention of inhaled sulfuric
acid aerosol, the changes in respiratory pattern induced by the acid aerosol,
and the sensory threshold for olfactory detection of sulfuric acid rnist.
The aerosol was generated from fuming H2S04; the particle size was reported
to be 1 urn. Calculated respiratory tract aerosol particle retention averaged
77 percent and ranged from 50 percent to 87 percent in the exposure concentra-
tion range of 0.4 to 1.0 mg/m . Aerosol concentrations of less than 1 mg/m
could not be detected by either odor or taste and apparently caused no irrita-
tion. All subjects were able to detect a concentration of 3 mg/m . At
5 mg/m3, a deep breath usually produced coughing.
Changes in respiratory pattern were reported at 0.35 to 0.50 mg/m sul-
furic acid aerosol (SAA). A reduction in both maximum inspiratory (-15 per-
cent) and expiratory (-20 percent) flow was accompanied by a modest tachypnea
(+35 percent increase in respiratory frequency) and a decrease (-28 percent)
in tidal volume. These findings were interpreted as a typical response to
respiratory irritants. This study did not, unfortunately, generate the
necessary interest at the time for a large number of subsequent investiga-
tions of the effects of acid aerosol exposure in man.
One subsequent study, conducted by Sim and Rattle (1957), reported the
responses to relatively high concentrations of large-particle sulfuric acid
aerosols. Because of the high concentrations used and the somewhat uncon-
trolled nature of the exposures, this study provided little useful information.
The next reported study of human exposure to sulfuric acid aerosol was
that of Larson et al. (1977). This paper reported the first evidence that oral
ammonia could effectively neutralize a portion of the inhaled acid aerosol; it
is discussed in more detail in Chapter 3. Although interest in sulfuric acid
aerosol as an air contaminant dates back to the "fog" episodes, virtually all
of the studies that address human health effects, which are relevant to
ambient exposures, have been published since 1977. This important study served
as a lead-in to a number of subsequent studies of the effects of acid aerosols.
The studies described in this section deal with human experimental expo-
sures to inhaled acids and their salts; such studies are frequently referred to
February 1988 5-2 DRAFT—DO NOT QUOTE OR CITE
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as human "clinical" studies. The methods used in these studies are similar to
those used in experimental studies of criteria pollutants such as ozone, N02>
and S02. A detailed discussion of the methodology is beyond the scope of the
chapter but some points may be important in evaluating the studies discussed
subsequently.
Inhaled substances may be breathed directly through a mouthpiece or from
air within an environmental chamber or a facemask. One of the major consider-
ations is that air breathed orally bypasses the nose, which may remove soluble
pollutants from the air as well as humidify the incoming air. On the other
'hand, air breathed nasally encounters greater flow resistance and bypasses a
potential source of ammonia in the mouth. The volume of air exchanged is a
function of the metabolic rate or level of activity of the exposed individual;
exercising subjects will therefore inhale more of the pollutant gas or aerosol.
The temperature and humidity of the inspired air may be an important factor,
especially for asthmatics. Of course, the duration of the exposure and the
concentration of pollutant are essential in quantitating the exposure.
5.2 PULMONARY FUNCTION EFFECTS OF H£S04 IN NORMAL SUBJECTS
The effects of sulfuric acid aerosol have been studied extensively in
healthy subjects without history of respiratory disease. Such subjects are
typically young adult males whose atopic status has usually not been deter-
mined. Studies completed since 1978 include exposures to a range of concen-
trations from 75 to 1,500 ug/m3 with a variety of aerosol particle sizes from
0.1 to 1.5 urn. This section includes only the data from "normal" subjects.
If data on asthmatics or other types of subjects were also included in a
report, these data are discussed separately in the appropriate subsection
(Section 5.6). Many of the details of the experimental procedures are presented
in the tables to avoid a cumbersome text. • ~ • .
Newhouse et al. (1978) exposed 10 subjects to 1,000 ug/m sulfuric acid
aerosol (0.5 urn) under temperate (22°C), humid (70 percent RH) conditions for a
period of 2 h. The exposure period included a total of 20 min of heavy
exercise (70 to 75 percent of maximal aerobic power); oral breathing was
obligatory throughout exposure. There were no significant changes in VC,
FEVX 0, or MMFR as a result of this exposure.
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Sackner et al. (1978) reported the results of a series of exposures of
both normal and asthmatic humans to sulfuric acid aerosol concentrations
2
ranging from 10 to 1,000 ug/m . These studies involved a total of" 17 normal
subjects of mixed age and gender and were performed with oral breathing at
3
rest. There were no significant effects of up to 1,000 ug/m sulfuric acid
aerosol of any of the extensive series of tests of lung function performed
after exposure in these subjects.
3
Six subjects exposed to 75 ug/m sulfuric acid aerosol were studied by
Avol and associates (1979). Exposures included light intermittent exercise and
lasted for 2 h. There were no significant respiratory function effects of
this exposure in these subjects.
In a study primarily designed to examine the effects of sulfuric acid
aerosol on mucociliary clearance, Leikauf et al. (1981) exposed 10 healthy
o
nonsmokers for one hour to 110, 330, and 980 ug/m of 0.5 urn sulfuric acid
aerosol via nasal mask. There were no significant effects of H^SO. exposure
on airway resistance, partial maximum expiratory flow at 25 percent of vital
capacity (V25; partial expiratory flow-volume test), or on an index of
distribution of ventilation based on multiple breath nitrogen washout.
o
Kerr et al. (1981) examined the effects of a longer exposure to 100 ug/m
sulfuric acid (0.1 to 0.3 urn). Two groups of 14 subjects each, one consisting
of smokers (11 M, 3 F) and the other of nonsmokers (8 M, 6 F) were exposed for
4 hr in an environmental chamber; moderate exercise was performed for two
15-min periods during exposure. There were no significant alterations in lung
function (forced expiratory tests, single breath nitrogen washout, airway
resistance, or pulmonary compliance). :
In a study using a similar protocol, Horstman et al. (1982) confirmed the
absence of significant change in pulmonary function following exposure to low
sulfuric acid aerosol levels (108 ug/m of 0.5 urn aerosol). A control group of
17 and an experimental group of 18 male subjects were exposed on two consecu-
tive days for 4 h including two 15-min periods of moderately heavy exercise.
Each group received a clean air exposure on the first day. On the second
exposure day, the control group received clean air and the experimental group
received H^SO.. The exposure had no effect on breathing pattern, spirometry,
or airway resistance. ;
Horvath et al. (1982) exposed 11 male subjects to clean air and to 233,
418, and 939 ug/m of 0.9 urn sulfuric acid aerosol. Exposures lasted 2 hr and
February 1988 5-4 DRAFT—DO NOT QUOTE: OR CITE
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included four 15-min periods of mild intermittent exercise. A small decrease
(101 ml; -2.1 percent) in FEV-j^ Q was reported for the 939 ug/m exposure.
Since this change was similar in relative magnitude to other spirometry mea-
surements in the study, it is quite possible that the "significance" of this
result occurred by chance (i.e., a total of 12 measurements were tested for
significance at the P <0.05 level, which increases the likelihood of finding a
"significant" response by chance alone). Although there was no convincing
evidence of pulmonary function effects, symptoms of cough and dry or irritated
3
throat were more prevalent at the highest (939 \ig/m ) concentration and were
noted mainly at the beginning of the exposure period. The occurrence of
significant symptoms suggests that the significance of the small change in
FEV-, n reported at the 939 pg/m concentration could be real. However, Avol
et al. (1986) noted increased symptoms, in the absence of changes in spirometry
at both 1,000 and 2,000 ug/m3 of H2S04 "acid fog" aerosol.
Utell et al. (1982) exposed normal volunteers to 100 and 1,000 ug/m of
0.5 to 1.0 |jm "dry" sulfuric acid aerosol for 16 min via mouthpiece breathing.
This resting exposure produced no significant effect on airway conductance yet
induced "quite small" but significant changes (magnitude not reported) in
maximum expiratory flow on maximum expiratory flow volume curves (MEF60%TLC)
and partial expiratory flow volume curves (PMEF60%TLC, PMEF40%TLC) after the
1,000 ng/m exposure.
From a comprehensive exposure study including several pollutants, Stacy
• • ,3
et al. (1983) reported results for 11 subjects exposed to 100 (jg/m sulfuric
acid aerosol. The 4-h exposure, which included 30 min of moderate exercise,
produced no significant effects on pulmonary function.
Utell et al. (1984) reported results of a study in which 14 normal sub-
3
jects were exposed to 100 and 1,000 pg/m sulfuric acid aerosol for 16 min;
there were no effects on SGaw, FEV, Q, or V60%TLC.
During a study examining the effects of ozone plus H,,SOA, Horvath et al.
3
(1987) exposed 9 men to a range of 1,200 to 1,600 |jg/m sulfuric acid aerosol
for 2 h. In contrast to their previous study (Horvath et al., 1982), an
extremely fine aerosol (<0.1 (jm) was used. The exposures were conducted under
warm, humid conditions and included a total of 60 min of moderate intermittent
exercise. There were no significant changes in FVC, FEV.^ Q, ^^25-75% or ^aw
attributable to sulfuric acid aerosol exposure. Although evaluation of subject
symptoms was apparently conducted, the symptom results were not included in
their report.
February 1988 5-5 DRAFT—DO NOT QUOTE OR CITE
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Avol et al. (1986) have exposed subjects to 0, 500, 1,000, and 2,000 ug/m
of acid fog (see details in 5.6 or Table 5-1). In the healthy normal subjects,
there was no indication of pulmonary function effects after any of the expo-
sures. However, upper and lower respiratory symptoms increased after all
exposures but most notably after the 2,000 ug/m exposure. Airway reactivity
to methacholine was unchanged after the exposures.
The results of the above 11 studies, which investigated the effects of
sulfuric acid aerosols over a broad range of particle sizes (0.1 to 10 |jm) and
under a variety of exposure conditions (duration, temperature, humidity,
inhalation route, activity level), consistently demonstrated that there were no
3
pulmonary function effects of up to 500 ug/m sulfuric acid aerosol for dura-
tions up to 4 hr. Although there is some suggestion that pulmonary function
2
effects may begin at concentrations of approximately 1,000 ug/m , the demon-
stration of responses is confined to only a few of many studies and the effects
were very small in magnitude and not consistently demonstrated across a variety
of exposure conditions. However, symptoms of upper respiratory discomfort were
reported after exposure to 1,000 ug/m in two studies of normal subjects.
5.3 EFFECTS OF ACID AEROSOLS ON BLOOD BIOCHEMISTRY
Chaney and co-workers (1980a) examined the effects of sulfuric acid
aerosol exposure on blood biochemical markers. Twenty subjects were exposed to
100 ug/m3 of 0.5 urn sulfuric acid aerosol for 4 h at rest on two consecutive
days. Blood samples were taken immediately before and after exposure, and
then again one day after exposure. There was no effect of acid aerosol
exposure on any of the measured blood parameters: glutathione, red blood cell
(RBC) glutathione reductase, RBC glucose-6-phosphate dehydrogenase,, lysozyme,
SGOT (serum glutamic-oxaloacetic transaminase), serum vitamin E, and 2,3-
diphosphoglycerate (DPG). \
The above study was repeated (Chaney et al., 1980b) using a.slightly
modified experimental design and an exposure protocol that incorporated
exercise. (The exercise protocol is identical to that described in Section 5.2
for Horstman et al., 1982). The blood parameters measured were the same as in
the resting study except that G6PD was omitted. .This study demonstrated no
effects of sulfuric acid aerosol exposure on these human blood biochemical
markers.
February 1988
5-6
DRAFT—DO NOT QUOTE OR CITE
-------
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5.4 EXPOSURE TO MIXTURES OF ACID AEROSOLS WITH OTHER POLLUTANT GASES
In the ambient environment, many pollutants coexist. When individuals are
exposed to two or more inhaled pollutants, either simultaneously or sequen-
tially, there is potential for an additive or interactive effect. These
possible combined effects have been studied for sulfuric acid aerosol in
combination with 03, S02, and NOp. Although a variety of pollutant combina-
tions have been utilised, rarely, if ever, are the ambient conditions approxi-
mated. More consideration of actual ambient conditions is required, especially
consideration of the gas and aerosol concentrations in areas impacted by
plumes.
Kleinman et al. (1981a) studied the effect of the combination of ozone
o
(0.37 ppm), SOp (0.37 ppm), and sulfuric acid aerosol (100 ug/m ) under warm,
humid conditions in an environmental chamber. Nineteen subjects participated
in the 2-h intermittent exercise exposures using a non-randomized exposure
sequence: exposure to the pollutant was always preceded several days earlier
by a clean air "sham" exposure. Exposure to the pollutant mixture caused
significant reductions in FVC (-2.8 percent), FEV-, Q (-3.7 percent), and other
spirometric measurements. There was a trend for symptoms to increase during
the exposures but the symptoms reported during the pollutant mixture exposures
were not significantly different from those reported during the clean air
exposures. The authors indicated that more than 90 percent of the H?SO. was
partially neutralized to ammonium bisulfate. The decrease in FEvy Q (-3.7 per-
cent) was only slightly larger than for a previous group of subjects exposed
to ozone alone (FEV-, Q; -2.8 percent), using a similar exposure protocol. It
was therefore concluded that the presence of sulfuric acid aerosol did not
enhance the effects of ozone-S0? mixtures.
Kulle et al. (1982) reported the results of a study in which ozone and
sulfuric acid exposure were combined in a sequential manner; the 4-hr exposure
to sulfuric acid aerosol was preceded by a 2-h exposure to 0.3 ppm ozone.
Twelve nonsmokers participated in this study in which the effects of 0.3 ppm
3 '
ozone and 100 ug/m of 0.13 urn sulfuric acid aerosol were studied individually
and then in combination. The order of exposures was identical for all sub-
jects: ozone, sulfuric acid aerosol, and ozone plus sulfuric acid aerosol,
each exposure separated by one week. The exposures each included one 15 min
period of moderate cycling exercise. None of the exposures produced signifi-
cant changes in spirometry or plethysmography. The authors suggested that the
bronchial reactivity to methacholine may have decreased following sulfuric acid
February 1988 5-13 DRAFT—DO NOT QUOTE OR CITE
-------
aerosol exposure but the apparent difference was not statistically significant.
It was concluded that the prior exposure to ozone did not enhance the response
to sulfuric acid aerosol (or at least did not help to induce a response where
none was previously evident). It was nevertheless suggested that the use of a
larger-particle-size sulfuric acid aerosol may have produced different results
since a larger aerosol would tend to deposit by impaction to a greater extent
on the larger airways, the apparent site of the symptomatic effects of ozone.
In a study involving a total of 231 subjects, Stacy et al. (1983) examined
3
the effects of 4-h exposures to sulfuric acid aerosol (100 ug/m ), ammonium
3 3
sulfate aerosol (133 ug/m ), ammonium bisulfate aerosol (116 ug/m ), and
q
ammonium nitrate aerosol (80 pg/m ) in combination with ozone (0.4 ppm), NOp
(0.5 ppm) and S0? (0.75 ppm). In addition to exposures to each individual
pollutant, there were a total of 12 combination exposures to a mixture of
one of the four aerosols and one of the three gaseous pollutants. There were
two 15-min periods of moderately heavy exercise during the exposure. With
the exception of the ozone plus aerosol exposures, none of the aerosols or
gas-aerosol mixtures caused any significant changes in plethysmography or
spirometry. Similarly, only subjects exposed to ozone reported symptoms
indicative of respiratory tract irritation (e.g., coughing or. throat
irritation).
Kagawa (1986) recently reported the results of a series of studies Of
exposure to air pollutant combinations, some of which included sulfuric acid
aerosol. The subjects were young adult Japanese; approximately half were
smokers. A 2-h intermittent exercise protocol was used which included four
15-min exercise periods at 50 W (300 kpm). Exposures to either 200 or
3 '
400 jjg/m sulfuric acid aerosol occurred in a body plethysmograph maintained
at 28 to 29°C and 50 to 60 percent RH. Unfortunately the data for individual
exposures to only sulfuric acid aerosol are omitted from the tables and
figures. The addition of sulfuric acid aerosol to exposure atmospheres —
most contained ozone (0.15 to 0.30 ppm) — produced no obvious additional
effects on specific airway conductance over and above those caused by the
other pollutants. Airway reactivity to acetylcholine was determined after
3
one series of exposures to 200 ug/m of sulfuric acid aerosol; no effect on
airway reactivity was observed. In several different series of ozone plus
sulfuric acid aerosol exposures, the author observed no apparent health-
related synergistic effects of sulfuric acid aerosol with ozone.
February 1988 5-14 DRAFT—DO NOT QUOTE OR CITE
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Horvath and co-workers (1987) studied the effects of exposure to much
higher concentrations of sulfuric acid aerosol (1,200 to 1,600 (jg/n>3) in'
combination with ozone. As indicated in Section 5.2, there was no effect of
the sulfuric acid aerosol alone on pulmonary function. The combination of a
"no-effect level" of ozone with the sulfuric acid aerosol also produced no
significant changes in pulmonary function. Although the investigators chose a
somewhat conservative probability level for indicating significance (P <0.01),
their findings of no significance would also have held at P <0.05.
The studies cited in this section examined the pulmonary function
responses to exposure to sulfuric acid aerosol, over a broad range of concen-
trations, in combination with various other pollutants including ozone,
nitrogen dioxide, and sulfur dioxide. There was no evidence to suggest an
interactive effect between sulfuric acid aerosol and the other pollutants.
However, these studies primarily used the physiological measurement endpoints
derived from spirometry or plethysmography. Further studies using different
endpoints should be considered.
5.5 EXPOSURE TO OTHER ACID AEROSOLS OR MIXTURES OF AEROSOLS
Human exposure to a number of aerosol species including sodium nitrate
(NaN03), ammonium nitrate (NH4N03), ammonium bisulfate (NH4HS04), ammonium
sulfate C(NH4)2S04), zinc ammonium sulfate (ZnS04-(NH4)2S04), and ferric
sulfate (Fe2(S04).~) has been studied over the past several years. Ambient
levels of airborne nitrate salts are typically less than 5 ug/m and rarely
3
exceed 50 pg/m (Sackner et a'!., 1979).
5.5.1 Nitrates
A series of sodium nitrate and ammonium nitrate aerosol exposures in both
normals and asthmatics was performed by Sackner and colleagues (1979). Groups
of 5 or 6 normal or asthmatic subjects breathed NaCl or NaNOQ aerosol at
3 6 • •
concentrations ranging from 10 to 1,000 jjg/m for 10 minutes while resting. In
the normal subjects, possibly significant differences in V50o/, VC and SGaw
between NaNO, and NaCl exposures were observed. However, a decrease in flow
was accompanied by an increase in airway conductance. Because of the large
number of specific comparisons, the authors concluded that these observations
were probably due to chance alone. They concluded that NaNO- exposure up to
3
1,000 ug/m caused no acute effects on cardiopulmonary function.
February 1988 5-15 DRAFT—DO NOT QUOTE OR CITE
-------
Utell et al. (1979) studied' both normal and asthmatic volunteers exposed
to 7,000 ug/m3 of 0.46 urn NaNOg aerosol for 16 min via mouthpiece. The major
health effect endpoints measured in their study included airway resistance,
both full and partial expiratory flow-volume curves, airway reactivity to
carbachol, and aerosol deposition. Aerosol deposition as a percentage of
inhaled aerosol averaged about 50 percent for normals and about 56 percent for
asthmatics; the group differences were not significant. The effect of exposure
to NaN03 aerosol was indistinguishable from the control NaCl exposure in
normals. Similarly, there were no effects of NaN03 exposure in asthmatics.
Utell et al. (1980) subsequently studied 11 subjects with influenza
exposed to the same NaN03 regimen as above. The subjects were initially
exposed at the time of illness and then reexposed 1, 3, and 6 weeks later.
Aerosol deposition ranged from 45 to 50 percent over the four exposure
sessions. All subjects had cough and fever and 10 of 11 had viral or
immunologic evidence of acute influenza. Baseline measurements of FVC and
FEV1 n were within normal limits and did not change throughout the six-week
period. There were small but significant decreases in airway conductance
following NaNO- inhalation. This difference was present during acute illness
sJ
and one week later but was not seen at 3 and 6 weeks post-ill ness. The
decrease in SGaw seen on the initial exposure was accompanied by a decrease in
partial expiratory flow at 40%TLC; this was also observed at the one week
follow-up exposure. This study suggests that the presence of an acute viral
respiratory tract infection may render humans more susceptible to the acute
effects of nitrate aerosols. Nevertheless, the concentration of nitrates used
in this exposure study exceeded maximum ambient levels by more than 100-fold.
In addition to NaNO- aerosols., NH4N03 exposure has been studied by
Kleinman and associates (1980). Twenty normal and 19 asthmatic subjects were
^
exposed to a nominal 200 M9/m of i-1 M"i ammonium nitrate aerosol. The 2-h
exposures included mild intermittent exercise and were conducted under warm
conditions (31°C, 40 percent RH). There were no significant physiologically
meaningful effects of the NH4N03 exposure in either subject group.
5.5.2 Other Sulfates
Linn et al. (1981) studied a group of 21 normal and 19 asthmatic subjects
exposed to 15 to 16 ug/m3 of zinc ammonium sulfate aerosol. Exposures lasted
2 h in an environmental chamber at 20°C and 85 percent RH and included light
February 1988 5-16 DRAFT-DO NOT QUOTE OR CITE
-------
intermittent exercise. Although there were some very small changes in function
between and within exposure conditions which apparently reached statistical
significance, there was no overall pattern of response which indicated that
zinc ammonium sulfate resulted in pulmonary dysfunction. The authors concluded
that this study "fails to demonstrate convincingly any effects of zinc ammonium
sulfate exposure important to health."
In a subsequent study with zinc ammonium sulfate, Kleinman and co-workers
(1985) exposed 20 normal subjects to a mixture of S09 (0.5 ppm), N09 (0.5 ppm),
3
and zinc ammonium sulfate (26 ug/m , 1.1 urn) combined with NaCI aerosol ; these
2-h exposure sequences incorporated light intermittent exercise. There were
no significant pulmonary function effects of this exposure. Symptom data
suggested that the SO^NOp- (NaCI aerosol -zinc ammonium sulfate) aerosol
mixture was somewhat more irritating than the NaCI aerosol alone but the
difference was not significant. Only the total symptom score was reported and
thus the individual symptoms responsible for the increased score cannot be
ascertained from this report. This study confirms the absence of effect of
zinc ammonium sulfate observed in the prior Linn et al. (1981) study.
Another metal-sulfate aerosol that has been evaluated as a potential
respiratory irritant is ferric sulfate (Kleinman et al., 1981b). Twenty normal
3
and 18 asthmatic subjects were exposed to 75 ug/m of 2 urn Fe(S0)o aerosol.
In the presence of ammonia, ferric ammonium sulfate may be formed, which was
assumed to be the case in this study. There were no statistically significant
changes in the physiologic tests performed before and after the exposures
(these included spirometry, plethysmography, single breath nitrogen washout,
forced oscillation, and oxygen saturation). Neither normal nor asthmatic
groups reported a significant increase in symptoms as a result of the exposure
to ferric sulfate. Even when data were analyzed on an individual basis, there
was no consistent pattern indicative of dysfunction induced by the ferric
sulfate aerosol.
Kulle and co-workers (1984) examined the possibility that a mixture of
SOy (1.0 ppm) and ammonium sulfate (528 yg/m , I urn) could produce greater
effects on the respiratory system than either pollutant alone. The exposures
lasted 4 h and included two 15-min sessions of moderate bicycle exercise.
Twenty subjects (10 M, 10 F) completed the study.. There were no significant
changes in spirometry , plethysmography, or airway reactivity to methacholine
with either ammonium sulfate alone or ammonium sulfate plus S02- Nevertheless,
February 1988 5-17 DRAFT— DO NOT QUOTE OR CITE
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there were increased symptoms as a result of the combined exposure in particu-
lar, in which 9 of 20 subjects reported upper airway irritation. Only 4 of
20 subjects reported upper respiratory tract symptoms for S02 exposures alone.
This observation suggests that the upper respiratory symptoms observed in
normals after S02 exposure (Witek et al., 1985) could possibly be enhanced in
the presence of ammonium sulfate.
While testing the hypothesis that a carbon aerosol could potentiate the
conversion of S02 to sulfates and enhance the effect of S02, Kulle and
associates (1986) exposed subjects to a mixture of S02 (1 ppm) and 500 ug/m3
of 1.5 urn activated carbon aerosol. Although it was demonstrated that most
of the S02 which was sorbed onto the carbon was converted to sulfate, the
sorption of S02 by carbon constituted only a very small fraction of the total
S02 dose. The effects of S02, which are not of interest for the purposes of
the current document, were neither enhanced nor mitigated by the addition of
carbon aerosol. This study provided no evidence to support the hypothesis
that the inert aerosol worsened the effects of S02 in normal healthy subjects
as a result of sulfate formation.
These studies of exposure to a variety of sulfate and nitrate aerosols
point to the absence of an effect on spirometry, plethysmography, arid various
other physiological indicators of pulmonary function in asthmatics and healthy
normal subjects. The only group of subjects which demonstrated a possible
effect were a group of normal individuals who had recently contracted
influenza. The health significance of the small alterations in pulmonary
function as a result of exposure to "massive" concentrations of NaNO- is
unclear at this time. Even at concentrations much higher than would be
anticipated in the ambient air, the nitrates and sulfates that have been
studied to date do not appear to produce any meaningful effects on pulmonary
function measurements in exposed individuals. ;
5.6 EFFECTS OF ACID AEROSOLS ON RESPIRATORY FUNCTION OF ASTHMATICS
The effects of sulfuric acid aerosol in asthmatics have been studied in a
number of laboratories in the past decade. There is considerable variability
in the results of these studies, much of which may be attributed to variability
in severity of asthma, in the procedures for withholding or continued use of
medication, and in exposure conditions. Asthmatics represent a "sensitive
subgroup" who are potentially more susceptible to the effects of several air
February 1988 5-18 DRAFT-DO NOT QUOTE OR CITE
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pollutants. One of the more obvious examples is the approximately tenfold
greater sensitivity of asthmatics to SOp, a gas that not only is a precursor
of sulfuric acid aerosol but is also likely to coexist with HUSO.. Asthmatics
also show increased airway resistance as a result of other stimuli such as
exercise, or from breathing cold airs dry air, or hyposmolar aerosols.
The cause of increased resistance is often presumed to be in large
conducting airways (bronchoconstriction). However, constriction of the larynx
or of smaller airways may make an important contribution to increased airway
resistance. The regional ization of changes in airway resistance is not
typically evaluated.
Characteristics of the asthmatics who participated in the studies reported
in this section are shown in Table 5-2.
Sackner and associates (1978) performed a series of sulfuric acid aerosol
exposure studies in a diverse group of 17 asthmatics exposed to 10, 100, and
o
1,000 ug/m . Most of the asthmatics were taking theophylline, prednisone, or
both. .The exposures to 0.1 to 0.3 urn sulfuric acid aerosol lasted for 10 min.
None of the physiological tests performed showed evidence of significant
dysfunction resulting from the exposures.
