SEPA
United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA/600/8-86/O2OA
July 1986
Review Draft
Research and Development
Second
Addendum to
Air Quality
Criteria for
Particulate
Matter and Sulfur
Oxides (1982):
Assessment of
Newly Available
Health Effects
Information
Review
Draft
(Do Not
Cite or Quote)
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
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-------
(Do Not
Cite or Quote)
EPA/600/8-86/020A
July 1986
Review Draft
Second Addendum to
Air Quality Criteria for
Participate Matter and
Sulfur Oxides (1982):
Assessment of Newly Available
Health Effects Information
NOTICE
This document is a preliminary draft. It has not been formally released by EPA and should not at this
stage be construed to represent Agency policy. It is being circulated for comment on its technical
accuracy and policy implications.
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Developent
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
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DISCLAIMER
This document is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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CONTENTS
LIST OF FIGURES .... v
LIST OF TABLES vi
AUTHORS AND CONTRIBUTORS vii
REVIEWERS yiii
OBSERVER ' xi
1. INTRODUCTION l-i
1.1 PHYSICAL AND CHEMICAL PROPERTIES OF AIRBORNE PARTICULATE
MATTER AND AMBIENT AIR MEASUREMENT METHODS 1-2
1.2 PHYSICAL/CHEMICAL PROPERTIES OF SULFUR OXIDES AND THEIR
TRANSFORMATION PRODUCTS AND AMBIENT MEASUREMENTS METHODS ... 1-9
1.3 KEY AREAS ADDRESSED IN EMERGING NEW HEALTH EFFECTS DATA .... 1-14
2. RESPIRATORY TRACT DEPOSITION AND FATE ! 2-1
2.1 RESPIRATORY TRACT DEPOSITION AND FATE OF INHALED AEROSOLS .. 2-1
2.2 SULFUR OXIDES DEPOSITION AND CLEARANCE 2-14
2.3 POTENTIAL MECHANISMS OF TOXICITY ASSOCIATED WITH INHALED
PARTICLES AND S02 2-15
2.4 SUMMARY 2-18
3. EPIDEMIOLOGICAL STUDIES OF HEALTH EFFECTS ASSOCIATED WITH
EXPOSURE TO AIRBORNE PARTICLES AND SULFUR OXIDES ,3-1
3.1 HUMAN HEALTH EFFECTS DUE TO SHORT-TERM EXPOSURES TO
PARTICLES AND SULFUR OXIDES 3-1
3.1.1 Mortality Effects of Short-Term Exposures 3-2
3.1.2 Morbidity Effects of Short-Term Exposures 3-12
3.2 EFFECTS OF ASSOCIATED WITH LONG-TERM EXPOSURES TO AIRBORNE
PARTICLES AND SULFUR OXIDES 3-18
3.2.1 Mortality Effects of Chronic Exposures 3-18
3.2.2 Morbidity Effects of Long-Term Exposures 3-26
4. CONTROLLED HUMAN EXPOSURE STUDIES OF SULFUR DIOXIDE HEALTH
EFFECTS 4-1
4.1 NORMAL SUBJECTS EXPOSED TO SULFUR DIOXIDE 4-2
4.2 CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS EXPOSED
TO S02 4-9
4.3 FACTORS AFFECTING THE PULMONARY RESPONSE TO S02 EXPOSURE
IN ASTHMATICS 4-9
4.3.1 Dose-Response Relationship : 4-9
4.3.2 S02-Induced Versus Nonspecific Airway Reactivity .. 4-21
4.3.3 Oral, Nasal, and Oronasal Ventilation 4-23
4.3i4 Time Course of Response to S02 in Asthmatics 4-26
4.3.5 Exacerbation of the Responses of Asthmatics to
S02 by Cold/Dry Air 4-29
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r
CONTENTS (continued)
4.4 MECHANISM(S)
4.4.1 Mode of Action •
4.4.2 Breathing Mode and Interaction with Dry Air
4.4.3 Tolerance (Attenuation of Response) to S02 with
Repeated Exposure
4.5 CONCLUSIONS •
5. EXECUTIVE SUMMARY
5.1 RESPIRATORY TRACT DEPOSITION AND FATE SUMMARY
5.2 SUMMARY OF HEALTH EFFECTS ASSOCIATED WITH EXPOSURE TO
AIRBORNE PARTICLES
5.3 SUMMARY OF CONTROLLED HUMAN EXPOSURE STUDIES OF SULFUR
DIOXIDE HEALTH EFFECTS
6. REFERENCES
4-34
4-34
4-36
4-37
4-39
5-1
5-1
5-2
5-7
6-1
iv
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LIST OF FIGURES
2
3
4
5
Idealized representation of typical fine and coarse
particle mass and chemical composition distribution in an
urban aerosol
Regional deposition of monodisperse aerosols by indicated
particle diameter for mouth breathing (alveolar) ...-..:..,
Estimates of thoracic deposition of particles between 1
and 15 urn by Miller et al. (1986) for normal augmenters
(solid lines) and mouth breathers ,
Predicted initial dose to the TB region as a function of
body mass by Phalen et al. (1985)
Adjusted frequency of cough for the 27 region-cohorts
from the Six-Cities Study at the second examination
plotted against mean TSP concentration during the
previous year
Adjusted mean percent of predicted FEVi at the first
examination for the 27 region-cohorts from the'Six Cities
Study plotted against mean TSP concentration during the
previous year
Page
1-3
2-3
2-9
2-11
3-34
3-35
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LIST OF TABLES
Table
1
3B
Summary of quantitative conclusions from epidemiological
studies relating health effects to acute exposure to
ambient air levels of S02 and PM
Summary of quantitative conclusions from epidemiological
studies relating health effects to chronic exposure to
ambient air levels of S02 and PM
Summary of asthmatic subject characteristics from newly
available controlled human exposure studies of effects of
sulfur dioxide on pulmonary function
Summary of normal subject characteristics from newly
available controlled human exposure studies of effects of
sulfur dioxide on pulmonary function
Summary of results from controlled human exposure studies
of pulmonary function effects associated with exposure of
asthmatics to S02
Page
3-4
3-28
4-3
4-6
4-11
vi
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AUTHORS AND CONTRIBUTORS
The following people served as authors or otherwise contributed to pre-
paration of the present addendum. Names are listed in alphabetical order.
Dr. Lawrence J. Folinsbee
Environmental Monitoring and Services, Inc.
Chapel Hill, NC 27514
Dr. Lester D. Grant, Director
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Timothy R. Gerrity
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Chapel Hill, NC 27514
Dr. Donald H. Horstman
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Chapel Hill, NC 27514
Dr. Howard Kehrl
Health Effects Research Lab
U.S. Environmental Protection Agency
Chapel Hill, NC 27514
Dr. Dennis Kotchmar
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Fred Miller
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. L. Jack Roger
Environmental Monitoring and Services, Inc. -
Chapel Hill, NC 27514 ;^
vii
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REVIEWERS
review.
A preliminary draft version of the present addendum was circulated for
Written or oral review comments were received from the following
individuals, most of whom participated (along with the above authors and con-
tributors) in a peer-review workshop held at EPA's Environmental Research
Center in Research Triangle Park, NC on May 22-23, 1986.
Dr. Karim Ahmed
Natural Resources Defense Council
122 E. 42nd Street
New York,.NY 10168
Mr. John Bachmann
Ambient Standards Branch (MD-12)
Office of Air Quality Planning and Standards
Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. David Bates
Department of Medicine
St. Paul's Hospital
University of British Columbia
Vancouver, British Columbia
Canada V6Z 1Y6
*Dr. Robert Bechtel
National Jewish Center for Immunology
& Respiratory Disease
1400 Jackson Street
Denver, CO 80206
Dr. Per Camner
The Karolinska Institute
P.O. Box 60400
S-104 01 Stockholm
Sweden
Mr. Jeff Cohen
Ambient Standards Branch (MD-12)
Office of Air Quality Planning and Standards
Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Jack Hackney 213/922-7561
•Room 51
Environmental Health Service
Rancho Los Amigos Hospital
7601 Imperial Highway
Downey, CA 90242
vm
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REVIEWERS (continued)
Dr. Carl Hayes
HERL (MD-55)
Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Ian Higgins
American Health Foundation
320 E. 43rd Street
New York, New York 10017
Dr. Steve Horvath
Prof. Inst. of Eny. Stress
University of California
Santa Barbara, CA 93106
*Dr. Jane Koenig
Dept. of Environmental Health, SC-34
University of Washington
Seattle, WA 98195
Dr. Emmanuel Landau
American Public Health Assoc.
1015 15th Street, N.W.
Washington, DC 20005
Dr. Alan Marcus
Department of Mathematics
Washington State University
Pullman, WA 99164-2930
Dr. Bart Ostro
California Air Resources Board (IPA)
Research Division
1800 15th Street
Sacramento, CA 95812
Dr. Haluk Ozkaynak
KSG-EEPC
Harvard University
79 JFK Street
Cambridge, MA 02138
*Dr. William Pierson
Northwest Asthma & Allergy Center
•4540 Sand Point Way, N.E.
Seattle, WA 98105
IX
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REVIEWERS (continued)
Mr. Larry J. Purdue
EMSL (MD-77)
Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Neil Roth
6115 Executive Blvd.
Rockville, MD 20852
Dr. Neil Schacter
Mt. Sinai Medical Center
24-30 Annenberg
1 Gustave L. Levy Place
New York, NY 10029
*Dr. Dean Sheppard
Cardiovascular Research Institute
University of California
San Francisco, CA 94143
Dr. Frank Speizer
Channing Laboratory
180 Longwood Avenue
Boston, MA 02115
Dr. John Spengler
Harvard School of Public Health
Department of Environmental Science
665 Huntington Avenue
Boston, MA 02115
Dr. David L. Swift
Johns Hopkin University
School of Hygiene
615 N. Wolfe Street
Baltimore, MD 21205
Physiology
^Written reviews only.
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OBSERVER
The following member of the Clean Air Scientific Advisory Committee
(CASAC) of EPA's Science Advisory Board attended the May 22-23, 1986 work-
shop as an observer on behalf of CASAC.
Dr. Timothy Larson
Environmental Engineering and Science Program
Dept. of Civil Engineering EX-100
University of Washington
Seattle, WA 98195
XI
.s
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CHAPTER 1. INTRODUCTION
The United States Clean Air Act and its 1977 Amendments mandate that the
U.S. Environmental Protection Agency (U.S. EPA) periodically review criteria
for National Ambient Air Quality Standards (NAAQS) and revise such standards as
appropriate. The most recent periodic review of the scientific bases under-
lying the NAAQS for particulate matter (PM) and sulfur oxides (SOX) culminated
in the 1982 publication of the EPA document Air Quality Criteria for Particulate
Matter and Sulfur Oxides (U.S. EPA, 1982a), an associated PM staff paper (U.S.
EPA, 1982b) which examined the implications of the revised criteria for the
review of the PM NAAQS, an addendum to the criteria document addressing further
information on health effects (U.S. EPA, 1982c), and another staff paper re-
lating the revised scientific criteria to the review of the SOV NAAQS (U.S. EPA
/\
1982d). Based on the criteria document, addendum and staff papers, revised
24-hr and annual-average standards for PM have been proposed (Federal Register,
1984a) and public comments on the proposed revisions have been received both in
written form and orally at public hearings (Federal Register, 1984b). Consid-
eration of possible revision of the sulfur oxides NAAQS is still under way.
Since preparation of the above criteria document, addendum, and staff
papers (U.S. EPA, 1982a, b, c, d), numerous new scientific studies or analyses
have become available that may have bearing on the development of criteria for
PM or SO and thus may notably impact proposed revisions of those standards now
/\
under consideration by EPA. In December 1985 the Clean Air Scientific Advisory
Committee (CASAC) of EPA's Science Advisory Board met to discuss the PM proposals
and possible implications of the newly available information. CASAC recom-
mended that a second addendum to the 1982 Criteria Document (U.S. EPA, 1982a)
be prepared to evaluate new studies and their implications for derivation of
health-related criteria for the PM NAAQS. In the process of responding to
CASAC's recommendations, the Agency also determined that it would be useful to
examine studies that have emerged since 1982 on the health effects of sulfur
oxides.
1-1
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Accordingly, the present addendum (1) summarizes key findings from the
1982 EPA criteria document and first addendum (U.S. EPA, 1982a,c) as they
pertain to derivation of health-related criteria, and (2) provides an updated
assessment of newly available information of potential importance for deriva-
tion of health criteria for both the PM and SOX standards, with major emphasis
on evaluation of human-health studies published since 1981. Certain background
information of crucial importance for understanding the assessed health effects
findings is also summarized. This includes information on physical and chemi-
cal properties of PM, sulfur oxides, and associated aerosols (including acid
aerosols) and ambient monitoring techniques. However, new studies on associa-
tions between acid aerosols and health effects are being evaluated in a separate
issue paper.
1 1 PHYSICAL AND CHEMICAL PROPERTIES OF AIRBORNE PARTICIPATE MATTER AND
' AMBIENT AIR MEASUREMENT METHODS
As noted in the 1982 EPA criteria document (U.S. EPA, 1982a), airborne
particles exist in many sizes and compositions that vary widely with changing
source contributions and meteorological conditions. However, airborne particle
mass tends to cluster in two principal size groups: coarse particles, general-
ly larger than 2 to 3 micrometers (um) in diameter; and fine particles, gener-
ally smaller than 2 to 3 um in diameter. The dividing line between the coarse
and the fine sizes is frequently given as 2.5 um, but the distinction according
to chemical composition is neither sharp nor fixed; it can depend on the con-
tributing sources, on meteorology, and on the age of the aerosol.
Fine particle volume (or mass) distributions often exhibit two modes.
Particles in the nuclei mode (which includes particles from 0.005 to 0.05 um in
diameter) form near sources by condensation of vapors produced by high tempera-
ture processes such as fossil-fuel combustion. Accumulation-mode particles
(i e those 0.05-2.0 um in diameter) form principally by coagulation or growth
through vapor condensation of short-lived particles in the nuclei mode. Typi-
cally 80 percent or more of the atmospheric sulfate mass occurs in the accu-
' mulation-mode'. Particles in the accumulation mode normally do not grow into
the coarse mode. Coarse particles include re-entrained surface dust, salt
spray, and particles formed by mechanical processes such as crushing and
grinding.
1-2
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Primary particles are directly discharged from manmade or natural sources.
Secondary particles form by atmospheric chemical and physical reactions, and
most of the reactants involved are emitted as gaseous pollutants. In the air,
particle growth and chemical transformation occur through gas-particle and
particle-particle interactions. Gas-particle interactions include condensation
of low-vapor-pressure molecules, such as sulfuric acid (H2$04) and organic
compounds, principally on fine particles. The only particle-particle interac-
tion important in atmospheric processes is coagulation among fine particles.
As shown in Figure 1, fine atmospheric particles mainly include sulfates,
carbonaceous material, ammonium, lead, and nitrate. Coarse particles consist
mainly of oxides of silicon, aluminum, calcium, and iron, as well as calcium
carbonate, sea salt, and material such as tire particles and vegetation-related
particles (e.g., pollen, spores). The distributions of fine and coarse parti-
cles overlap; some chemical species found mainly in one mode may also be found
in the other.