3
Avol et al. (1979) exposed 6 asthmatic subjects to 100 |jg/m sulfuric acid
aerosol for 2 h on two consecutive days. These subjects were also exposed to
ammonium sulfate and ammonium bisulfate. There were no significant group
effects on lung function that could be attributed to any of the aerosols. It
was noted, however, that two of the asthmatics exposed to sulfuric acid aerosol
showed "possibly meaningful changes in respiratory resistance." Because these
changes were observed on both sulfuric acid aerosol exposure days, it is
unlikely that the responses were due to chance alone. There was a tendency for
group mean symptom responses to increase on the sulfuric acid aerosol exposure
days. Nevertheless, the authors concluded that there were "no obvious group or
individual reactions."
Utell et al. (1982, 1983) studied 17 asthmatics (none requiring steroid
therapy) exposed to a variety of aerosols including NaCl , NaHSO.,
NH.HSO-, and H0SO, . The aerosols were submicrometer (0.5 to 1.0 urn) and
^r T1 £. *r ^
concentrations were 100, 450, and 1,000 jjg/rn . The relative humidity was
maintained below 25 percent. H2S04 deposition ranged from 54 to 62 percent of
the inhaled aerosol. All asthmatics were initially reactive to carbachol
inhalation challenge. Following the 16-min exposures to any of the sulfate
aerosols none of the asthmatics reported symptoms at any of the concentrations.
February 1988 5-19 DRAFT— DO NOT QUOTE OR CITE
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3
The low-concentration (100 ug/m ) exposure produced no significant group
changes. After exposure to the 450 ug/m dose of sulfuric acid aerosol there
was a 19 percent drop in SGaw, compared with only a 3 percent decrease after
NaCl aerosol. None of the other pulmonary function parameters was affected by
the exposure. Exposure to NH,HSO, aerosol tended to decrease SGaw but the
other forms of sulfate aerosol had no significant effect on lung function at
3 3
the 450 pg/m level. Following the 1,000 |jg/m exposure series, there was a
21 percent decrease in SGaw with sulfuric acid aerosol and a 13 percent
decrease with NH4HS04 aerosol (Figure 5-1). Neither NaHS04 or (NH4)2S04
produced significant effects. In addition, HpSO. aerosol caused a 5 percent
decrease in FEV-. Q. Both t-LSO. and NHJHSO. exposures resulted in significant
decreases in flow on both maximum and partial expiratory flow-volume curves.
3
Ten adolescent asthmatics were exposed via mouthpiece to 110 pg/m of
0.6 urn sulfuric acid aerosol by Koenig et al. (1983). In contrast to the work
of Utell et al. (1983), the studies were carried out under humid conditions
(>75 percent RH). The exposure sequence involved 30 min of rest followed by
10 min of moderate exercise (VV = 40 1/min); NaCl aerosol was used as a control
exposure. The regular medication of most subjects included theophylline and
a sympathomimetic bronchodilator (2 subjects used cromolyn sodium, 2 used
antihistamines, and 1 used prednisone). The hypothesis that there was no
difference between the NaCl aerosol and the sulfuric acid aerosol was
originally tested by the use of repeated t-tests. This data has been
subsequently reanalyzed by the authors (letter on file with ECAO) using an
analysis of covariance for repeated measures. There was a tendency for
FEV-. 0, V rQ, and V 75 to decrease after exposure, both to NaCl aerosol
and sulfuric acid aerosol. FEV-, n was decreased 8 percent when measured 2 to
3 min after exercise while breathing sulfuric acid aerosol but was decreased
only 3 percent after NaCl aerosol. The analysis of covariance confirmed the
significant decreases in FEVn n, V Rn, and V 7I. immediately (2-3 min)
J. • U luclX OU ~ fflclX /O
postexposure. FEV.. Q was also significantly reduced 4-5 min after exposure;
the flow variables also tended to be reduced after 4-5 min but the changes did
not attain statistical significance. The results of the analysis of covariance
are presented in Table 5-3.
February 1988 5-21 DRAFT—DO NOT QUOTE OR CITE
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25
&20
Cfl
v>
ui
10
1. SIGNIFICANTLY DIFFERENT FROM PRE-EXPOSURE VALUES:
*-p<0.001
**« p< 0.005
***- p<0.050
2. SIGNIFICANTLY DIFFERENT FROM VALUES AFTER
"~ EXPOSURE TO NaCI.
+ « p<0.001
•H-«p<0.05
4-M--p<0.01
1000 450
AEROSOL SULFATE CONCENTRATION,
100
Figure 5-1. Mean percent change in specific airway conductance (SGaw) produced
by a 16-minute inhalation of sulfate aerosols by asthmatics.
Source: Utell et al. (1983).
February 1988
5-22
DRAFT—DO NOT QUOTE OR CITE
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TABLE 5-3. ANALYSIS OF COVARIANCE OF TEN ADOLESCENT ASTHMATICS EXPOSED
VIA MOUTH PIECE TO 110 ug/m3 SULFURIC ACID AEROSOL
Pulmonary
Function Time of
Value Measurement F Tail Prob Adjusted Mean
FEVj 2-3 min post exp. 20.46 0.0019 H2S04 = 2.68; NaCl .= 2.91
4-5 min post exp. 7.85 0.0231 H2S04 = 2.79; NaCl = 2.92
later points N.S.
2-3 min post exp. 10.23 0.0126 H2S04 = 1.81; NaCl =2.12
later points N.S.
2-3 min post exp. 6.64 0.0328 H2S04 = 0.66; NaCl = 0.80
later points N.S.
max'
RT 4-5 min post exp. 3.21 0.1107 H2S04 = 7.32; NaCl = 5.52
later points
also N.S.
Source: Koenig et al. (1987).
There was also a 40 percent increase from preexposure to postexposure in the
forced oscillation measurement of total respiratory resistance (RT), but the
magnitude of this change associated with sulfuric acid aerosol exposure was
primarily due to an unusually low preexposure baseline value; the difference
in postexposure measurements between NaCl and HpSO, was only 15 percent, which
is within the measurement error of this test. The results of this study were
compared with a previous study (Koenig et al., 1982) of exposure to 0.5 ppm
SOp in seven subjects who participated in both studies; the effects of the
0.5 ppm SOp exposure were similar to those seen with sulfuric acid aerosol.
The investigators concluded that, in this group of adolescent asthmatics,
3
exposure to 100 (jg/m of sulfuric acid aerosol accompanied by exercise led to
significant changes in pulmonary function.
In a study aimed primarily at the effects of sulfuric acid aerosol on
mucociliary clearance, Spektor and associates (1985) also reported effects on
pulmonary function. Ten asthmatics (6 M, 4 F) were exposed to 110, 319, and
o
971 ug/m of 0.5 urn sulfuric acid aerosol via nasal mask at 27°C and 47 percent
RH. Six mild asthmatics who used no regular medication were designated
group I. Four subjects who regularly used methylxanthine and sympathomimetic
bronchodilators were designated group II (one of these subjects also used
steroids). Following the series of three 20 min inhalations of 1,000 ug/m of
February 1988 5-23 DRAFT—DO NOT QUOTE OR CITE
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sulfuric acid aerosol in the group I subjects, airway conductance, FEV^
^^25-75%' anc* \>ax25 were S19nificant^y decreased. When measured 3 hours
after the exposure, the magnitude of these decreases had become greater; SGaw
was decreased 5 percent immediately after exposure and 10 percent after
3 hours. There were no effects of the two lower HpSO. concentrations on
respiratory mechanics in these subjects.
In a second study of adolescent asthmatics, Koenig et al. (1985) exposed a
o
different group of 10 subjects to 100 jjg/m sulfuric acid aerosol either via
mouthpiece or facemask. Although the intent of the study, in part, was to
examine the differences in response to sulfuric acid aerosol between oral and
oronasal breathing, this comparison was not made because the subjects reported
that they breathed mostly through the mouth (rather than oronasally) when
wearing the mask. In addition to other measures of pulmonary function, nasal
flow-pressure (power) measurements were obtained. Resting exposures of 30 min
were followed by 20 min of moderate treadmill exercise (VV = 43 1/min).
Although associated S02 (0.5 ppm) exposures indicated an effect on nasal
"power," there was no change in this measurement following sulfuric acid
aerosol exposure. FEV-, Q was decreased by 7 percent and 8 percent following
the two sulfuric acid aerosol exposures but these changes were slightly less
than the 9 percent decrease observed with filtered air and considerably less
than the 16 to 24 percent decrease after the SO,, exposure. Although there were
significant pre- and postexposure changes in VmaxcQ and Vmf.y-jci there were also
large nonsignificant changes in clean air of similar or greater magnitude
against which these data were not compared. The use of the repeated t-test in
this repeated measures design obscures the effect of changes in respiratory
function which occurred with clean air exposures and which are presumably due
to modest exercise-induced bronchoconstriction. The results from this study
are summarized in Table 5-4.
In more recent work, presented at the 1987 NIEHS Acid Aerosol Symposium,
Koenig et al. (1988) indicated that 68 ug/m sulfuric acid aerosol produced a
3
5.9 percent decrease in FEV-, Q. Exposure to a mixture of H^SO, (68 ug/m ) and
S02 (0.1 ppm) produced slightly smaller changes in FEV, Q (-3.5 percent). A
small decrease was also observed with clean air exposures; the next decrease
with hLSO., after correction for the air exposure, was 4.1 percent. Similarly,
FEF5QV was decreased by 13.4 percent (8.2 percent after correction) after
sulfuric acid aerosol.
February 1988 5-24 DRAFT—DO NOT QUOTE OR CITE
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TABLE 5-4. A SUMMARY OF THE PERCENTAGE CHANGE IN PULMONARY FUNCTIONAL
VALUES AFTER 10 MINUTES OF MODERATE EXERCISE
Pulmonary
Function Value
RT
FRC
^max50
\ax75
FEVi
Air
+24 percent
NS
+8 percent
NS
-10 percent
NS
-23 percent
NS
-9 percent
p <0.005
Exposure Mode
Mouthpiece (H2S04)
+45 percent
p <0.05
+5 percent
NS
-22 percent
p <0.005
-18 percent
p <0.005
-7 percent
p <0.005
Mask (H2S04)
+35 percent
p <0.05
+4 percent
NS
-16 percent
p <0.005
-16 percent
p <0.010
-8 percent
p <0.005
NS = nonsignificant.
Source: Koenig et al . (1985).
Linn et al. (1986) studied 27 young adult asthmatics exposed to 0.6 (jm
sulfuric acid aerosol at three different concentrations (122, 242, and
O "'
410 |jg/m ). Studies were conducted in an exposure chamber at 22°C and
50 percent RH; each exposure lasted 60 min and included three 10-min periods of
moderate exercise (V£ = 42 L/min). The subjects were a diverse group of
asthmatics but all would be considered clinically mild with the exception of
one subject who used inhaled steroids. All were sensitive to either cold air
inhalation challenge (24 of 27) or 0.75 ppm S02 inhalation challenge (23 of
27), and most were sensitive to both challenges. Only 7 of the 27 subjects
used regular oral or inhaled medication and all were able to withhold medica-
tion prior to exposure (48 h antihistamine, 12 h oral bronchodilators, 8 h
inhaled bronchodilators, 8 h steroids). In addition to pre- and postexposure
measurements, pulmonary function was also measured after the first 10-min
exercise period. In all exposures to sulfuric acid aerosol and clean air there
was a significant main effect of time; specifically, pulmonary function tended
to worsen with time of exposure regardless of exposure atmosphere. There
was no significant effect of sulfuric acid aerosdl exposure at any of the
concentrations tested. Even when the subjects were divided into reactive and
nonreactive groups, there were no apparent differences that could be attributed
February 1988
5-25
DRAFT—DO NOT QUOTE OR CITE
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to acid aerosol exposure. Symptom scores were not significantly affected by
the sUlfuric acid aerosol exposures, but in the week following the exposure to
•z
410 ug/m , the symptom score was "noticeably higher." This observation of an
apparently delayed response is in accord with the observations of Utell et a.l.
(1985) and Spektor et al. (1985). The authors concluded that these subjects
experienced modest exercise induced bronchoconstriction during these exposures
and that these responses were modified only slightly, if at all, by,sulfuric
acid aerosol inhalation. A preliminary summary of these findings was also
reported by Hackney et al. (1986) at the 1985 U.S.-Dutch International
Symposium.
o
Utell et al. (1987) exposed two groups of asthmatics to 100 or 450 |jg/m
sulfuric acid aerosol either via mouthpiece or while freely breathing in a
3
chamber. There were no effects of exposures to 100 ug/m sulfuric acid
3
aerosol. Resting exposures to 450 pg/m lasted 16 min and resulted in a
o
19 percent decrease in SGaw. Chamber exposures to 450 ug/m lasted 1 hr and
included 10 min of exercise at a power output of 50 watts; SGaw decreased
22 percent after these exposures. The authors estimated that the tracheo-
bronchial deposition of aerosol was 27 ug for mouthpiece and 36 ug for chamber
exposures, respectively. Despite the considerable differences in overall
respired aerosol mass between the two exposure conditions (72 micrograms —
mouth; 230 micrograms — chamber), the similarity between the airway responses
and the tracheobronchial sulfuric acid aerosol deposition suggested to the
authors that a possible causal relationship existed between sulfuric acid
aerosol deposition and decreased airway conductance. ;
Horstman and colleagues (1986) have presented preliminary evidence of a
study in which mild asthmatics were exposed to a combination of.sulfur dioxide
3
(0.75 ppm) and sulfuric acid aerosol (100 ug/m ) to determine if small amounts
of sulfuric acid aerosol could influence the asthmatic's response to SOp. The
subjects were exposed in a chamber to SOp alone, sulfuric acid aerosol alone,
and the combination of sulfuric acid aerosol and S02, as well as to clean air.
Subjects exercised throughout the 20-min exposures at a ventilation of 40 to
44 1/min. under warm (26°C) and humid (70 percent RH) conditions. Because the
study was only partially complete when the report was prepared, the investiga-
tors did not present statistical analyses of the data. The exercise performed
during the exposure produced a modest 75 percent increase in SRaw and a
3.9 percent decrease in FEV-, Q. The increase in SRaw and the decrease in
February 1988 5-26 DRAFT—DO NOT .QUOTE OR CITE
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FEV-, 0 were slightly smaller after the H2$04 exposure than after air. After
S02 exposure, SRaw increased from 7.5 to 29.0 cmH20«s. After H2$04 plus S02
exposure, SRaw increased from 7.1 to 33.1 cmH20-s. Changes in FEV^g were also
larger after S02 or S02 plus H2$04, averaging 0.50 and 0.55 liters respectively.
It is not clear whether the slightly larger responses after the combined
exposure will prove to be significant when the data from the completed
study are analyzed. Symptom responses followed a similar pattern to the
spirometry and plethysmography measurements in that they were most pronounced
with the two exposures involving SOg. The authors suggested the possibility
that the sulfuric acid aerosol could enhance the responses of asthmatics to
sulfur dioxide.
Avol et al. (1986) have studied the effects of "acid fog" in both normal
and asthmatic subjects. They exposed subjects to nominal concentrations of
0, 500, 1,000 or 2,000 ug/m3 of sulfuric acid "fog" aerosol (10 urn) under
"fog" conditions (10°C and 100 percent RH). Three 10 minute periods of exercise
(Vr = 43 L/min) were performed during the one hour chamber exposure. Half the
subjects gargled grapefruit juice prior to exposure in order to minimize oral
ammonia levels. The efficacy of this procedure in reducing oral ammonia was
not reported. All asthmatics were clinically mild; less than half used regular
medication. The only significant effect of the acid fog exposure appeared to
3
be a decrease in peak expiratory flow after exposure to 2,000 ug/m . There
was a trend for FEM-^ Q and FVC to decrease after the 2,000 ug/m exposure
but these trends were not significant. There were no significant effects
attributable to gargling acid juice prior to exposure. Symptoms classified as
"lower respiratory" were significantly increased during acid fog exposures,
especially at 2,000 ug/m . These symptoms were largely resolved at one hour
post exposure. "Upper respiratory symptoms" also increased during the
2,000 pg/m exposure. Airway reactivity to methacholine was not changed
following exposure to any of the concentrations of acid fog. The responses of
the asthmatics were similar to those of normals. In this study, it was
demonstrated that with larger aerosols, which deposit in the major pulmonary
and extra-thoracic respiratory airways, asthmatics were not more reactive than
healthy normal subjects.
Hackney et al-. (1988) recently presented additional studies of adult
3
asthmatics exposed to nominal concentrations of 500, 1,000, and 2,000 ug/m of
0.9 urn sulfuric acid aerosol. (Actual high concentration was closer to
February 1988 5-27 DRAFT-DO NOT QUOTE OR CITE
-------
o
1,500 |jg/m ). Whereas the acid fog studies (Avol et al., 1986) shovi/ed increased
respiratory symptoms in the absence of changes in spirometry, subjects exposed
to the smaller aerosol experienced significant changes in FEV-, and increased
lower respiratory symptoms. These observations are in accord with aerosol
deposition models which would predict substantially greater .intratho.rac.ic
deposition of the smaller aerosol.
Utell et al. (1986) recently summarized the importance of three factors
that affect the responses of asthmatics to sulfuric acid aerosols^ One, of
these factors, exercise, is known to exacerbate the effects of most inhaled
pollutants due to the increase in ventilation and is also known to produce
bronchoconstriction in asthmatics. The mode of breathing (i.e., nasal,
oronasal, or mouthpiece) affects the tracheobronchial deposition of inhaled
aerosols; the extent to which deposition patterns are altered depends, in part
upon the initial particle size, the hygroscopic growth of the particle, and
the velocity of airflow. Within the size range of ambient sulfuric acid,
aerosol (0.2-0.6 urn), the deposition is only slightly higher with nasal than
with oral breathing. Deposition of aerosol has been demonstrated to be
directly related to the observed responses. A third factor that appears to be
specifically related to acidic aerosols is the observation that oral and/or
respiratory ammonia may mitigate the response to inhaled acid aerosol, because
of neutralization of the acid.
These studies on acid aerosol exposure of asthmatics indicate that
asthmatics are more reactive than normals to inhalation of these aerosols. The
observation was made in several studies (Avol et al., 1979; Utell et al., 1985)
that symptoms tended to increase immediately and also with some time delay
after sulfuric acid aerosol exposure. It appears that these delayed symptom
responses may be more likely to occur after longer exposures, when they may
possibly overwhelm the capacity of the respiratory surface liquids,to buffer
the hydrogen and sulfate ions present in the aerosols. The most acidic,sulfate
aerosols (i.e., HgSO^ and NH^HSO^) tended to be the ones that caused^the
greatest pulmonary function effects. Pulmonary function responses in adult
q
asthmatics have been observed after exposure to 400 to 1,000 pg/m? sulfuric
acid aerosol; no pulmonary function effects have been reported for normals
3 3
below 900 ug/m . Responses for adolescent asthmatics exposed to 68 ug/m have
been reported but these results have not been confirmed in. studies, of adult
February 1988 5-28 DRAFT—DO NOT QUOTE OR CITE
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asthmatics. Folinsbee (1988) summarized the effects of various concentrations
of sulfuric acid aerosol on changes in FEV-, Q in asthmatics (Figure 5-2).
Studies of asthmatics exposed to "acid fog", even at high sulfuric acid aerosol
concentrations do not so far indicate that asthmatics are more reactive than
normal subjects to these larger aerosols.
5.7 EFFECT OF ACID AEROSOL INHALATION ON PULMONARY CLEARANCE MECHANISMS
Inhalation of acid aerosols has been shown to alter the pulmonary defense
mechanisms, in particular mucociliary clearance and alveolar macrophage func-
tion. Animal studies have indicated that the relative potency of sulfates in
altering mucociliary clearance [H2S04 > NH4HS04 > (NH4)2S04 > Na2S04] is
related to their acidity (Schlesinger, 1985).
Acid aerosols could alter mucociliary clearance by altering the physical
properties of the mucociliary blanket, influencing mucus production, or by
altering the beat frequency of the cilia. Physical damage to the cells that
produce mucus or damage to the cilia that move the mucous layer would also
alter clearance. A reduction in pH of the surface liquid of the trachea and
bronchi results in an increase in mucus viscosity and a decrease in the beating
frequency of cilia (Schlesinger, 1985) (see Section 4.5.1 and 3.4.1).
Sulfuric acid can either stimulate or inhibit mucociliary clearance,
depending on the regional airway dose. Low doses stimulate (slightly more
viscous mucus moves more rapidly) and higher doses inhibit (because of de-
creased ciliary motility) clearance. The effects may vary from place to place
within the respiratory system depending on the site of aerosol deposition
associated with a given particle (Lippman, 1985). This latter point is of
considerable importance in interpretation of the results. For best indication
of effects, test aerosols used to measure clearance should deposit in the same
region of the lung as the pollutant aerosol. Clearance is typically measured
by following the clearance of radioactively labelled particles that have been
deposited in the lung by inhalation. External detectors are used to measure
the amount of remaining test aerosol at various times following inhalation (see
Clark and Pavia, 1980 for discussion of methodology).
In 1978, Newhouse et al. (1978) examined the effects of threshold limit
3
value (TLV) levels of S0? (5 ppm) and HpS04 (1,00 [jg/m , 0.5 pro) on mucociliary
clearance of healthy adults. They measured clearance using a 3 pm aerosol of
February 1988 5-29 DRAFT—DO NOT QUOTE OR CITE
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Ul
u.
-10
•15
-J*-
I
-*{r
I
o
o
O KOENIG et al. (19(1:5)
Q AVOL et al. (1986)
£± HORSTMAN et al, {1986)
UTELLWal. (1983)
SPEKTOR et al. (1985)
KOENIG at al. (19(117)
HACKNEY at al. (11987)
o
D
=
100
200
300
400
500
•i*-
950
-U-
1500
H2SO4 AEROSOL CONCENTRATION,
Figure 5-2. Change in FEV-] in asthmatics exposed to various concentrations and
particle sizes of sulfuric acid aerosol. Dashed and dotted lines indicate data for the:
two studies presented at this symposium. Horizontal axis scale is non-linear.
February 1SS
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Tc-Albumin in saline administered by a bolus technique intended to achieve
deposition in the large airways. The subjects were exposed to either sulfuric
acid aerosol or distilled water aerosol in a chamber. Mouth breathing was
obligatory throughout. The exposure lasted 2.5 h and consisted of 30 min
rest, 30 min intermittent heavy exercise (4X5 min at 70 to 75 percent of
maximum aerobic power, estimated ventilation 60 to 90 L/min), and 90 min rest.
Bronchial clearance was 15 percent faster following the HUSO, exposure than
following water aerosol exposure. With the small aerosol used in this study,
it is likely that the central airway deposition was minimal. Furthermore, oral
breathing would promote neutralization of the sulfuric acid aerosol by ammonia.
The combination of a small aerosol MMAD and high levels of oral ammonia would
result in a minimization of hydrogen ion deposition in the central airway.
Since the test aerosol was intended to measure central airway clearance, the
measurements were made at a site different from that where the sulfuric acid
aerosol was deposited. It is known that small amounts of sulfuric acid aerosol
can stimulate central airway clearance but the effects of sulfuric acid aerosol
on peripheral airway clearance in the subjects of Newhouse et al. (1978) is
unknown.
Leikauf et al. (1981) studied the responses of 10 healthy nonsmokers to
3
distilled water aerosol (sham) or 110, 330, or 980 ug/m of 0.5 u sulfuric acid
aerosol administered via nasal mask (see Figure 5-3). Following these 1-hr
resting exposures, clearance of Fe^O- radioactively labelled with Tc (which
was administered prior to exposure) was followed for 7 to 10 hours and then
measured again at 24 hours. In addition to measurements of bronchial clearance
from the right lung by whole lung imaging, trachea! mucociliary transport rates
were also determined by focusing on the head and neck region. There was no
effect of sulfuric acid aerosol exposure on tracheal mucociliary transport
3
rates. At the lowest exposure concentration (110 pg/m ), the bronchial
mucociliary clearance rate (BMCR) was accelerated (clearance half-time was
3
reduced 38 percent). At the highest exposure concentration (980 ug/m ), BMCR
was apparently significantly slower (clearance half-time increased 48 percent).
However, there was a marked variability in the response and the data were
analyzed by the use of a paired t-test, which is not appropriate in the case of
a repeated measures design such as used in this study. The evaluation of the
significance of the paired t-test was not adjusted for multiple comparisons
(e.g., Bonferroni), and furthermore the t distribution for one-tailed tests was
February 1988 5-31 DRAFT—DO NOT QUOTE OR CITE
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used. If the more appropriate two-tailed distribution is used, only,the change
o
(i.e.; increased clearance) at 110 pg/m is significant using a t-test. A
follow-up test on the four subjects with the most rapid baseline clearance was
performed. Because much of the clearance in these subjects would have been
completed before the sulfuric acid aerosol exposure ended, the tagged Fe^Oj was
administered after rather than before the 1,020 pg/m sulfuric acid aerosol
exposure. Three of these four subjects had previously demonstrated an apparent
acceleration, rather than a depression, of clearance after the 980 ug/m
o
exposure. After the 1,020 pg/m exposure, evidence of slowing of mucociliary
clearance was seen in three of these four subjects. This study suggested that
o
sulfuric acid aerosol at TLV levels (approximately 1,000 pg/m ) causes a
depression of mucociliary clearance in healthy nonsmokers. However, the
results of this study cannot be considered conclusive because of the flaw in
the data analysis methodology and the unfortunate flaw in the experimental
3
design that probably caused the investigators to miss the effects of 980 pg/m
sulfuric acid aerosol exposure in subjects with normally rapid clearance.
The effect of sulfuric acid aerosol on clearance was clearly an acute response
since there were no differences in 24-h retention of the marker aerosol
regardless of the sulfuric acid aerosol exposure concentrations. .
An earlier report of the above study was presented by Lippman et al.
(1980) at the Fourth Inhaled Particles Symposium. The above study and a series
of animal studies with both cigarette smoke and sulfuric acid aerosol exposures
were summarized by Lippmann et al. (1982) at the Fifth Inhaled Particles
Symposium. ;
The test aerosol (99mTc labeled Fe203) used to measure mucociliary clear-
ance in the initial Leikauf et al. (1981) study had a MMAD of 7.6 pm and
deposited primarily in the large bronchi and trachea. However, the 0.5 pm
sulfuric acid aerosol deposited primarily in the more peripheral airways. In
order to determine the effect on peripheral airway clearance, Leikauf et al.
(1984) performed a second study using a smaller test aerosol (MMAD = 4.2 pm)
(see Figure 5-3). Five never smokers and three light ex-smokers participated
in this study; one ex-smoker had previously contracted pneumonia and one
never-smoker had experienced two previous episodes of bronchitis. , One-hour
exposures via nasal mask were performed in three 20-min segments with brief
(3 min) measurement periods interposed between exposure segments. The sulfuric
acid aerosol concentrations studied were 0, 110, 310, and 980 pg/m ;of 0.5 pm
February 1988 5-32 DRAFT-DO NOT QUOTE OR CITE
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100
Source: Leikauf et al. (1981).
I I I_J_J
— Source: Leikauf et al. (1984).
I
180
TIME, min
270
360
Figure 5-3. Effect of H2SO4 aerosol exposure on group mean tracheo-
bronchial mucociliary retention of """To-labeled Fe2C>3 particles.
A: The response of ten healthy subjects who inhaled a 7.6 fim Fe2O3
aerosol before a 1-hr H2SO4 aerosol exposure and B: The response of
eight healthy subjects who inhaled a 4.2 Aim Fe2<33 aerosol before a
1-hr H2$O4 aerosol exposure.
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aerosol. The test aerosol (Fe203) was administered immediately before the
sulfuric acid aerosol exposure. Tracheal mucus transport rate (TMTR) was not
significantly altered by any of the sulfuric acid aerosol exposure concentra-
tions, which confirms their (Leikauf et al., 1981) previous observation; TMTR
for the 0, 110, 330, and 980 exposures were 5.7, 5.9, 5.0, and 5.5 mm/min,
respectively. Tracheobronchial mucociliary clearance rate (TBMC) was assessed
by Ten, the time for 50 percent of the initial test aerosol to clear the lung,
and the mean residence time (MRT), defined as the area under the tracheo-
bronchial retention curve (i.e., the graph of percent retention of marker
aerosol versus time). The 980 ug/m3 exposure caused marked slowing of TBMC tas
indicated by the increase in the T5Q from 80 to 142 mini Clearance was
similarly slowed after the 110 and 330 ug/m3 exposures (T5Q increased to 110
and 106 min respectively) although only the increase at 110 ug/m was statis-
tically significant. Mean residence time increased for all three exposure
conditions but was significant for only the 330 and 980 ug/m3 exposures. There
was no evidence for a dose-response relationship between sulfuric acid aerosol
concentration and either T5Q and MRT, the indices of mucociliary clearance.
However, there was a small subject population (n=8) and the inter-:and intra-
subject variability of mucociliary clearance measures is quite large.
The results of these two studies by Leikauf and co-workers (1981, 1984)
suggest that while none of the tested levels of sulfuric acid aerosol affect
tracheal mucus transport velocity, low doses (<200 ug/m ) may stimulate
clearance in large conducting airways (i.e., less than ninth generation) but
may at the same time depress clearance in small conducting airways; the
regional anatomical location where stimulation ends and depression begins
obviously cannot be determined with precision. Higher doses of sulfuric acid
aerosol, on the order of 1,000 ug/m3 and possibly lower, inhibit clearance in
both large and small conducting airways but not, apparently, in the trachea.
To determine whether subjects with hyperreactive airways would demonstrate
similar effects on mucociliary transport following sulfuric acid aeroso.l .
exposure, Spektor et al. (1985) studied a group of 10 asthmatics exposed to
sulfuric acid aerosol levels which were similar to those used for the normal
subjects of Leikauf et al. (1981, 1984). Four of the subjects (designated
group II) required daily medication (either aminophylline or isoproterenol);
one took corticosteroids. All subjects withheld medication for six hours prior
to the study except for the steroid-dependent subject. FEV1 Q/FVC ranged from
February .1988 5-34 DRAFT-DO NOT QUOTE OR CITE
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46 percent to 87 percent. The asthmatics not requiring daily medication were
designated group I; two of these subjects were current smokers. The exposure
techniques were similar to those used by Leikauf et al. (1981, 1984). Resting
nasal mask exposures to 0.5 urn sulfuric acid aerosol concentrations of 0, 110,
2
319, and 971 |jg/m lasted for a total of one hour (three 20-min inhalation
periods separated by 3-min measurement periods). Tracheal mucus transport
rates were within the same range as those reported by Leikauf et al. (1981,
1984) for healthy nonsmokers. There was no significant effect of sulfuric acid
aerosol at any of the tested levels on TMTR. For the six subjects who did not
require daily medication, TBMC was reduced after exposure to the highest
o
concentration (917 |jg/m ) of sulfuric acid aerosol. Mean retention time of the
test aerosol was unaffected by sulfuric acid aerosol, indicating a transient or
short-lasting depression of clearance rate. For the subjects requiring daily
medication there was no clear pattern of response, although clearance tended to
be accelerated rather than depressed.
The authors concluded that the mucociliary clearance of the Group I
subjects (mild asthmatics not dependent on medication) was slowed in a dose-
dependent manner as a result of the sulfuric acid aerosol exposure. This
conclusion was based on the regression of the group mean values for clearance
at each of the four concentrations. However, examination of the individual
data indicated that an individual dose-response relationship was apparent for
only one of the six subjects (who also happened to be a smoker). Mucociliary
clearance (T5Q; time to clear half the aerosol) tended to be slower in the
asthmatics than in previously tested normals although mean retention times
and TMTR were similar for normals and asthmatics. These results suggest a
possible increased risk for asthmatics from the transient reductions .of
mucociliary clearance since their normal baseline mucociliary clearance tends
to be somewhat compromised. The added reduction of clearance as a result of
sulfuric acid aerosol exposure resulted in a clearance rate that was less
than 50 percent of the baseline clearance rate of normal healthy nonsmokers.
However, since two of the six subjects in Group I were current smokers, this
comparison may not be valid because of the possible direct or interactive
effects of smoking on clearance.
Spektor et al. (1988) have recently completed a study which addresses
many of the problems in earlier studies of the effects of acid aerosol on
mucociliary clearance (1987 NIEHS Acid Aerosol Symposium). Ten healthy normal
February 1988 5-35 DRAFT—DO NOT QUOTE OR CITE
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subjects were exposed to 100-110-ug/m3 of 0.5 urn H2$04 aerosol for 1 hour and
2 hours on separate occasions. A control exposure to distilled water aerosol
was also conducted. The gamma-label led tracer aerosols, used to measure
clearance, were varied in size for each subject (range 4.0 to 5.8 urn MMAD) in
order to achieve a similar initial deposition pattern of approximately
30 percent alveolar and 70 percent tracheobronchial. A controlled respiratory
pattern was used to ensure reproducible deposition of tracer aerosol. Two
tracer aerosols were administered to each subject, one tagged with Au and
the other with 99mTc. The gold-198 tagged aerosol was administered before
exposure to H?S04 and the technetium-99m was administered following acid
exposure. Clearance was measured during and for 5 hours after exposure.
There was no difference in tracer aerosol deposition, whether inhaled
prior to or after the acid aerosol exposure. This is an important observation
for future studies since it demonstrates that the tracer may be administered
following exposure when there are no significant alterations in respiratory
mechanics, as observed in this study. Furthermore, the clearance measurements
indicated a greater effect on clearance when the tagged aerosol was
administered after acid exposure. After a 1 hour acid aerosol exposure,
average clearance half times increased 100 percent. After a two hour
exposure, half time was elevated 162 percent relative to the control. The
authors suggested that there was an approximate 40 min delay, after the
beginning of acid aerosol inhalation, before there were noticeable alterations
in clearance. There was a considerable difference in the persistence of the
alterations in clearance, depending on exposure duration. With a 1 hour
exposures, clearance was approaching normal rates by 2-3 hours after'
exposure. However, with the 2 hour exposure, the clearance rate continued to
slow for at least 3 hours after the completion of acid aerosol inhalation.
These studies clarify and extend previous observations of slow-ing.- of
mucociliary clearance after acid aerosol .exposure. They indicate that the
response depends not only on acid concentration but also on duration of
exposure.
As part of the summary of human acid aerosol exposure studies presented
at the 1987 NIEHS Acid Aerosol Symposium, Folinsbee (1988) presented a-figure
summarizing changes in clearance half-time as a result of exposure to varying
concentrations of sulfuric acid aerosol (Figure 5-4). ;
February 1988 5-36 DRAFT-DO NOT QUOTE OR CITE
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200
150
100
uu
o
cc
UJ
_J
o
50
O LEIKAUF etal. (1981)
Q LEIKAUF etal. (1984)
A SPEKTOR et al. (1985)
<^ SPEKTOR et al. (1987) (1 hr)
V SPEKTOR et al. (1987) (2 hr)
1
J_
200 400 600
ACID AEROSOL CONCENTRATION,
800
1000
Figure 5-4. Clearance half-time (i. e. time required to clear half the deposited tracer
aerosol) as a function of the concentration of acid aerosol to which the subjects
were exposed. All exposures were for one hour to 0.5 /mi sulfuric acid aerosol,
except for the one 2-hour exposure reported by Spektor et al, 1987. Note the broad
range of baseline clearance rates.
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5.8 EFFECTS OF SULFURIC ACID AEROSOL ON AIRWAY REACTIVITY
Many inhaled substances, including air pollutants, can alter the response
of the airways to pharmacologic (e.g., histamine, methacholine, carbachol) or
physical (e.g., cold and/or dry air) stimuli that induce bronchoconstriction.
The normal range of reactivity to agents that provoke bronchoconstriction is
quite large. Although there are marked group differences between normals and
asthmatics, there is considerable overlap between the least reactive, asthmatics
and the most reactive "normals". The mechanisms by which airway reactivity is
altered are still being elucidated and different inhaled substances may act in
different ways. Among other possibilities, sulfuric acid aerosols could
directly influence the responsiveness of smooth muscle, alter the sensitivity
of airway irritant receptors, produce airway edema, or change airway caliber.
Bronchial reactivity has recently been reviewed by Boushey et al. (1980).
Airway reactivity to methacholine was tested by Kulle et al. (1982) in
subjects who were exposed to 100 MQ/m3 sulfuric acid aerosol. There was a
trend for postexposure airway reactivity to decrease but this was not
significant.
The effects of sulfate exposure on airway responsiveness, in both
asthmatics and normals, were assessed by Utell et al. (1982). In normals,
exposure to both sulfuric acid aerosol and NH4HS04 (1000 pg/m3) caused greater
decreases in SGaw with carbachol challenge than was observed with carbachol
challenge after the control NaCl aerosol. The range of decrease in SGaw was
between 6 and 13 percent after NaCl exposure (+ carbachol). SGaw was reduced
17 percent and 22 percent respectively with NH4HS04 and sulfuric acid aerosol
(+ carbachol) respectively. In asthmatics, the increase in carbachol reac-
tivity following H£S04 exposure was greater than after the control (NaCl)
exposure. In addition, Utell et al. (1983) reported that the decrease in SGaw
after control carbachol exposures (i.e., an index of baseline airway reactivity)
was well correlated with the decrease in SGaw after sulfuric acid aerosol
exposures (r = 0.90), suggesting that carbachol reactivity may be a good
predictor of the bronchoconstrictor response to sulfuric acid aerosol. However,
this relationship needs to be examined in a larger subject population with a
broad range of response to both carbachol (or another cholinergic agonist) and
sulfuric acid aerosol. It was also noted that the.most acidic (i.e,, H2S04- and
NH4HS04) sulfates produced the greatest response.
February 1988 5-38 DRAFT-DO NOT QUOTE OR CITE
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3
In normals exposed for 16 min to 100 to 1,000 |jg/m of sulfuric acid
aerosol (as well as other sulfates), Utell et al. (1984) examined the airway
reactivity to carbachol following exposure. Airway reactivity was assessed by
comparing airway resistance and spirometry both before and after a five-breath
dose of a 1 percent carbachol aerosol. As in the study of Kulle et al. (1982),
1 3
no effects on airway reactivity were observed after exposure to 100 ug/m,
sulfuric acid aerosol. However, airway reactivity was increased after exposure
3
to 1,000 pg/m of either sulfuric acid aerosol or ammonium bisulfate aerosol.
Using similar exposure conditions, asthmatics were exposed to 100, 450, and
o
1,000 ug/m sulfate aerosols. Airway reactivity to carbachol was increased in
o
the asthmatics after both 1,000 and 450 ug/m sulfuric acid aerosol exposures.
The other, sulfates did not alter airway reactivity.
In a subsequent study (Utell et al. , 1985), the effects of 100 and
3
450 ug/m sulfuric acid aerosol on airway reactivity was reexamined. In this
study, normal subjects participated in 4-hour exposures that incorporated
three 10-min periods of mild exercise. Airway reactivity to carbachol was
measured immediately after exposure and again at 24 hours postexposure.
Immediately after exposure, airway reactivity was unchanged. However, 24 h
3
after the 450-(jg/m exposure, carbachol reactivity was increased; the response
to the carbachol challenge was a -21 percent reduction in SGaw. Twenty-four
hours after NaCl aerosol exposure, the same carbachol challenge caused only
a -8 percent reduction in SGaw. In addition, at the 24-h test, 8 of the
14 subjects reported throat irritation that had first been noticed between 12
and 24 hr postexposure. As in the previous study, there were no immediate or
3
delayed effects of exposure to 100 |jg/m sulfuric acid aerosol. The results
of the above studies were more recently summarized by Utell and Morrow (1986).
The airway reactivity to a cold air challenge following sulfuric acid
aerosol exposure in asthmatics was recently reported by Linn et al. (1986).
3
One-hour exposures to 0, 122, 242, and 410 ug/m sulfuric acid aerosol were
followed by a cold air challenge. The subjects breathed subfreezing air for
4 min, and the response was determined by the percent decrease in FEV-. Q.
There was no difference in response among the four exposure conditions;
sulfuric acid aerosol did not exacerbate the bronchoconstriction caused by
breathing cold-dry air. .
February 1988 5-39 DRAFT—DO NOT QUOTE OR CITE
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These reports of altered airway reactivity in both normals and asthmatics
exposed to sulfuric acid aerosol may indicate altered responsiveness of one or
more components of the bronchoconstriction reflex arc, such as airway receptors
or airway smooth muscle. The effects occurred at concentration levels similar
to those at which changes in airway conductance or spirometry have also been
demonstrated. Change in airway reactivity may be an indirect indicator of
inflammation in the airways or of disruption of the normal status of the airway
epithelium.
5.9 SUMMARY AND CONCLUSIONS
Normal subjects have been exposed to sulfuric acid aerosols ranging in
concentration from 10 to approximately 1,500 (jg/m under both resting and
intermittent exercise conditions. No effects of spirometry or plethysmography
3
have been observed after exposure to concentrations of less than 500 ug/m .
Small changes in spirometry have been observed after exposures to approximately
1,000 ug/m but these changes have not been consistently observed. Responses
to extended exposures (e.g., 6 to 8 hours) at lower concentrations should be
evaluated.
Exposure studies in man have been conducted using a number of different
sulfate and nitrate aerosols. Studied of exposure to a variety of sulfate and
nitrate aerosols point to the absence of an effect on spirometry, plethysmo-
graphy, and various other physiological indicators of pulmonary function in
asthmatics and healthy normal subjects. Exposures to combinations of sulfates
with other pollutant gases, most notably ozone and SOp, have not demonstrated
any evidence of synergistic or interactive effects with endpoints that have
been measured in human exposure studies.
Asthmatics have been exposed to a range of sulfuric acid aerosol concen-
3
trations from 10 to 1,000 pg/m . Exposures to concentrations of approximately
O
400 to 1,000 ug/m typically produced modest bronchoconstriction and small ,
3
decrements in spirometry. At aerosol concentrations near 100 (jg/rn , small
decrements in spirometry have been observed for adolescent, but not for adult,
asthmatics. More information is required for asthmatics exposed to sulfuric
o
acid aerosol at lower concentrations (<200 ng/m ) for extended periods (4 to
8 hours).
February 1988
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There is a suggestion in studies of normals and asthmatics that there may
be delayed responses to sulfuric acid aerosol in addition to the acute respons-
es measured immediately after exposure. These delayed responses may include
both symptomatic and functional effects that persist or worsen within the
24-hour period following exposure. The delayed responses appear more likely to
follow longer duration exposures (i.e., 1 to 4 hours with exercise) rather than
brief resting exposures. These observations suggest that, while small quanti-
ties of acid aerosol may be neutralized by ammonia or buffered by airway
surface liquids, larger quantities of acid aerosol may cause more persistent
changes in airway surface pH and hence may be more toxic. Further study of the
possible mechanisms and potential importance of delayed effects is needed.
The effects of sulfate and nitrate aerosols appear to be related to their
acidity or more specifically their titratable acidity. High levels of oral or
respiratory ammonia tend to reduce the effects of inhaled acidic aerosols.
Furthermore, unbuffered aerosols have less effect than buffered aerosols of the
same pH, suggesting that alteration of airway surface pH may be one of the
stimuli provoking cough and bronchoconstriction.
3
Inhalation of high concentrations (1,000 [jg/m ) of sulfuric acid aerosol
cause a reduced rate of mucociliary clearance in both normals and asthmatics.
This is an acute response and does not affect the overall retention of aerosol
(over a 24-hour period). The acid aerosol has no apparent effect on trachea!
mucociliary transport rates measured in the most proximal portion of the main
airway. Additionally, low doses of sulfuric acid aerosol may result,
initially, in an increased rate of mucociliary clearance in the major airways
of both normals and asthmatics. Effects on H^SO, on slowing of mucociliary
clearance in small airways begin at concentrations as low as 100 ug/m .
Airway reactivity to bronchoconstrictive drugs such as carbachol or
3
methacholine is increased after exposure to 1,000 ug/m of sulfuric acid
3
aerosol in both normal and asthmatic subjects. 100 ug/m of HUSO, does not
appear to alter airway reactivity in either normals or asthmatics. Inter-
mediate concentrations (~500 [jg/m ) may result in either immediate or delayed
(post -24 h) increases in airway reactivity.
February 1988 5-41 DRAFT—DO NOT QUOTE OR CITE
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5.10 REFERENCES
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Avol, E. L; Jones, M. P.; Bailey, R. M.; Chang, N.-M. N. ; Kleinman, M. T.;
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of human volunteers to sulfate aerosols: health effects and aerosol
characterization. Am. Rev. Respir. Dis. 120: 319-327.
Avol, E. L.; Linn, W.
ambient acid fog
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S.; Hackney, J.
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Boushey, H. A.; Holtzman, M. J.; Sheller, J. R.; Nadel, J. A. (1980) Bronchial
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Chaney, S.; Blomquist, W.; Muller, K.; DeWitt, P. (1980a) Biochemical effects
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Hackney, J. D.; Linn, W. S.; Avol, E. L. (1988) Acid fog: effects on respira-
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Horstman, D. H. ; Kehrl, H. ; Weinberg, P.; Roger, L. J. (1986) Pulmonary func-
tion changes for asthmatics performing exercise while exposed to combined
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Publishers, Inc.; pp. 703-709.
Horvath, S. M. ; Folinsbee, L. J. ; Bedi, J. F. (1982) Effects of large
(0.9 urn) sulfuric acid aerosols on human pulmonary function. Environ. Res.
28: 123-130.
Horvath, S. M. ; Folinsbee, L. J. ; Bedi, J. F. (1987) Combined effect of ozone
and sulfuric acid on pulmonary function in man. Am. Ind. Hyg. Assoc. J.
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Kagawa, J. (1986) Experimental studies on human health effects of aerosol and
gaseous pollutants. In: Lee, S. D. ; Schneider, T.; Grant, L. D.; Verkerk,
P. J., eds. Aerosols: research, risk assessment, and control strategies:
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Kerr, H. D. ; Kulle, T. J.; Parrel!, B. P.; Sauder, L. R.; Young, J. L.; Swift,
D. L.; Borushok, R. M. (1981) Effects of sulfuric acid aerosol on pulmo-
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Kleinman, M. T.; Linn, W. S.; Bailey, R. M.; Jones, M.
(1980) Effect of ammonium nitrate aerosol on human
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P. ; Hackney, J. D.
respiratory function
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Linn, W. S. ; Hackney, J. D. (1981a) Exposures of human volunteers to a
controlled atmospheric mixture of ozone, sulfur dioxide and sulfuric acid.
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Kleinman, M. T. ; Linn, W. S. ;* Bailey, R. M. ; Anderson, K. R. ; Whynot, J. D. ;
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aerosol: effects on pulmonary function and respiratory symptoms. Am. Ind.
Hyg. Assoc. J. 42: 298-304.
Kleinman, M. T. ; Bailey, R. M. ; Whynot, J. D.; Anderson, K. R. ; Linn, W. S. ;
Hackney, J. D. (1985) Controlled exposure to a mixture of S02, N02, and
particulate air pollutants: Effect on human pulmonary function and
respiratory symptoms. Arch. Environ. Health 40: 197-201.
Koenig, J. Q.; Pierson, W. E.; Horike, M.; Frank, R. (1982) Bronchoconstrictor
responses to sulfur dioxide or sulfur dioxide plus sodium chloride drop-
lets in allergic, nonasthmatic adolescents. J. Allergy Clin. Immunol.
69: 339-344.
Koenig, J. .Q.; Pierson, W. E. ; Horike, M. (1983) The effects of inhaled sulfu-
ric acid on pulmonary function in adolescent asthmatics. Am. Rev. Respir.
Dis. 128: 221-225.
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Koenig, J. Q.; Morgan, M. S.; Horike, M.; Pierson, W. E. (1985) The effects of
sulfur oxides on nasal and lung function in adolescents with extrinsic
asthma. J. Allergy Clin. Immunol. 76: 813-818.
Koenig, J. Q.; Marshall, S. G.; Horike, M.; Shapiro, G. G.•; Furukawa, C,• T.;
Bierman, W.; Pierson, W. E. (1987) The effects of albuterol,on sulfur
dioxide-induced bronchoconstriction in allergic adolescents. J. Allergy
Clin. Immunol. 79: 54-58.
Kulle, T. J.; Kerr, H. D.; Parrel!, B. P.; Sauder, L. R.; Bermel, M. S. (1982)
Pulmonary function and bronchial reactivity in human subjects with expo-
sure to ozone and respirable sulfuric acid aerosol. Am. Rev. Respir. Dis.
126: 996-1000.
I
Kulle, T. J.; Sauder, L. R.; Shanty, F. ; Kerr, H. D.; Parrel 1, B. P."; Miller,
W. R.; Milman, J. H. (1984) Sulfur dioxide and ammonium sulfate effects on
pulmonary function and bronchial reactivity in human subjects. Am, Ind.
Hyg. Assoc. J. 45: 156-161. \
Kulle, T. J.; Sauder, L. R.; Hebel, J. R.; Miller, W. R.; Green, D. J.; Shanty,
F. (1986) Pulmonary effects of sulfur dioxide and respirable carbon
aerosol. Environ. Res. 41: 239-250.
Larson, T. V.; Covert, D. S.; Frank, R.; Charlson, R. J. (1977) Ammonia in the
human airways: neutralization of inspired acid sulfate aerosols. Science
(Washington, DC) 197: 161-163.
Leikauf, G.; Yeates, D. B.; Wales, K. A.; Spektor, D.; Albert, R. E. ; Lippmann,
M. (1981) Effects of sulfuric acid aerosol on respiratory mechanics and
mucociliary particle clearance in healthy nonsmoking adults. Am. Ind. Hyg.
Assoc. J. 42: 273-282.
Leikauf, G. D.; Spektor, D. M. ; Albert, R. E. ; Lippmann, M. (1984) Dose-
dependent effects of submicrometer sulfuric acid aerosol on particle
clearance from ciliated human lung airways. Am. Ind. Hyg. Assoc. J.
45: 285-292.
Linn, W. S.; Kleinman, M. T.; Bailey, R. M.; Medway, D. A.; Spier, C, E.;
Whynot, J. D.; Anderson, K. R. ; Hackney, J. D. (1981) Human respiratory
responses to an aerosol containing zinc ammonium sulfate. Environ. Res.
25: 404-414. ;
Linn, W. S.; Avol, E. L.; Shamoo, D. A.; Whynot, J. D. ; Anderson,, K. Ri. ;
Hackney, J. D. (1986) Respiratory responses of exercising asthmatic
volunteers exposed to sulfuric acid aerosol. J. Air Pollut. Control Assoc.
36: 1323-1328.
Lippmann, M. (1985) Airborne acidity: estimates of exposure and human health
effects. EHP Environ. Health Perspect. 63: 63-70.
Lippman, M.; Albert, R. E.; Yeates, ; D. B. ; Wales, K. ; Leikauf, G. (1980)
Factors affecting tracheobronchial mucociliary transport. In: Walton,
W. H., ed. Inhaled particles IV: v. 1. Oxford, United Kingdom: Pergamon
Press; pp. 305-319.
i
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Lippmann, M.; Schlesinger, R. B.; Leikauf, G.; Spektor, D. ; Albert, R, E.
(1982) Effects of sulphuric acid aerosols on respiratory tract airways.
In: Walton, W. H. , ed. Inhaled particles V: proceedings of an inter-
national symposium organized by the British Occupational Hygiene
Association; September 1980; Cardiff, United Kingdom; Ann. Occup. Hyg.
26: 677-690.
Newhouse, M. T.; Dolovich, M. ; Obminski, G.; Wolff, R. K. (1978) Effect of TLV
levels of S02 and H2S04 on bronchial clearance in exercising man. Arch.
Environ. Health 33: 24-32.
Sackner, M. A.; Ford, D. ; Fernandez, R. ; Cipley, J. ; Perez, D. ; Kwoka, M. ;
Reinhart, M.; Michaelson, E. D.; Schreck, R.; Wanner, A. (1978) Effects of
sulfuric acid aerosol on cardiopulmonary function of dogs, sheep, and
humans. Am. Rev. Respir. Dis. 118: 497-510.
Sackner, M. A.; Dougherty, R. D.; Chapman, G. A.; Zarzecki, S.; Zarzemski, L.;
Schreck, R. (1979) Effects of sodium nitrate aerosol on cardiopulmonary
function of dogs, sheep, and man. Environ. Res. 18: 421-436.
Schlesinger, R. B. (1985) Effects of inhaled acids on respiratory tract defense
mechanisms. EHP Environ. Health Perspect. 63: 25-38.
Sim, V. M.; Pattle, R. E. (1957) Effect of possible smog irritants on human
subjects. JAMA J. Am. Med. Assoc. 165: 1908-1913.
Spektor, D. M.; Leikauf, G. D. ; Albert, R. E.; Lippmann, M. (1985) Effects of
submicrometer sulfuric acid aerosols on mucociliary transport and respira-
tory mechanics in asymptomatic asthmatics. Environ. Res. 37: 174-191.
Spektor, D. M. ; Yen, B. M. ; Lippman, M. (1988) Effect of concentration and
cumulative exposure of inhaled sulfuric acid on tracheobronchial particle
clearance in healthy humans. In: International symposium on the health
effects of acid aerosols: addressing obstacles in an emerging data base;
October 1987; Research Triangle Park, NC. EHP Environ. Health Perspect.:
in press.
Stacy, R. W. ; Seal, E., Jr.; House, D. E.; Green, J.; Roger, L. J.; Raggio, L.
(1983) A survey of effects of gaseous and aerosol pollutants on pulmonary
function of normal males. Arch. Environ. Health 38: 104-115.
Utell, M. J. ; Morrow, P. E. (1986) Effects of inhaled acid aerosols on human
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Schneider, T.; Grant, L. D.; Verkerk, P. J., eds. Aerosols: research, risk
assessment and control strategies: proceedings of the second U. S.-Dutch
international symposium; May 1985; Villiamsburg, VA. Chelsea, MI: Lewis
Publishers, Inc.; pp. 671-681.
Utell, M. J.; Swinburne, A. J.; Hyde, R. W. ; Speers, D. M.; Gibb, F. R.;
Morrow, P. E. (1979) Airway reactivity to nitrates in normal and mild
asthmatic subjects. J. Appl. Physio!. 46: 189-196.