CRUSTAL MATERIAL
(SILICON COMPOUNDS
IRON. ALUMINUM). SEA
SALT, PLANT PARTICLES
SULFATES. ORGANICS.
AMMONIUM. NITRATES.
CARBON. LEAD. AND
SOME TRACE CONSTITUENTS
1 3
Particle Diameter -
100
300
Figure 1. Representative example of typical bimodal mass distribution (measured
by impactors) and chemical composition in an urban aerosol. Although some
overlap exists, note substantial differences in chemical composition of fine versus
coarse modes. Chemical species of each mode are listed in approximate order of
relative mass contribution. Note that the ordinate is linear and not logarithmic.
Source: Modified from Whitby (1975) and NAS (1977).
1-3
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The carbonaceous component of fine particles contains both elemental
carbon (graphite and soot) and nonvolatile organic carbon (hydrocarbons in
combustion exhaust and secondary organics formed by photochemistry). In many
urban and nonurban areas, these species are the most abundant fine particles,
after sulfates. Secondary organic particles form by oxidation of primary
organics by a cycle that involves ozone and nitrogen oxides. Atmospheric
reactions of nitrogen oxides yield nitric acid vapor (HMO,) that may accumulate
as nitrate particles in the fine or coarse modes. Most atmospheric sulfates
and nitrates are water-soluble and tend to absorb moisture. Hygroscopic growth
of sulfate-containing particles markedly affects their size, reactivity, and
other physical properties which influence their biological and physical
effects.
The relative proportions of particles of different chemical composition
and size ranges can vary greatly in ambient air, depending upon emission
sources from which they originate and interactions with meteorological condi-
tions, e.g., relative humidity (RH) and temperature. Particles from combustion
of fossil fuels or high-temperature processes, e.g., metal smelting, tend to
fall in the fine (<2.5 urn) or small coarse mode (<10 um'MMD) range; those from
crushing or grinding processes, e.g., mining operations, tend to be mainly in
the coarse mode (>2.5 urn), with a substantial fraction in excess of 10 urn.
Another important distinction concerning airborne particles is the broad
characterization that can result from different methods commonly used for rou-
tine monitoring purposes. The most commonly used methods for collection and
measurement of airborne particles were described in U.S. EPA (1982a). As noted
there, differences in measurements obtained from various instruments and
methods used to measure PM levels have important implications for derivation of
quantitative dose-response relationships from epidemiologic studies and for
establishing air quality criteria and standards. It is generally not practic-
able to discriminate on the basis of either particle size or chemical composi-
tion when assessing particulate matter data from routine monitoring networks.
Characteristics of the collected samples are dependent on the types of sources
in the vicinity, weather conditions and sampling procedures. Difficulties that
result and limitations of measurements were also discussed in detail in the
1982 EPA criteria document (U.S. EPA, 1982a).
When considering measurements of airborne particles it is essential to
specify the method used and to recognize that results obtained with one method
1-4
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and under a given set of conditions are not necessarily applicable to other
situations. For example, attempts have been made to relate findings based on
smoke measurements (that relate mainly to dark-colored characteristics of
particles from incomplete combustion of coal or other hydrocarbon fuels) to
situations involving total suspended particulate matter (TSP) or size-specific
fractions thereof (measured directly in terms of weight). Because the former
(smoke) methods were used in many early epidemiological studies and the Tatter
are now more often used for monitoring purposes in many countries, conversion
from one type of measurement to the other would be desirable, but for reasons
noted below, there can be no generally applicable conversion factor. Compara-
tive evaluation of the two methods has been undertaken at numerous sites (Ball
and Hume, 1977; Commins and Waller, 1967: Lee et al., 1972), but the results
emphasize that they measure different qualities of the particulate matter and
cannot be directly compared with one another (U.S. EPA, 1982a).
Sampling airborne particles is a complex task because of the wide spectrum
of particle sizes and shapes. Separating particles by aerodynamic size pro-
vides a simplification by disregarding variations in particle shape and relying
on particle settling velocity. The aerodynamic diameter of a particle is not a
direct measurement of its size but is the equivalent diameter of a spherical
particle of specific gravity which would settle at the same rate as the mea-
sured particles. Samplers can be designed to collect particles within sharply
defined ranges of aerodynamic diameters or to simulate the deposition pattern
of particles in the human respiratory system, which exhibits a more gradual
transition from acceptance to exclusion of particles. High-volume (hi-vol)
samplers, dichotomous samplers, cascade impactors, and cyclone samplers are the
most common devices with specifically designed collection characteristics.
These samplers rely on inertia! impaction techniques for separating particles
by aerodynamic size, filtration techniques for collecting the particles and
gravimetric measurements for determining mass concentrations. Mass concen-
trations can also be estimated using methods that measure an integral property
of particles such as optical reflectance, and empirical relationships between
mass concentrations and the integral measurement can be used to predict mass
concentration, if a valid physical model relating to the measurements exists
and empirical data verify the model predictions.
The hi-vol sampler collects particles on a glass-fiber filter by drawing
air through the filter at a flow rate of -1.5 m3/min, and is used to measure
1-5
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total suspended participate matter (TSP). The hi-vol sampler has outpoints of
«25 urn at a wind speed of 24 kph and 45 |jm at 2 kph. Although sampling effec-
tiveness is wind-speed sensitive, no more than a 10 percent day-to-day variabi-
lity occurs for the same ambient concentration for typical conditions. The
hi-vol is one of the most reproducible particle samplers in use, with a typical
coefficient of variation of 3 to 5. One major problem associated with the
glass-fiber filter used on the hi-vol is formation of artifact mass caused by
the presence of acid gases in the air (e.g., artifactual formation of sulfates
o
from SOg), which can add 6 to 7 ug/m to a 24-h sample. The hi-vol has been
the sampler most widely used in the U.S. for routine monitoring and has yielded
TSP mass estimates used in many American epidemiological studies.
Hi-vol samplers with size-selective inlets (SSI) Jiave recently been devel-
oped which collect and measure particles <10 urn or <15 urn. Except for the
inlet, these samplers are identical in design and operation to the TSP hi-vol.
Versions are now being used in epidemiologic health effects studies, and
several models are being evaluated for possible routine monitoring use.
The dichotomous sampler is a low-volume gravimetric measurement device
which collects fine (<2.5 urn) and coarse (>2.5 urn to <10 or 15 urn) ambient
particle fractions. The sampler uses Teflon® filters which minimize artifact
mass formation. The earlier inlets used with this sampler were very wind-speed
dependent, but newer versions are much improved. Because of low sampling flow
rate, the sampler collects submilligram quantities of particles and requires
microbalance analyses, but is capable of reproducibility of +10 percent or
better. The method, however, has only begun to be employed on any major scale
to generate size-selective data on PM mass assessed in relation to health
effects evaluated in epidemiological studies.
Cyclone inlets with cutpoints around 2 urn have long been used to separate
the fine particle fraction, can be used with samplers designed to cover a range
of sampling flow rates and are available in a variety of physical sizes.
Applications of cyclone inlets are found in 10- and 15-um cutpoint inlets for
both dichotomous and hi-vol samplers. Samplers with cyclone inlets could be
expected to have coefficients of variations similar to those of the dichotomous
or SSI hi-vol samplers, and until recently have also found only limited use in
epidemiological studies of PM health effects.
Cascade impactors have been used to obtain mass distribution by particle
size. Because care must be exercised to prevent errors (e.g., those due to
1-6
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particle bounce between stages), these samplers are normally not used as
routine monitors. A study by Miller and DeKoning (1974) comparing cascade
impactors with hi-vol samplers showed inconsistencies in mass collections by
the impactors.
Samplers that derive mass concentrations by analytical techniques other
than direct weight have been used extensively. One of the earliest was the
British smokeshade (BS) sampler, which measures the reflectance of particles
collected on a filter and uses empirical relationships to estimate mass concen-
trations. These relationships are more sensitive to carbon concentrations than
mass (Bailey and Clayton, 1980) and hence are very difficult to interpret as
either total or size-selective PM mass present in the atmosphere. The BS
method and its standard variations typically collect PM with an =4.5 urn DJ-Q
cutpoint under field conditions, with some particles ranging from 7 to 9 urn at
times being collected (McFarland et al., 1982). Thus, even if larger particles
are present in the atmosphere, the BS method collects mainly fine-mode and
small coarse-mode particles. The BS method neither directly measures mass nor
determines chemical composition of collected PM. Rather, it measures light
absorption of particles indicated by reflectance from a stain formed by parti-
cles collected on filter paper. Reflectance of light from the stain depends
both on density of the stain, or amount of PM collected, and optical properties
of collected PM. Smoke particles composed of elemental carbon in incomplete
fossil-fuel combustion products typically make the greatest contribution to
darkness of the stain, especially in urban areas. Thus, the amount of elemen-
tal carbon, but not organic carbon, in the stain tends to be most highly
correlated with BS reflectance readings. Other nonblack, noncarbon particles
also have optical properties which can affect the reflectance readings, but
usually with negligible contribution to optical absorption.
Because the relative proportions of atmospheric carbon and noncarbon PM
can vary greatly from site to site or from one time to another at the same
site, the same absolute BS reflectance reading can be associated with very
different amounts (or mass) of collected particles or even with very different
amounts of carbon. Site-specific calibrations of reflectance readings against
actual mass measurements from collocated gravimetric monitoring devices are
therefore mandatory in order to obtain credible estimates of atmospheric
concentrations of particulate matter based on the BS method, A single calibra-
tion curve relating mass or atmospheric concentration (in pg/m ) of particulate
1-7
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matter to BS reflectance readings obtained at a given site may serve as a basis
for crude estimates of the levels of PM (mainly particles <10 urn) at that site
over time, so long as the chemical composition and relative proportions of
elemental carbon and noncarbon PM do not change. However, the actual mass or
smoke concentration at a given site may differ markedly from values calculated
from a given reflectance reading on either of the two most widely used standard
curves (the British and OECD standard smoke curves). Thus, much care must be
taken in interpreting the meaning of any BS value reported in terms of ug/m ,
and such "nominal" expressions of airborne particle concentrations are not
meaningful unless related to direct determinations of mass by gravimetric
measurements carried out at the same geographical location and close in time to
the BS readings.
The AISI light transmittance method is similar in approach to the BS
technique, collects particles with a D5Q cutpoint =5.0 urn aerodynamic diameter,
uses an air intake similar to that of the BS method, and has been used for
routine monitoring in some American cities. Particles are collected on a
filter-paper tape periodically advanced to allow accumulation of another stain,
opacity of the stain is determined by transmittance of light through the
deposited material and tape, and results are expressed in terms of optical
density or coefficient of haze (CoH) units per 1000 linear feet of air sampled
(rather than mass units). Readings of COH units are more responsive to non-
carbon particles than are BS measurements, but again, the AISI method does not
directly measure mass or determine chemical composition of collected particles.
o
Attempts to relate COH to ug/m also require site-specific calibration of COH
readings against mass measurements determined by a collocated gravimetric
device, but the accuracy of such mass estimates are subject to question.
Since the hi-vol method collects particles much larger than those collec-
ted by BS or AISI methods, intercomparisons of PM measurements by the BS or
AISI methods to equivalent TSP units, or vice versa, are very limited. For
example, as shown by several studies, no consistent relationship exists between
BS and TSP measurements taken at various sites or at the same site during
various seasons. One exception is the relationship observed between BS and TSP
'during severe London air pollution episodes when low wind-speed conditions
caused settling out of larger coarse-mode particles. Because fine-mode particles
predominated, TSP and BS levels (in excess of ~500 ug/m3) tended to converge,
as expected if mainly fine-mode particles were present.
1-8
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Many analytical techniques are available to determine chemical properties
of particles collected on a suitable substrate. Most of the techniques, such
as those for elemental sulfur, have been shown to be more precise than the
analyses for gravimetric mass concentration. Methods are available that
provide reliable analyses for sulfates, nitrates, organic fractions, and
elemental composition (e.g., sulfur, lead, silicon), but not all analyses can
be used for all particle samples because of factors such as incompatible
substrates or inadequate sample size. Results can be misinterpreted when
samples have not been appropriately segregated by particle size and when
artifact mass is formed on the substrate rather than collected in particulate
form, e.g., positive artifacts likely in nitrate and sulfate determinations (as
noted below).
1.2 PHYSICAL/CHEMICAL PROPERTIES OF SULFUR OXIDES AND THEIR TRANSFORMATION
PRODUCTS AND AMBIENT MEASUREMENT METHODS
The only sulfur oxide that occurs at significant concentrations in the
atmosphere is sulfur dioxide, one of the four known gasrphase sulfur oxides
(sulfur monoxide, sulfur dioxide, sulfur tn'oxide, and disulfur monoxide). As
discussed in U.S. EPA (1982a), sulfur dioxide is a colorless gas detectable by
taste at levels of 1000 to 3000 yg/m3 (0.35-1.05 ppm). Above 10,000 ug/m3 (3.5
ppm), it has a pungent irritating odor.
As also discussed in U.S. EPA (1982a), S02 is mainly removed from the
atmosphere by gaseous, aqueous, and surface oxidation to form acidic sulfates.
Gas-phase oxidation of S02 by the hydroxyl (OH) radical is well understood; not
so well understood, however, is oxidation of S02 by hydroperoxyl (H02) and
methyl peroxyl (CH302) radicals. The ready solubility of S02 in water is due
mainly to formation of bisulfite (HS03~) and sulfite (SOj2-) ions, which are
easily oxidized to form acidic sulfates by reacting with catalytic metal ions
and dissolved oxidants. Sulfur dioxide reacts on the surface of a variety of
airborne solid particles, such as ferric oxide, lead dioxide, aluminum oxide,
salt, and charcoal. '
Sulfur trioxide (S03), which can be emitted into the air directly or
result from reactions mentioned earlier, is a highly reactive gas. In the
presence of moisture in the air, it is rapidly hydrated to form sulfuric acid.
In the air, then, it is sulfuric acid in the form of an aerosol that is found
1-9
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rather than S03, and it is generally associated with other pollutants in
droplets or solid particles of widely varying sizes. The acid is strongly
hygroscopic, and droplets containing it readily take up further moisture from
the air until they are in equilibrium with their surroundings. If any ammonia
is present, it reacts with sulfuric acid to form various ammonium sulfates,
which continue to exist as an aerosol (in droplet or crystalline form, depend-
ing on the relative humidity).
The sulfuric acid may also react further with other compounds in the air
to produce other sulfates. Some sulfates reach the air directly from combus-
tion or industrial sources, and near oceans, sulfates exist in aerosols gene-
rated from ocean spray. As discussed in U.S. EPA (1982a), sulfate particles
fall mainly in the fine-mode (<2.5 urn) size range. These particles, in the
presence of moisture in air, combine with water to form coarse-mode aerosols
(i.e., >2.5 urn).
Many sulfur compounds are present in the complex mixture of urban air
pollutants. Some are naturally occurring and some are manmade. Total biogenic
sulfur emissions in the United States have been estimated to be in the range of
5 to 6 million metric tons annually. Additional contributions from coastal and
oceanic sources may also be significant. Anthropogenic (manmade) sources are
estimated to emit about 26 to 27 million metric tons of SOX (mostly S02)
annually in the United States. Most manmade sulfur oxide emissions are from
stationary point sources; over 90 percent of these are S02 and the rest are
sulfates.