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Utell, M. J.; Aquilina, A. T.; Hall, W. J.; Speers, D. M.; Douglas, R. G,, Jr.;
Gibb, F. R.; Morrow, P. E. ; Hyde, R. W. (1980) Development of airway
reactivity to nitrates in subjects with influenza. Am. Rev. Respir. Pis.
121: 233-241. !
\
Utell, M. J.; Morrow, P. E.; Hyde, R. W. (1982) Comparison of normal arid
asthmatic subjects' .responses to sulphate pollutant aerosols. In: Walton,
W. H., ed. Inhaled particles V: proceedings of an international symposium
organized by the British Occupational Hygiene Association; September 1980;
Cardiff, United Kingdom; Ann. Occup. Hyg. 26: 691-697. ;
Utell, M. J>, Morrow, P. E.; Speers, D. M. ; Darling, J. ; Hyde, R. W. (1983)
Airway responses to sulfate and sulfuric acid aerosols in asthmatics: an
exposure-response relationship. Am. Rev. Respir. Dis. 128: 444-450.
Utell, M. J.; Morrow, P. E.; Hyde, R. W. (1984) Airway reactivity tiD sulfate
and sulfuric acid aerosols in normal and asthmatic subjects. J. Air
Pollut. Control Assoc. 34: 931-935. ;
Utell, M. J.; Morrow, P. E. ; Hyde, R. W. (1985) Latent development of airway
hyperreactivity in human subjects after sulfuric acid aerosol exposure. J.
Aerosol Sci. 14: 202-205. :
Utell, M. J.; Morrow, P. E. ; Bauer, M. A.; Hyde, R. W. ; Schrek, R. H. (1986)
Modifiers of responses to sulfuric acid aerosols in asthmatics. In:
Aerosols: formation and reactivity. London: Pergamon Press.
,i
Utell, M. J.; Morrow, P. E.; Hyde, R. W.; Cox, C.; Schrek, R. M. (1987) Compar-
ison of responses and deposition following human exposure via oral or
nasal inhalation of sulfuric acid aerosols. Ann. Occup. Hyg.: in press.
Witek, T. J., Jr.; Schachter, E. N.; Beck, G. J.; Cain, W. S.; Colice, G. ;
Leaderer, B. P. (1985) Respiratory symptoms associated with sulfur dioxide
exposure. Int. Arch. Occup. Environ. Health 55: 179-183.
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6. EPIDEMIOLOGY STUDIES OF HEALTH EFFECTS ASSOCIATED WITH
EXPOSURE TO ACID AEROSOLS
6.1 INTRODUCTION
To date, no epidemiologies! studies have directly demonstrated health
effects to be associated with measured elevated ambient acid concentrations.
This sparsity of data is due in part to the absence of adequate ambient acid
measurement techniques until recent years and, conceivably, also to the current
relatively low levels of ambient acid aerosols in many areas. Nevertheless,
some evidence exists which is suggestive of human health effects being associ-
ated with exposures to ambient acid aerosols both (1) as derived from reexami-
nation of older, historically important data on air pollution episode events in
the U.S. and Europe and (2) as can be deduced from certain recent epidemiology
studies carried out in the U.S., Canada, and Europe. This chapter concisely
reviews such evidence first as it relates to acute exposure effects and then as
it pertains to chronic exposure effects.
Because of the sparsity of concrete evidence, most of this chapter is
devoted to identifying studies of situations in which there is good reason to
suspect that high ambient acid concentrations existed in the .evaluated study
areas. From these studies the nature of the observed health effects are
summarized as a basis for drawing tentative conclusions and suggesting
directions for future research. However, no clear quantitative relationships
are delineated because of the lack of sufficient ambient acid measurements by
which to define exposure-response effects levels. Hopefully, several
continuing studies currently underway in Canada, the United States, and Europe
may provide useful information in the near future. These face the difficult
task of separating out effects due to relative contributions of various air
pollutants present (e.g., differentiating between 00 effects and between those
+ -'•'•- -3 '•. '
of H ). The extremely critical need for extensive additional research becomes
obvious as a consequence of the present examination of currently available
information.
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6.2 ACUTE EFFECTS STUDIES
6.2.1 Acute Episode Studies '
Some of the earliest indications that ambient air acid aerosols may be
associated with human health effects can be discerned upon reexamination of
historically important air pollution episode events. These include, for
example, the Meuse Valley (Belgium), Donora, PA (USA), and well-known London
(UK) episodes, as discussed below. ,
6.2.1.1 Meuse Valley. Firket (1931) describes the fogs of December 1930 in
the Meuse Valley and the morbidity and mortality related to them. A detailed
discussion of the causes is presented which concludes that the main component
of the fog that caused the health effects that occurred was sulfuric acid.
This conclusion was based both upon consideration of the emissions in the
valley, the weather conditions and the aerometric chemistry required for the
production of sulfuric acid. Additionally, the pathophysiology seen was
thought to relate to sulfuric acid exposure more so than to other possible
agents. More than 60 persons died from this acid fog and several hundred
suffered respiratory problems, with a large number becoming complicated with
cardiovascular insufficiency. The mortality rate during the fog was over ten
times higher than the normal rate. Those persons especially affected by the
fog were the elderly, those suffering from asthma, heart patients and the
debilitated. Most children were not allowed outside during the fog and few
attended school. Unfortunately, no actual measurements of acid aerosols in
ambient air during the episode are available by which to establish clearly
their role in producing the observed health effects versus the relative
contributions of other specific pollutants.
6.2.1.2 Donora. Schrenk et al. (1949) reported on the health effects and
atmospheric pollutants of the smog episode in Donora of October 1948. A total
of 5,910 persons (or 42.7 percent) of the total population of Donora experi-
enced some effect from the smog. The air pollutant-ladened fog lasted from the
28th to the 30th of October, and during a 2-week period 20 deaths took place,
18 of them being attributed to the fog. An extensive investigation by the
American Public Health Service concluded that the health effects observed were
mainly due to an irritation of the respiratory tract. Mild upper respiratory
tract symptoms were evenly distributed through all age groups: and, on the
average, were of less than four days duration. Cough was the most predominant
symptom; it occurred in one-third of the population and was evenly distributed
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through all age groups. Dyspnea was the most frequent symptom in the more
severely affected, being reported by 13 percent of the population, with a steep
rise as age progressed to 55 years; above this age, more than half of the
persons affected complained of dyspnea.
It seems reasonable to state that, while no single substance can be
clearly identified as being responsible for the October 1948 episode, the
observed health effects syndrome could have likely been produced by two or more
of the contaminants, i.e., sulfur dioxide and its oxidation products together
with particulate matter, as among the more significant, contaminants present.
Hemeon (1955) examined the water soluble fraction of solids on a filter of an
electronic air cleaner operating during the smog in ;Donora and concluded that
acid salts were an important component.
6.2.1.3 London Acid Aerosol Fogs. Based on the mortality rate in the Meuse
Valley, Firket (1931) estimated that 3,179 sudden deaths would likely occur if
a pollutant fog similar to that in the .Meuse Valley occurred in London. An
estimated 4,000 deaths did later indeed occur during the London Fog of 1952,
as noted by Martin (1964). During the fog of 1952, evidence of bronchial
irritation, dyspnea, bronchospasm and, in some cases, cyanosis is clear from
hospital records and from the reports of general practitioners. There was a
considerable increase in sudden deaths from respiratory and cardiovascular
conditions. The nature of these sudden deaths remains a matter for speculation
since no specific cause was found at autopsy. Evidence of irritation of the
respiratory tract was, however, frequently found and it is not unreasonable to
suppose that acute anoxia due either to bronchospasm or exudate in the
respiratory tract was an important factor. Also, the United Kingdom Ministry
of Health (1954) reported that in the presence of moisture, aided perhaps by
the surface activity of minute solid particles in fog, some sulfur dioxide is
oxidized to trioxide. It is probable, therefore, that sulfur trioxide,
dissolved as sulfuric acid in fog droplets, appreciably augmented the harmful
effects of sulfur dioxide and/or other particulate matter species.
Martin and Bradley (1960) reported increases .In daily total mortality
among the elderly and persons with preexisting respiratory or cardiac disease
in relation to S02 and PM (British Smoke; BS) levels in London during the
winter of 1958-1959. The pathological findings in 12 fatal cases and- the
clinical evidence of practitioners seem to indicate clearly that the harmful
effects of the fog were produced by the irritating action of polluted air drawn
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into the lungs. These effects were more obvious in people who already suffered
from a chronic respiratory disease and whose bronchi were presumably more
liable to bronchospasm. r
Waller (1963) reported that sulfuric acid was one of the pollutants
considered as a possible cause of the increased morbidity and mortality noted
during the London fog of December 1952. Because of this, as noted earlier in
Chapter 2, following the 1952 pollution episode daily measurements; were made in
London of BS and SCL levels starting in 1954 and, later, concentrations of
sulfuric acid were calculated from net aerosol acidity or actually measured
during air pollution episodes on a daily basis starting in 1964. No regular
measurements of sulfuric acid were made during the winter of 1955-!'1956 but some
was detected at times of high pollution. For example, Waller and Lawther
(1957) detected the presence of acid droplets in samples collected in January
of 1956. Insufficient measurements were made, however, during the rest of the
winter of 1955-1956 to study the effects of the acid aerosol present.- Waller
(1963) later reported measuring acid droplets in London in the; winter of
1958-1959 with mass median diameter of 0.5 urn. Commins (1963) measured
particulate acid in the city of London and found concentrations especially high
at times of fog reaching levels of 678 ng (calculated as sulfuric acid)/m of
air. Typical winter daily concentrations were 18 ug/m compared to 7 ug/m in
the summer. The sulfuric acid content of the air in the city of London at the
time could range up to 10 percent of the total sulfur. ,
The concentration of sulfuric acid rises with that of smoke, and it may be
partly responsible for health effects observed for chronic bronchitic patients
in London during the late 50's and throughout the 60's. Since many patients
become worse even at times of relatively low humidity, this suggests that small
droplets of strong acid may have had more effect than larger one*;. Lawther et
al. (1970) reported an association between daily pollutant levels (BS and SO^)
and worsening of health status among a group of over 1,000 chronic bronchitis
patients in London during the winters of 1959-1960 and 1964-1965. A daily
technique for self-assessment of day-to-day change in health status was used.
An interesting study was also conducted on a smaller sample of the patients
during in the winters of 1964-1965 and 1967-1968 when pollutant levels were
somewhat lower than in earlier years. Approximately 50 subjects selected for
their susceptibility to air pollutant effects formed the sample. Daily
sulfuric acid, measured at St. Bartholomew Hospital Medical College, was
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reported as having a relatively high correlation with health effects in the
1964-1965 winter. For 1967-1968, all these correlation coefficients were
lower but still significant. The authors comment that the patients selected
must have been particularly sensitive to pollution, since from past experience
no correlation would have been expected with such very low levels of pollution
encountered by such a small group.
Relationships between London air pollution levels and mortality have been
extensively reexamined during recent years, using more sophisticated statis-
tical analyses techniques, e.g., time-series analyses and various "filtering"
approaches to deal with potential confounding by extraneous cyclical factors.
Several authors (Mazumdar et a!., 1982; Ostro, 1984; Schwartz and Marcus,
1986) have reported significant associations between BS and S0? levels and
mortality during 14 London winters (1958-72), with associations of mortality
with BS being much stronger than with S02 at levels, below 500 |jg/m . Thurston
et al. (1988) have also presented a preliminary report on reanalyses for those
portions of the 1958-1972 London mortality data for which daily direct acid
aerosol measurements were made at St. Bartholomew's Medical College (see
Chapter 2, Section 2.5.1). The authors found that acid aerosol concentrations
were more strongly associated with unadjusted total mortality than were BS or
SC^. This was in spite of the fact that seven sites were used for the BS and
SOp measurements versus one site for the acid aerosols. The authors also found
that lags of one day provided better fits for the pollution variables than did
the same day variables. Additional analyses using models that involve more
sophisticated time series methods are in progress and are .needed in order to
provide more definitive confirmation of acid aerosol contributions to London
mortality.
In summary, the early historically important air pollution data discussed
above provide some limited evidence for mortality and morbidity effects being
associated with ambient air concentrations of acid aerosols. The calculations
:-'.-. , • o
and measurements of sulfuric acid levels (estimated to range up to 678 [jg/m )
during some London episodes in the late fifties provide plausible bases for
hypothesizing contributions of sulfuric acid aerosols to the health effects
observed during those episodes. The recent preliminary analyses by Thurston
et al. (1988) of daily direct acid aerosol measurements over a longer span of
time (1958-1972) in London are especially important in providing more direct
evidence for likely associations between ambient acid aerosols and mortality.
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6.2.2 European Acid Event of 1985
In addition to evidence derived from the above historically important
data, indications of possible involvement of ambient acid aerosols iin the
induction of human health effects can be discerned through recent, analyses of
a 1985 European air pollution episode. During January 1985,, large parts, of
Europe from western Germany to Great Britain experienced a pollution eveint.
This event was tracked by monitoring stations in several countries as. it moved
from east to west, and then finally dissipated over the North Sea. Unfortur
nately, very few measurements of ambient acidity are available.. Only the data
of de Leeuw and van Rheineck Leyssius (1988) suggest that sul.fu.Hc and m'trtc
3
acid levels exceeded 50 ug/m during these periods.
Wichmann et al. (1988) studied mortality, hospital admissions, ambulance
transports and outpatient visits for respiratory and cardiovascular disease in
West Germany during the 1985 event. During this time, daily suspended partic-
ulates reached 600 |jg/m3, S02 reached 830 (jg/m , and N02 reached 410 ug/m ,
Total mortality rose immediately with the increase in pollution (January 16,
1985), and reached a maximum on January 18. The increase in mortality was
about 8 percent. Similarly, increases in hospital admissions (15 percent),
outpatient visits (12 percent), and ambulance transports (28 percent) were
seen. ;
The progress of the event was monitored by de Leeuw and van Rheineck
Leyssius (1988) as it passed through the Netherlands. The event started on
o
January 15 and ended on January 21, 1985. The S02 levels peaked at 28Q |jg/m
on January 20, 1985. No actual acid measurements were presented for the event
itself. Dassen et al. (1986) measured pulmonary function in primary school
children before, during, and after the event. The authors found that pulmonary
function indices were significantly lower by 3 to 5 percent when; compared to
baseline values taken 4 to 6 weeks earlier. The decrements were still present
16 days later, but not 25 days later.
Ayres et al. (1988) studied respiratory morbidity in patients of general
practitioners in England during the same period. Although acute bronchitis
rates were elevated for children aged 14 or less during the third week of
January, 1985, the rates during this period were also elevated in other years
because of the immediately preceding holiday period. As a result, no clear
conclusions could be drawn from the British data that relate health effects to
the January 1985 episode.
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Collectively the above analyses are indicative of notable increased health
effects occurring in several countries during the 1985 European episode.
Certain of the analyses, Wichmann et al. (1988) and Dassen et al. (1986),
appear to provide clear linkages between the observed health effects and
measured air pollutants (e.g., PM, SCO. The presence of elevated acidic
species (sulfuric and nitric acid) in the polluted air mass makes it plausible
that acid aerosols may have contributed to the observed health effects, but
the sparsity of actual acid measurements during and: after the event makes it
difficult to evaluate their potential role. If they were involved, then acid
levels ranging up to 50 ug/m or more would likely be implicated.
6.2.3 'Acute Exposure Studies of Children
Several studies have recently been carried out in the United States and
Canada that examine the effects of exposures to air pollutants on pulmonary
function in children at summer camps. Some of the available data derived from
these studies allow evaluation of possible involvement of acid aerosols in the
health effects observed.
Lippmann et al. (1983) studied 83 nonsmoking, middle class, healthy chil-
dren (ages 8 to 13) during a 1980 2-week summer camp program in Indiana, PA.
The children were involved in camp activities which resulted in their exer-
cising outdoors most of the time. At least once, each child had height and
weight measured and performed spirometry on an 8 liter Collins portable
recording spirometer in the standing position without nose clip. During the
study, peak flow rates were obtained by Mini-Wright® peak flow meter at the-
beginning of the day or at lunch and adjusted for both age and height. Ambient
air levels of TSP, hydrogen ions, and sulfates were monitored by a high-volume
sampler on the rooftop of the day camp building. Ozone levels were estimated
using a model that used ozone data from monitoring sites located 32 and 100 km
away. The hi-vol samples were collected on H?SO. treated quartz fiber filters
for the determination of the concentration of H+ and total suspended partic-
ulate matter (TSP). H+ was determined from filter extract using a Gran
titration. Peaks in acid concentration occurred on four days, when the acid
3 •
values ranged between 4 and 6.3 |jg/m (as FLSO,), On many occasions there was
no HpSO. in the atmosphere. While effects were reported as being significantly
associated with exposure to ozone, no effects were found to be related to
exposure to H?S04 at the acid levels observed during the study.
/ • .-.••'.
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Bock et al. (1985) and Lioy et al... (1985) examined pulmonary function of
39 children at a camp in Mendham, ;New Jersey during a 5-week period in July-
August, 1982. Ozone was continuously monitored using chemiluminescent analysis.
Ambient aerosol samples were collected on Teflon filters with, a dichotomous
sampler having a 15 urn fractionation inlet and a coarse/fine cut-size of
2.5 urn (Sierra Mod 244-E). Aerosol acidity as measured by strong acid (H+)
content, was determined using the pH method. Highly significant changes in
peak expiratory flow rate (PEFR) were found to be related to ozone exposure,
as well as a baseline shift in PEFR lasting approximately one week following a
haze episode in which the 0,, exposure exceeded the NAAQS for four consecutive
days that included a maximum concentration of 185 ppb. There was no apparent
effect of H+ on pulmonary function. The authors did state, however, that the
persistent effects associated with the ozone episode could have been due to
acid sulfates as well as, or in addition to, ozone but additional uncollected
data were needed to evaluate this possibility.
During a four-week period in 1984, Lioy et al. (1987) and Spekter et al.
(1988a) measured respiratory function of 91 active children who, were residing
at a summer camp on Fairview Lake in northwestern New Jersey. Continuous data
were collected for ambient temperature, humidity, wind speed and direction;,, and
concentrations of 03, HpSO and total sulfates. Ozone was measured by U.V.
absorbance, and H?S04 and total sulfates were alternately determined by a flame
photometric sulfate analyzer (Meloy Model 285) preceded by a programmed thermal
pretreatment unit. The ambient aerosol samples were collected on quartz fiber
filters with a dichotomous sampler having a 15 urn fractionating inlet (PM15)
and a coarse/fine cut-size of 2.5 \M (Sierra Model 244-E). Aerosol acidity, as
measured by strong acid (H+) content, was determined using the pH method. The
maximum values recorded for H2S04 and NH4HS04 were 4 and 20 ug/m respectively.
While effects were reported as being associated with exposure to ozone, no
effects were found to be related to exposure to the moderate acid aerosol
concentrations experienced in this study.
Raizenne et al. (1987a) studied possible relationships between respiratory
function parameters and environmental factors at Camp Kiawa, Ontario, Canada
during the summer of 1986. Twelve young females (9 to 14 years old) at a
residential summer camp for girl guides performed pre- and post-exercise spiro-
metry on a day of low air pollution and at the peak of an air pollution episode.
Clinical interviews, atopy, and methacholine airway hyperresponsiveness tests
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were performed at the camp on the first 2 days of the study. Seven subjects
had positive responses to methacholine challenge (+MC) and five did not (-MC).
A standardized ergometric physical capacity test was also administered, in
which minute volume, heart rates, and total work achieved were recorded. Air
monitoring was performed on site and, during the episode, air pollution concen-
trations were: Og exceeded 130 ppb; H2$04 exceeded 40 ng/m3; total sulfate
exceeded 80 p.g/m . Additional discussion of the aerometric monitoring is given
by Spengler et al. (1988). Lung function responses were modelled by multi-
variate normal methods on the indicator of airway hyperresponsiveness. For
the entire group (N = 12), post exercise FVC and FEV-j^ were observed to increase
on the control day and decrease on the episode day. On the control day, an
average 40 ml increase in FVC due to exercise was observed (p <.05) for the
whole group, with a 71 ml increase in -MC subjects and a 17 ml increase in
+MC subjects. Although not statistically significant at the 10 percent level,
mean FVC for the entire group was 30 mL less on the day of high pollution versus
low pollution, and this difference was more pronounced in -MC (-65 ml) than
+MC (-4 ml) subjects. The effect of exercise in the model was statistically
significant (p'<.05), whereas the pollution day effect was not. These results
suggest that lung function responses to exercise differ in +MC and -MC. subjects
under field research conditions and that the expected normal FVC response to
exercise in both groups is altered during periods of elevated ambient pollution.
However, no analyses were presented that evaluated possible acid aerosol
relationships to health effects.
Raizenne et al. (1987b) also studied 112 young girls who participated in
one of three two-week camp sessions at Camp Kiawa, Ontario, Canada during June
to August, 1986. A self-administered questionnaire was completed by a parent
before the camp; daily spirometry was taken between 3:00 and 5:00 p.m. during
the camp; and methacholine bronchial challenge testing was completed on day 3
or 4 of the camp. During the study, air pollutant monitoring was performed
for ozone, sulfur dioxide, nitrogen oxides, particulate matter, pH, and sulfuric
acid. Raizenne et al. (1987b) indicate that analyses of possible air pollutant
effects,are being carried out by using regression analyses to estimate separate
slopes for pulmonary function parameters for each child, but the results are
not yet available.
Raizenne et al. (1988) examined acute lung function response in the
112 subjects at Camp Kiawa in relation to four ambient acid aerosol events
- I • , , „ ' •'•'.'
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*\ ,
(the highest H2$04 level was 47.7 ug/m during one event on July 2S,
The influence of air pollution on lung function was evaluated first by e
paring responses on the day of a pollutant event (high acid and -ozone levels)
to the mean of the responses on corresponding control days of liOw pollutant
levels. For FEV-,, there was a tendency for the lung function decrements 'on
the event day to be greater than the response on the eorrespohdling control
days, except for the last event (when an increase in function was observed).
The largest decrements for FEV-,^ and PEF (48-66 ml decline for Mv^) were
observed on the morning after the highest H£S04 event on Ouly 25, 1986, No
analyses were presented, however, that attempted to separate out pollutant
effects of H2S04 from those of 03- ;
Airway hyperresponsiveness using a methacholine bronchocisnstfiction
provocation test, was assessed for 96 of the subjects in the Rairenne et al.
(1988) study. Children with a positive response to methacholifre challenge
had larger decrements compared to their nonresponsive counterparts* These
preliminary results do not allow definitive statements to be made on the
susceptibility of methacholine sensitive subjects; however, there are indica-
tions in these data of differential lung function profiles and responses to air
pollutants in children with and without airway hyperrespohsiveni&ss. Further
analyses and research are indicated. . , . ,
Franklin et al. (1985) and Raizenne et al, (1987b) reported preliminary
analyses on data from another study in Canada, In 1983, fifty-two campers
(23 were asthmatics) at the Lake Couchiching Summer Camp, Ontario were studied
to examine lung function performance in relation to daily pollutant concentra-
tions. The health assessment included a precamp clinical evaluation, a tele-
phone administered questionnaire on respiratory health, daily symptomatology
questionnaire, assessments of activity level, and twice daily lung function
measurements. Pollutants measured included 03, respirable particles, sulfates,
N02, and SCv. Respirable sulfates were highly variable and ranged frOffi 10 to
26 ng/m3. Sulfate as sulfuric acid was usually very low. Preliminary analyses
suggest that minimal, if any, acute health effects can be attributed directly
to the air pollutants monitored. Raizenne et al. (1986) report further analyses
showing that, for individual pollutants, a time lag function for fine partieless
average sulfate concentrations, maximum daily 03 levels and temperature were
all associated with decrements in specific lung function indices. Further
analyses are still underway or not yet published. Pollutant specific data were
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not discussed in Raizenne et al. (1986). Although the results are suggestive
of a short-term pollutant, effect: on lung function, details of the actual
pollutant levels were not given. The weightings given to each specific
pollutant were also not given, but are critical for adequate evaluation of the
study.
It is of interest to compare results obtained between the above summer
camp studies and in relation to findings of certain controlled human exposure
studies or other epidemiology studies. For example, Spengler et al. (1988)
calculated that the children in the Raizenne et al. (1988) study received an
average one-hour respiratory tract dose of 1,050 nmoles of H+ ions, based on an
exposure model which takes into account not only the concentration of exposure
but also minute ventilation rate. Spengler et al. (1988) further noted that
the asthmatic subjects in the human clinical studies of Utell et al. (1983) and
Koenig etal. (1983) had experienced an airway dose of approximately
1,200 nmoles of H , which evoked a response at reported concentrations of
3 3
450 (jg/m and 100 ug/m H2S04 respectively. These calculations suggest that,
because of differences in minute ventilation rates, the peak levels occurring
at Camp Kiawa during an ambient acid aerosol event may have produced exposures
similar to those seen in clinical studies of asthmatic subjects. It remains to
be determined as to what extent comparable C x T total respiratory tract
dose(s) for H ions may be effective in producing pulmonary function decrements
beyond the short exposure times employed in the controlled human exposure
studies or in producing other types of effects. For example, Spektor et al.
(1988b) found that the effect of doubling the length of exposure to sulfuric
acid increased average tracheobronchial clearance half-time from 100 to
162 percent relative to control.
6.2.4 Acute Studies Relating Health Effects to Sulfates
Sulfate and nitrate levels may represent crude surrogates for potential
acid aerosol levels; however, the appropriateness of use of sulfate and/or
nitrate concentrations as indices of exposure to acid aerosols has not yet
been well evaluated. In Section 2.4.2 it was indicated that sulfate species
represent the principal component of most acid aerosols. The problem is that
measurements of total sulfate and/or nitrate levels may not only represent acid
aerosol exposures but sulfate/nitrate exposures that am not acidic as well.
Thus, the studies discussed below which present sulfate and/or nitrate data but
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not acid aerosol data may provide only limited insight into the potential
health effects that may be related to acid aerosol exposure.
Bates and Sizto (1983, 1986) reported results of an ongoing correlational
study relating hospital admissions in southern Ontario to air pollutant levels.
Data for 1974, 1976, 1977, and 1978 were discussed in the 1983 paper. The
1986 analyses evaluated data up to 1982 and showed: (1) no relationship
between respiratory admissions and SCL or COHs in the winter; (2) a complex
relationship between asthma admissions and temperature in the winter; and (3) a
consistent relationship between respiratory (both asthma and nonasthma) admis-
sions in summer and sulfate and ozone concentrations, but not to summer COH
levels. However, Bates and Sizto note that the data analyses are complicated
by long-term trends in respiratory disease admissions unlikely related to air
pollution, but they nevertheless hypothesize that observed effects may be due
to a mixture of oxidant and reducing pollutants which produce intensely irri-
tating gases or aerosols in the summer but not in the winter. .j
Bates and Sizto (1987) later studied admissions to all 79 acute-care
hospitals in Southern Ontario, Canada (i.e., the whole catchment area of
5.9 million people) for the months of January, February, July cind August for
1974 and for 1976 to 1983. Air pollution data for 0-, NO,, S02, coefficient of
haze (COH), and aerosol sulfates were obtained from 17 stations between Windsor
and Peterborough. Total admissions and total respiratory admissions declined
about 15 percent over the course of the study period, but asthma admissions
appeared to have risen. Evaluating the asthma category of admissions is
complicated by the effects of a change in International Classification of
Disease (ICD) coding in 1979. The analyses demonstrate that there is a
consistent summer relationship between (1) sulfates, ozone and temperature and
(2) respiratory admissions with or without asthma. This conclusion is
strengthened by the continuing lack of any association of these variables with
non-respiratory conditions. The present data raise the question of whether the
association of increased respiratory admissions in the summer in this region
can be associated with ozone or sulfates. It would be surprising for the
effects to be related to ozone since it is aerosol sulfates that, in summer,
explain the highest percentage of the variance in respiratory admissions; yet
these are not correlated with respiratory admissions in the winter. In view
of this, the possibility exists that the observed health effects might be
attributable neither to ozone nor to sulfates, but to some other air pollutant
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species that "travel" with them over the region in the summer (but not in the
winter).