Once S02 is emitted into the lower atmosphere, maintenance of a tolerable
environment depends on the ability of wind and turbulence to disperse the
pollutants. Factors affecting the dispersion of S02 from combustion sources
include (1) temperature and efflux velocity of the gases, (2) stack height, (3)
topography and the proximity of other buildings, and (4) meteorology. Some of
the S02 emitted into the air is removed unchanged onto various surfaces,
including soil, water, grass and vegetation. The remaining S02 is transformed
into sulfuric acid or other sulfates by various processes in the presence of
moisture, and.these transformation products are then removed by dry deposition
'processes or by precipitation. The relative proportion of S02 and its trans-
formation products resulting from atmospheric processes varies with increasing
distance from emission sources and residence time (age) in the atmosphere.
With long-range transport (over hundreds or thousands of kilometers), extensive
1-10
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transformation of S02 to sulfates occurs, with dry deposition of acidic sulfates
or their wet depositon in rain or snow contributing to acidic precipitation
processes.
The most commonly used collection and measurement methods for sulfur
oxides were described in the 1982 EPA criteria document (U.S. EPA,. 1982a). A
clear understanding of the underlying bases and limitations of particular
methods is essential for adequate interpretation of epidemiological studies
discussed later. If S02 were the only contaminant in air, all measurement
methods for that gas would give comparable results, indicating the true concen-
tration of S02. In typical urban environments, however, other pollutants are
always present and although sampling procedures can be arranged to minimize
interference from particulate matter by first filtering the air, errors still
arise due to other gases and vapors. Thus, variations in specificity and
accuracy of methods must be taken into account in comparing results from
various studies.
Methods for measurement of SOp include (1) manual methods, which involve
collection of the sample over a specified time period and subsequent analysis
by a variety of analytical techniques, and (2) automated methods, in which
sample collection and analysis are performed continuously and automatically.
In the most commonly used manual methods, the analyses of the collected samples
are based on colorimetric, titrimetric, turbidimetric, gravimetric, x-ray fluo-
rescent, chemiluminescent, and ion exchange chromatographic measurement prin-
ciples. : "/
The most widely used manual method for determination of atmospheric SO,, is
the West-Gaeke pararosaniline method. An improved version of this colorimetric
method, adopted in 1971 as the U.S. EPA reference method, can measure ambient
o
S02 at levels as low as 25 ug/m (0.01 ppm) with 30 min to 24 hr sampling time.
The method has acceptable specificity for S02, if properly implemented; how-
ever, samples collected in tetrachloromercurate(II) can undergo temperature-
dependent decay leading to the underestimation of ambient S02 concentrations.
A variation of the method uses a buffered formaldehyde solution for sample
collection, reducing the temperature-dependent decay problem. Certain American
'epidemiological studies employed the West-Gaeke or other variations of the
pararosaniline method.
A titrimetric (acidometric) method, whereby S02 is collected in dilute
hydrogen peroxide and the resultant H2SO, is titrated with standard alkali, is
1-11
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the standard method mainly used in Great Britain and by the Organization for
Economic Cooperation and Development (OECD). The method requires long sampling
times (24 h), is subject to interference from atmospheric acids and bases, and
can be affected by errors due to evaporation of reagent during sampling,
titration errors, and alkaline contamination of glassware. It has been used to
provide aerometric S0« estimates reported in many British and European epidemi-
ological studies.
Some other methods use alkali-impregnated filter papers for collection of
S02 and subsequent analysis as sulfite or sulfate. Most involve extraction
prior to analysis; but nondispersive x-ray fluorescence allows direct measure-
ment of S0« collected on sodium carbonate-impregnated membrane filters. These
methods have not been widely used for routine air monitoring or epidemiological
studies.
Two of the most sensitive methods for measuring SQ2 are based on chemilu-
minescence and ion exchange chromatography. With the former, SO,, is absorbed
in a tetrachloromercurate solution and then oxidized with potassium permanga-
nate; oxidation of the absorbed S0« is accompanied by chemiluminescence de-
tected by a photomultiplier tube. With the latter, ion exchange chromatography
can be used to determine ambient levels of S02 absorbed into dilute hydrogen
peroxide and oxidized to sulfate, or S02 absorbed into a buffered formaldehyde
reagent. These methods have not yet been widely employed for routine monitor-
•^
ing uses.
Sulfation methods, based on reaction of airborne sulfur compounds with
lead dioxide paste to form lead sulfate, have been used both in the United
States and Europe to estimate ambient S02 concentrations over extended time
periods. However, data obtained by sulfation methods are affected by many
physical and chemical variables and other interferences (such as wind speed,
temperature, and humidity); and they are not specific for S02, since sulfation
rates are also affected by other airborne sulfur compounds (e.g., as sulfates).
Thus, although sulfation rates (mg S03/100 cm2/day) have been converted to
rough estimates of S02 levels (in ppm), these cannot be accepted as accurate
measurements of atmospheric S02 levels. This is notable here because lead
dioxide gauges provided estimates of S02 data used in some pre-1960s British
epidemiological studies and also in some American epidemiologic studies.
Automated methods for measuring ambient S02 levels have been widely used
for air monitoring. Some early continuous S0*2 analyzers, based on conductivity
1-12
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and coulometry, were subject to interference by many ambient air substances.
More recent commercially available analyzers using these measurement principles
exhibit improved specificity for SO^ through incorporation of sophisticated
chemical and physical scrubbers.
Continuous SO^ analyzers that use flame photometric detection (FPD),
fluorescence, or seconds-derivative spectrometry are now commercially available.
The FPD method involves measurement of the band emission of excited S02
molecules formed from sulfur species in a hydrogen-rich flame and can exhibit
high sensitivity and fast response, but must be used with selective scrubbers
or coupled with gas chromatographs to achieve high specificity. Fluorescence
analyzers detect characteristic fluorescence of the SQy molecule when irra-
diated by UV light, have acceptable sensitivity and response times, are in-
sensitive to sample flow rate, and require no support gases. However, they can
be affected by interference due to water vapor (quenching effects) and certain
aromatic hydrocarbons and must employ ways to minimize such effects. Second-
derivative spectrometry can provide highly specific measurement of SO* in the
air, with continuous analyzers based on this principle being insensitive to
sample flow rate and requiring no support gases. U.S. EPA has designated con-
tinuous analyzers based on many of the above principles (conductivity, coulome-
try, flame photometry, fluorescence, and second-derivative spectrometry) as
equivalent methods for measurement of atmospheric SC^.
Two main methods have been used to measure total water-soluble, sulfates
collected on filters along with other suspended particulate matter. With the
turbidimetric method, samples are collected on sulfate-free glass fiber or
other efficient filters, the sulfate is extracted and precipitated with barium
chloride, and the turbidity of the suspension is measured spectrophotometrically.
Samples are normally collected over 24-h periods by hi-vol sampler. However,
no distinction can be made between sulfates and sulfuric acid present in the
air and collected on the filters; and some material present as acid in the air
may be converted to neutral sulfate on the filter during sampling. With the
methyl thymol blue method, samples are collected as in the turbidimetric method
and the extract is reacted with barium chloride, but the barium remaining in
solution is then reacted with methylthymol blue and the sulfate determined
colorimetrically by measurement of uncomplexed methylthymol blue. This modifi-
cation allows the procedure to be automated, but the same limitations -as noted
1-13
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for the turbidimetric method apply, including lack of distinction between
sulfates and sulfuric acid.
As for sulfuric acid, no fully satisfactory method exists for its measure-
ment in the presence of other pollutants in the air, but some procedures exist
for examining acidic properties of suspended particles or acid aerosols in
general. Almost all of the strong acid content of ambient aerosols consists of
sulfuric acid (HpSO.) and its partial atmospheric neutralization product,
ammonium bisulfate (NH^HSO^); however, ammonium sulfate [(NH.^SO^], the final
neutralization product, is only v/eakly acidic. Nitric acid (HN03) and hydro-
chloric acid (HC1) are other strong acids found in the ambient air (mainly as
vapors or, when incorporated into fog droplets, as constituents of acid
aerosols). Ambient air acidic aerosol concentrations can be expressed in terms
+ 3 3
of umols H /m or as H2S04 equivalent in ug/m (at 98 ug/umol). Unfortunately,
no systematic surveys of average acid aerosol concentrations in United States
airsheds were available at the time the 1982 EPA criteria document (1982a) was
prepared, nor is such systematic survey information available for more current
acidic aerosol levels. However, Lioy and Lippmann (1985) have recently sum-
marized some of the highest levels reported for recent years in North America,
including levels in the range of 20 to 30 ug/m H2S04 (1 hr mean). This is in
contrast to the highest level (680 ug/m H2S04 1 hr mean) recorded in the
United Kingdom in London in 1962 and even higher levels almost certainly
present during earlier London air pollution episodes.
1.3 KEY AREAS ADDRESSED IN EMERGING NEW HEALTH EFFECTS DATA
Important new health effects information has emerged in three main areas
since preparation of the 1982 EPA criteria document and addendum: (1) new data
which permit more definitive characterization of respiratory tract deposition
patterns for inhaled particles of various size ranges, e.g., fine-mode (<2.5
urn) vs. larger coarse mode particles (>2.5 urn, <10 pm, <15 urn, etc.); (2) new
reanalyses of certain key British epidemiology studies, which used BS methods
for measuring PM levels, and additional new epidemiologic studies, employing
other non-gravimetric or gravimetric PM measurement methods, that assess health
effects associated with exposures to PM and SO in contemporary urban airsheds
J\
of the 1970s and 1980s; and (3) new controlled human exposure studies which
1-14
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more precisely define exposure-response relationships for pulmonary function
decrements and respiratory symptoms due to acute SC exposure.
1-15
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CHAPTER 2. RESPIRATORY TRACT DEPOSITION AND FATE
2.1 RESPIRATORY TRACT DEPOSITION AND FATE OF INHALED AEROSOLS
As discussed in U.S. EPA (1982a), the respiratory system is the major
route of human exposure to airborne suspensions of particles (aerosols) and
gases such as S02- In inhalation toxicology, deposition refers to removal from
inspired air of inhaled particles or gases by the respiratory tract and the
initial regional pattern of these deposited materials. Clearance refers to
subsequent translocation (movement of material within the lung or to other
organs), transformation, and removal of deposited substances from the respira-
tory tract. It can also refer to removal of reaction products formed from SOp
or particles. Retention refers to the temporal pattern of uncleared deposited
particulate materials or gases and reaction products. These phenomena are
complicated by interactions that occur among particles, gases such as S0? or
endogenous ammonia, and water vapor in the airways.
Deposition patterns of inhaled aerosols and gases are affected by physical
and chemical properties, e.g., aerosol particulate size distribution, density,
shape, surface area, electrostatic charge, hygroscopicity or deliquescence,
chemical composition, gas diffusivity and solubility, and related reactions.
The geometry of the respiratory airways from nose and mouth to the lung
parenchyma also influences aerosol deposition; important morphological parame-
ters include diameters, lengths, inclinations to vertical, and branching angles
of airway segments. Physiological factors that affect deposition include
breathing patterns, respiratory tract airflow dynamics, and variations of
relative humidity and temperature in the airways. Clearance from the respira-
tory tract depends on many factors, including site of deposition, chemical
composition and properties of deposited particles, reaction products, muco-
ciliary transport in the tracheobronchial tree, macrophage phagocytosis, and
pulmonary lymph and blood flow. An understanding of respiratory tract anatomy
and regional deposition and clearance of particles is essential for interpreta-
tion of the results of health effects studies discussed later.
2-1
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The respiratory tract includes the passages of the nose, mouth, nasopharynx,
oropharynx, epiglottis, larynx, trachea, bronchi, bronchioles, and small ducts
and alveoli of the pulmonary acini. In regard to respiratory -tract deposition
and clearance of inhaled aerosols, three main regions can be considered: (1)
the extrathoracic (ET) region, which includes the airways extending from the
nares down to the epiglottis and larynx at the entrance to the trachea (the
mouth is included in this region during mouth breathing); (2) the tracheo-
bronchial (TB) region, which includes the primary conducting airways of the
lung from the trachea to the terminal bronchioles (i.e., that portion of the
lower respiratory tract having a ciliated epithelium); and (3) the pulmonary
(P) region, which consists of the parenchyma! airspaces of the lung, including
the respiratory bronchioles, alveolar ducts, alveolar sacs, atria, and alveoli
(i.e., the gas-exchange region). The extrathoracic region, as defined above,
corresponds exactly to the nasopharynx, as defined by the International
Commission on Radiological Protection (ICRP) Task Group on Lung Dynamics
(Morrow et a!., 1966). The thoracic region corresponds to that portion of the
respiratory tract distal to, and including, the trachea (i.e., TB + P).
As discussed in U.S. EPA (1982a), evaluation of 'mechanisms by which
inhaled particles ultimately affect human health requires recognition of the
importance of deposition and clearance phenomena in the respiratory tract.
Major regions of the respiratory tract differ markedly in structure, size,
function, and sensitivity or reactivity to deposited particles. They also have
different mechanisms-for particle elimination or clearance.
The 1982 EPA criteria document depicted available experimental deposition
data for total and regional deposition in a series of figures (i.e., Figures
11-3 to 11-9 of U.S. EPA, 1982a). Curves for alveolar deposition and estimates
of tracheobronchial deposition, along with an extrapolation of the upper bound
of the TB curve to the point predicted by Miller et al. (1979), are reproduced
here in Figure 2. Added to the figure are the more recent data of Svartengren
(1986), Heyder (1986), and Emmett et al. (1982) for deposition of particles >10
urn in aerodynamic diameter (DQe) in healthy adult subjects breathing through a
mouthpiece..
In the studies reported by Heyder (1986), mean inspiratory flow rates of
250 and 750 cm3s"1 were used with a four-second breathing cycle, resulting in
minute ventilations of 7.5 and 22.5 L min"1, respectively. At the higher flow
rate, TB deposition of 10 urn Dae particles was 0.14; fractional deposition for
2-2
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1.0
cc
LL
o
o_
111
O
0.8
0.7
z
o
ir 0.6
ESTIMATE OF ALVEOLAR DEPOSITION, NOSE BREATHING
| RANGE OF TRACHEOBRONCHIAL DEPOSITION,
I MOUTH BREATHING
" EXTRAPOLATION OF ABOVE TO POINT ( gS ) PREDICTED
BY MILLER et al., (1979)
-Q9 EMMETT et al. (1982); 337 cm3 s'1, 6s BREATHING CYCLE /g
n« ucvncR (19RB): 750 cm3 s'1. 4s BREATHING CYCLE jK-V.