Bates and Sizto (1987) note that recent observations suggest the presence
of unusual peaks of H+ aerosol of small particle size in this region of Canada
in the summer, concomitant with elevated 03 and S0~ levels. On two days in
July 1986 in Eastern Toronto when ozone and sulfate levels were elevated, but
not higher than on other days, peaks of H+ acid aerosol lasting for up to two
hours were recorded at levels of 10 to 15 ug/m3. The particle size was small
(about 0.2 pm). Similar observations were recorded on the same days by another
H+ air sample operation west of Toronto. This raises the possibility that the
types of health effects noted above might be attributable neither to ozone, nor
to sulfates but rather perhaps to acid aerosols.
The evidence from Bates and Sitzo (1983, 1986, 1987, 1988) neither
conclusively relates sulfates nor ozone to hospital admissions. Instead, the
results suggest that some other pollutant(s) may be responsible, e.g., sulfuric
acid that has been measured in the region. More aerometric data will be
required, however, to confirm or disprove this possibility, and a new study is
underway to examine these factors.
6.3 CHRONIC EXPOSURE EFFECTS STUDIES
As was the case for acute exposure effects, only very limited
epidemiologic study data currently exist by which to attempt to evaluate
possible relationships between chronic exposures to ambient acid aerosols and
human health effects. These include one study from Japan relating effects to
estimated or measured acidity and several other North American studies, which
relate effects to sulfate levels or other surrogate measures thought to
roughly parallel acid aerosol concentrations.
6.3.1 Acid Mists Exposure In Japan
Kitagawa (1984) examined the cause of the Yokkaichi asthma events (1960
to 1969) by examining the potential for exposure to concentrated sulfuric acid
mists and the location and type of health effects noted. He concluded that
the observed respiratory diseases were due not to sulfur dioxide but to
concentrated sulfuric acid mists emitted from stacks of calciners of a titanium
oxide manufacturing plant located windward of the residential area. This was
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based on the fact that the S03/S02 ratio of 0.48 was much higher than the
normal range of 0.02 to 0.05. The higher ratio indicates a higher acid aerosol
level. The acid particles were fairly large (0.7 to 3.3 urn) compared with acid
aerosols seen in the United States of America (see Chapter 2). More than six
hundred patients with respiratory disease were found between 1960 and 1969
with chronic bronchitis, allergic asthmatic bronchitis, pulmonary emphysema and
sore throat. In 1969, measures of acid aerosol exposures were pbtained from
litmus paper measurements collected near the industrial plant which showed that
acid mist particles were distributed leeward of the industrial plant. The
author notes that the physiological effects of concentrated sulfuric acid mists
must be quite different from that of dilute sulfuric acid mists formed by
atmospheric oxidation of sulfur dioxide, and that the distinction between the
two types of acid mists is very important.
6.3.2 Chronic Studies Relating Health Effects to Sulfates
Franklin et al. (1985) described a Canadian cross sectional study done in
fall, 1983 and winter, 1984, which examined potential chronic health effects of
exposure to pollutants in 7- to 12-year-old children. Health indices used
included an initial self-administered health questionnaire, biweekly health
diaries done through telephone interviews, and pulmonary function tests. A
control town, Portage la Prairie Manitoba, had lower pollutant levels than
Tillsoburg, Ontario, the study community. Ambient pollution monitoring for
S00, NO,,, PMnn, SOT, and N0~ was performed in both towns. Preliminary analysis
Ct £ J.U T* «J
indicated that a difference (adjusted for the age, sex, and height of child)
may exist between towns in several parameters related to pulmonary function.
But caution was urged, because important confounding factors had not yet been
considered. Later, Raizenne et al. (1987b) reported that of the 1,414 children
studied, 81 percent provided sufficient questionnaire data arid produced
acceptable pulmonary function tests for proper analysis.
The results indicate that residence in the polluted region was signifi-
cantly associated with pulmonary decrements of 2.2 percent for FVC and
1.7 percent for FEV, Q. Although not statistically significant, the reported
incidence of chronic respiratory symptoms was higher in Tillsonburg compared to
the control community. These results were not influenced by parental smoking,
length of residence, cooking fuel, schools, indoor air pollution and subject
morphometric data. Pollutant-specific analyses were not discussed, but further
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analyses are anticipated. The statistically significant differences in
observed chronic respiratory symptom rates must be viewed with caution. The
measurement itself is somewhat subjective and naturally has significant differ-
ences from one geographic area to another. The air pollutant concentrations
observed were all quite low compared with comparable U.S. cities.
Ware et al. (1986) have reported results of analyses from the ongoing
Harvard study of outdoor air pollution and respiratory health status of
children in six eastern and midwestern U.S. cities. Between 1974 and 1977,
approximately 10,100 white preadolescent children were enrolled in the study
during three successive annual visits to the cities. On the first visit, each
child underwent a spirometric examination, and a parent completed a standard-
ized questionnaire regarding the child's health status and other important
background information. Most of the children (8,380) were seen for a second
evaluation one year later. Measurements of TSP, sulfate fraction, and S02
concentrations at study-affiliated outdoor stations were combined with data
from other public and private monitoring sites to create a record of pollutant
levels in each of nine air pollution regions during a one-year period preceding
each evaluation, and for TSP during each child's lifetime up to the time of
evaluation. TSP levels ranged from 32 to,163 pg/rn3 (annual average). S02
levels ranged from 2.9 to 184 Mg/m3, and sulfate levels ranged from 4.5 to
19.3 (jg/m3.
Analyzing data across all six cities, Ware et al. (1986) found that
frequency of chronic cough was significantly associated (p <0.01) with the
average of 24-h mean concentrations of all three air pollutants during the year
preceding the health examinations. Rates of bronchitis and a composite measure
of lower respiratory illness were significantly (p <0.05) associated with
annual average particle concentrations. However, within the individual cities,
temporal and spatial variation in air pollutant levels and symptom or illness
rates were not significantly associated. The history of early childhood
respiratory illness for lifetime residents was significantly associated with
average TSP levels during the first two postnatal years within cities, but not
between cities. Furthermore, pulmonary function parameters (FVC and FEV-,) were
not associated with pollutant concentrations during the year immediately
preceding the spirometry test or, for lifetime residents, with lifetime average
concentrations. Ferris et al. (1986), however, reported a small effect on
February 1988 6-15
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lower airway function (MMEF) related to fine particle concentrations. Spengler
et al. (1986) report the occurrence of acid aerosol peak concentrations of 30
to 40 ug/m3 in two of the cities during recent monitoring.
Overall, these results appear to suggest'that risk may be increased for
bronchitis and some other respiratory disorders in preadolescent children at
moderately elevated levels of TSP, sulfate fraction, and S02 concentrations,
which do not appear to be consistently associated with pulmonary function
decrements. However, the lack of consistent significant associations between
morbidity endpoints and air pollution variables within individual cities argues
for caution in interpreting the present results.
In an hypothesis-generating discussion preceding a presentation of a new
multicity study (see Section 6.5 and 8.4), Speizer (1988) presents city-
specific bronchitis prevalence rates from four of the above six cities where
H* concentrations were measured. While no direct aerosol acidity measurements
were actually made during or before the 1980/81 school year (when the children
were examined), Speizer (1988) utilized data that Spengler et al. (1988)
gathered in Kingston/Harriman and St. Louis from December 1985 through
September 1986 and in Steubenville and Portage from November 1986 to early
September 1987. When the city-specific bronchitis rates are plotted against
mean H+ concentrations instead of PM15, there is a relative shift in the
ordering of the cities which suggest a better correlation of bronchitis
prevalence with H+ than with PM15 (see Figures 6-1 and 6-2). This qualitative
information points toward the need for research evaluating ,the role acid
aerosols may play in the development of bronchitis.
The potential role of acid aerosols in the development of bronchitis is
suggested by the results of animal studies discussed in Chapter 4. Results
from animal studies indicate that at low levels (250 ug/m3), and with chronic
exposure, the main response is hypertrophy and/or hyperplasija of mucus
secretory cells in the respiratory epithelium; these alterations may extend to
the small bronchi and bronchioles, where secretory cells are normally rare or
absent. This could result in an increase in secretory rate and mucus volume in
such airways which could be a possible factor in the pathogenesis of obstruc-
tive lung disease. But no study documents an actual increase in secretory rate
or mucus volume. Although mucus hypersecretion is a characteristic of obstruc-
tive lung disease, particularly chronic bronchitis, respiratory epidemiologists
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11
10
K
K _
u
o
ec
at
UJ
o
ui
S.
UJ
cc
0.
10
20
30 40
PM15
50
60 0
10
Figure 6-1. Bronchitis in the last year, children
10 to 12 years of age in six U.S. cities, by PM^.
(P = Portage, Wl; T = Topeka, KS; W = Water-
town, MA; K = Kingston, TN; L = St. Louis, MO;
S = Steubenville, OH)
Source: Speizer (1988).
20
H+, nmoles/m^
30
40
Figure 6-2. Bronchitis in the last year, children
10 to 12 years of age in four U.S. cities, by
hydrogen ion concentrations. (K = Kingston,
TN; L = St. Louis, MO; P = Portage, Wl;
S = Steubenvjlle,OH)
Source: Speizer (1988).
February 1988
6-17
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have produced conflicting results regarding its importance in the development
of obstructive lung disease. Annesi and Kauffmann (1986) concluded that the
presence of chronic phlegm production was predictive of subsequent, mortality
based upon their study of 1, 061 men working in the Paris, area, followed for a
period of 22 years. Peto et al. (1983) concluded that mucus, hypersecretion is
not a link in any important causal chain that accelerates the development of
air-flow obstruction based upon their study of 2,718 British men in a 2.0 year
follow-up study. Bates (1983) comments that the work of Peto and his,
colleagues (1983) add an important epidemiological perspective to, the clinical
and pathological observation supporting the thesis of probable dissociation-.
between the development of chronic air flow limitations and mucus hyper-
secretion. Thus, new studies that may add to the data base on the natural
history of chronic bronchitis represent a basic epidemiology research need.
Chapman et al. (1985) report the results of a survey done in early 1976
that measured the prevalence of persistent cough and phlegm ambng 5,623 young
adults in four Utah communities. The communities, were stratified to represent
a gradient of sulfur oxides exposure. Community specific annual mean SO,,,
levels had been 11, 18, 36, and 115 ug/m3 during the five years prior to, the
survey. The corresponding annual mean sulfate levels were 5, 7, 8, and,
14 Hg/m . No gradients for TSP or suspended nitrates, were observed. The;
analyses were made using multiple logistic regression in order to adjust, for
confounding factors such as smoking, age and education. Persistent cough and
phlegm rates in fathers were about 8 percent in the high exposure community,,
versus about 3 percent in the other communities. For mothers, the rates in. the
high exposure community were about 4 percent as opposed to about 2, percent in
the other communities. Both differences were statistically significant.
Schenker et al. (1983) studied 5,557 adult women in a rural area, of
western Pennsylvania using respiratory disease questionnaires. Air pollution;
data (including S0? but not particulate matter measurements) were derived from
17 air monitoring sites and stratified in an effort to define lew, medium and
high pollution areas. The four-year means (1975-1978) of SO- in each stratum;
•3 ^
were 62, 66, and 99 yg/m respectively. Respiratory symptom rates were modeled
using multiple logistic regression, which controlled for several potentially
confounding factors, including smoking. A model was used to estimate; air
pollutant concentrations at population-weighted centroids of 36. study districts.
The relative risk (odds ratio) of "wheeze most days or nights" in nonsmokers
February 1988 6-18 D,RAFT--DQ; NOT QUOTE QR
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residing in the high and medium pollution areas was 1.58 and 1.26 (p = 0.02)
respectively, as compared with the low pollution area. For residents living
in the same location for at least five years, these relative risks were 1.95
and 1.40 (p <0.01). Also, the increased risk of grade 3 dyspnea in nonsmokers
was associated with S02 levels at p = <0.11. However, no significant associ-
ation was observed between cough or phlegm and air pollution variables. The
results of this study suggest that wheezing may be associated with S02 levels,
but these results must be viewed with caution since the grartiant between areas
was small and there were no particle or other pollutant measures. Lippmann
(1985) suggested that it was plausible that the effects in this study are
associated with submicrometer acid aerosol which deposits primarily in small
airways, rather than with SCL levels.
Dodge et al. (1985) reported on a longitudinal study of children exposed
to markedly different concentrations of S02 and moderately different levels of
particulate sulfate in Southeastern U.S. towns. In the highest pollution area,
the children were exposed to 3 hour peak S02 levels exceeding 2,500 MQ/m3 and
annual mean particulate sulfate levels of 10.1 M9/m3- The prevalence of cough
(measured by questionnaire) correlated significantly with pollution levels
(chi-square for trend = 5.6, p = 0.02). No significant differences existed
among the groups of subjects over 3 years, and pulmonary function and lung
growth over the study were roughly equal over all groups. The results tend to
suggest that intermittent high level exposure to SO", in the presence of
moderated particulate sulfate levels, produced evidence of bronchial irrita-
tion (increased cough) but no chronic effect on lung function or lung function
growth.
Jedrychowski and Krzyzanowski (1988) related S02 and PM levels to
increased rates of chronic phlegm, cough and wheezing in females living in and
near Cracow, Poland. The authors suggest that the effects may have been due to
hydrogen ions, but no measurements were available.
Several authors (Lave and Seskin, 1972, 1977; Chappie and Lave, 1982;
Mendelsohn and Oratt, 1979; Lipfert, 1984; Ozkaynak and Spengler, 1985;
Ozkaynak and Thurston, 1987) have attempted to relate mortality rates to
sulfate and other pollution measurements using ecological or macroepidemio-
logical analyses. There are significant problems and inconsistencies in
results obtained across many of these analyses, as reviewed extensively by the
U.S. Environmental Protection Agency (1986, 1982). For example, Lave and
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Seskin (1977) reported that mortality rates were correlated with sulfates.
Lipfert (1984), reanalyzing the same data, found that it was not possible to
conclude whether sulfates or total respirable particulate matter had a statis-
tically significant effect on total mortality.
In more recent extensive analyses employing a variety of model specifica-
tions and controls for possible confounding, Ozkaynak and Spengler (1985),
Ozkaynak et al. (1986), and Ozkaynak and Thurston (1987) have' used more
sophisticated statistical approaches in an effort to improve upon some of the
previous analyses of mortality and morbidity associations with air pollution in
U.S. cities. The principal findings presented by Ozkaynak and Spengler (1985);
concern cross-sectional analysis of the 1980 U.S. vital statistics and,avail-
able air pollution data bases for sulfates, and fine, inhalable and total
suspended particles. In these analyses, using multiple regression methods, the
association between various particle measures and 1980 total mortality were-
estimated for 98 and 38 SMSA subsets by incorporating recent information, on
particle size relationships and a set of socioeconomic variables to control for
potential confounding. Issues of model misspecification and spatial auto-
correlation of the residuals were also investigated. Results from the various
regression analyses indicated the importance of considering particle size,
composition, and source information in modeling of PM-related health effects.
In particular, particle exposure measures related to the respirable and/or
toxic fraction of the aerosols, such as FP (fine particles) and sulfates were
the most consistently and significantly associated with the reported (annual)
cross-sectional mortality rates. On the other hand, particle mass measures
that included coarse particles (e.g., TSP and IP) were often found to be
nonsignificant predictors of total mortality.
The Ozkaynak and Spengler (1985) results noted above for analysis of 1980
U.S. mortality provide an interesting overall contrast to the findings of
Lipfert (1984) for 1969-70 U.S. mortality data. In particular, whereas Lipfert
found TSP coefficients to be most consistently statistically significant
(although varying widely depending upon model specifications, explanatory
variables included, etc.), Ozkaynak and Spengler found particle mass measures
including coarse particles (TSP, IP) often to be nonsignificant predictors of
total mortality. Also, whereas Lipfert found the sulfate coefficients to be
even more unstable than the TSP associations with mortality (and questioned the
credibility of the sulfate coefficients), Ozkaynak and Spengler found that
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particle exposure measures related to the respirable or toxic fraction of the
aerosols (e.g., FP or sulfates) to be most consistently and significantly
associated with annual cross-sectional mortality rates. It might be tempting
to hypothesize that changes in air quality or other factors from the earlier
data sets (for 1969-70) analyzed by Lipfert (1984) to the later data (for 1980)
analyzed by Ozkaynak and Spengler (1985) and Ozkaynak et al. (1986) may at
least partly explain their contrasting results, but there is at present no
basis by which to determine if this is the case or which set of findings may or
may not most accurately characterize associations between mortality and chronic
PM or S0x exposures in the United States. Ostro (1987) also reported a
stronger association between several measures of morbidity (work loss days,
restricted activity days, etc.) and lagged fine particle estimates than
associations with prior 2-week average TSP levels in 84 U.S. cities.
Taken as a whole, these analyses are suggestive of an association between
mortality or morbidity and fine particle or sulfate fraction levels found in
contemporary American urban airsheds. Much still remains to be done, however,
to evaluate the relative contribution of acid aerosols formed from the fine
particles or sulfates to the reported health effects.
6-3.3 Chronic Studies Relating Health Effects to Oxides of Nitrogen
Nitrates, formed from nitrogen dioxide and other oxides of nitrogen, can
ultimately contribute to acid aerosol formation in ambient air .under certain
atmospheric conditions. Studies evaluating nitrate (as a crude surrogate for
acid aerosols) effects on human health are, therefore, of some interest here.
The area surrounding the city of Chattanooga, Tennessee provided a unique
opportunity to study the effects of the oxides of nitrogen without the high
concentrations of other pollutants usually associated with automotive and
industrial pollution. A large TNT plant, located northeast of Chattanooga,
produced a substantial proportion of all trinitrotoluene (TNT) made in the
United States during World War II and the Korean War. The plant was reopened
in April, 1966 to supply munitions for use in Vietnam. By the this time, the
area surrounding the plant had become an upper-middle-class residential
neighborhood. Epidemiological studies were done in the late 1960's and early
1970's. There were, however, no measurements made of acidity and, furthermore,
many of the N02 measurements made using the Jacobs-Hochheiser method had a
number of instrumental and analytical problems. The measured levels of the
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oxides of nitrogen were nevertheless clearly quite high. For example, annual
averages of nitrogen dioxide reached 412 ug/m3 near the arsenal, and nitrate
•fraction levels reached 4.1 ug/m3 at tne downtown post office. It is likely
that the elevated nitrogen dioxide levels were accompanied with elevated nitric
acid levels, although no direct measurements were made. The U.S. Environmental
Protection Agency (1971) measured several factors related to ambient air
pollution including corrosion of zinc, steel and nylon. The, corrosion levels
in Chattanooga in 1967 and 1968 were among the highest, and in,the case of
nylon, were 10 to 100 times the levels of most other cities. According to the
report, the arsenal was known to emit acid aerosols. Thus it is likely that
any adverse health effects, seen in Chattanooga during this time period were
associated either with N02 itself or with the nitric acid rather than other
oxides of nitrogen.
Shy et al. (1970) reported the results of a lung function study done in
the same area during the 1968-1969 school year. Ventilatory lung function
(FEVn 7c) was measured in elementary school children in four areas near
Chattanooga. Average annual nitrogen dioxide levels ranged from 412 ug/m in
the high exposure area to 59 ug/m3 in the low exposure area. Suspended nitrate
levels ranged from 7.3 ug/m3 in the high area to 1.6 ug/m in the low area, but
the results were not completely consistent with the gradient.
Pearlman et al. (1971) reported the results of a respiratory disease
survey done in the Chattanooga area in 1969. The study reported illness rates
in children for the period June, 1966 to June, 1969. Higher rates of
bronchitis in school aged children were found in both the intermediate and
high exposure areas as compared with the low exposure area. The results were
not completely consistent with the gradient since the rate in the intermediate
area was just as high as the high pollution area.
Love et al. (1982) studied acute respiratory disease in the same area
during the years 1972 to 1973. Fathers, mothers, school children and preschool
children all showed significantly higher rates in the. area designated as high
pollution area during the beginning of 1972. There were almost no significant
differences in rates during the periods September to December, 1972, and
January to April, 1973. During the period January to June, 1972 nitrogen
dioxide levels ranged from 60.2 ug/m3 in the high area to 28.9 M9/m in the low
area. However, by the second half of 1972, the exposures in all areas were
quite comparable because of reduced emissions. Thus the results of the study
February 1988 6-22. DRAFT-DO NOT QUOJE OR CITE
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tend to confirm the chronic effect of nitrogen dioxide or its by-products on
acute respiratory disease, including quite plausibly nitric acid effects.
6.3.4 Chronic Exposure Effects in Occupational Studies
The last remaining type of information considered here concerns the
effects of chronic exposures to acid aerosols in occupational settings. Such
studies are discussed mainly in order to provide some perspective on the
variety of health effects associated with acid aerosol exposures, even at
extremely high concentrations not likely to occur in ambient air.
Gamble et at. (1984a) studied pulmonary function and respiratory symptoms
in 225 workers in five lead battery acid plants. This acute effect study
obtained personal samples of HUSO, taken over the shift. Most personal samples
3
were less than 1 mg/m H2S04- Mass median aerodynamic diameter of hLSCK
averaged about 5 pm. The authors concluded that exposure to sulfuric acid mist
at these plants showed no significant association with symptoms or with acute
effect on pulmonary function. The ability of the" body to neutralized acidity
of H2S04 was considered as a factor is this outcome. Additionally, the authors
noted that tolerance to H2S04 may develop in workers habitually exposed.
In a related study of chronic effects of sulfuric acid on the respiratory
system and teeth, Gamble et al. (1984b) measured in the same workers respira-
tory symptoms, pulmonary function, chest radiographs, and .tooth erosion.
Concentrations measured at the time of the study were .usually 1 mg/m3 or less.
Exposure to the concentration of acid mist showed no significant association
with cough, phlegm, dyspnea, wheezing, most measures of pulmonary function, and
abnormal chest radiographs. Tooth etching and erosion were strongly related to
acid exposure. The authors noted that the absence of a marked effect of acid
exposure on respiratory symptoms and pulmonary function may be due to the size
of the acid particles. The range of the mass median diameter in the 5 plants
was 2.6 to 10 |jm. The relative humidity of the lung would at least double
particle size and many acid particles would be deposited in the upper respira-
tory tract. The particle size distribution.of acid mist in battery plants is
larger than that observed in ambient air pollutants (several micrometers in
diameter compared to submicron diameters). Finally the authors note that the
lack of any convincing finding in this study relating to the respiratory
symptoms is not completely unexpected because of the relatively low exposure
3 • ..." - ' ,
(<1 mg/m ) compared to previous occupational studies.
February 1988 6-23 DRAFT—DO NOT QUOTE OR CITE
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Williams (1970) studied sickness absence and ventilatory capacity of
workers exposed to high concentrations of sulfuric acid mist in^he forming
department of a battery factory (location not stated). Based on; 38 observa-
tions made on two days, the forming department had a mean H9SCL concentration
•3 O £ t
of 1.4 mg/m , ranging from a trace to 6.1 mg/m . In a different forming
department, the mass median diameter of the acid particles was 14 urn. Compared
with control groups, men exposed to the high concentrations of sulfuric acid
mist in the forming department had slight increases in respiratory disease,
particularly bronchitis. There was no evidence of increased lower respiratory
disease, which might be explained by the large particle size. After adjusting
for circadian variations, there was no evidence of decreased ventilatory
function.
El-Sadik et al. (1972) studied lung function, salivary pH, and dental
anomalies in 33 workers in the manufacturing department of two battery
factories (presumably in Egypt). Control subjects were taken from comparably
aged workers in the same plants who were not exposed to chemicals. Air samples
3
showed concentrations of sulfuric acid vapor ranging from 26 to 35 mg/m in one
plant, and from 12 to 14 mg/m in another. Changes were found in FEV-^ dental
lesions, tooth erosion, and pH of saliva, and bronchopulmonary diseases. These
changes were either not statistically significant, or were not tested due to
the small sample sizes. The results were suggestive, however.
6.4 SUMMARY AND CONCLUSIONS
To date, no epidemiological studies have related health effects to measured
elevated ambient acid concentrations alone. The following summary contains
studies where acid levels were measured and studies where the presence of acid
aerosols is assumed in the ambient air mixture of pollutants but where no actual
measurements were made. The results are summarized in Tables 6-1 and 6-2.
Historically important fog episodes believed to contain high levels of
acids resulted in mortality and morbidity. The health effects are believed to
have resulted from intense local irritant action on the lungs, which may have
led to acute anoxia due to Cither bronchospasm or exudate in the respiratory
tract. Those persons especially affected by the fogs were those suffering from
asthma, chronic bronchitis and heart disease. Common symptoms were cough and
dyspnea. Limited estimates or actual measurements of acid levels present
February 1988 6-24 DRAFT—DO NOT QUOTE OR CITE
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TABLE 6-1 ACUTE EXPOSURE HEALTH EFFECTS SEEN UNDER CONDITIONS
OF MEASURED OR PRESUMED ACID AEROSOL EXPOSURE
Study
Lippmann et al. (1983) lung
function study of 83 chil-
dren aged 8 to 13 at a
summer camp in Indiana, PA
Bock et al. (1985) lung
function study of
39 children at summer
camp in Mendham, NJ
Lioy et al. (1985) lung
function study of
91 children at a summer
camp in Fairview Lake, NJ
Franklin et al. (1985)
lung function study of at
summer camp at Lake
Couchiching, Ontario,
Canada
Raizenne et al. (1988)
lung function study of
112 children at Camp
Ki awa, Ontari o, Canada
Bates and Sizto (1983,
1986, 1987, 1988) hospital
admissions study in
Southern Ontario, Canada
Exposure
H2S04 less
5 pg/m3
than
Low levels of H+
H2S04 less than
4 ug/m3
H2S04 less than
5 pg/m3
H2S04 exceeding
40 pg/m3
Daily sulfate
levels as high
as 38 pg/m3
Health Effects Seen
None related to H2S04
None related to
None related to H2S0
No association reported
FEV± and PEF decrements
associated with air
pollutant events (high
acid and ozone levels)
Respiratory admissions
(e.g., for asthma)
significantly related
to sulfates and ozone
in the summer
Martin and Bradley (1960);
Waller (1963); Commins
(1963); Lawther et al.
(1970); Mazumdar et al.