—I 1—I I I I I I
RANGE OF ALVEOLAR DEPOSITION,
MOUTH BREATHING
i_iviivib.i • **fc "•• \ i w*. — it — T< —*•• — '
QB HEYDER (1986); 750 cmi? s], 4s BREATHING CYCLE
A A HEYDER (1986); 250 cm3 s'1, 4s BREATHING CYCLE
0.5 —O^ SVARTENGREN (1986)
OPEN SYMBOLS: TRACHEOBRONCHIAL DEPOSITION
SOLID SYMBOLS: ALVEOLAR DEPOSITION
0.3 0.4 0.5
2.0 3.0 4.0 5.0
PHYSICAL DIAMETER,
AERODYNAMIC DIAMETER, p.m
10 121416 20
Figure 2 Regional deposition of monodisperse aerosols by indicated particle diameter for mouth
breathing (alveolar, tracheobronchial) and nose breathing (alveolar). The alveolar band indicates
the range of results found by different investigators using different subjects and flow parameters
for alveolar deposition following mouth breathing. Variability is also expected following nasal
inhalation The tracheobronchial band indicates intersubject variability in deposition over the
range of sizes as measured by Chan and Lippmann (1980). Deposition is expressed as fraction
of particles entering the mouth (or nose). Also shown is an extrapolation of the upper bound of
the TB curve to the point predicted by Miller et at. (1979). The extrapolation illustrates the hkely
shape of the curve in this size range but is uncertain. However, the data of Emmett et al. (1982),
Heyder (1986), and Svartengren (1986) tend to substantiate this extrapolation. In the Svartengren
(1986) studies, subjects took maximally deep inhalations at a flow of 500 cnr* s''.
2-3
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12 pm D particles was 0.09. In contrast, the lower flow rate yielded deposi-
tion fractions of 0.17 and 0.12, respectively, for 10 pm and 12 pm Dae
particles. Emmett et al. (1982) observed an average TB deposition of 0.36 in
three subjects who inhaled 10 |jm Dao particles at a mean inspiratory flow rate
O 1 ClG _ "I
of 337 cm s with 10 breaths/min (i.e., minute ventilation of 10.1 L min ).
Under these breathing conditions the alveolar region deposition fraction for 10
pm particles averaged 0.06.
The deposition of 11.5, 13.7, and 16.4 pm DQe particles was studied by
Svartengren (1986) using a different exposure regime. Subjects took four
maximally deep inhalations at a flow of 500 cms from a glass bulb apparatus
each time particles were sprayed up into the bulb. Exposure times varied from
2 to 5 min. Six subjects were studied at the 11.5 and 13.7 pm sizes, while
five subjects were studied at 16.4 urn Dae. The average alveolar deposition
fraction was 0.01 at the largest particulate size and 0.04 at the 11.5 and 13.7
pm sizes. By subtracting alveolar deposition from the measured total lung
deposition, the average TB deposition fractions of the 11.5, 13.7, and 16.4 pm
D particles were 0.27, 0.17, and 0.12, respectively. The data of Svartengren
36
(1986), along with the data of Heyder (1986) and Emmett et al. (1982), tend to
substantiate the extrapolation of the upper bound of the TB curve in Figure 2
to the point predicted by Miller et al. (1979).
Numerous subject-related and environmental factors can influence deposi-
tion and clearance of aerosols, including inhalation patterns (rate and route),
airway dimensions in relation to pulmonary function measurements, disease
state, particle composition, and the presence of pollutant gases. Detailed
discussion of effects of such factors on deposition patterns is beyond the
scope of this addendum (for more details, see U.S. EPA, 1982a,b; Lippmann et
al., 1980; Garrard et al., 1981; Svartengren et al., 1986; Lippmann and
Schlesinger, 1984). However, the results of Heyder et al. (1982) on the
biological variability of particulate deposition in controlled and spontaneous
mouth breathing are of interest since this was an important issue raised in the
1982 EPA criteria document. Using both breathing patterns and particulate
sizes ranging, from 1 to 7pm D , they studied total deposition and deposition
'rate in 20 subjects. The variability of deposition rate between subjects
spontaneously breathing the same aerosol is associated with morphological and
physiological factors but is mainly governed by physiological factors (i.e.,
primarily individual flow rate). Heyder et al. (1982) contend that this type
2-4
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of variability is the most important when considering health-related issues of
inhaled particulate matter.
Data on respiratory tract deposition can be used to provide an evaluation
of deposition of typically observed ambient particulate distributions. The
similarity of experimental deposition data from human subjects breathing
monodisperse aerosols in a laboratory setting to the general population breath-
ing multimodal urban aerosols was examined in studies published after prepara-
tion of the 1982 EPA criteria document (U.S. EPA, 1982a). Miller et al. (1982)
studied total respiratory tract deposition in five subjects using a mixture of
monodisperse polystyrene latex spheres 0.6, 1, and 2 tim in size. Their experi-
mental results suggest that the deposition of mixed monodisperse and monodis-
perse single aerosols is similar for fine particles. However, the theoretical
modeling of Diu and Yu (1983) indicate that the regional deposition patterns of
polydisperse aerosols can be quite complex. They assumed a log. normal size
distribution and studied total and regional deposition with nasal and mouth
breathing for geometric standard deviations (a ) of 1.0 (monodisperse), 1.5,
2.5, and 3.5. The results of Diu and Yu (1983) support the observation of
Morrow (1981) that the mass deposition of mono- and polydisperse aerosols
differs little if a <2. .Typically, a values reported for distribution of
urban and rural aerosols is usually around 2 (see Chapter 5, U.S. EPA, 1982a).
In the theoretical studies of Diu and Yu (1983), larger values of ag are pre-
dicted to impart significant complexities in regional deposition patterns due
to competing mechanisms interacting with the sequential filtering effect of the
respiratory tract.
Over half of the total mass of a typical ambient mass distribution would
be deposited in the extrathoracic region, most of this being coarse particles,
during normal nasal breathing (see Chapter 11 of U.S. EPA, 1982a). Clearance
of most of this material to the esophagus would occur within minutes. Some
fraction of the hygroscopic fine mass (e.g., sulfates and nitrates that grow to
2-4 urn in the respiratory tract) might also be deposited and dissolve in the
extrathoracic region. Smaller fractions of both the hygroscopic and non-
hygroscopic fine particles (mostly <1 urn) would be deposited in the tracheo-
bronchial and alveolar regions, respectively. Clearance of hygroscopic
material by dissolution and reaction would be relatively rapid in both regions.
Clearance of insoluble coarse-mode substances would increase from less than an
2-5
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hour for the larger particles deposited in the upper portion of the tracheo-
bronchial region to as much as a day for that deposited more distally.
Insoluble fine and coarse particles deposited in the alveolar region have
clearance half-times varying from weeks to years for the fast phase and slow
phase, respectively.
With mouth-only breathing, the regional deposition pattern changes mark-
edly, with extrathoracic deposition reduced and both tracheobronchial and pul-
monary deposition enhanced. Extrathoracic deposition, although reduced, still
would be dominated by coarse mode aerosols and contain little fine-mode contri-
bution. Endogenous ammonia in human airways may, however, reduce the deposi-
tion of acid aerosols (U.S. EPA, 1982b). Remaining non-hygroscopic fine
particle deposition efficiency would change little over nasal breathing (<20
percent).
In essence, regional deposition of ambient particles in the respiratory
tract does not occur at divisions clearly corresponding to atmospheric aerosol
distributions. Coarse-mode and hygroscopic fine-mode particles are deposited
in all three regions. A fraction (5 to 25 percent) of the. remaining fine-mode
particles (e.g., organics and carbon not associated with hygroscopic material)
is deposited in the tracheobronchial/alveolar regions. With mouth-only breath-
ing, as illustrated in Figure 2, little particulate mass in excess of 15 pro is
deposited in the thoracic region, and little mass greater than 10 urn is
deposited in the alveolar region.
Oronasal breathing (partly via the mouth and partly nasally) typically
occurs for healthy adults while undergoing moderate to heavy exercise. Swift
and Proctor (1982) computed deposition for oronasal breathing as a function of
particulate size, correcting for deposition in the parallel nasal and oral
airways, and compared these results to those for mouth breathing via tube.
Using minute ventilations of 24.5 and 15 Lmin , their analyses predicted that
total thoracic deposition at all sizes is more or less essentially the same as
for pulmonary deposition noted above for mouth only breathing, i.e., with very
few particles over 10 pm D in size being likely to reach tracheobronchial
regions. Trac'heobronchial deposition with oronasal breathing at a higher
minute ventilation (45 Lmin"1) has been examined by Miller et al. (1984). Data
for extrathoracic and tracheobronchial deposition were fit to logistic regres-
sion models yielding significantly improved fits of the deposition data. As
done by Swift and Proctor (1982), a 50/50 split in airflow between the nasal
2-6
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and oral pathways was assumed. Simulated oronasal breathing at a minute
ventilation of 45 Lmin resulted in tracheobronchial deposition fractions of
0.21, 0.17, 0.14 and 0.09 for particles of 8, 9, 10, and 12 urn in aerodynamic
diameter, respectively. When the experimental deposition data of Heyder
(1986), separately for nasal and oral breathing, are combined to simulate
oronasal breathing, the results are in agreement with the analyses of Miller et
al. (1984).
More recently, thoracic deposition and its component parts have been
examined by Miller et al. (1986), as a function of particulate size, for
ventilation rates ranging from normal respiration to heavy exercise in individ-
uals who, as per Niinimaa et al. (1981), habitually breathe oronasally (mouth
breathers) and in those who normally employ oronasal breathing when minute
ventilations exceed about 35 Lmin" (normal augmenters),, Published data from
various laboratories for ET and TB deposition, along with previously unpub-
lished data of Lippmann and co-workers at New York University, were fit to
logistic regression models prior to examining the influences of breathing mode
and activity level on TB, P, and thoracic (TB + P) deposition. For the ET
region, an impaction parameter was used that was a function of aerodynamic
diameter and inspiratory flow rate, and the logistic models provided signifi-
cantly improved fits of the nasal and oral inspiration data compared to the
linear models of Yu et al. (1981) that also used an impaction parameter and
that formed the basis of the Swift and Proctor (1982) analyses. Since TB
deposition is due primarily to inertia! impaction in the upper airways and to
sedimentation in the lower airways, the logistic analysis for the TB region was
based upon aerodynamic diameter rather than on an impaction parameter. The
proportionality of airflow between the nose and mouth as a function of activity
level was determined from Figure 2 of Niinimaa et al. (1981).
Thoracic deposition results given by Miller et al. (1986) are shown in
Figure 3, along with the thoracic deposition results of Swift and Proctor
(1982). With minute ventilations (V£) of 40 or 60 Lmin"1 (panel A), there is
not much difference between normal augmenters and mouth breathers in thoracic
deposition for Dge beyond the peak of the deposition curve. For vV less than
'35 Lmin" , the Miller et al. (1986) analyses-result in substantially lower
deposition in normal augmenters compared to mouth breathers. As vV increases,
thoracic deposition for normal augmenters initially decreases for a given D ,
06
increases through the oronasal switching point, and then decreases. For mouth
2-7
-------
breathers, however, there are minimal changes in thoracic deposition at lower
ventilation rates with monotonic declines in deposition as vV increases beyond
30 train"1.
Swift and Proctor (1982) computed bands of total thoracic deposition as a
fraction of particles entering the mouth and nose during oronasal and oral
breathing, using vV of approximately 24.5 Lmin and 15 Lmin , respectively.
The shaded area of Panel B (Figure 3) represents a composite of these data
based on the lower band of the low vV and the upper band of the higher vV.
While neither Swift and Proctor (1982) nor the U.S. EPA (1982a,b) extended the
bands for TB deposition beyond 8 urn, some thoracic deposition could be projec-
ted for 10 to 15 ug particles with oronasal breathing. More recent experi-
mental data utilized in Miller et al. (1986) indicate that there is a gradual
decline in thoracic deposition for large particulate sizes and that there can
be significant deposition of particles greater than 10 urn, particularly for
mouth breathers.
It should be noted that the deposition studies cited previously all used
adult subjects, yet many of the epidemiology studies cited in the PM/SO
• /\
criteria document (U.S. EPA, 1982a) and in this addendum report effects
observed in children. Anatomical and functional differences between adults and
children are likely to yield complex interactions with the major mechanisms
affecting respiratory tract deposition. In a study of over 1800 Mexican-
American, white, and black children 7 to 20 years of age, Hsu et al. (1979)
found significant differences of lung volume and flow rate among the three
races, and between male and female subjects. Further analyses of these data by
Hsi et al. (1983) demonstrated that using sitting height as a predictor greatly
reduced the racial differences of ventilatory function and allowed the applica-
tion of a single set of prediction equations for children of all three groups.
Other studies are available on normal pulmonary function values (Swiniarski et
al., 1982), intrasubject variability (Hutchinson et al., 1981), influence of
physical performance capacity on the growth of lung volumes (Anderson et al.,
1984), and postnatal growth and size of the pulmonary acinus (Osborne et al.,
1983).
To date, experimental deposition data in children's lungs are not avail-
able. Analogous to the development of mathematical models for deposition in
adults, the thrust for age-dependent dosimetry modeling has been from
2-8
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0.5
0.4
O
80.3
o.
LU
Q
O
§0.2
ec
O
X
0.1
'A
obi.
I I I I Mill 1 I I IlltU
MOUTH BREATHERS
—— NORMAL AUGMENTERS
J I I I
JtU
i mm
\\
i i i-ni-ri
1.0
10.0 1001.0
AERODYNAMIC DIAMETER,
10.0
100
Figure 3. Estimates of thoracic deposition of particles between 1 and 15 jum by Miller et al. (1986)
for normal augmenters (solid lines) and mouth breathers (broken lines) are shown for minute venti-
lation (VE) exceeding the switch point of 35 L min'1 (A) and for lower ^g (B). Normal augmenters
are individuals who normally use oronasal breathing to augment respiratory airflow when ^E exceeds
about 35 L min'T, while mouth breather refers to those individuals who habitually breathe oronasally
(Niinimaa et al., 1981). The shaded area (B) is a composite of the .computed bands of thoracic depo-
sition of particles less than 8 /urn by Swift and Proctor (1982) for Vg of approximately 24.6 and 15
L min"'.
2-9
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scientists dealing primarily with radiological protection issues (Hofmann et
al., 1979; Hofmann, 1982a,b; Crawford, 1982). More recently, Phalen et al.
(1985) have studied the postnatal enlargement of human tracheobronchial airways
and its implication for the deposition of particles ranging from 0.05 to 10 urn
in size. They made some morphometric measurements in replica lung casts of
people aged 11 days to 21 years. The model predictions for deposition during
inspiration only were computed for three states of physical exertion — low
activity, light exertion, and heavy exertion. Scaling techniques were employed
to make age-dependent adjustments from adult flow rates.
While the predictions of Phalen et al. (1985) indicate that, in general,
increasing age is associated with decreasing particulate deposition efficiency,
high flow rates and large particulate sizes do not exhibit consistent age-
dependent differences. Since ^E at a given state of activity is approximately
linearly related to body mass, children will inhale more air per unit body
mass, resulting in higher TB doses. For resting ventilation, this age-related
dose effect, as a function of particulate size, is illustrated in Figure 4.
While children may be at greater risk than adults from exposure to particulate
matter on the basis of deposition during inspiration, information is needed on
possible age-dependent differences in ET deposition, deposition over the entire
breathing cycle, mucociliary clearance, and tissue sensitivity, to put this
risk into perspective relative to health effects evaluations.
Other deposition characteristics of individuals and atmospheric distribu-
tions (as well as other factors) can cause variations in regional deposition.
The following examples illustrate potentially important variations in exposure/
deposition patterns:
(1) The peak in alveolar deposition efficiency for nasal and mouth-only
breathing (Figure 2) tends to occur at or near the normal minimum in the ,
bimodal distribution (2 to 4 pm MMAD). However, near emission sources or in
other polluted conditions, substantial increases can occur in the coarse- or
fine-mode contribution to this most efficiently deposited range.
(2) The deposition of both coarse and fine particles in the tracheobron-
chial region can be increased over normal ranges by increased breathing rates
during exercise and by cigarette smoking, in both bronchitic and asthmatic
subjects, generally reducing alveolar deposition. Since retention of particles
at 24 hr was significantly lower when bronchoconstriction was induced before
2-10
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4
T
AGE - YEARS
8 10 12
14
r
16
T
18
0.00
10
20 30 40
BODY MASS -KG
60
Figure 4. Predicted initial dose to the TB region as a
function of body mass. Assumptions include equivalent
upper airway deposition for all ages, inhalation of
particles at 1 mg/m3 concentration in air, and resting
minute ventilation.
Source: From Phalen et al. (1985).
2-11
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inhalation of particles than when bronchoconstriction was induced after inhala-
tion, Svartengren et al. (1984) postulated that bronchoconstriction may serve
as a defense mechanism for the alveolar region. However, enhanced tracheo-
bronchial deposition may not be protective, especially for disease states
(e.g., bronchitis) or other conditions that constrict, inflame, or cause mucous
build-up in airways. Further complicating our understanding of lung clearance
mechanisms in obstructive airways disease is the variety of mucociliary trans-
port patterns that can be observed, including regurgitation, stasis, spiral
motion, and movement toward the opposite bronchus (Isawa et al., 1984).
(3) Regional mass deposition data do not provide insights regarding local-
ized "hot spot" deposition. Significantly higher particulate mass to lung
surface ratios can occur in the extrathoracic and tracheobronchial regions as
compared to the alveolar region. Gerrity et al. (1979) computed the average
particle surface concentration of an inhaled 8 urn MMAD aerosols in each genera-
tion of the Weibel lung model (Weibel, 1963) and predicted as much as two
orders of magnitude difference between particulate surface concentration in the
segmental bronchi compared to terminal bronchioles. Local surface concentra-
tions of deposited particles within large airways are probably higher than the
average. Also, respiratory disease states that result in altered breathing
patterns (e.g., increased oral breathing) may lead to increased deposition of
particles in particular respiratory tract regions.
(4) Although the probability of deposition of particles larger than 10 urn
in the alveolar region is low, small numbers of such particles have been found
in human lungs (U.S. EPA, 1982a,b). Some evidence suggests that those large
insoluble coarse substances that do penetrate may be cleared at a much slower
rate. Animal tests indicate that 15 pm particles instilled in this region
clear much more slowly than smaller particles of the same composition (U.S.
EPA, 1982a,b).
Besides variations in regional deposition patterns found for inhaled
particles and factors affecting typical deposition patterns, regional differ-
ences exist for clearance mechanisms by which inhaled particles penetrating
various levels of the respiratory tract are removed. The effects of inhaled
particulate matter and other noxious agents, e.g., irritative gases, on clear-
ance mechanisms represent one of the major categories of toxic actions exerted
by such air pollutants. Detailed reviews of clearance mechanisms and effects
on them due to inhaled particles and sulfur dioxide (S02) are presented else-
2-12
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where (U.S. EPA, 1982a,b; Lippmann et al., 1981; Lippmann and Schlesinger,
1984).
Mucocillary clearance and alveolar clearance mechanisms are of most
concern here. Lung mucociliary clearance is the major defense mechanism by
which inhaled particles deposited in the tracheobronchial airways are removed
from the respiratory tract. Particle-laden mucus is transported by the tips of
cilia which are immersed in an aqueous sol layer. Airway mucus transport rates
decrease distally from the trachea (Asmundsson and Kilburn, 1970; Foster et
al., 1980) with particle residence times of potentially as much as 300 minutes
in the terminal bronchioles (Lee et al., 1979). Mucociliary clearance half-
times of the healthy lung can range typically between 30 minutes and several
hours, depending on the initial distribution of particles and mucus transport
rates within each airway. Lung mucociliary clearance can be impaired by
disease states of the lungs (Lippman et al., 1980). Svartengren et al. (1986)
have observed marked dysfunction of lung mucociliary clearance (Camner et al.,
1973; Levandowski et al., 1985; Garrard et al., 1985) and a virtual halt in
tracheal mucus transport (Levandoswki et al., 1985) unless supplemented by
cough. Retarded mucus transport within the lungs can lead to increased
residence times of inhaled particles.
Two general types of alveolar clearance mechanisms are generally recog-
nized: absorptive and non-absorptive. Absorptive mechanisms involve active
and passive transport processes, whereby deposited particles permeate the
alveolar epithelium and penetration of endothelial barriers occurs prior to
uptake into the blood or lymphatic transport. These processes are most effec-
tive in removing highly soluble particles. Phagocytosis of deposited particles
by alveolar macrophages is generally accepted as the chief non-absorptive
clearance process. Some low-solubility materials may escape phagocytosis and
accumulate as focal deposits within parenchyma! tissues. In the ICRP (1979)
lung model it has been suggested that as much as 40 percent of particles
deposited in alveoli migrate, either free or phagocytized, to the distal
portions of the ciliated airways for subsequent removal by mucociliary clear-
ance. Alveolar clearance rates depend in large part on particle solubility.
Several studies of long-term clearance of highly insoluble particles in the 1-
to 4-ug range (Bailey et al., 1982; Bohning et al., 1982; Philipson et al.,
1985) report two phases with half times of approximately 20 and 300 days,
though Philipson et al. (1985) observed slow half-times of as much as 2500
2-13
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days. Stahlhoffen et al. (1980) measured the long-term clearance of ferric
oxide particles (moderately insoluble) between 1 and 9 urn MMAD and found single
phase clearance half-times of between 70 and 110 days that appeared to depend
on particle size.
Continuous exposures to ambient aerosols result in the simultaneous
deposition and redistribution of particles. The regional dose of particles
inhaled continuously may thus differ significantly from the regional pattern of
acute aerosol deposition. Brain and Valberg (1974) developed a model of
retention of continuously inhaled particles based on the ICRP (1966) lung
model. Gerrity et al. (1983) further defined it to the Weibel (1963) lung
model, taking into account individual airway mucus transport rates. The
Gerrity et al. (1983) model predicts maximum doses to the trachea and respira-
tory bronchioles for a moderately insoluble 10-um aerosol.
Deposition of inhaled sulfate compounds in the respiratory tract is
complex and depends upon breathing patterns and physical properties of the
inhaled particles. Deposition patterns and clearance mechanisms for sulfates
depend upon their particular size ranges (mainly fine particles <2.5 um) as
discussed above. Of most importance is the fact that deeper penetration of
particles into the respiratory tract occurs during breathing through the mouth
or oronasally than during nasal breathing.
Of particular concern from a health standpoint is the fact that acidic
aerosols exist in ambient air mainly in the size range of 0.3 to 0.6 um (MMAD),
well within the range of readily inhalable fine-mode particles capable of pene-
trating deeply into tracheobronchial and alveolar regions of the respiratory
tract. Under fog conditions, where acidic components are often incorporated
into water droplets of larger sizes up to 10-15 pm, concern exists in regard to
the potential for health effects being associated with the increased deposition
of acidic fog droplets in the tracheobronchial regions of the respiratory
tract.
2.2 SULFUR DIOXIDE DEPOSITION AND CLEARANCE
As discussed in U.S. EPA (1982a,c), sulfur dioxide is soluble in water and
readily absorbed upon contact with the moist surfaces of the nose and upper
respiratory passages. It is well established that the gas is almost completely
removed (95 to 99 percent) by nasal absorption under resting conditions in both
2-14
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man and laboratory animals. A recent study by Schachter and coworkers (in
press) also indicates similar, almost complete, removal of S02 in nasal
passages during nasal breathing under increased exercise conditions. Schachter
et al. (in press) exposed six subjects to 2.62 mg S02/m (1 ppm) in an environ-
mental chamber to study nasal absorption of inhaled S02. A 6 min rest was
followed by 4 to 6 min of exercise at 450 kpm during which subjects breathed
only via the nose. A catheter was placed in the oral cavity and connected to
an S02 analyzer. No detectable quantities of S02 could be measured when
sampling from the mouth. In addition, saliva samples were analyzed for
dissolved S02; no dissolved S02 was detected. These results confirm previous
observations that the nose is extremely efficient in removing S02-
Other human studies indicate that S02 penetration to the lower respiratory
tract increases with activity and increased ventilation associated with a shift
from nasal to oronasal breathing at a mean ^ of 30 L min (Niinimaa et al.,
1980, 1981; D1Alfonso, 1980). Most studies on deposition of SO, in animals and
humans have been done at concentrations greater than 2.62 mg/m (1 ppm). The
95 to 99 percent removal of S02 by the upper respiratory tract has not been
confirmed at levels ordinarily found in ambient air (generally less than 0.1
mg/m3 [0.038 ppm]). It is expected, however, that similar deposition patterns
would be observed at these lower concentrations of S02- Once inhaled, S02 is
absorbed quickly into the mucus layer lining the ET and TB regions, where
reactions can occur which might result in alterations in the viscosity of
mucus. Absorbed S02 can also be transferred rapidly into the systemic circula-
tion. Less than 15 percent of the total inhaled S02 is likely to be exhaled
immediately, with only small amounts (about 3 percent) being desorbed during
the first 15 minutes after the end of exposure (U.S. EPA, 1982a,b).
2.3 POTENTIAL MECHANISMS OF TOXICITY ASSOCIATED WITH INHALED PARTICLES AND S02
U.S. EPA (1982a) noted that numerous possibilities exist by which a wide
variety of toxic effects may be exerted by inhaled particles once deposited in
the respiratory tract. Certain general types of mechanisms of toxicity can be
identified to apply across a wide range of mixtures of inhaled particles,
either acting alone or in combination with other common gaseous air pollutants,
such as S00, NO , or ozone. These include, for example, possible irritant
2-15
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effects that result in decreased air flow due to airway constriction, altered
mucociliary transport and effects on alveolar macrophage activity. Other toxic
effects and underlying mechanisms of action are much more chemical-specific,
and depending on the particular materials involved, may include forms of
systemic toxicity involving non-respiratory system organs and functions. The
main focus of discussion here is on general mechanisms of toxicity rather than
more chemical-specific ones.
The tracheobronchial portion of the respiratory system is the site of de-
position of a mixture of fine (especially hygroscopically fine) and relatively
small (<10-15 urn) coarse-mode particles. Bronchoconstriction is one common
response to deposition of particles in this region and has been reported in
response to short-term exposure to high levels of various "inert" dusts, as
well as acid and alkaline aerosols of varying particle sizes. Bronchoconstric-
tion produced by acute exposures is likely because of neurologically-mediated
reflexive actions arising from chemical and/or mechanical stimulation of irri-
tant neural receptors in the bronchi. Since particle deposition and epithelial
nerve endings tend to concentrate near airway bifurcations, deposition at such
points may exert an influence on pulmonary mechanical changes due to chemical
or mechanical stimulation of receptors. Reflex coughing and bronchoconstric-
tion due to irritant effects of particles or SO,, on tracheobronchial region
receptors may be related to effects observed in various epidemiological
studies, e.g., aggravation of chronic respiratory disease states such as
asthma, bronchitis, and emphysema. Also, as noted earlier, some persons with
asthma or other respiratory diseases may have elevated particle deposition
rates in the tracheobronchial region which may contribute to a cascading effect
of further bronchoconstriction and increased particle deposition in that
region.
Referring to the earlier discussion of particle clearance mechanisms,
several more potential mechanisms of toxicity associated with inhalation of
airborne particles can be readily discerned. This includes a plausible sequence
of events by which inhaled particles can contribute to chronic obstructive
pulmonary disease (Albert et al., 1973; Lippmann et al., 1980). That is, in-
haled particles and noxious gases can stimulate changes in the distribution and
activities of various cell types lining the tracheobronchia'l airways. Acute
exposures to high levels of airborne particles initially stimulate increased
mucus secretion and mucociliary flow useful in clearing inhaled particles.
2-16
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However, with continuous or repeated exposures, more marked changes can occur,
e.g., marked and persistent depression in bronchial clearance, increase in
secretory cell number, increase in the thickness of the mucous layer (Lippman
and Schlesinger, 1984). Also, certain particles and gases affect the number of
ciliated cells or their functioning so as to alter (i.e., speed or slow)
mucociliary clearance rates. Mucociliary clearance is affected by fine
sulfuric acid aerosols, high levels of carbon dust, and cigarette smoke.
Because of the above mucociliary clearance phenomena, airborne particles
may be importantly involved as etiological factors that contribute to various
types of chronic lung diseases, as discussed by U.S. EPA (1982a,b) and Lippmann
et al. (1980). This includes: likely involvement in the pathogenesis of
chronic bronchitis; increasing susceptibility to acute bacterial and viral
infections, especially in populations or groups (e.g., children, the elderly
and cigarette smokers) already predisposed to such infections by other factors;
and likely aggravation of preexisting disease states, e.g., chronic bronchitis
or emphysema, or other respiratory conditions such as bronchial asthma. Also,
some individuals (e.g., those with Kartagener's syndrome) have genetically
inherited defects in ciliated cell function or other disease states, which
result in much reduced mucociliary clearance of inhaled particles and poten-
tially greater vulnerability to toxic effects of such particles.
Particle deposition within the alveolar region of the lungs is mainly
limited to fine and coarse particles of less than 10 urn D_ . Several important
we
characteristics in the alveolar region affect responses to inhaled particles.
Clearance from the alveolar region is much slower than from the tracheobron-
chial region. The alveolar region is the site of oxygen uptake and of various
non-respiratory functions of the lungs that may be affected by pollutant expo-
sures. Many victims of London air pollution episodes were patients suffering
from cardiopulmonary diseases (e.g,, emphysema and bronchitis), which normally
reduce the lungs' ability to transfer oxygen to blood. Individuals with
chronic lung disease and nonuniform ventilation distribution will be sensitive
to pollution if only because the delivered dose to the region that is being
ventilated will be higher than it would be if ventilation were normally distri-
buted. Although this added load (due to pollution exposure) is usually
tolerable in normal individuals, the added stress and chain of events may lead
to fatal or irreversible damage in individuals already compromised with cardio-
pulmonary disease.
2-17
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2.4 SUMMARY
Studies published since preparation of the earlier criteria document (U.S.
EPA, 1982a) and the previous addendum (U.S. EPA, 1982c) support the conclusions
reached at that time and provide clarification of several issues. In light of
previously available data, new literature was reviewed with a focus towards (1)
the thoracic deposition and clearance of large particles, (2) assessment of
deposition during oronasal breathing, (3) deposition in possibly susceptible
subpopulations, such as children, and (4) information that would relate the
data to refinement or interpretation of ancillary issues, such as inter- and
intrasubject variability in deposition, deposition of monodisperse versus
polydisperse aerosols, etc. Major results for the first three areas are given
below.
The thoracic deposition of particles >10 urn D3Q and their distribution in
"~ etc
the TB and P regions was studied by a number of investigators (Svartengren,
1986; Heyder, 1986; Emmett et al., 1982). Depending upon the breathing regimen
used, TB deposition ranged from 0.14 to 0.36 for 10-pm Dae particles, while the
range for 12-um Dge particles was 0.09 to 0.27. For particles 16.4 urn Da , a
maximally deep inhalation pattern resulted in TB deposition of 0.12.