(1982); Ostro (1984);
Schwarts and Marcus (1986)
analyses of London
mortality and morbidity
during 1950's to 1970's
Thurston et al. (1988)
reanalysis of London
mortality data for
1963-1972 winters
Typical daily acidity
concentration of
18 pg/m3 (winter)
and 7.0 pg/m3
(summer), but very
high acid droplet
levels ranging up
to 678 pg/m3 during
severe episodes
Daily direct acid
aerosol measurements
with maximum 24-hr
levels ranging up to
40-134 pg/m3.(as
H2S04 equivalent)
Bronchial irritation,
dyspnea, and other
symptoms. Deaths from
respiratory and car-
diovascular conditions
February 1988
6-25
Stronger correlation
of acid aerosols with
unadjusted total
mortality than for
BS or S02, but associ-
ation remains to be
confirmed by more
sophisticated time-
series analysis
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TABLE 6-2. CHRONIC EXPOSURE HEALTH EFFECTS SEEN .UNDER 'CONDITIONS
OF MEASURED OR PRESUMED ACID AEROSOL EXPOSURE
Study
Exposure
Health Effects Seen
Kitagawa (1984) study
of asthma episodes in
Yokkaichi, Japan from
1960 to 1969
Franklin et al. (1985)
chronic cross-sectional
study of 1,141 children
in Canada
Ware et al. (1986) six
city Harvard study of
children in the eastern
and midwestern U.S.
Speizer (1988) bron-
chitis prevalence rates
in 4 of Harvard's six
city study
Chapman et al. (1985)
four city study of
chronic disease in
young adults in Utah
Schenker et al. (1983)
study of respiratory
disease in women in
rural Pennsylvania
Dodge et al. (1985)
longitudinal study of
children in south-
eastern U.S. towns
Shy et al. (1970)
study of lung function
in children in
Chattanooga
Pearlman et al. (1971)
study of respiratory
disease rates in
children in Chattanooga
High S03/S02
ratios. Presumed
high levels of
H2S04
Sulfate, S02, N02,
PM10, and N03
Annual sulfate
levels ranged from
4.5 to 19.3 ug/m3.
H , PM15
Annual sulfate
levels ranged from
5 to 14
Four year average
S02 levels ranged
from 62 to 99
Peak 3 hour S02
exceeded 2,500
ng/m3. Sulfates
also present
Annual N02 levels
ranged from 59 to
412 |jg/m3, nitrate
levels from 1.6 to
7.3 ng/m3, probably
HN03
Annual N02 59 to
412 |jg/m3> nitrate
1.6 to 7.2 .(jg/m3,
probably HN03
Increased asthma .epi-
sodes
Two percent decrease in
FVC
Chronic cough was
related to sulfates,
but lung function
was not
Better coryeTatto;n -of
bronchitis iprevalence
with H than with PM15
Persistent cough and
phlegm were related
to S02 and s.ulfate
levels
Wheeze was ".associated1
with increased S02,
but cough and phlegm
were not
Prevalence of cough
was related to inter-
mittent high ;S02 in
the presence of
sulfates
Inconsistent decreased
pulmonary function
related to both
pollutants
Ineonsistent increased
bronchitis rates
February 1988
6-26
DRAFT—00 WOT QUOTE W CliTE
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during London episodes, provide some indications of likely involvement of
ambient acid aerosols in producing reported health effects.
United States and Canadian acute summer camp studies measured H+ concen-
trations, all but the Razienne et al. (1988) study, had acid (hLSO.) concentra-
tions less than 5 pg/m . No changes in pulmonary function could be found
related to these lower levels. The one study with acid (H^SO,.) levels above
3 c. *\
40 ng/m did not separate the effects of acids from copollutants such as ozone
(Raizenne et al., 1988). Further analysis may do this. Bates and Sizto (1983,
1986, 1987, 1988) related hospital admissions for respiratory diseases
(including asthma) to sulfate and ozone levels in the summer in Canada and
speculate that acid aerosols may be more directly related.
Several researchers examined the European acid event of 1985 which
extended from western Germany to Great Britain. However, no studies had
adequate acid aerosol data by which to attempt detailed analyses that might
demonstrate direct health effects relationships to acid levels.
Among the chronic studies, Kitagawa (1984) attempted to measure acidity
in the air of one city of Japan where chronic health effects episodes occurred.
The study found increased bronchitis, pulmonary emphysema, and mortality from
asthma and chronic bronchitis. Actual acid mist levels are difficult to
estimate from this study. '
Franklin et al. (1985) and Raizenne et al. (1987b) report pulmonary
function decrements for a pollution mix in Canada but not for acid aerosols or
sulfates alone. The Ware et al. (1986) study suggests that sulfate levels are
related to bronchitis and some other respiratory disorders in young children,
but sulfate levels are not related to pulmonary function measures. Speizer
(1988) notes that, in four cities of the Harvard six city study where acid
levels were determined, there was a better correlation of bronchitis prevalence
with H than with PM15. The Chapman et al. (1985) study suggests that S02 and
sulfate levels are related to persistent cough and phlegm in young parents.
Dodge et al. (1985) found that prevalence of cough in children correlated with
S02 and sulfate levels. Ozkaynak and Spengler (1985) also found that mortality
is also more strongly related to fine particles and sulfate levels than to
total suspended particulate levels. Consistent with this are Ostro's (1988)
reported similar stronger associations between morbidity indicators and
estimated fine particle levels versus TSP levels.
February 1988 6-27 DRAFT—DO NOT QUOTE OR CITE
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Elevated levels of oxides of nitrogen may also have been correlated with
elevated acid levels in Chattanooga, TN, Pear1man et al. (1971) found some
suggestion of increased bronchitis rates in school aged children associated
with N02 and nitrate fraction levels. Love et al.. (1982) found ,that fathers,
mothers, school children, and preschool children all showed significantly
higher rates of acute respiratory disease in the areas with higher pollution
levels. Shy et al. (1970) found slightly decreased lung function in school
aged children in the areas of higher pollution, although the results were not
completely consistent. .
Lioy and Lippman (1986) comment that situations exist where atmospheric
H2SO. at current North American exposure levels may be the active agent in
causing respiratory responses. There are at least two scales on which this may
occur: (1) locally, downwind of a plume, and (2) regionally, downwind of major
source areas. The highest acid concentrations observed appear to be associated
with direct plume impacts. Therefore, these locations warrant considerable
attention in future epidemiological studies. i
From among the occupational studies, the Williams (1970) results are most
notable. This study found that men exposed to H?SO. levels of 1.4 to
o £ 4- .
6.1 mg/m had increases in respiratory disease, particularly bronchitis.
When taken as a whole, the epidemiological studies can provide indications
that ambient acid aerosols have likely been associated with certain types of
observed health effects in some situations and the available results help to
highlight directions for future research. It appears that respiratory disease
effects such as asthma, persistent cough and phlegm, and bronchitis are easier
to detect than are decreases in pulmonary function. This is consistent with
the results of the human clinical studies reported in Chapter; 5. Also,
alterations in mucociliary transport rates could be seen with repeated expo-
o
sures of 100 ug/m in animal toxicological studies as discussed in Chapter 4,
which may be related to the development of chronic obstructive pulmonary
disease (Lippmann et al. , 1987), Lippmann et al. (1982) have also shown that
the effects of FLSO, and cigarette smoke are essentially the same on bronchial
mucociliary clearance patterns.
The one clear conclusion that can be reached from these studies is that
there is a compelling need for additional research. Although there are a few
new studies that may be published irr the near future, it is likely that the
results of these studies will be inconclusive due to the sparsjty of actual
February 1988 6-28 DRAFT—DO NOT QUOTE OR CITE
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measurements of ambient acidity levels. New studies using improved acid
measurement technology and measuring some of the health endpoints described
earlier are critical in order to provide more definitive evaluations of health
effects associated with ambient acids. As one example, Speizer (1988) has
reported on a new large scale study just begun which would directly assess the
chronic effects of acid aerosols on the respiratory health of children. That
multi-city study is to be done collaboratively by Harvard University and Health
and Welfare, Canada. The study will have three sets of eight sites, with
approximately 700 children being examined at each site. Sites will be chosen
to represent gradients in ozone, hydrogen ions from sulfur oxides, and hydrogen
ions from nitrogen oxides. Hopefully, such measurements of acid aerosol
parameters will allow for critically needed direct evaluations of acid aerosol
effects on human health under ambient conditions.
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(1987a) Exercise and lung function responses during an air pollution
eS°d " ^ t"*™*™**™**. to me'thacholine.
Raizenne M. ; Burnett, R ; Stern, B. ; Meranger, J. C. (1987b) Transported air
pollutants and respiratory health in two Canadian communities Chest
R'; Franklin' C. A.; Spengler, J. D.
chdrpn in Tt esponses to ambient acid aerosol exposures in
children. In; . International symposium on the health effects of acid
aerosols: addressing obstacles in an emerging data base; October 1987 ••
Research Triangle Park, NC. EHP Environ. Health Perspect.: in press
Mit . •• M'; SP^'2er' F- E-; Gruhl, J.; Batterman, S. (1983)
Health effects of air pollution due to coal combustion in the Chestnut
Ridge region of Pennsylvania: results of cross-sectional analysis in
adults. Arch. Environ. Health 38: 325-330.
Schrenk, H. H. ; Heimann, H. ; Clayton, G. D. ; Gafafer, W, M. ; Wexler, H (1949)
nrt^ ±«°n 1n7D.onora. P^: epidemiology of the unusual smog episode of
October 1948 preliminary report. Washington, DC: Federal Security Agency
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mor^riVVt-' A'nH;- (1986) Statistica1 reanalyzes of data relating
mortality to air pollution during London winters 1958-1972. Washington
Evaluation EnV1ronmental p^tection Agency, Office of Policy, Planning and
Shy, C. M. ; Creason, J. P.; Pearlman, M. E. ; McClain, K. E.; Benson F B •
Young M. M. (1970) The Chattanooga school children study effects of
community exposure to nitrogen dioxide. 1. Methods, description of
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Soeizer F E (1988) Studies of acid aerosols in six cities and in a new
multicity investigation: design issues. In: International symposium on the
health effects of acid aerosols: addressing obstacles in ah emerging data
base; October 1987; Research Triangle Park, NC. EHP Environ. Health
Perspect.: in press.
Spektor, D. M. ; Lippmann, M.; Lioy, P. J.; Thurston, G. D.; Citak, K.; Bock,
N ! Speizer, F. E.; Hayes, C. (1988a) Effects of ambient ozone on
respiratory function in active normal children. Am. Rev. Respir. Dis.:
in press.
Spektor, D. M.; Yen, B. M.; Lippman, M. (1988b) Effect of concentration and
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Spengler, J. D.; Allen, G. A.; Foster, S.; Severance, P.; Ferris, B., Jr.
(1986) Sulfuric acid and sulfate aerosol events in two U.S.. cities, in:
Lee, S. D.; Schneider, T. ; Grant, L. D. ; Verkerk, P., eds. Aerosols:
research, risk assessment and control strategies: proceedings of the 2nd
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MI: Lewis Publishers, Inc.; pp. 107-120.
Spengler, J. D.; Keeler, G. J.; Koutrakis, P.; Raizenne, M. (1988) Exposure to
acidic aerosols. In: International symposium on the health effects oT acid
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Health and Environmental Assessment, Environmental Criteria and Assessment
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Springfield, VA; PB84-156777.
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criteria for particulate matter and sulfur oxides (1982): assessment of
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Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office; EPA report no. EPA/600/8-86/020F.
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Airway responses to sulfate and sulfuric acid aerosols in asthmatics: an
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Speizer, F. E. (1986) Effects of ambient sulfur oxides and suspended
particles on respiratory health of preadolescent children. Am. Rev
Respir. Dis. 133: 834-842.
Wichmann, H. E.; Mueller, W.; Allhoff, P.; Beckmann, M.; Bocter, N.; Csicsaky,
M. J.; Jung, M.; Molik, B.; Schoenberg, G. (1988) Health effects during a
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health effects of acid aerosols: addressing obstacles in an emerging data
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Perspect.: in press. , .
Williams, M. K. (1970) Sickness absence and ventilatory capacity of workers
exposed to sulphuric acid mist. Br. J. Ind. Med. 27: 61-66.
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7. CONSIDERATIONS FOR LISTING ACID AEROSOLS AS A CRITERIA POLLUTANT
7.1 INTRODUCTION
7.1.1 Purpose
This chapter assesses and integrates the most relevant scientific and
technical discussion in the preceding chapters that the EPA staff believes
should be considered for the possible listing of acid aerosols as a criteria
air pollutant. This assessment is intended to help bridge the gap between the
scientific review and the judgments required of the Administrator in a listing
decision. As such, particular emphasis is placed on identifying those
conclusions and uncertainties in the available scientific literature that the
staff believes should be considered in a possible listing decision.
Because this document is concerned only with the health risks of acid
aerosols, a discussion of the potential welfare effects of acid aerosols is
beyond the scope of this chapter.
7,1.Z Background
Section 108 of the Clean Air Act provides for.the listing of certain
ubiquitous ambient air pollutants that are reasonably anticipated to endanger
public health. Once an air pollutant is listed, Sections 108-109 of the Act
require issuance of air quality criteria and proposal of national ambient air
quality standards (NAAQS) for the pollutant within 12 months. 'Section 110 then
requires the development of State implementation plans (SIPs) to implement the
standards.
In response to these requirements, EPA has listed a number of air
pollutants under Section 108, including particulate matter, sulfur oxides, and
nitrogen oxides; issued the requisite air quality criteria and NAAQS for these
pollutants; and approved or promulgated SIPs to implement the NAAQS. As a
result, acid aerosols and their principal precursors are currently regulated to
varying degrees by these existing national ambient air quality standards. In
general, the existing standards are met throughout most of the U.S., and levels
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of these pollutants in the ambient air have generally been stable or declining
in recent years. Major increases in emissions of such pollutants are not
anticipated in most areas of the country. !
7.1.3 Approach :
The approach used in this chapter is to assess and integrate information
derived from the preceding chapters in order to address the central question
of whether the available information provides sufficient and compelling
evidence to proceed with the separate listing of acid aerosols. Particular
attention is drawn to those critical elements that the staff believes should be
considered in a decision whether to proceed with a separate listing of acid
aerosols and to those judgments that must be based on the careful interpreta-
tion of incomplete or uncertain evidence.
Section 7.2 examines the major considerations for listing acid aerosols.
Section 7.2.1 discusses available data for characterizing and defining acid
aerosols. This section also examines possible exposure scenarios to support
discussions of the available health effects studies. Section 7.2.2 presents
information on health effects of concern and of sensitive population groups,
and summarizes the most relevant animal, controlled human, and epidemiological
studies. Section 7.2.3 reviews the sources of acid aerosols and their
precursors. Section 7.2.4 examines briefly the implications of listing acid
aerosols for the ambient standards program.
The final section of the chapter (7.3) presents alternative courses of
action regarding a listing decision in light of the available scientific
information.
7.2 CONSIDERATIONS FOR LISTING ACID AEROSOLS UNDER SECTION 108 OF THE
CLEAN AIR ACT
7.2.1 Characterization of Acid Aerosols
Acid aerosols can be defined and measured in several ways. Chapter 2
discusses the available information to characterize atmospheric acids as well
as available monitoring techniques. Acid sulfates are the major species in
ambient acid aerosols; at times, sulfuric acid (H2S04) and ammonium bisulfate
(NH4HS04) may account for all of the aerosol strong acidity (Morandi et al.,
1983). Other species, particularly nitric acid (HN03), may be of importance
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in certain exposure situations, such as acid fogs i'n western coastal cities.
Under typical ambient conditions, nitric acid is usually a vapor.
A number of different "indicators," defined by the measurement method
employed, have been used to characterize acid aerosols in the ambient air.
As discussed in Chapter 2, measurement methodologies have various degrees of
species resolution, time resolution, recovery abilities, neutralization
control, and sampling anomalies. Table 7-1 presents various indicators with
comments regarding the merits of each to characterize human exposures.
A key consideration in a decision to list acid aerosols is whether any
one of these measures is sufficient and appropriate to define acid aerosols
clearly, and thus serve as the pollutant indicator for regulatory purposes. A
standardized measurement method is essential, but to date no organized program
exists to develop recommended techniques or to systematically evaluate the
relative uncertainties of the available methods and data from individual
studies. In addition, it is not clear that the health effects data are
sufficiently developed at this time to identify an indicator that best
encompasses ambient exposures of concern.
Ambient monitoring data available to characterize spatial and temporal
relationships of acid aerosols are sparse and interpretation must be tempered
by the limitations of the diverse methodologies employed. Chapter 2 reviews
the available studies. Although limited, this information does yield the
following general conclusions regarding ambient levels of .acid aerosols and
their spatial and temporal relationships.
1) A wide range of acid levels (H2SQ4 or H+ as H2S04) and acid
"events" have been observed in contemporary North American
atmospheres (see Tables 2-8 to 2-15),. Concentrations of H2S04
from zero to nearly 50 pg/m3, In maximum (Spengler et al, ,
1988), have been measured, with most levels <5 \ig/m3. In
studies where only H2S04 was measured, total aerosol strong
acidity is probably underestimated; at times the majority of
strong acid appears to be associated with partially neutralized
ammonium salts (i.e., NH4HS04) rather than H2S04 (Morandi
etal., 1983; Thurston and Waldman, 1987).
2) Ammonia neutralization plays a key role in determining the
persistence of atmospheric acids (see Section 2.2.5). Addition-
ally, ammonia sources may locally modify acid levels of regional
events (Thurston and Waldman, 1987). ,
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TABLE 7-1. ALTERNATIVE INDICATORS FOR CHARACTERIZING EXPOSURE TO ACID AEROSOLS
Indicator
Comments
Individual species
e.g., H2SO<, NILHSO.,
HN03
Strong acid sulfates
(i.e.. H2SO, + NH4HS04)
Strong acid
Total titratable acidity
Sulfates
-H2S04 directly relatable to many of the existing health -studies,
other species less so at this time
-individual species may be the active component over a more generic
measure, such as strong acid. On the other hand individual species
may not adequately reflect the major ambient exposures of concern;
species such as H2S04 may not be common constituents of aerosols,
yet acidity may still be high at times (e.g., high NH4IJS04 c&mponeht)
-need to choose one as appropriate to establish standards, or set
separate standards for each
-probably includes the major components of most acid aerosol events
-most studied species
-may not adequately reflect the complete range of possible acid
exposure, for example, strong acid gases such as HN03
-cannot directly measure NH4HS04 at this time
-includes all species which readily contribute to free H* in aerosols
-health effects data suggest that H* of strong acids is the most
important active species
-does not distinguish possible importance of specific strong acjds
-possibly need to measure strong acid particles and gases
-does not encompass total titratable H+ i.e., weak acids '
-inclusive, all species that contribute to available H+ are i
measured ,
-blurs the distinction between strong and weak acids, and
individual species
-not clear that weak acids are of health concern or are important
constituents in ambient aerosols
-large ambient data set available
-relatable to existing epidemiological studies
-includes major acid sulfate species
-does not consistently relate to aerosol acidity
-includes the nearly neutral ammonium sulfate, which at times nray
dominate sulfate mass
-excludes other acidic species, e.g., HN03
7-4
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3) Levels of sulfates and H appear to be highest in the summer
(Ferek et al. , 1983; Spengler et al. , 1988). Large areas of the
Northeast, extending into Canada, may be affected by elevated
acid concentrations over extended periods at this time (Pierson
et/,V^198°; L17 et a1-' 1980; Stevens et al.., 1978; Thurston
and Waldman, 1987).
4) Urban areas may be a significant source of ammonia and there is
evidence that acid levels are lower in urban areas than in
rural or upwind areas, particularly during regional events
(Tanner et al., 1981; Thurston and Waldman, 1987, see also
Section 2.7.1 and Table 2-8). However, elevated acid levels
and acid events do occur in urban areas.
5) Acid levels will often show a pronounced diurnal cycle with
peak levels during daytime (cf. Stevens et al., 1980; Cobourn
and Husar, 1982; Spengler et al., 1986). Ozone often has a
similar pattern and hence elevated levels of ozone and acid
may occur together, particularly in the summer.
6) Sulfate events may show fairly rapid swings in acidity varying
from mostly strong acid (H2S04) to mostly weakly acidic ammonium
salts UNH4)2S04), over periods of hours to days; weak and
strong acid species, however, can occur simultaneously (see
Section 2.7.1).
7) With the exception of measurements made in California nitric
acid concentrations are typically less than 10 Mg/m3 (see
section 2.7.3). There are very few ambient data for HN03 there-
fore it is difficult to compare the contribution of H exposures
from nitric acid with acid sul.fates.
8) Nitric acid vapor can be neutralized by NH3, which coalesces
into particulate NH4N03. The presence of HN03 therefore may
scavenge available ammonia, either ambient or respiratory NHo
and influence acidity of sulfate aerosols.
9) Acid fogs, discussed in Section 2.2.4, are a special type of
atmospheric aerosol. Fog droplets are very effective at
scavenging pollutant materials from the air and can be highly
concentrated with a variety of chemical components includinq
acids (see Table 2-4). ,
Based on the available data characterizing ambient acid aerosols, the
primary human exposures of interest are: large scale regional episodes, local
plume impacts, .and acid fogs.
: Regional episodes, manifested by high H2S04 and/or NH4HS04 occurring over
periods of one hour or more throughout a day or sequence of days, could poten-
tially involve very large numbers of people. Moreover, elevated ozone could
February 1988 7-5
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frequently be associated with these events. Since these episodes occur in the
summer when large segments of the population, children in particular, will be
participating in outdoor activities, elevated ventilation rates due to exercise
and prolonged exposures may be key variables to consider in assessing health
risk. Additionally, the penetration of acid aerosols indoors is estimated to
be high at this time of year (Spengler et al., 1988). i
The second type of exposures are confined to areas downwind ;of strong
sources such as power plants, smelters, or combined sources in urban areas.
Exposures can occur throughout the year, although most significantly in summer.
Plume impacts may be different from regional sulfate episodes in Having 'higher
SO and NO levels, high particle levels, primary acid sulfates dominated by
H SO (i.e., recently formed and little neutralized), and possibly other acids,
such as HC1 as well. , •
Acid fogs will be associated with cool temperatures and diverse chemical
composition, which may be modifying factors for possible health effects of such
fogs. Nitric acid is effectively scavenged to droplets in fogs (see
Section 2.2.4), and thus may significantly affect acidity..
Limited data are available to characterize particle size of typical
ambient acid aerosols, yet it is clear that most mass is in the fine particle
fraction (<2.5 urn) and, in fact, most studies have shown mean or median mass in
the submicrometer range (see Section 2.2.2). Regional acid events and plumes
are probably dominated by these fine particles, whereas a key feature of acid
fogs is the relatively large particle size (most mass between 5-30 urn, see
Section 2.2.4). Particle size has a significant influence on regional
deposition in the respiratory tract and possible health effects (see
Chapter 3).
Animal studies (Chapter 4) and controlled human studies (Chapter 5)
indicate that health effects may result from acute, subchronic (or repeated
peak), or chronic exposures. Similarly, epidemiological studies (Chapter 6)
are suggestive that acute or chronic exposures are associated with health
effects. However, ambient data are insufficient at this time to assess
adequately the frequency, magnitude, and duration of acid aerosol events;
moreover the limited health effects data base makes interpretation of available
ambient data difficult. There is a great need for focused research to quantify
ambient exposures, including data on acid sulfates, nitric acid and ammonia.
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In summary, the level of knowledge to characterize ambient acid aerosols
is limited. There has been, as yet, no precise definition of acid aerosols,
rather they are a class of pollutants that may be considered to be a subset of
pollutants already regulated by existing NAAQS. Acid sulfates appear to be
the major species of concern, but other acids, both particles and vapors, may
be important in certain situations. There are several possible measurement
techniques, but there is no accepted "standard" method, which further compli-
cates interpreting the meager quantitative data. It is difficult, therefore,
to assess exposures accurately given these limitations. Nevertheless, there is
the potential for large segments of the population to be exposed to'elevated
acid levels, at times in combination with high levels of other pollutants such
as ozone. The significance of ambient exposures in terms of health effects,
however, is unclear, as will be discussed next.
7-2.2 Available Health Effects Data on Acid Aerosols
To make the decision to list acid aerosols under Section 108 of the Act,
the Administrator must conclude that current ambient levels of acid aerosols
may reasonably be anticipated to endanger public health. Such a judgment
requires a sufficient body of supporting evidence that includes data on health
effects of concern, sensitive populations, and concentration-response informa-
tion from appropriate studies to measure against expected ambient exposures.
The bulk of the quantitative health effects data base for acid aerosols
involves acid sulfates, primarily submicrometer H^SCK. There are no animal
data, and limited controlled human data, for larger droplets that would be
typical of acid fogs. Few data are available for nonsulfur constituents of
acid fogs or other acidic atmospheres, such as nitric acid. It is essential
to have a clear idea of which acid species are toxicologically important to
direct efforts aimed at quantifying ambient exposures and before possible
regulatory action is taken. As indicated in Chapters 4 and 5, it appears that
toxicological potency is related to the strength of the acid, i.e., H?SO >
NH4HS04 > (NH4)2S04. However, Amdur et al. (1978b) found that (NH4)2S04 had a
greater effect than NH4HS04 on respiratory function in guinea pigs, whereas
Schlesinger (1988) provides evidence that the H+ associated with H2S04 may be
more "potent" for altering respiratory region clearance than that associated
with NH4HS04. There is a need to explore concentration-response relationships
February 1988 7-7 DRAFT—DO NOT QUOTE OR CITE
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further in controlled studies, for example by examining different acid species
and mixtures with the same pH or the same titratable acidity.
The use of distinct acid species (singly or in mixtures of pollutants)
under well defined exposure conditions (i.e., concentration, particle size,
time and route of exposure) are strengths of the controlled laboratory studies.
At present, these studies provide the best quantitative exposure-response data
and information on possible health effects of acid aerosols.
Animal studies in particular are valuable to provide data on the full
range of possible effects, and are especially valuable for the study of chronic
effects,- providing information generally unavailable from epidemiological or
controlled human studies. However, quantitative extrapolation to humans is a
major limitation of animal studies; with acid aerosols some unique problems
exist. Initial particle size, hygroscopic growth, ammonia neutralization,
airway buffering capacity, and regional deposition, in addition to species
sensitivity, may influence dose-response relationships and hence extrapolation
of the data. As discussed in Chapter 4, neutralization by both endogenous and
exogenous ammonia in particular may be a key variable in animal studies and may
explain some of the wide variation in response among the available studies.
Controlled human studies, in addition to the advantages of controlled
exposure conditions, avoid extrapolation problems of animal studies, yet they
are limited inasmuch as they may not characterize the most sensitive popula-
tions (e.g., elderly, most reactive asthmatics, individuals with preexisting
respiratory disease). Moreover, these studies generally examine specific,
predetermined endpoints (for acid aerosols these have included respiratory
function and symptoms, blood biochemistry, mucociliary clearance, and airway
reactivity-See Chapter 5) and do not "search" for effects or address chronic
exposures.
Lastly, controlled animal or human studies focus on single pollutants or a
limited mixture of pollutants, whereas typical ambient exposures often involve
a complex and changing mixture of pollutants. ;
In any case, the available animal and controlled human studies, while
providing convincing evidence that at high enough concentrations health effects
will occur, have not demonstrated effects of acid aerosols alone at concentra-
tions in the range of known ambient conditions. However, epidemiology provides
suggestive evidence that current ambient levels of acid aerosols are associated
with health effects.