The experimental data cited above were obtained from human exposure
studies in which the subjects inhaled through a mouthpiece. Some of the minute
ventilations employed would more normally occur with oronasal breathing (partly
via the mouth and partly nasally). Various studies (Swift and Proctor, 1982;
Miller et al., 1984, 1986) have simulated deposition during oronasal breathing
by adjusting for parallel nasal and oral deposition as a function of air flow
through the respective compartments. While the magnitude of deposition in
various regions depends heavily upon minute ventilation, there is, in general,
a gradual decline in thoracic deposition for large particle sizes, and there
can be significant deposition of particles greater than 10 urn D , particularly
36
for individuals who habitually breathe through their mouth. Thus, the deposi-
tion experiments wherein subjects inhale through a mouthpiece are relevant to
examining the potential of particles to penetrate to the lower respiratory
.tract and pose a potentially increased risk. Increased risk may be due to
increased localized dose or to the exceedingly long half-times for clearance of
larger particles (Gerrity et al., 1983).
Although experimental data are not currently available for deposition of
particles in the lungs of children, some trends are evident from the modeling
2-18
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results of Phalen et al. (1985). Phalen and co-workers made morphometric
measurements in replica lung casts of people aged 11 days to 21 years and
modeled deposition during inspiration as a function of activity level. They
found that, in general, increasing age is associated with decreasing particu-
late deposition efficiency. However, very high flow rates and large particu-
late sizes do not exhibit consistent age-dependent differences. Since minute
ventilation at a given state of activity is approximately linearly related to
body mass, children receive a higher TB dose of particles than do adults and
would appear to be at a greater risk, other factors (i.e., mucociliary clear-
ance, particulate losses in the head, tissue sensitivity, etc.) being equal.
2-19
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-------
CHAPTER 3. EPIDEMIOLOGICAL STUDIES OF HEALTH EFFECTS ASSOCIATED WITH
EXPOSURE TO AIRBORNE PARTICLES AND SULFUR OXIDES
Extensive published information exists concerning health effects associ-
ated with exposure to airborne particulate matter and sulfur oxides. Detailed
evaluations of this extensive literature (including discussions of potential
mechanisms of toxicity and findings emerging from animal toxicology experi-
ments, controlled human exposure studies, and epidemiological studies) are
provided in the 1982 EPA criteria document (U.S. EPA, 1982a), as well as
several other critical reviews of the subject (WHO, 1979; Holland et al., 1979;
Lippmann et al., 1980; Lippmann and Schlesinger, 1984). Key health effects
findings emerging from the earlier criteria review (U.S. EPA, 1982a) are sum-
marized below, providing a perspective against which more recently published
studies are then highlighted and evaluated.
3.1. HUMAN HEALTH EFFECTS DUE TO SHORT-TERM EXPOSURES TO PARTICLES AND
SULFUR OXIDES
As reviewed by U.S. EPA (1982a), much information has been generated by
experimental animal studies and controlled human exposure studies in regard to
health effects associated with short-term (<24 hr.) exposures to airborne
particles and sulfur oxides. However, the most crucial information gained in
regard to effects on human health of exposure to realistic concentrations of
airborne particles has come from epidemiological studies. Complicating such
studies is the frequent co-occurrence of elevated levels of sulfur oxides along
with airborne particles. Attention is directed here mainly to epidemiological
studies concerning the health effects of exposure to particulate matter and
sulfur oxides that yield information relevant to the development of exposure-
effect and exposure-response relationships.
3-1
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3.1.1. Mortality Effects of Short-Term Exposures
As discussed in U.S. EPA (1982a), the most clearly defined effects on
mortality arising from exposure to sulfur oxides and particulate matter have
been sudden increases in the number of deaths occurring, on a day-to-day basis,
during episodes of high pollution. The most notable of these occurred in the
Heuse Valley in 1930, in Donora in 1948 and in London in 1952. Additional
episodes with notable increases in mortality occurred in London during various
winters from 1948 to 1962. Besides evaluating mortality associated with major
episodes, epidemiology studies also focused on more moderate day-to-day varia-
tions in mortality within large cities in relation to PM and SO pollution.
f\
The large body of literature concerning such studies carried out in the
United Kingdom, elsewhere in Europe, the United States and Japan was critically
reviewed in detail by U.S. EPA (1982a). As discussed there, various method-
ological problems with most of the studies precluded drawing of quantitative
conclusions regarding exposure-effect or exposure-response relationships of
importance for deriving air quality standards. Among the main problems were
inadequate measurement or control for potentially confounding variables and
inadequate quantisation of exposure to airborne particles, $62 or other associ-
ated pollutants (e.g., sulfates). <•
Despite such problems, U.S. EPA (1982a) concluded that the then available
studies collectively indicated that mortality was clearly and substantially
o
increased when airborne particle 24-hr concentrations exceeded 1000 ug/m (as
measured by the BS method) in conjunction with elevations of SO, levels in
o £-
excess of 1000 pg/m (with the elderly or others with severe preexisting
cardiovascular or respiratory disease mainly being affected). As for evalua-
tion of risks of mortality at lower exposure levels, U.S. EPA (1982a) concluded
that studies conducted in London by Martin and Bradley (1960) and Martin (1964)
yielded useful, credible bases by which to derive conclusions concerning
quantitative exposure-effect relationships. Table 1 summarizes key conclusions
drawn from these and other critical studies of mortality and morbidity effects
associated with short-term (24-hr) exposures to particulate matter and S02, as
stated earlier in the 1982 EPA criteria document (U.S. EPA 1982a).
The studies by Martin and Bradley (1960) and Martin (1964) dealt with a
relatively small body of data on relationships between daily mortality in
Greater, London and daily variations in pollution (smoke and sulfur dioxide)
during the winter of 1958-59. Aerometric data from multiple sampling sites
3-2
-------
used in their analysis can be considered reasonably representative of outdoor
concentrations in the areas where people lived, although the inclusion of
outer, less-densely populated areas meant that average exposure may have been
underestimated. During the winter of 1958-59', Martin and Bradley (1960)
reported that mortality increased on some days when smoke concentrations
increased by more than 100 ug/m over the previous day or when S02 concentra-
tions increased by 70 ug/m3 (0.025 ppm). Increases in daily mortality were up
to about 1.2 times expected values assessed from 15-day moving averages. Thick
fog (visibility less than 200 meters) was also associated with increases in
mortality. The relative importance of the three factors (smoke, S02, fog)
could not be clearly determined, but on the basis of other work, the authors
considered that smoke was probably most important. When results were con-
sidered on an absolute basis (Lawther, 1963), it was concluded that increases
in mortality became evident when the 24-hr mean concentrations of smoke and
3 3
sulfur dioxide exceeded 750 ug/m and 710 ug/m (^0.25 ppm), respectively.
Studies on day-to-day variations in mortality in London were continued if»
successive winters and coupled with the records of emergency hospital admis-
sions. Martin (1964) showed correlations between both the daily mortality and
hospital admission data and concentrations of smoke or S02- There was no
clearly defined level (threshold) above which effects were seen, but fairly
consistent increases in both mortality and hospital admissions occurred when
concentrations of smoke and sulfur dioxide each exceeded a 24-hr mean of about
500 ug/m . Based on the above analyses and a reanalysis of the Martin and
Bradley data set by Ware et al. (1981), U.S. EPA (1982a) concluded that small
increases in mortality among the elderly and chronically ill may have been
associated with BS and S02 levels in the range of 500 to 1000 ug/m . Much less
certainty was attached to suggestions of possible slight increases in mortality
at still lower BS or S02 concentrations, based on the Ware et al. (1981)
reanalyses.
In subsequent years, because of reductions in London BS levels brought
about by implementation of the British Clean Air Act and more gradual S02
reductions, only few occasions occurred when smoke or S09 levels exceeded 500
3
ug/m . Analyses of daily mortality in London in relation to variations in
smoke and S02 levels during winters from 1958-59 to 1971-72 were reported by
Mazumdar et al. (1981). These analyses are of special value in attempting to
define lowest levels of exposure to particulate matter and/or S02 associated
3-3
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with increased mortality, because they include winters when levels of those
pollutants never exceeded 500 ug/m . The results obtained for airborne parti-
cles (measured in terms of BS) were analyzed in relation to linear and quadra-
tic models, which Mazumdar et al. (1981) found to provide good fits to the data
examined after relevant potentially confounding variables, e.g., temperature
and humidity, were taken into account statistically. U.S. EPA (1982a) con-
cluded that both of the models suggest small increases in mortality at smoke
levels below 500 ug/m3 and, possibly, to as low as 150-250 ug/m3.
In a publication newly available since completion of U.S. EPA (1982a),
Mazumdar et al. (1982) reported further on three types of analyses of London
mortality during the 1958-59 to 1971-72 winters: (1) year-by-year multiple
regressions, (2) stratification using nested quartiles of one pollutant within
another, and (3) multiple regression of a subset of high-pollution days. Steps
were taken in each analysis to control for potentially confounding factors.
Mortality and pollution variables were first divided by their winter means
(indexed or percent) to adjust for year-to-year variation. Seasonal trends
were adjusted for by treating each variable as a deviation (residual) from
15-day moving averages; these residuals were then corrected for weather factors
by regressing separately indexed mortality, S02 and smoke residuals in tempera-
ture and humidity residuals of the same day, previous day and lag days up to 1
wk; and dummy variables were used to remove day-of-week effects. The corrected
indexed pollution variables were then reconverted to absolute units by multiply-
ing each value by the corresponding winter mean, but the mortality values were
left in indexed form.
Mazumdar et al. (1982) reported that the year-by-year multiple regressions
yielded generally much smaller coefficients for S00 (14 winter x = 1.17 percent
3 -
mortality increase/mg/m S02; p >0.10) versus those for smoke (14 winter x =
25.09 percent/mg/m3 smoke; p <0.01). Also, the nested quartile analyses using
16 cells (i.e., 4 quartiles of smoke within 4 quartiles of S02 and vice versa),
were reported as only partially successful, in that substantial covariation
remained between the two pollutants in the highest and lowest quartiles.
Visual inspection of other cells, the authors noted, nevertheless suggested a
much larger smoke than S02 effect. Last, multiple regression analyses, using
the 100 days during the 14 winters when the two pollutants were in their
highest deciles (excluding 5 days during the 1962 episode), were reported as
showing that mortality increases monotonically with smoke for fixed S02 levels
3-5
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but mortality only increased with S02 levels above 0.7 mg/m3 for fixed smoke
levels. The authors concluded that their analyses of London data for 14
winters support the conclusion that mortality was significantly positively
associated with air pollution, but the mortality/pollution association was
almost entirely due to smoke. They also noted possible contributions of S0? at
sufficiently high pollutant levels (i.e., both S02 and smoke >0.7 mg/m3). *
Results from linear and quadratic models of mortality regressed on smoke alone
led the authors to state a preference for the quadratic model supplemented by a
hypothesis that at low smoke levels (<0.3 mg/m ), smoke serves as a surrogate
for an unidentified variable (e.g., a highly toxic fraction of particulate
emissions).
More recently, Ostro (1984) reported that new analyses of the same 1958-59
to 1971-72 London winter data indicate some risk of mortality even at smoke
levels below 150 ug/m . Specifically, Ostro (1984) employed a variation of a
standard multiple regression model to test whether the data supported the
existence of a "threshold" at BS = 150 ug/m3. Observations across the range of
pollutant levels were divided into two segments, those falling below versus
those above 150 ug/m . Regression analyses for data below 150 ug/m3, con-
trolling for important potentially confounding factors (e.g., temperature,
humidity, etc.), indicated a statistically significant pollutant effect on
mortality below the BS = 150 ug/m3 level. For 11 of 14 winters, the coeffi-
cients for mortality associations with BS values below 150 were statistically
different from zero at p <0.10. Additional analyses focused on the last seven
winters, starting in 1965-66, during which there were no BS values above 500
o
ug/m . The mortality coefficients were significant at p <0.05 for six years
and at the 0.01 level in four of the years. Ostro (1984) concluded that these
results are suggestive of a strong association of BS with mortality, holding
temperature and humidity constant, at levels below 150 ug/m3.
The Mazumdar et al. (1982) and Ostro (1984) analyses produced generally
analogous results in relation to reported findings on PM effects: (1) each
found significant positive associations between- increased mortality and BS
levels for most of the 14 London winters from 1958-59 to 1970-71, when the data
were analyzed on a year-by-year basis; (2) the coefficients obtained for
mortality associations with lower BS values were generally larger than values
obtained with higher BS levels, a counterintuitive result; and (3) no clearly
defined threshold for BS-mortality associations could be identified based on
3-6
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either set of analyses, both of which showed small but significant, associations
O
at levels below 500 ug/m BS.*
No readily obvious reasons stand out as explaining the reported stronger
correlations between lower BS values and mortality than associations seen at
higher BS levels, although both Mazumdar et al. (1982) and Ostro (1984)
tendered some possibilities (for example, the low levels of smoke in later
years may have contained higher proportions of respirable particles or specific
toxic materials). Still other questions can be raised in regard to these
analyses; for example: (1) whether or not the effects of smoke and S02 can be
credibly separated out, given the very high correlation (generally >0.80 or
0.90) between BS and S02 levels in the subject data set; (2) whether unmeasured
variables, such as indoor air pollution levels, might have also covaried with
outdoor BS and S02 concentrations and contributed to observed mortality
effects; or (3) whether other uhevaluated longer-term changes in demographic
characteristics of the London population (age, socioeconomic levels, ethnic
mix, etc.) over the 14 winters might not be such as to contribute to spurious
apparent associations between mortality increases and BS or S02. Also, Roth et
; al. (1986) present findings suggesting that use of deviations of mortality from
15-day moving averages may hide the true relationship between pollution and
mortality. None of these issues can be definitively resolved at this time,
although it seems unlikely that long-term demographic shifts during the 14 year
study period could account for significant year-by-year associations; nor is
it likely that indoor air exposures would be consistent from year to year,
given variations in yearly climatic conditions coupled with gradual changes in
heating practices (shifts away from open hearth burning of coal in residences)
that occurred during the 14 year study period.
*Note: An unpublished analysis of the 1958-71 London winter data, set by
Shumway et al. (1983) also produced results indicative of risk below the 500
ug/m3 level of smoke. These analyses used a general multiple regression model
and detrending of data to correct for temperature and autocorrelation
effects. The best model for predicting cardiovascular, respiratory or overall
mortality used lagged temperature and logs of same day levels of S02 or smoKe.
Results were reported to indicate that pollution acts, positively and
instantaneously, whereas temperature acts negatively, with the strongest
component a lag of two days. Also, the strongest associations, as measured by
multiple coherence, occur at periods of 7-21 days, implying that pollution and
temperature episodes must persist in order to influence mortality.
3-7
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Regardless of the above considerations, the following conclusions appear
warranted based on the earlier criteria review (U.S. EPA, 1982a) and present
evaluation of newly available analyses of the London mortality experience: (1)
markedly increased mortality occurred, mainly among the elderly and chronically
ill, in association with BS and S02 concentrations above 1000 ug/m , especially
during episodes when such pollutant elevations occurred for several consecutive
days; (2) the relative contributions of BS and S02 cannot be clearly distin-
guished from those of each other, nor can the effects of other factors be
clearly delineated, although it appears likely that coincident high humidity
(fog) was also important (possibly in providing conditions leading to formation
of HoSO/, or other acidic aerosols); (3) increased risk of mortality is associ-
£ T" ^
ated with exposure to BS and S09 levels in the range of 500 to 1000 ug/m ,
O
clearly at concentrations in excess of ^700 to 750 ug/m ; and (4) less certain
evidence suggests possible slight increases in the risk of mortality at BS
levels below 500 ug/m3, with no specific threshold levels having yet been
demonstrated or ruled out at lower concentrations of BS (e.g., at 150 ug/m )
nor potential contribution of other plausibly confounding variables having yet
been fully evaluated.
In another study of air pollution relationships with mortality reported
since the earlier criteria review (U.S. EPA, 1982a), Mazumdar and Sussman
(1983) evaluated associations between mortality events and daily particulate
matter and S02 levels in Pittsburgh, PA. The analysis, limited to investiga-
tion of same-day events, reported a possible relationship between heart disease
mortality/morbidity and same day particulate levels (measured in terms of COH),
but not same-day S02 levels. The analyses specifically evaluated daily mortal-
ity rates during 1972-1977 for all of Allegheny County, PA in relation to daily
average COH and S02 measurements obtained at each of three air monitoring
stations: one at the center of the County within a high pollution section of
Pittsburgh; another situated relatively near the first in a somewhat less
polluted area; and a third in a distinctly cleaner area on the northeast edge
of the County. Corrections for trend and seasonal factors were made by use of
daily deviations from 15-day moving averages for air pollution, temperature and
mortality variables. Multiple regression analyses revealed no statistically
significant associations between mortality for all ages or heart disease
mortality in relation to either S02 or COH when regressed on each variable
alone. When S02 and COH were considered jointly, only the associations between
3-8
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total or heart disease mortality and COH measurements at the Hazelwood (high
pollution area) station were significant at p <0.05. These results, however,
cannot be accepted as providing meaningful information on mortality-air pollu-
tion associations in the Pittsburgh area in view of: (1) inadequate character-
ization of county-wide air pollution levels against which to compare mortality
rates for the entirety of Allegheny County, the S02 and COH levels at each of
the three monitoring stations used not being highly correlated (mostly r < 0.4
to 0.5) with values at the other stations; (2) internal inconsistencies whereby
larger coefficients were obtained for associations of mortality to COH readings
at the cleaner air station on the edge of the County than the intermediate
pollution station near the center of the County; and (3) the use of a large
number of separate mortality regression analyses, from among which only two
were significant at p <0.05.
In addition to the above reanalyses of London mortality data, reanalyses
of mortality data from New York City in relation to air pollution have been
recently reported by Ozkaynak and Spengler (1985). These investigators carried
out time-series analyses on a subset of New York City data included in a prior
analysis by Schimmel (1978) which was critiqued during the earlier criteria
review (U.S. EPA, 1982a). The present reanalyses by Ozkaynak and Spengler
(1985) evaluated 14 years (1963-76) of daily measurements of mortality (the sum
of heart, other circulatory, respiratory, and cancer mortality), COH, S02, and
temperature. Prior to regression analysis, efforts were made to remove assumed
low-frequency confounding by "filtering" each variable to remove its slow-
moving components. This included not only use of residuals from 15-day moving
averages, but also evaluation of sensitivity of results to other filters.
Initial exploratory analyses estimated regression coefficients for COH and S02
after all variables were preprocessed with one of several filters (e.g., taking
residuals from 7-, 15-, or 21-day moving averages and other filters that
removed all cycles in the data that fell beyond indicated periods measured in
days). Overall, the regression coefficients for COH ranged from 1.2 to 5.4
daily deaths per unit of COH, most being statistically significant (p <0.05).
.Also, a reasonable range of variation in temperature specifications produced
coefficients ranging from 1.3 to 1.8 deaths per COH unit. The risk coeffi-
cients of Schimmel (1978) were near the lower end of the range of coefficients
found by Ozkynak and Spengler (1985). The latter investigators noted then that
they were able to generate a fairly consistent set of estimates by performing a
3-9
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number of sensitivity analyses. They also correctly note that these initial
estimates were subject to several technical limitations: (1) misc]assification
of population exposure can occur in using aerometric data from one fixed
monitoring site; (2) the exposure index, COH, is imperfectly related to respi-
rable particle mass levels; and (3) the range of exploratory models initially
fit may not have been diverse enough. Consequently, an additional reanalysis
was undertaken.
Specifically, more recent reanalysis of the New York City data reported by
Ozkaynak and Spengler (1985) used standard time-series methods to control for
covariates such as temperature and to handle the problem of autocorrelation.
Their previous analysis was also extended by adding records of visibility and
weather from three New York City airports, in order to examine spatial homoge-
neity of daily air pollution in New York City and to use visibility as f
surrogate for aerosol extinction (bext) or for fine particle (FP) pollution
as discussed by Ozkaynak et al. (1985). The most salient feature of the
mortality data found by this reanalysis was a strong seasonal component which
confounds direct regressions involving mortality, air pollution and weather
variables. A simple trigonometric expression was used that removed the tempera-
ture cyclic component and rendered nonseasonal temperature nonsignificant.
Another stationary autoregressive term was also used to exhaust the time-series
structure of the mortality records. Consideration of lagged regressions and
interactions did not improve the model's predictive ability. Time-series
analyses were then performed with a linear model and in a rnultivariate manner
in which corrections for seasonality and autocorrelation were introduced into
the linear model. Preliminary estimates of excess deaths (e.) or elasticities
for the pollutant variables were thereby calculated, resulting in the following
findings: (1) the time-series analysis showed S02 levels to be significantly
correlated with mortality (e$02 = 2.3 percent); (2) COH also contributed
significantly to excess deaths (eCQH =2.4 percent); (3) Bfixt, a variable used
as a surrogate for FP pollution was also a significant contributor to excess
daily deaths (~1.2 percent); and (4) the total estimated excess deaths attri-
butable to air pollution was -6.0 percent. The authors concluded that although
these are interim results (they are also analyzing the data one year at a time
and by each quarter), these findings: (1) indicate that during the study period
ambient air pollution of a large urban area was contributing to mortality, (2)
appear to corroborate results from cross-sectional mortality studies, and (3)
3-10
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Indicate that particulate air pollution, even at current levels, could be of
concern for public health. However, the authors again correctly noted limita-
tions of their analyses which preclude full reliance on these preliminary
results for risk assessment purposes: (1) the results reflect aggregate
analyses of 14 years of data and more thorough analyses need to be done to take
into account changing S02 and aerosol composition over the period (preliminary
analyses indicate no differences in pollutant coefficients for 1963 to 1970 and
1971 to 1976); (2) the results are based on aerometric data from one monitoring
station and visibility data from one airport (JFK); and (3) the effects of heat
waves and influenza epidemics during the study period have not been considered
in any detail in these preliminary analyses.
Hatzakis et al. (1986) recently published a study of short-term effects of
air pollution on mortality in Athens, Greece, during 1975-82. Daily concentra-
tions of S02 (acidimetric method) and smoke (standard British Method) measured
by a five-station network in Athens were evaluated in relation to mortality
data abstracted from the Joint Registries of Athens and 18 other contiguous
towns in the Greater Athens area. The authors reported that adjusted daily
mortality (estimated by subtracting the observed mortality value from an
"expected" value, calculated after fitting a sinusoidal curve to the empirical
mortality data) was significantly and positively related to S02 levels .(b =
+0.0058, p = 0.05), but not to smoke levels. Separate multiple regression
analyses were done for S02 and smoke, controlling in each case for temperature,
relative humidity, secular, seasonal, monthly and weekly variations in mortality
as well as interactions of the above variables with season. Evaluation of a
possible threshold for the S02-mortality effect was carried out by successively
deleting from the regression model days with the highest S02 values. These
analyses resulted in the authors suggesting that, if there is an S02 threshold,
it must lie slightly below 150 ug/m3 (mean daily value).
The latter result, as stated by the authors, is not consistent with
results of other studies in which S02 mortality thresholds have been placed
around the value of 300 ug/m3 (or, more credibly, around 500 M9/m , as per U.S.
EPA, 1982a): Nor is the failure to find significant associations between
mortality and smoke consistent with other more usual published findings
(although differences in chemical composition of PM in Athens and lack of
calibration of smoke readings against gravimetric measurements make it diffi-
cult to compare smoke levels from Athens versus elsewhere). Other questions
3-11
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also arise which make it difficult to fully accept the reported findings, e.g.:
(1) how representative are the aerometric data for the entire Athens metropoli-
tan area from which the mortality data were abstracted, although the typography
of the area, with Athens and adjoining towns situated in a coastal "bowl"
surrounded by mountains, and high correlations (mostly r >0.50-0.60) between
pollutant readings from the five network stations suggest thait the aerometric
data may well be quite representative; (2) whether use of deviations of
observed mortality data for 1975-82 from expected values derived from 1956-58
mortality data as a pre-high pollution baseline period is statistically sound;
and (3) whether separate regression analyses for S02 and smoke alone are
sufficient versus analyses with both these pollutants included.
In summary, the above newly available reanalyses of New York City data
raise possibilities that, with additional work, further insights may emerge
regarding mortality-air pollution relationships in a large U.S. urban area.
However, the interim results reported thus far do not now permit'definitive
determination of their usefulness for defining exposure-effect relationships,
given the above-noted types of caveats and limitations. Similarly, it is
presently difficult to accept the findings of mortality associated with rela-
tively low levels of S02 pollution in Athens, given questions stated above
regarding representativeness of the monitoring data and the statistical sound-
ness of using deviations of mortality from an earlier baseline relatively
distant in time. Lastly, the newly reported analyses of mortality-air pollu-
tion relationships in Pittsburgh (Allegheny County, PA) utilized inadequate
exposure characterization and the results contain sufficient internal incon-
sistencies, so that the analyses are not useful for delineating mortality
relationships with either S02 or PM.
3.1.2. Morbidity Effects of Short-Term Exposures
As noted by WHO (1979), epidemiological studies can be useful in assessing
morbidity effects associated with air pollution in different communities or in
areas where changes in air pollution occurred over time. In such studies, where
. respiratory diseases are followed, it is necessary to control for age distribu-
tion, socioeconomic status, and other possibly confounding factors. It is also
crucial that adequate characterization of exposure to air pollutants of
interest be carried out, if quantitative conclusions are to be drawn regarding
exposure-effect or dose-response relationships. However, very few of the
3-12
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available epidemiological studies on morbidity effects associated with short-
term exposure to airborne particles allow for such conclusions, as evaluated by
U.S. EPA (1982a).
Those reported by Lawther for London populations (see Table 1) were
identified by U.S. EPA (1982a) as providing credible bases for drawing quanti-
tative-type conclusions about morbidity effects associated with airborne
particles (measured as smoke) and elevated S02 levels. Lawther et al. (1970)
reported on studies carried out from 1954 to 1968 mainly in London, using a
diary technique for sel^assessment of day-to-day changes in conditions among
bronchitic patients. A daily illness score was calculated from the diary data
and related to BS and $Q2 levels and weather variables. Pollution data for
most of the London studies were mean values from the group of sites used in the
mortality/morbidity studies of Martin (1964); those aerometric measurements
likely provide reasonable estimates of average exposure in areas where study
subjects lived or worked. In early years of the studies, when pollution levels
were generally high, well defined peaks in illness score were seen when concen-
trations of either BS or S02 exceeded 1000 ug/m3. With later reductions in
pollution, the changes in condition became less frequent and of smaller size.
From the series of studies as a whole, up to 1968, it was concluded that the
minimum pollution levels associated with significant changes in the condition
of the patients was a 24-hr mean BS level of -250 ug/m3 together with a 24-hr
mean S02 concentration of -500 ug/m3 (0.18 ppm). A later study reported by
Waller (1971) showed that, with much reduced average levels of pollution, there
was an almost complete disappearance of days with smoke levels exceeding 250
ug/m3 and S02 levels over 500 ug/m3 (0.18 ppm). As earlier, some correlation
remained between changes in the conditions of the patients and daily concentra-
tions of smoke and S02, but the changes were small at these levels and it was
difficult to discriminate between pollution effects and those of adverse
weather. Thus, as concluded by U.S. EPA (1982a), the observed effects (wors-
ening of health status among chronic bronchitic patients) were clearly associated
with BS levels of 250 to 500 ug/m3 and, possibly, somewhat lower levels (<250
ug/m3) for highly sensitive bronchitic patients.*
*Note: Roth et al. (1986) have recently raised questions regarding how well
the health indicator values used in the Lawther morbidity studies reflect
actual health status and suggest that associations between temperature and
health may be understated in this data set.
3-13
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Since preparation of U.S. EPA (1982a) evaluations summarized in Table 1,
additional studies have appeared concerning morbidity associated with short-
term exposure to airborne particles and/or sulfur oxides. Dockery et al.
(1982), fpr example, reported on pulmonary function evaluations carried out for
school children in Steubenville, OH as part of the Harvard Six-Cities Study.
Pulmonary function was evaluated immediately before and after air pollution
episodes in 1978, 1979 and 1980, by relating spirometric measurements (appro-
priately corrected for height, etc.) to aerometric data (e.g., TSP and S02
levels) obtained from state air pollution monitors. Data for each individual
child were evaluated. Linear decreases in forced vital capacity (FVC) with
increasing TSP concentrations were found, and slopes were determined for linear
relationships fitting the data for four different observation periods (fall,
1978; fall, 1979; spring, 1980; fall, 1980). The slope of FVC vs. TSP was
calculated for 335 children with three or more observations during any of the
four study periods. Of the 335 children examined, 194 were tested during more
than one study period. On average, estimated FVC was approximately 2 percent
lower following each alert, whereas forced expiratory volume in 0.75 sec
(FEVQ ?5) did not change during the 1978 study but was decreased by 4 percent
during the 1979 alert. In the spring of 1980, similar declines were seen in
FVC and FEVQ 75 values as were found following the previous alerts, but no
significant declines were seen in fall, 1980, when pollutant levels were
distinctly lower than for previous alerts (e.g., TSP levels did not exceed 160
ug/m3 in fall, 1980). The largest declines in lung function were observed one
to two weeks after the episodes. Fifty-nine percent of the children had slopes
less than zero (i.e., decreasing FVC with increasing TSP). The median slope
was -0.081 mL/Mg/m3, which is significantly less than zero (p <0.001) by a
Wilcoxan Signed Rank test. The median FVC vs. S02 slope was -0.057 mL/ug/m ,
also significantly (p <0.01) less than zero, but the relationship with mean
daily temperature was not significantly less than zero. Similar analyses
performed with FEVQ ?5 also showed the relationships (slopes) for S02 and TSP
to be significantly less than zero.
Overall-, these repeated measurements of lung function showed statistically
significant but physiologically small and apparently reversible declines of FVC
and FEV0 75 levels to be associated with increases of 24-hr mean TSP levels.
On days of testing for pulmonary function effects, the TSP levels ranged from
11.0 to 272 pg/m3 and S02 levels ranged from 0.0 to 281 ug/m . However,
3-14
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maximum TSP levels of 312 or 422 ug/m3 occurring in fall, 1978, 2 to 5 days
prior to spirometric testing may have contributed to the observed declines in
lung function for some children included in data analyses for that period.