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Some of the most interesting epidemiologies! studies show health effects
associations with plausible surrogate acid indices (e.g., sulfates, particles)
in contemporary North American environments and in areas where elevated acid
levels have been found in subsequent monitoring efforts (e.g., Bates and Sitzo
(1987) report the presence of elevated H+ in the region while Speizer (1988)
indicates that the prevalence of bronchitis in the 6-city study suggests a
better correlation with subsequently measured H+ data than PM15 data). It has
been speculated that H+ may be a more likely causal agent, traveling with the
measured surrogate pollutants, to explain the effects seen in some of the avail-
able epidemiologicaj studies (Bates and Sizto, 1987; .Lippmann, 1988). However,
sulfates or other surrogates do not consistently relate to aerosol acidity
(see Chapter 2) and thus these studies are limited for specific inferences
regarding current ambient levels of acid aerosols. Moreover, the exposures
consisted of a mixture of pollutants, making it difficult to identify the con-
tribution of any single pollutant to the effects seen. The few epidemiological
studies that have measured atmospheric acidity have often found low acid con-
centrations (see Section 6.2.3) or concurrently elevated ozone (Raizenne et al.,
1987, 1988) and it is difficult to separate the effect of acid from ozone for
the endpoint measured (pulmonary function).
The available health effects data indicate that acid aerosols have the
potential to deposit and act throughout the respiratory tract. As a result,
there is a broad range of health effects associated with exposure to acid
aerosols from both acute and chronic exposures at various concentrations; these
include effects on respiratory mechanics and symptoms, alteration of clearance,
and other host defense mechanisms, morphological and biochemical alterations,
aggravation of existing disease or illness, and mortality. The discussion of
these effects below will focus on animal and controlled human studies with
o
exposures <1,000 ug/m , and pertinent epidemiological studies.
7-2.2.1 Respiratory Mechanics and Symptoms. Effects on respiratory mechanics
and function can range from mild transient changes of little direct health
significance to incapacitating impairment of breathing. Symptomatic effects
such as coughing, wheezing, or bronchospasm also vary in severity, but at a
minimum are indicative of a biological response. Mild effects in normal
subjects may indicate potentially more serious responses in more sensitive
subjects.
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Animal, controlled human and epidemiological studies show mixed results
for effects of acid aerosols on respiratory mechanics and symptoms at concen-
trations <1,000 Hg/m3 (Table 7-2). Most animal studies have shown no effects
following acute acid sulfate exposures at these levels. Amdur and colleagues,
however, have observed changes in pulmonary function in guinea pigs following
1-hour exposures to various acid sulfates alone, and in mixtures, with
significant changes as low as 100 pg/m3 H2S04. Recently these investigators
have examined the effect of H2$04 coated ultrafine zinc oxide particles (Amdur
and Chen, 1988); levels as low as 20-30 ng/rn3 H£S04 delivered in this manner
resulted in significant changes in pulmonary function and produced increased
bronchial hypersensitivity whereas much higher levels of pure H2$04 aerosol
were needed to produce comparable results. Zinc oxide alone caused no effects.
This suggests that the physical state of acids in pollutant mixtures is an
important determinant of response.
Controlled human studies indicate that asthmatics are substantially more
reactive to inhaled acid aerosols than normals; small changes in FE\/l and
thoracic resistance have been observed in adolescent asthmatics with H2$04
concentrations as low as 68 pg/m3 (Koenig et al., 1988). However, there seems
to be substantial variability between studies, and even between subjects in any
one study, suggesting that numerous factors may influence susceptibility.
Effects on airway reactivity have been demonstrated following acute H2$04
exposures in humans (Utell et al., 1984, 1985) and chronic exposures in animals
(Gearhart and Schlesinger, 1986). The development of hyperresponsive airways
in otherwise normal subjects may be of special concern (see Sections 4.3 and
5.8).
Epidemiology provides suggestive, but indirect, evidence linking acute
exposure to functional effects and symptoms. The available studies that have
shown effects suffer from a lack of acid aerosol exposure data, or the effect
of the acid component cannot be separated from the mixture of pollutants
present (e.g., Raizenne et al., 1988).
Chronic exposures have produced functional effects in some animal studies
(see Table 7-2). The five and one-half year chronic exposure of dogs to a
mixture of H2$04 and S02 resulted in several interesting findings (Hyde et al.,
1978; Stara et al., 1980). Changes in pulmonary mechanics and structure were
found at exposure levels considerably lower than in other animal studies. The
functional changes became progressively more severe with time after exposure
February 1988
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had been terminated (2 yr later), at which time emphysema was also found,
implying the development of chronic, irreversible lung disease. It appears
that long-term low level exposures may eventually lead to functional and
morphological effects whereas other studies, limited to shorter exposure
durations, have found effects only with much higher concentrations; or no
effects at all.
Ware et al. (1986) from the ongoing Harvard six-city study found the
frequency of cough, bronchitis, and lower respiratory illness in school age
children to be significantly associated with annual mean TSP and total sulfate.
Interestingly, the authors note that city-specific illness rates for Kingston
and Steubenville were consistently highest—subsequent measurements of aerosol
acidity (H ) in four of the six cities show these two cities to be highest on
average (Spengler et al., 1988). In addition, Speizer (1988) indicates that
the subsequently measured H+ data suggest a better correlation with bronchitis
prevalence than does PM15 in 4 of six cities with H+ data. This qualitative
information combined with evidence from animal studies (discussed below)
indicates that further research is warranted to examine the role of acid
aerosols in the development of chronic bronchitis. Other epidemiological
studies discussed in Chapter 6 suggest that symptoms or functional changes may
be associated with chronic exposures to sulfur oxides or nitrogen oxides but it
is quite difficult to quantitatively relate these findings to possible acid
effects in current ambient situations because there are no acid exposure data
available.
7.2.2.2 Host Defense Mechanisms. The lungs have several defense mechanisms
to detoxify and physically remove inhaled material. Nonspecific particle
clearance mechanisms have been well-studied and appear to be sensitive to
inhaled H2S04 at relatively low levels (see Table 7-3). Bronchial mucociliary
clearance appears to be particularly sensitive to the effects of inhaled
3 : - •••"..•'•
H^SO^; levels as low as 100 pg/m have produced alterations in mucociliary
transport rates in humans and animals following either single or repeated
exposures. Respiratory region clearance in rabbits has been shown to be either
accelerated or retarded, suggesting a graded response that is dependent upon
both exposure concentration and time (see Section 4.5.1.2b). H?SO. may alter
alveolar macrophage (an important defense cell of the lung) function following
single or repeated exposures in animals (Naumann and Schlesinger, 1986;
Schlesinger, 1987), but the data are too limited at this time to provide a
February 1988 7-13 DRAFT—DO NOT QUOTE OR CITE
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complete understanding of the cellular mechanisms that may underlie changes
in respiratory region clearance.
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discussed previously (see Sections 4.5, 4.8) and, in short, the significance of
transient alterations after short-term exposure is unclear, but such changes
may be an indication of a lung defense response. On the other hand, persistent
impairment of clearance may lead to the inception or progression of chronic
respiratory disease, suggesting a plausible link between inhaled acid aerosols
and respiratory pathology. For example, Lippmann et al. (1982) emphasize the
similarities between clearance effects of cigarette smoke and HLSO'; smoking
has a well established role in the development of chronic bronchitis. Lippmann
et al. (1987) recently examined this evidence and other data suggesting a
possible link between H2$04 exposure and the pathogenesis of chronic
bronchitis.
Few other animal studies have provided evidence to indicate that acid
aerosols may compromise lung defense mechanisms. Acid aerosols are apparently
not very effective in enhancing susceptibility to bacterial-mediated respira-
tory disease in mice (see Table 4-6), but two studies indicate significant
interactions with ozone (Gardner et al., 1977; Grose et ai., 1982). As with
other endpoints, the effect of mixtures on infectivity needs further examina-
tion. No animal data directly examine the effects of acid on viral infectivity.
Little is known about the effects of acid aerosols on immunologic defense
mechanisms (see Section 4.5.2).
7-2.2.3 Morphological and Biochemical Alterations. Morphological or
biochemical changes are often detected by invasive techniques and hence most
data for acid aerosols are derived from controlled animal tests. Table 7-4
presents relevant studies with exposures <1,000 fjg/m3.
Few effects have been demonstrated in animal studies following acute
exposures at levels <1,000 (jg/rn3 (see Section 4.4). This may be due in part to
different sensitivities of various species or the endpoints studied. However,
three hour exposures to low levels of H2Sp4 delivered as a coating on ultrafine
zinc oxide particles have produced an increase in the protein content of
pulmonary lavage fluid and an increase in neutrophiIs (Amdur and,Chen, 1988),
indicating tissue damage and an inflammatory response. Amdur and colleagues
have not yet done animal exposures to coal combustion products, but suggest
that the response produced by the prototype acid coated zinc oxide aerosols may
February 1988 7-15 DRAFT—DO NOT QUOTE OR CITE
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7-16
-------
have considerable relevance for such exposures. Much higher levels of pure
H2S04 droplets were required to elicit similar responses; the levels of zinc
oxide used alone caused no effects.
Chronic or repeated peak exposures to acid aerosols have produced
morphological changes in animals (see Table 7-4). The dog study of Hyde
et al. (1978) provides unique insights into extended exposures (.5% yr) to a
mixture of sulfur oxides. Several morphological changes were observed. The
authors consider these changes to be analogous to an incipient stage of
emphysema. Stara et al. (1980) found that changes in pulmonary function of the
dogs correlated well with the morphological effects. Since the changes in
pulmonary function were progressive over the post-exposure period, it is likely
that morphological changes were also progressive. : There are several points to
consider to apply the dog studies to real world exposures (see U.S. Environ-
mental Protection Agency 1982a,b) including the possibility that actual acid
' ' 3
exposures may have been lower than 90 ug/m due to neutralization by chamber
ammonia. Progressive effects were also found by Gearhart and Schlesinger
(1988), on tracheobronchial clearance in rabbits exposed to HpSCL,. that
continued even after exposure ceased, again implying progressive, irreversible
effects.
It seems reasonable to attribute most of the deep lung effects in the dog
studies, and other studies with S02/H2S04 mixtures, to the acid component,
based on the probability of deep lung deposition of the aerosol. If the dog
studies of Hyde et al. (1978) and Lewis et al. (1973) can be directly compared,
they indicate that morphological effects of the SO mixture are more pronounced
f\
with extended lower level exposure than with much higher concentrations for a
shorter exposure period.
The studies of rabbits (see Table 7-4) provide evidence that low level
3 ..••"-..
(250 ug/m ) chronic exposure to H2S04 results in hypertrophy and/or hyperplasia
of mucus secretory cells in the epithelium; these alterations may extend to the
small bronchi and bronchioles, where secretary cells are normally rare or
absent (Gearhart and Schlesinger, 1988). These findings.are consistent with
the results of Alarie et al. (1973, 1975) for monkeys chronically exposed to
mixtures of H2S04 and S02. One result of these morphological alterations may
be an increase in mucus loading of these airways, which is a possible factor in
the pathogenesis of obstructive lung disease such as chronic bronchitis.
3 ' ,.'.•••••• . • .
Low levels of H2$04 (40 ug/m ) have been shown to react synergistically
February 1988 7-17 DRAFT—DO. NOT QUOTE OR CITE
-------
v/ith ozone in altering biochemical indices (Warren and Last, .19&7), I'h thfe
case, the disease associated with these changes is speculated to be fpci'tfflbh'aty
fibrosis (Last et al., 1983). As mentioned earlier, acid aerbsol.s will
frequently be associated with elevated ozone levels, and there Is -a need %r
further research addressing pollutant mixtures.
The limited data on morphological and biochemical enclpoints restricts
quantitative risk assessment of health effects occurring "at current aimbTent
levels of acid aerosols, but such data are critical to begin to understand the
range of potential health effects as well as the mechani-sms of toxic'ity of actd
aerosols from which to focus future work. |
7.2.2.4 Aggravation of Existing Disease or Illness. Evidence 'linking "aci'd
aerosol exposure to aggravation of existing disease or illness ;.i';s "reviewed
in Table 7-5. As is evident, animal data are limited. However, 'since ib'rdn'Chtr-
constriction may be an important mechanism by which acid aerosols aggravate
existing respiratory disease, animal and human clini'cal studies indieating
effects on respiratory mechanics are relevant here (see Table 7iia-;2). In any
event, controlled human studies indicate that asthmatics are markedly Wb're
sensitive to inhaled acid aerosols, but epidemiology provides evidence that
other individuals may be particularly sensitive to air pollution that includes
acid aerosols.
Lawther et al. (1970), in a classic study of chest clinic patients (mostly
bronchitics, but some patients had asthma or emphysema), fduncl day-to-day
changes in health status to depend on daily variations in London [pollution
(S02 and British Smoke), measured at seven sampling sites. (This study H
discussed at some length in U.S. Environmental Protection Agency ~1982a,b.)
Interestingly, daily sulfuric acid, measured from one central site beginning ifn
the winter of 1963, was most strongly correlated with effects 'in a group of
patients for the winter of 1964-1965, but less so for 1967-1968,, The authors
suggest that sulfuric acid may be of special interest as a respiratory
irritant. Pollution levels had declined substantially from previous years %
this time, although still quite high compared to current U,S. cofiditions.
The ongoing correlational study of Bates and Sizto (1983,, -1986, 1987)
relating hospital admissions in Southern Ontario to air pollutant levels is
of interest for more contemporary exposures. These analyses demonstrate a
consistent summer relationship between sulfates> ozone and temperature> and
acute respiratory admissions with or without asthma (see Section 6.2.4), There
February 1988 7-18 DRAFT-DO NOT QUOTE 'OR tlTE
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is a continuing lack of association of these variables with non-respiratory
conditions. Bates and Sitzo (1987) indicate that it is not clear whether
the association of increased respiratory admissions can be ascribed to ozone
or sulfates (the only two pollutants monitored on a regular basis,; which show, a
consistent association) or possibly to some unmeasured species that "travels11
with them over the region in the summer. Recent monitoring efforts in, the
area indicate peaks of H+ of small particle size (about Q.2 unO on days, when
ozone and sulfate levels were elevated. These data are interesting and are of
particular relevance for possible health effects at current ambient levels of
acid aerosols, but as yet, the hypothesis that hospital admissions in thte area
are more readily attributed to acid aerosols is untested becagse of a l^k of
H+ data.
A significant pollution event occurred in Europe in January 1985 (see
Section 6.2.2). Notable increases in several measures of morbidity were
observed in Germany (Wichmann et al., 1988), especially for cardipyascglar
disease. Acid levels for the study area were not determined, but the levels
of PM, S02 and N02 were quite high.
The available epidemiological studies, taken as a whole, syggest that
certain individuals or groups may be sensitive to air pollution that includes
acid aerosols, but ascribing the observed health effects to acid exposure is,
difficult because of a lack of sufficient ambient acid measurements.,
7.2.2.5 Mortality. Evidence linking mortality to acid aerosol exposures at
concentrations <1,000 ug/m3 is limited to epidemiological studies (Table 7-^6);
animal studies of H2$04 do not indicate mortality effects at these levels.
This strongly suggests that a mixture of pollutants may be important or that
individual sensitivity is crucial.
Excess mortality clearly resulted from acute exposures during'the severe
pollution episodes of Meuse Valley, Donora, and London. Of greater relevance
for the present discussion, however, are studies such as those of Schwartz and
Marcus (1986) that show mortality associations in London continuing to periods
of much lower pollution, with no evidence of a threshold, and a preliminary
analysis of the London mortality data for which dally acid aerosol measurements
are available from a, central site (Thurston et al., 1988). The results of the
latter study indicate that the log of acid aerosol concentrations is more
strongly associated with raw total mortality in bivariate analyses than is
British Smoke (BS) or S02- The H2S04 results may be more readily applied to
February 1988 7-20 DRAFT-^DO :NQT QUOTE OR;
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7-21
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other environments than is the case for existing BS results, yet differences
in the composition and levels of pollutants between current conditions in the
U.S. and those in London at the time the mortality data were gathered still
limits the applicability of the London mortality data to contemporary North
American atmospheres.
A more recent study (Ozkaynak and Spengler, 1985) provides qualitative
support for an association between daily mortality and particle concentrations
in nearly contemporary U.S. atmospheres (14 years of New York city data,
1963-1976). In this case, the mortality associations, although correlated
with plausible acid aerosol surrogate measures (coefficient of hiaze and atmos-
pheric visibility readings), do not appear to support possible acid aerosol
effects; limited data available for the New York City region show very low
levels of strong acid present for urban New York City, indicating substantial
neutralization of acid sulfates from urban ammonia sources (Tanner et. al.,.
1981).
The recent study by Wichmann et al. (1988) indicated increased mortality
following a European pollution episode, but the levels of several pollutants
were quite high and it is not clear what part acid aerosols may have played,
if any, in this event.
Several ecological analyses have attempted to relate mortality rates to
chronic exposures of sulfate and other pollution measures (see Table 7-6 and
U.S. Environmental Protection Agency, 1982a,b, 1986). There are significant
problems with these kinds of analyses that limit both quantitative, and
qualitative conclusions (see U.S. Environmental Protection Agency, 1986). The
more recent cross-sectional analyses of Ozkaynak and Spengler (1985) and
Ozkaynak and Thurston (1987) address some of these problems. The predictors of
mortality due to air pollution examined in their analyses were expressed in
terms of four aerosol pollutant measures: TSP, IP (inhalable particles), FP
(fine particles), and S0^~ (sulfate). Among these, FP and S04 were most
consistently and significantly associated with the reported SMSA-»specific total
annual mortality rates, while TSP and IP were often nonsignificant predictors
of mortality. This is consistent with a hypothesis; that aerosol acidity may be
a stronger predictor of total mortality because the fraction of H in terms of
')>•—
mass concentration at a particular time and place would rank SQ-j > FP > IP >
TSP. However, as noted earlier, sulfate or other surrogate measurements do nbt
consistently relate to aerosol acidity and, without historical data, a acid-
mortality hypothesis cannot be examined for these data.
February 1988 7-22 DRAFT—DO MOT QUOTE OR CITE
-------
7.2.2.6 Summary of Health Effects. As is evident, there are many possible ;
health effects associated with acid aerosols, both with acute and chronic
exposures, but the available animal and controlled human data to assess
concentration-response relationships are limited to a small set of studies in
which exposures are relatively low (<250 |jg/m3); few concentration-response
studies have been performed, and no studies are available that report effects
of acid aerosol alone at levels in the range of ambient concentrations.
However, chronic studies of ambient acid levels using sensitive measurement
techniques have not been performed. Thus the no measurable effect level is not
adequately defined for risk assessment purposes. At present, epidemiology
provides no clear quantitative relationships because of a lack of sufficient
ambient acid measurements by which to define exposure-response effects levels.
Several factors that are not well understood at this time influence con-
centration-response relationships of acid aerosols, and controlled studies,
therefore, may not yet have adequately characterized potential effects in the
general population. These factors include:
Acutely sensitive groups may not yet be sufficiently identified.
Data from animal studies (e.g., Schlesinger et al., 1979; Wolff
et al., 1979) and human clinical studies (e.g., Avol et al.,
1979; Utell et al., 1983) suggest that certain individuals, even
within selected subgroups, may be particularly sensitive to acid
aerosols. Where possible, these "hyperresponders" should
receive increased study to allow extrapolation to populations at
greatest risk in the general public. For chronic exposures it
may be difficult to identify a sensitive group, rather all
sufficiently exposed people may be at risk.
Concentration x time relationships have not yet been fully
studied. Spengler et al. (1988) compare estimated dose between
the controlled exposure studies of Koenig et al. (1983)
(100 Mg/m3, 40 min. exposure), Utell et al. (1983) (450 ng/m3,
16 min. exposure), and a 1-hour peak ambient exposure at an
outdoor camp in Southern Ontario. By including variables on
concentration, aerosol retention, minute ventilation and time,
Spengler et al. calculate that children engaged in summertime
outdoor activities can experience H doses comparable to effects
levels in controlled human studies. Few animal or controlled
human data are available to assess CxT relationships.
Delayed or progressive effects may have been missed. There are
some data to suggest that such effects may occur including
delayed development of airway hypersensitivity (Utell et al.,
1985) and progressive functional and morphological effects
(Stara et al., 1980; Gearhart and Schlesinger, 1988).
February 1988 7-23 DRAFT—DO NOT QUOTE OR CITE
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Breathing mode (see Chapter 3) and breathing mechanics may
significantly alter deposition (and thus possible response) of
acid aerosols. For example, exercise exacerbates the effects of
inhaled H2S04 (Utell et alI., 1986). Additionally, disease
states (e.g., asthma, bronchitis) or age-related factors influ-
ence deposition (see U.S. Environmental Protection Agency,
1982a,b, 1986).
Oral and respiratory tract ammonia may be critical in neutral-
izing inhaled acids and mitigating responses (Larson et al. ,
1977; Utell et al. , 19§6; see also Section 3.4). In addition,
reduced buffering and H ion absorption capacity of airway mucus
may predispose certain individuals to effects of inhaled acids
(Holma, 1985, 1988).
Few data on ambient particle size are available. Animal data
indicate that particle size influences the potency and temporal
pattern of response (see Chapter 4); controlled human exposure
data indicate that submicrometer particles are more effective
per mass in altering respiratory mechanics than large particles
more typical at acid fogs (see Table 5-1). Regional niucoci 1 iary
clearance effects are apparently related to regional deposition
of H and hence particle size (Lippmann, 1985). In addition,
deposition depends on hydrated, rather than initial, particle
size, but the net effect of hygroscopicity is not adequately
understood (see Section 3.3).
There is inconclusive evidence on the effect of mixtures of
pollutants. Levels as low as 40 pg/m3 H2S04 may act synergis- 1
tically with 03 (Warren and Last, 1987); as yet, other animal or
controlled human studies have shown minimal effects due to
H2S04 at low levels in mixtures (see Sections 4.6 and 5.4)..
Acid aerosols will often be associated with multiple pollutants,""
especially 03. Epidemiology studies show effects ..in the.
presence of elevated levels of acids and ozone (Raizenne.,et al.,
1987, 1988). .
In summary, the available information derived from animal and controlled
human studies clearly indicates that., exposure to acid aerosols at.high enough
concentrations can produce health effects of concern, particularly in sensitive
subgroups of the population and after chronic exposure. The bulk of these
studies, however, have examined H?SO. exposures. Data for other acid species
and mixtures are extremely limited. The effects seen range from mild and
transient changes, such as small, reversible functional effects in exercising
asthmatics, to more substantial effects that may have acute or chronic health
consequences, such as persistently altered clearance and structural changes
that may be suggestive of chronics-bronchitis. It is less clear, however,
February 1988 7-24 I DRAFT—DO NOT QUOTE OR CITE
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-„« »„ .
whether effects are occurring at current peak,,ambient levels. The controlled
human studies have not yet demonstrated effects of acid aerosols at .concen-
trations within the known range of ambient concentrations Animal .studies
indicating the development of chronic, irreversible lung disease require
replication and extension .to lower concentrations for adequate risk assessment.
Most available community epidemiological studies, while indicating that effects
consistent with those observed in animal and human clinical studies may occur
at current ambient exposures, suffer significant limitations because of their
reliance on surrogate pollutant indices. The lack of direct measurement data
for acid aerosols limits the value of these studies for purposes of assessing
the health risks posed by current ambient levels of acid aerosols. The few
epidemiological studies -that do/have direct acid measurements generally
recorded low acid levels (see Section 6.2.3) or, where acid levels were
elevated, ozone was also "elevated • (Raizenhe et al., 1987, 1988) and the
contribution of the acid component for affecting endpoint measured (pulmonary
function) is not clear. Finally,: the,rf are several factors that may signifi-
cantly influence concentration-response relationships that are not completely
understood. It is difficult, /therefore, to make judgements at this time
regarding the level of protection provided by existing NAAQS for this
particular group of pollutants.
7.2.3 Sources of Acid Aerosols
A major consideration in reaching a decision to list a pollutant for
regulation under Sections 108 and 109 of the Act is whether the pollutant is
derived from numerous or diverse mobile or stationary sources.
As discussed in Chapter 2, acid aerosols are principally transformation
products of SO,, and N02- Other acids such as HC1 and some organic acids are
generally minor contributors to ambient strong acid aerosols.
The major precursors of acid aerosols (S02, NO,,) are emitted from
ubiquitous sources. S02 is emitted principally from combustion or processing
of sulfur-containing fossil fuels and ores. Emissions of NO result mainly
,/\
from combustion of fossil fuels such as coal, oil, or gasoline from mobile or
stationary sources.
Both S02 and N02 are currently regulated under Sections 108 and 109 of the
Act. :
February 1988 7-25 DRAFT—DO NOT QUOTE OR CITE
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7.2.4 Implications of Listing Acid Aerosols
While the subject is not a major focus of this paper, it is important to
recognize and briefly consider the implications of a decision tt> list acid
aerosols as a criteria air pollutant when assessing the available data. Once a
pollutant is listed, Sections 108 and 109 of the Act require issuance of air
quality criteria and the proposal of air quality standards within 12 months.
The practical effect of these requirements is that the scientific and
technical data available at the time a decision 'to list is made must be
sufficiently developed to serve as the basis for criteria and standards.
Therefore, when assessing the existing data on acid aerosols, consideration
should also be given to whether it is adequate to provide the kind and amount
of technical information needed to:
1) define a pollutant indicatoir and associated measurement methodology;
2) select appropriate averaging times and forms for standards; and
," ^-- •' £•• •' ' „'"' i'* '"•f -' '
3) establish appropriate standard levels.
7.3 ALTERNATIVE ^
The focus of this chapte^has^e^h^bltiliiiose critical elements that EPA
'" •' t,*1'*1*' ''\^"^'i'' .*"•" , •'":.-, .'••*- '" •"' ' ' *'£ • ;
staff believe should be considered in a,listing decision. The major consider-
ations included: 1) characterizing and defining acid aerosols as a pollutant
entity for purposes of regtjlatJQrf;'-;^) possible health effects of acid aerosols
at current ambient levels;,and 3) the sources of acid aerosols. Each of these
elements is of central relevance f91^:l/sting decisions under Section 108 of the
Act. . .•;.•:•• \.:-^'r'''-'--^r.lS^fy-^ :'..••?..•:.'•••-. •••••••• •'•'•'-^••, - "'''•:.
The key findings of this assessment are summarized below:
1) Limited data are ayailable.to characterize and define acid
aerosols. Several speei.esymay 'qontribute to aerosol: acidity but ,
acid sulfates appear to be' the* primary component. At present, .
acid aerosols 'have .not^een: defined as a single pollutant
entity; rather diffjj|ent^measures "and measurement techniques
have been employed;X.vCn:4a;ddi|ion, few data are available'to
quantify 'ambient ^acjcl level;sf;:and acid events, thus possible; -
human exposures a're"rib:t" wel 1 documented. '"7^-''** \
February 1988 ^ 7-26^'^:|J^^iT:; DRAFT—1)0'-NOT"QUoi;Ef.OR GITE'
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2) Available information from animal and controlled human studies
is limited, but clearly indicates that at high enough concentra-
tions acid aerosols can produce health effects of concern,
particularly in sensitive subgroups of the population and after
chronic exposure. It is less clear, however, whether effects
of concern are occurring at current peak ambient levels.
Controlled human studies have not yet demonstrated effects of
acid aerosols within the range of known ambient concentrations.
Animal studies indicate chronic, irreversible effects but
require replication and extension to lower concentrations for
adequate risk assessment. Most of the available community
epidemiological studies, while indicating that effects
consistent with those observed in animal and controlled human
studies may occur at current ambient levels, have significant
limitations because of their reliance on surrogate pollutant
indices. The few studies with concurrent acid measurements
provide limited information for the specific importance of the
acid component of the atmosphere. Epidemiological studies,
therefore, have limited value at this time for assessing the
health risk associated with current ambient levels of acid
aerosols.
3) The principal precursors (S02 and N02) of acid aerosols are
emitted from numerous and diverse sources.
As indicated earlier, the central question to be addressed in this review
is whether the available scientific and technical information provides suffi-
cient and compelling evidence to proceed with the separate listing of acid
aerosols. When assessing the adequacy of the available data in light of this
question, consideration must be given to the fact that acid aerosols and their
principal precursors are currently regulated to varying degrees by the existing
national ambient air quality standards (NAAQS) for particulate matter, sulfur
oxides and nitrogen oxides. Thus, a decision to list acid aerosols should be
based on a clearly established need to provide additional public health
protection beyond that afforded by the current NAAQS. Finally, the implica-
tions of a listing decision should be considered. Because the statutory
schedule requires the issuance of air quality criteria and standards within
12 months of such a decision, the available scientific and technical informa-
tion must be sufficient to serve as the basis for criteria and provide the kind
and amount of technical information needed to set standards.
Given the above information, three alternative courses of action should
be considered.
February 1988 7-27 DRAFT—DO NOT QUOTE OR CITE
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1) Recommend that the Administrator consider listing acid aerosols
under Section 108 of the Act. This implies a judgement that
the available health effects information is compelling enough
to require additional protection beyond the current NAAQS.
Within 12 months of a listing decision, EPA must issue air
quality criteria and propose standards.
2) Recommend that the Administrator not consider listing acid
aerosols under Section 108. The available health effects
information as well as any new research would be considered
during the next review of the particulate matter standards.
3) Recommend that the Administrator defer judgement regarding
action to list acid aerosols pending further research on the
critical needs identified in Chapter 8.
Based on the staff's assessment of the available information, it appears
that the scientific and technical basis is not sufficient at this time to
proceed to list acid aerosols as a criteria pollutant and to develop a national
ambient air quality standard. The; most convincing data clearly indicate that
at high enough concentrations, health effects of concern are associated with
exposure to acid aerosols, but these data do not show effects within the range
of known ambient levels. Nevertheless, data of a more qualitative nature
suggest some risk at ambient levels, but are not sufficient for reaching any
firm conclusions regarding the health risks associated with current ambient
exposures. This uncertainty regarding health risks at ambient exposures,
coupled with the need to better characterize and define acid aerosols, suggests
that it is difficult to make conclusions regarding the level of protection
provided by existing NAAQS and therefore adoption of either alternative 1) or
2) would be premature. With the concern arising from what is known, the staff
believes that additional research is warranted and therefore the most appro-
priate course of action would be to recommend that the Administrator defer
judgement pending further research on the critical needs identified in
Chapter 8.
February 1988
7^28 DRAFT—DO NOT QUOTE OR CITE
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8. RESEARCH NEEDS
Throughout earlier chapters in this issue paper, numerous gaps in the
current data base for acid aerosols were noted. The present chapter summarizes
some of the more crucial research needs that are critical to be addressed in
order to provide a firmer basis by which to judge the need for listing ambient
aerosols as a criteria air pollutant and for developing any consequent criteria
and standards. The research needs discussed reflect inputs from chapter
authors of this report, external peer reviewers of drafts of this document, and
EPA scientists and represent critical areas where significant gaps exist in the
data base concerning acid aerosols and associated health effects. They are
identified below by subject area and include needs related to: characteriza-
tion and exposure; animal toxicology studies; controlled human, exposure
studies, and epidemiological research.
8.1 CHARACTERIZATION AND EXPOSURE
Development and Evaluation of Measurement Methods — Currently, there are
a multitude of techniques to detect various acid species in the atmosphere.
Ideally, before initiating extensive studies to characterize components,
levels, and distribution of ambient acid aerosols, it would be desirable to
have a consensus by the scientific community on measurement techniques that are
accepted as reliable and that reflect the indicator(s) of concern from health
effects studies. Available health studies have not unequivocally identified a
unique entity as the "correct" indicator, although the available.evidence
suggests that either the H+ of strong acids or sulfuric acid (H^SO,) specifi-
cally is the toxicologically important component. Therefore, until and unless
health studies can define the species of concern more explicitly, it is
desirable to measure individual acid species (both in particles and gases) and
more inclusive measurements of .titratable H+, which can include strong acidity
and weak acidity, if desired.
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There are a number of similar techniques, used by different research;
groups, which are based on removal of acidic and basic gases by various types
of denuders, collection of acid particles on filters, preservation of the
samples from NH3, and analysis for H by pH measurements or titration, and
analysis of S0?~, NO^, NO^, Cl~, and NH4+ by ion chromatography.; These can
give time resolution of as low as one or a few hours or for periods of 24 hours
or longer.
HpSO. may be determined semicontinuously by flame photometry using a
temperature-cycled diffusion denuder tube. However, 95% of the aerosol acid
sulfate is typically not in the form of H2S04- Other techniques utilizing
thermal treatment applications have been used for semicontinuous measurements
and measure most of H2$04 and possibly NH4HS04. In any event, a program is
needed to evaluate existing methods and to develop or modify techniques, with a
goal of developing recommended approaches that are accepted by the scientific
community and which will thereby provide some uniformity by which to evaluate
ambient conditions and, ultimately, human exposures to acid aerosols.
Application of Measurement Techniques -- There are a variety of applica-
tions that place different requirements on measurement techniques. In con-
junction with methods development and evaluation, the range of potential
applications needs to be considered. Research applications require a variety
of special measurements but do not necessarily require low cost, unattended
use, or easy operation. Characterization studies, which need to be conducted
over longer time periods for ambient, indoor, and personal exposure, place
additional constraints on measurement techniques in terms of time resolution,
reliability and accuracy, and ease of operation. For these purposes, scien-
tific acceptance and good quality control are essential. Measurements must be
as complete as possible in terms of species measured.
Both batch and continuous (or at least semicontinuous) techniques will be
needed for research and characterization studies. Continuous techniques are
typically more expensive to setup and more difficult to operate than batch
techniques, but provide information not available from batch measurements and
may be cheaper on a per-sample basis.
An overriding concern for various applications and sampling strategies is
their relevance to available health effects information. For example, there
appears to be a significant diurnal variation in acid levels; the time
resolution of batch measurements ideally would differentiate this variation
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(e.g., 6-hour intervals) yet would still be compatible with longer term
integrated measurement, and thus allow extrapolation to a variety of possible
exposure scenarios.
Characterization of Ambient Acid Levels -- At present, there are extremely
limited data to characterize ambient acid aerosol levels. Once appropriate
measurement techniques are available, an ambient characterization study should
be conducted to give a better indication of the potential exposure to atmo-
sphere acids. Sampling sites should include, as a minimum, an urban and an
upwind (in terms of expected acidity) station. Species measured should include
H2S04 and strong acidity, and for gases, HN03, HN02, and NH3- Measurement of
other species and parameters would be useful, especially fine particle mass,
2~ -
SO^ , N03, 03, S02, and N02. Time resolution should be adequate to charac-
terize the diurnal cycle. Geographic coverage should include, as a minimum, a
site in the mid-west source region, a site in the sulfate impacted NY or PA
area, and two sites farther south in the east. At least two should be in areas
with acid soil and therefore presumably low MM-,.
Additional Characterization Needs — Several factors that may affect
concentration-response relationships for ambient acid aerosols need further
study. These include ambient size distributions of acid particles, ammonia
neutralization, aerosol dynamics and chemistry, and spatial and temporal
relationships.
Penetration and deposition in the respiratory tract is a function of
particle size. Acidity is expected to be confined to the fine particles
(0 - 2.5 urn) but the possibility of acidity in coarse particles capable of pene-
trating the tracheobronchial region of the respiratory tract should be examined.
Within the fine fraction, the exact particle size, and the distribution between
the nuclei mode (0-0.1 |jm) and the fine mode (0.1 - 2.5 pro) needs to be deter-
mined for various concentrations and pollutant,conditions.
Changes in particle size with increasing relative humidity, as encountered
in the respiratory system, can be modeled for pure compounds. For acid parti-
cles which contain nitrate and soluble organics as well as sulfate, additional
theoretical and experimental work is needed.
With respect to acid fog, current research is limited to characterization
of bulk fog or cloud water. Unfortunately the efficiency of the collectors
are low and not well known for sizes where lung deposition is high. Measure-
ment techniques are adequate but need to be applied to size-differentiated
samples.
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Measurements have shown that N(L reacts rapidly with pure H>|SO. aerosoli
However, in the atmosphere acid particles may be coated with a film which wi 11
impede the diffusion of NH- into the liquid droplet. Thus, it may be that acid
O I
particles can coexist with NFL- Information on the rate of neutralization is
needed for design of new measurement techniques, to model acid air quality,
to calculate exposure, and to understand the role of endogenous NhL in
influencing the acidity of acid particles in the respiratory syste!itu
Current research suggests the occurrence, especially during summer
episodes, of a strong diurnal pattern with sulfate and acidity both peaking
between 12 noon and 6 pm. Since health effects may depend on the short-term,
high-level exposures, over a threshold, measurement techniques must be adequate
to resolve these peaks. Thus, batch measurements with one-hour Resolution or
continuous or semicontinuous measurements may be required.
Acidity may come from regional scale sulfate pollution which is almost
continuous in some parts of the country and more episodic in others, acidity
may also come from near-source impacts of plumes. Exposure studies will heed
to cover these spatial determinants of ambient acidity.
Exposure — If health effects studies support health concerns with acid
aerosol at expected ambient exposure levels, personal monitors and personal
exposure studies will be needed to augment available ambient data. This should
include indoor measurements to study penetration of outdoor acidity into indoor
environments in homes, schools, and offices; the influence of indoor NFL
i J •
sources; and the possible generation of acid aerosol by indoor combustion
sources. Activity models should be available from other studies.,
Air Quality Models — At some point, it may become necessary to model acid
aerosol air quality. Over the next few years, major advances in air quality
models are expected in terms of transport and removal processes land sulfuric
acid formation (from the Regional Acid Deposition Model), and aerosol £fze
distribution from Visibility and Fine Particle Models. There are several
i
considerations which will be especially important for an acid aerosol; model
which may not be adequately addressed in existing programs. It may be appro-
priate to add or put more emphasis on these considerations. They include NFL
emissions and influence of soil acidity on NHL emissions and removal, and
diurnal variations in acidity and sulfate concentration. More effort may be
needed to differentiate between pollutant processes in the near ground^level
well-mixed layer, and in that portion of the well-mixed layer which is isolated1
from the ground during night-time and early morning.
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8.2 ANIMAL TOXICOLOGICAL STUDIES
Identification of the Hazardous Chemical Species -- Concern about the
health risks of acidic aerosols is derived from epidemiological studies, most
of which did not include direct acid measurements in their exposure assessment,
and controlled human and animal studies of H2$04 and other less acidic sulfate
species. While this work forms the basis for numerous research needs, there is
a major need to identify the causative chemical species so that future health
and monitoring studies are properly directed and that ultimately the causative
species can be controlled. The relative potency of various acid species needs
further study; most work has focused on H2S04 but NH4HS04 may dominate ambient
aerosol acidity of times. In addition, there is a need to understand the rela-
tive role of the cation and the anion associated with various acid species, and
the toxicological effects of acidic particles compared to acidic gases. A more
complex issue has arisen from recent research by Dr. Amdur and her colleagues
(see Chapter 4). They found that H2$04 adsorbed onto ultrafine zinc oxide
particles was 3 to 10 times as potent in changing pulmonary function as an
equivalent-sized aerosol of H2S04 mist. This raises several questions, not
only for H2S04, but also for HC1 since it is emitted from hazardous and
municipal waste incinerators, perhaps in association with particles.
Determination of Concentration Times Time (C x T) Relationships -- Health
effect outcomes are dependent on many factors, with C x T being one of the
major ones. Ambient air patterns of acids, as of other pollutants, are not
steady-state, so it is critical to determine which exposure patterns are of
greater risk and hence must be monitored in research studies, .and be controlled
if control is warranted. Given the, paucity of C x T health and monitoring
data, it is important to develop a research strategy between both health and
monitoring scientists so that each may be guided by the other iteratively. The
alternative is a plethora of health data bearing no relationship to ambient
exposures or a plethora of monitoring data with averaging times uninterpretable
with respect to health risk. Health study components would focus on only a few
sensitive indicators of response, perhaps clearance and/or pulmonary function.
Focus is necessary to simplify what will be a complex matrix design.
Determine Influence of Pattern of Exposure on Effects '--'- This topic has
elements in common with the C x T studies described above, but focuses more on
the effects of timing of the pattern of exposure vis-a-vis pattern of response.
Only rarely are delayed responses studied, although they can occur and may
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provide important guidance to design and interpretation of human clinical and
epidemiological studies. In the Cincinnati dog study (see Chapter 4) in which
dogs exposed to H2S04 plus S02 were examined 2 years post-exposure,, pulmonary
function effects were progressive, arguing further for the incorporation of
delayed response studies in experimental designs. Another issue of importance
to explore is the response to short-term repeated exposures. Over a week, the
pattern of pulmonary function responses changes, in some cases worsening and in
others plateauing.. To interpret the degree of adversity, it is necessary to
know whether there are "silent" changes' to one endpoint that progress while
other endpoints adapt, as is the case with ozone.
Quantitative Animal to Man Extrapolation of Effective Acid Exposures and
Regional Pulmonary Deposition in Man - It. is reasonably expected that animal
studies will provide cause-effect data on the chronic effects of acids, mecha-
nisms of effects, and the full range of effects, thereby providing information
unavailable from epidemiological or human clinical studies. These animal data
are therefore of great importance to risk assessment, but quantitative extrapo-
lation to man is required. This extrapolation must be rigorous inasmuch as
small differences in effective concentrations have major impacts on risk
management. To achieve the animal-to-man extrapolation, two primary factors
must be considered: dosimetry and species sensitivity. Research on the
relationship between concentration and delivered dose in animals and man will
be complex since 1) acids are hygroscopic aerosols for which more fundamental
data are needed, 2) neutralization by breath ammonia and, in whole body expo-
sure, ammonia from excrement, can be important, 3) tissue dose will be highly
dependent on mucus buffering capacity, requiring data on mucus biochemistry,
and 4) mi credosimetry (i.e., dose within lung regions) is quite important since
health studies on a single endpoint (i.e., clearance) show responses to be
dependent on regional dose. Of course, other dosimetric factors are equally
important, but acids present some special cases. It is also of interest to
compare dosimetric relationship within subpopulations of "man", e.g., normal,
asthmatic, exercising, etc. Understanding these relationships will enhance the
accuracy of predicting susceptibility factors, since ultimately U is dose that
causes an effect. Even once dose-equivalency in different species is known,
species sensitivity to a given dose is likely to have some differences which
must be quantified and linked with dosimetry to provide a full extrapolation.
It is already recognized that the guinea pig is more sensitive for some
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endpoints than other animal species to a given inhaled concentration. How does
the sensitivity of a guinea pig compare to "man", whether "he" be normal,
asthmatic, or otherwise more susceptible?
Determine the Effects of Acids(s) on Development of Chronic Lung
Disease — There are sufficient data to hypothesize that long-term exposure to
low levels of H2S04 may cause chronic bronchitis. Because of the significance
of these findings, it is essential to test the hypothesis. Several approaches
are of interest. A few would include conducting a study similar to the rabbit
study of Schlesinger et al. (see Chapter 4) in at least one additional species;
repeating the Schlesinger et al. , study at a lower concentration; increasing
the knowledge of the relationship between alterations in lung clearance and the
development of chronic bronchitis; applying state-of-the-art lung morphometric
methods in a time-course study.
Define a Fuller Range of Classes of Effects of Acids — Generally, the
literature on the health effects of acids is sparse, with the more important
findings resulting from the application of newer methods and technologies.
Recently, low levels of H2S04 have been observed to result in inflammatory
responses and effects on alveolar macrophages. These changes have implications
to the development of chronic lung disease. The alveolar macrophage effects
and lung clearance effects may portend decrements in host resistance to infec-
tion, most probably viral infection" since bacterial infectivity is apparently
not affected. Taking the literature as a base, several findings require
follow-up so that risk potential can be understood. As examples, is the influx
of neutrophils associated with other inflammatory changes; are defenses against
viral infection compromised?
Determination of Susceptible Subpopulations — Several subpopulations are
known or suspected to be more susceptible to acid aerosols. While some of this
research is incorporated under extrapolation modeling discussed earlier, animal
toxicological research on this topic is needed to supplement human studies to
explore mechanisms more fully. . ,
Interaction of H^SO^ With Other Co-occurring Common Pollutants -- The
issue of the enhanced potency of H^SO^ adsorbed onto particles was discussed
briefly under the first recommendation in this section and will not be repeated
here. Sulfuric acid in association with other pollutants such as ammonium
sulfate, 03, and N02 has been found to be additive, synergistic, antagonistic
or non-influential, depending upon the endpoint, the co-pollutant, and whether
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the exposure was in sequence or in mixture. From a risk perspective, under-
standing the synergism is of major importance. Such studies need to be
designed to mimic ambient occurrences of HgSO^ and co-pollutant exposures,
insofar as possible. For example, the temporal relationship and concentration
ratios of 03 and H2S04 that actually occur should be investigated for effects
using sensitive endpoints such as edema, lung clearance, and other endpbfnts as
well, since there can be a dependence on endpoint. Once the phenomenon is
understood better, mechanism studies are needed to enable predictions of
interactions in risk assessments. Such predictions are important since it is
not feasible to collect data on every potential interaction of interest.
8.3 CONTROLLED HUMAN EXPOSURE STUDIES
Studies of Adolescent Asthmatics — Further studies of adolescent asth-
matics are required to confirm the apparent susceptibility of this patient
group. Specific attention should be focused on exposures to acid aerosols in
the concentration range of 0-200 ug/m3. As an adjunct to such studies, deter-
mination of differences in mucus buffering capacity or oral and airway ammonia
levels in young asthmatics should be made.
Studies of Mucociliary Clearance in Humans — Further work on mucociliary
clearance measurements in humans is needed, emphasizing standardization of
measurement methods and independent confirmation of findings. This work should
focus on estimation of airway acid burdens and, ultimately, identification of
acid deposition "hot spots". Effects of longer (2-8 h) exposures to lower
concentrations (0-100 ug/m3) of acid aerosol are necessary to examine further
the predictive validity of the concentration-time product model. Further baste
work is needed to attempt to understand the large "normal" range of mucociliary
clearance rates.
Studies of Airway Hyperreactivity — Further work on the relationship
between induction of airway hyperreactivity and acid aerosol exposure is
needed. It is important to determine whether acids induce airway inflammatory
responses that may be associated with hyperreactivity. At present, only
hyperresponsiveness to carbachol has been demonstrated. Investigation of
post-exposure reactivity to other stimuli, such as histamine, methacholine, or
antigens, would help to clarify the specific or general nature; of the airway
response.
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Titratable Acids — All studies should report the titratable acidity of
the aerosol in addition to particle size distribution, acid concentration of
liquid that is aerosolized, and mass concentration of aerosol.
Studies of Hyperresponsive Subjects — Efforts should be made to focus on
the susceptible members of the population. Specifically, responses of
hyperreactive subjects should be confirmed. Further study of hyperresponsive
individuals should be initiated to attempt to discern possible mechanisms of
reactivity. Both longer-duration and repeated-exposure studies in humans with
acid aerosols will be necessary to evaluate cumulative effects and possible
adaptive responses. The possibility that repeated acid aerosol exposure may
result in airway hyperresponsiveness should be evaluated.
Buffering Capacity of Airway Secretions — More information is needed
regarding the ability of airway secretions to buffer inhaled acids. Suscepti-
ble subjects need to be identified. Regional variation within the lung of
buffer capacity needs to be better defined. Buffering capacity of mucus from
asthmatics needs to be further evaluated. ',
Variation of Ammonia Production -- Interindividual, regional, and species
variation in ammonia production must also be evaluated. When possible, studies
should measure ammonia levels in conjunction with acid aerosol exposures.
Effects on Respiratory Epithelium -- The effects of acid aerosols on the
respiratory epithelium need to be studied more extensively. Changes in epithe-
lial permeability are expected to occur as a result of acute acid inhalation.
Small Airway Effects -- Improved methodology for non-invasive evaluation
of small-airway responses is necessary because aerosol deposition models
indicate that a large portion of inhaled acid in the ambient size range is
deposited in the vicinity of the alveoli and respiratory bronchioles.
Effects of Mixtures of Pollutants --' Effects of acid in mixtures ,of other
pollutants need to be studied in more detail. Specifically, exposure sequences
and simulation of ambient exposures should be examined. Both ozone and H?SO,
appear to cause increased epithelial permeability. Further examination of the
effects of ozone and H2$04 mixtures thus appears warranted. Further work with
asthmatics exposed to mixtures of S02 and acid or possibly NO 'and acid is also
needed.
Delayed Responses — Further study of delayed response, seen in studies of
normals and asthmatics, is needed to evaluate possible mechanisms of delayed
effects of potential importance. Specifically, a series of follow-up measure-
ments is necessary to evaluate delayed effects and their time course.
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Other Acids ~ There have been a substantial number of studies on sulfuric
acid aerosols. Further work should be conducted using vapor phase acids such
as HN03 and HC1, as well as NH.HSO., which may be a major contributor to
aerosol acidity.
Deposition and Neutralization of Hygroscopic Acid Particles ,— Several
models have been developed to describe deposition and neutralization of hygro-
scopic acidic particles. Further experimental work is necessary to verify
these models and to provide information that might explain the differences
between model prediction.
8.4 EPIDEMIOLOGY STUDIES
Epidemiology provides an approach for directly studying the effects of
ambient acid aerosol mixtures on human health endpoints. Such studies con-
ducted to date, however, have been markedly limited due to the lack or sparsity
of actual acid measurements or to the relatively low concentrations of acids
present at the time of particular studies. Nevertheless, the data derived from
epidemiological and other types of studies thus far do suggest that certain
health endpoints are more likely than others to be affected by acid aerosols.
Based on the available epidemiological, controlled human exposure, and
animal toxicological studies, future research should clearly include evaluation
of pulmonary function and respiratory diseases as possible health endpoints.
Increased incidence or aggravation of respiratory diseases or symptoms, such
as persistently increased cough and phlegm, bronchitis, and asthma have all
been indirectly implicated. Specifically, chronic bronchitis rates have been
consistently elevated in those situations where it was also likely or confirmed
that ambient air acid levels were elevated. It is also possible that well-
conducted epidemiological studies of short-term exposure effects on lung
function may yield significant effects, especially if geographic study loca-
tions can be found with higher ambient acid aerosol levels than those typically
seen thus far in the summer camp studies discussed in Chapter 6. As for
asthmatics, a reactive population not taking medication may be indicated as
a group to study. Hyperresponsiveness and delayed responses may need to be
evaluated. Also, since inflammatory processes are found to increase in the
airways following exposure to acid, studies examining reversible changes in
pulmonary function may be appropriate.
I1
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Further development of better methods to more accurately measure ambient
acid levels (see Section 8.1) and the deployment of adequate monitoring sites
are crucial for the success of future epidemiological study efforts. Realis-
tically, given anticipated funding limitations, increasing support to already
ongoing large-scale epidemiology investigations, so that they can be expanded
to include sufficient acid aerosol aerometric measurements and analysis of.
health endpoints in relationship to such measurements will probably provide
the best near-term opportunity to notably improve the acid aerosols health
data base. For example, existing ongoing or planned epidemiology studies
should be extended to include additional health endpoints, larger numbers of
subjects, increased numbers of chemical species measured, additional study
areas, and greater numbers of monitoring sites in study areas. Some specific
examples of what might be done are concisely highlighted below.
New Harvard Multicity Investigation -- (Primary Sponsors NIEHS and Health
and Welfare, Canada). This study is to directly assess the chronic effects of
acid aerosol on the respiratory health of children. This prevalence cross-
sectional study is discussed in Section 6.4. It is designed to clarify the
possible role acid aerosols may play in chronic respiratory disease that was
suggested in earlier epidemiology studies. Additional funding could be used
to improve acid aerosol exposure assessment and expedite reporting of results.
Canadian Hospital Admissions Study —' As discussed in Section 6.2.4 there
is a suggestion that acid aerosol levels may be related to respiratory
admissions to hospital in Southern Ontario, Canada. Acid aerosol measurements
have been obtained in this area during the past two years. Hospital admissions
data will become available to the researchers in the near future. Additional
funding to expedite analyses and reporting of results would be beneficial.
Studies in the Netherlands — Several studies underway and planned in the
Netherlands would benefit from additional funding and potentially produce
data related to the health effects of acid aerosols in a shorter time frame.
One ongoing study is designed to examine the long-term effects of pollutants
on normal and sensitive adults. Every three years, this prospective study
examines respiratory function and symptoms of respiratory disease. The overall
goal is to examine the decline of pulmonary function and the onset of chronic
respiratory disease. Additional assistance related to the acid aerosol
component of the study would be beneficial, e.g., to expand acid aerosol
monitoring.
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The above study results may be influenced by short-term effects from
acute pollutant exposures that affect the general long-term trends. These
short-term effects will be examined to clarify this problem. Acid aerosol data
would be an important addition to this analysis.
Another acute study in the planning stage is examination of the respira-
tory effects on children of exposure to pollutant events. Acid aerosol data
would be important in this study as well. Of special importance would be to
develop monitoring and measurement capabilities sufficient to characterize
peak exposures. i
Studies in Other Countries — European study settings provide an oppor-
tunity to assess winter excursions of pollutants, including acid aerosols which
are not accompanied by elevated ozone as is typical of the summertime episodes
in the U.S. Respiratory morbidity in patients of general practitioners ttv,
England (see Section 6.2.2) is a potential area of study. Examining acute
bronchitis rates in children in relation to acid aerosol exposure is suggested.
Preliminary data from a study in West Germany (see Section 6.2.2) suggest that
study of respiratory disease and exposure to acid aerosols may be indicated in
that Country. Another possible location for a study of respiratory disease in
relation to acid aerosol exposure is in Italy in the area of the largest power
plant in Europe. Additional study opportunities should be explored in other
European countries and elsewhere, e.g., China.
Indoor Exposures — Preliminary results from chamber studies at Yale
University indicate that high indoor exposures to acid aerosols may result from
the use of kerosene heaters. Additional research is needed to determine the
extent to which these exposures occur in residential settings and if indicated
to assess their health effects. This might be effectively accomplished by
augmenting the above ongoing epidemiology studies
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