Similarly, the maximum S02 value of 455 ug/m recorded on days immediately
preceding the spirometric testing during the Fall, 1979 period may have
accounted for observed declines in lung function. The investigators noted that
it was not possible to separate the relative contributions of the two pollu-
tants, nor were any thresholds for the observed pulmonary function decrements
discernable within the above broad range of TSP and S02 levels. Nevertheless,
these results appear to demonstrate that small, reversible changes in pulmonary
function can occur as the consequence of increased concentrations of TSP and
SOp somewhere in the above ranges. Whether such pulmonary function changes
per se are adverse or can lead to other, irreversible changes or make the lung
more susceptible to later insults remains to be resolved, Evaluations of such
issues may need to take into account an apparent subset of "responders" within
the population of children studied, who showed greater than average declines in^
lung function in relation to TSP or S02 levels. For example, the lowest
quartile of slopes of FVC and FEVQ 75 versus TSP were -0.386 and -0.306
mL/ug/m , respectively. 4-••-.
In another series of studies conducted during the last few years, Ostro
and co-workers evaluated relationships between air pollution indices for 84
standard metropolitan statistical areas (SMSA's) mostly of 100,000 to 600,000
people in size, and indices of acute morbidity effects, using data derived from
the National Center for Health Statistics (NCHS) Health Interview Survey (HIS)
of 50,000 households comprising about 120,000 people (Ostro, 1983; Hausman et
al., 1984; Ostro, in press). In the most recent analyses reported, Ostro (in
press) used HIS results from 1976 to 1981 together with estimates of fine
particle (FP) mass. That is, for adults aged 18 to 65, days of work loss
(WLDs), restricted activity days (RADs) and respiratory-related restricted
activity days (RRADs) measured for a two-week period before the day of the
survey were used as measures of morbidity and analyzed in relation to estimated
.concurrent two-week averages of FP or lagged in relation to estimated 2-wk FP
averages from 2 to 4 weeks earlier. The FP estimates were produced from the
empirically derived regression equations of Trijonis. These equations, as used
here, incorporated screened airport data and two-week average TSP readings at
population-oriented monitors, using these data taken from the metropolitan area
of residence. Various potentially confounding factors (such as age, race,
3-15
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education, income, existence of a chronic health condition, and average two-
week minimum temperature) were controlled for in the analyses. Various morbid-
ity measures (WLDs, RADs, RRADs), for workers only or for all adults in
general, were consistently found to be statistically significantly (p <0.01 or
<0.05) related to lagged FP estimates (for air quality 2 to 4 weeks prior to
the health interview data period), when analyzed for each of the individual
years from 1976 to 1981. However, less consistent associations were found
between the health endpoints and more concurrent FP estimates.
The approach employed by Ostro to estimate PM levels introduces into his
analyses a number of uncertainties, e.g., those inherent in airport visibility
measurements, FP/visibility relationships, and TSP monitoring limitations (most
notably, use of the Trijonis equations characterizing FP relationships to
visibility in northeastern U.S. areas may not be appropriate for western U.S.
cities). On the other hand, use of this spatially averaged indicator over time
within a specific area reduces some of these uncertainties. Additional uncer-
tainties derive from use of the HIS data base, with the vast majority of data
points being "0", representing no incidences of indicator effects being
recalled in the prior two weeks. Questions therefore exist regarding the
distributions assumed to underlie the health endpoint results and appropriate
modeling, then, of morbidity-air pollution relationships. The overall patterns
of results obtained from the reported analyses are also difficult to interpret.
They may suggest that acute morbidity effects are associated with fine-mode
particle exposures occurring 2-4 weeks earlier, but less so with immediately
prior FP exposures. Variations in findings reported by other investigators
regarding lag structures in data bases relating mortality or morbidity to PM
exposures are not such as to rule out such a possibility. In any case, it is
not now clear as to how the effects reported by Ostro (1986) might be used to
estimate quantitative relationships between morbidity effects and more usual
24-hr or annual average direct gravimetric measures of particulate matter air
pollution (e.g., TSP, PM1Q, etc.).
Mazumdar and Sussman (1983), discussed earlier, not only studied relation-
ships between' mortality and measures of PM and SOX pollution in Pittsburgh, PA
during 1972-77, but also included evaluations of morbidity (indexed by emergency
hospital admissions) in relationship to daily COH and S02 concentrations
corrected for temperature and seasonal variations. Significant associations
were reported between same-day COH values (which ranged from near 0.0 to 3.5
3-16
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units) and total morbidity and heart disease morbidity for all ages (1 to 59
yr) and > 60 yr age groups, but no consistent statistically significant associ-
ations between morbidity categories and same-day SOp levels (ranging from near
0 to 0.14 ppm) monitored at the same stations. However, these results cannot
be taken as indicative of associations between increased morbidity and elevated
PM or S02 levels in the Pittsburgh area, given limitations identified earlier
in relation to the mortality analyses from the same study, i.e.: (1) inade-
quate characterization of air pollution concentrations representative of the
entirety of Allegheny County from which the morbidity data were drawn, and (2)
internal inconsistencies in the results, with various classes of morbidity
variously being more strongly associated with S02 or COM measured at lower
pollution stations than higher pollution stations.
Perry et al. (1983), followed 24 Denver asthmatic subjects from January
through March, 1979, using twice daily self-obtained measurements of each
subject's peak expiratory flow rates (from Mini-Wright Peak Flow Meters) and
recording use of "as-needed" aerosolized bronchodilators and reports of airway
obstruction symptoms characteristic of asthma. These measures of morbidity'
were tested for relationships to air pollutants using a random effects model.
Dichotomous, virtual impactor samplers at two fixed monitoring sites provided
2
daily measurements (in ug/m ) of inhaled PM (total mass, sulfates, and
nitrates), for coarse (2.5 to 15 |jm) and fine fractions (<2.5 urn). CO, S0«,
03, temperature and barometric pressure were also measured. Of the environmen-
tal variables measured, only fine nitrates were significantly associated with
increased symptom reports and increased bronchodilator usage. During the
course of this study, however, TSP levels were uncharacteristically low. This
limits interpretation of the study in relation to PM effects. Use of aero-
metric data from only two monitoring stations in Denver, with unknown distances
in relation to places of residence for subjects matched to the proximal sta-
tion, also limits the usefulness of the reported findings.
Bates and Sizto (1983, 1985) have also reported results of an ongoing
correlational study relating hospital admissions in southern Ontario to air
pollution levels. Data for 1974, 1976, 1977, and 1978 were discussed in the
1983 paper. The more recent 1985 analyses evaluated data up to 1982 and
showed: (1) no relationship between respiratory admissions and S02 or COHs in
the winter; (2) a complex relationship between asthma admissions and
temperature in the winter; and (3) a consistent relationship between
3-17
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respiratory admissions (both asthma and nonasthma) in summer and sulfates and
ozone, but not to summer COH levels. However, Bates and Sizto note that the
data analyses are now 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 pollu-
tants which produce intensely irritating gases or aerosols in the summer but
not in the winter. More definitive interpretation of these findings may be
limited until additional results findings are reported from this long-term
continuing study.
Of the newly-reported analyses of short-term PM/SOX exposure-morbidity
relationships discussed above, the Dockery et al. (1982) study provides the
.best-substantiated and most readily interpretable results. Those results,
specifically, point toward decrements in lung function occurring in associationj
with acute, short-term increases in PM and S02 air pollution. The small,
reversible decrements appear to persist for 1-2 wks after episodic exposures to|
these pollutants across a wide range, with no clear delineation of threshold
yet being evident. In some study periods effects may haye been due to TSP and
S0? levels ranging up to 422 and 455 ug/m3, respectively. Notably larger
decrements in lung function were discernable for a subset of children
(responders) than for others. The precise medical significance of the observedj
decrements £er se or any consequent long-term sequalae remain to be determined.
The nature and magnitude of lung function decrements found by Dockery et al.
(1982), it should be noted, are also consistent with: observations of
Stebbings and Fogelman (1979) of gradual recovery in lung function of childrenj
during seven days following a high PM episode in Pittsburgh, PA (max 1-hr TSP
estimated at 700 ug/m3); and the report of Saric et al. (1981) of 5 percent
average declines in PE^ Q being associated with high SO,, days (89-235 ug/m ).
3 2 EFFECTS ASSOCIATED WITH LONG-TERM EXPOSURES TO AIRBORNE PARTICLES AND
SULFUR OXIDES
3.2.1. Mortality Effects of Chronic Exposures
WHO (1979) notes that, in countries having reliable systems for the
collection and analysis of data on deaths, based on cause and area of resi-
dence, .death rates for respiratory diseases have -commonly been found to be
higher in towns than in rural areas. Many factors, such as differences in
smoking habits, occupation, or social conditions may be involved in these
3-18
-------
contrasts; however, in a number of countries, a general association between
death rates from respiratory diseases and air pollution has been apparent for
many decades. Analyses of these data have been of great value as a lead for
epidemiologic studies, but the absence of information concerning other relevant
variables, such as smoking, and the relatively crude nature of indices of
pollution used in many of these studies make them unsuitable for the quantita-
tive assessment of exposure-effect relationships.
The 1982 U.S. EPA criteria document (1982a) noted that certain large-scale
"macroepidemiological" (or "ecologic" studies as termed by some) have attracted
attention on the basis of reported demonstrations of associations between
mortality and various indices of air pollution, e.g., PM or SO levels. For
/\
example, Lave & Seskin (1970) reanalyzed mortality data from England and Wales,
and developed multiple regression equations in terms of pollution and socio-
economic indices. Their findings of positive correlations between mortality
rates and pollution are of general interest but cannot contribute to the
development of dose-response relationships because of inadequate exposure
indices used in the analyses. The authors also examined similar data for
standard metropolitan statistical areas (SMSAs) in the USA, and in a later
paper (Lave and Seskin, 1972) attempted to assess relative effects of air
pollution, climate, and home heating on mortality rates. Although equations
were obtained relating death rates to measurements of suspended particulate
matter and total sulfates (both by high-volume sampler), it is again doubtful
whether these can be regarded as valid in the absence of more adequate informa-
tion on smoking and because of inadequate characterization of exposure para-
meters.
Other studies reported in further publications (Lave and Seskin, 1977;
Chappie and Lave, 1981) extended their earlier analyses. Based on such later
work, analogous positive associations between mortality and air pollution
variables were reported for the United States. Many criticisms similar to
those indicated above for the earlier Lave and Seskin (1970) study apply here.
Of crucial importance are basic difficulties associated with all of their
analyses in terms of: (1) use of aerometric data without regard to quality
assurance considerations, notably including use of sulfate measurements known
to be of questionable accuracy due to artifact formation during air sampling;
and (2) questions regarding how representative the air pollution data used in
the analyses are as estimates of actual exposures of individuals included in
3-19
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their study groups. In some instances, for example, data from a single moni-
toring station were apparently used to estimate pollution exposures for study
populations from surrounding large metropolitan areas.
The 1982 U.S. EPA criteria document (1982a) noted that further difficul-
ties in discerning consistent patterns of association between mortality and air
pollution variables are encountered when results of Lave and coworkers are
compared with those obtained by others using analogous macroepidemiological
approaches. For example, Mendelsohn and Orcutt (1979) carried out regression
analyses of associations between 1970 mortality rates (for 404 county groups
throughout the United States) and air pollution exposures retrospectively
estimated on the basis of 1970 and 1974 annual average pollutant data from air.
monitoring sites in the same or nearby counties. Their results suggested fairly
consistent (though variable) associations between mortality for some age groups
(increasingly more positive with age) and sulfate levels but much less consis-
tent and sometimes negative associations with TSP or other pollutants. The
combined TSP-SO, pollution-health elasticity obtained by Mendelsohn and Orcutt
(1979) is similar to that obtained in the earlier studies by Lave and coworkers,
all falling in the range of 0.1 to 0.2.
Other results obtained by Thibodeau et al. (1980) in carrying out large
scale cross-sectional analyses of the above type indicate that the regression
coefficients for mortality relationships with air pollution variables are
quite unstable. Also, Lipfert (1980) reported results from an analysis taking
into account a smoking index based on state tax receipts, which he interpreted
as showing sulfates to be least harmful of seven air pollutants (including S02
and TSP), although no adjustments for urban-rural differences in study popula-
tion residences were used. This is in contrast to unpublished analyses of 1970
United States mortality data by Crocker et al. (1979), which found no signifi-
cant relationships between air pollution and total mortality when taking into
account retrospectively estimated nutritional variables and a smoking index.
Also, results of Gerking and Schultz (1981), using the same data base, indi-
cated a significant positive relationship between-TSP and total mortality when
_using an OLS model similar to that of Lave and Seskin (1977) but found nega-
tive, though significant, air pollution coefficients after adding smoking,
nutrition, exposure-to-cold, and medical-care variables to a two-equation
model.
3-20
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U.S. EPA (1982a) also noted that various criticisms of the above studies
have been advanced by authors of the other respective studies, but it was not
possible to ascertain which findings may be more valid than others. Thus,
although many of the studies qualitatively suggested positive associations
between mortality and chronic exposure to certain air pollutants in the United
States, many key issues remained unresolved concerning reported associations
and whether they are causal or not. Since preparation of the earlier Criteria
Document (U.S. EPA, 1982a) additional ecological analyses have been reported
regarding efforts to assess relationships between mortality and long-term
exposure to particulate matter and other air pollutants.
Lipfert (1984) conducted a series of cross-sectional multiple regression
analyses of 1969 and 1970 mortality rates for up to 112 U.S. SMSA's, using the
same basic data set as Lave and Seskin (1978) for 1969 and taking into account
various demographic, environmental and lifestyle variables (e.g., socioeconomic
status and smoking). Also included in the Lipfert (1984) reanalysis were the
following additional independent variables: diet; drinking water variables;
use of residential heating fuels; migration; and SMSA growth. New dependent
variables included age-specific mortality rates with their accompanying sex-
specific age variables. Both linear and several nonlinear (e.g., quadratic or
linear splines testing for possible threshold model specifications) were
evaluated. Efforts to replicate the basic analyses of Lave and Seskin (1978)
and to improve upon the fit of models using various specifications led Lipfert
(1984) to conclude that: (1) differences existed between high and low pollu-
tion SMSAs unrelated to the magnitude of the air pollution variables, i.e. that
there appear to be important variables missing from the specification; (2)
correction of errors in the Lave-Seskin data improved the regression fit and
significance of some of the coefficients; but (3) it was not possible to
conclude whether S04 or TSP has a statistically significant effect on total
mortality or whether either response is linear.
Lipfert (1984) then introduced additional variables of the type listed
above into the reanalysis in hopes of improving the specification and to
evaluate possible collinearity with the pollution variables. The fact that
some observations were incomplete for some of the newly added variables neces-
sitated the analysis of certain subsets of the original Lave-Seskin data set.
Overall, for these reanalyses, in which regressions were extended to include
3-21
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new variables in stepwise fashion (but retaining the 7 Lave-Seskin variables as
the first step in each case), adding new variables significantly improved the
fit, but several of the original Lave-Seskin variables (including S04) became
non-significant as the result of the additional variables. Further analyses
included regressions for mortality restricted to central city areas versus
SMSA-based regressions, with agreement between coefficients for sulfates being
quite poor (and negative for central city regressions broken down by age groups
<65 or >65 yr). Many of the additional explanatory variables in the above
reanalyses (both for central city and SMSA regressions) were found to be
statistically significant and were then employed in regressions using total
mortality rates adjusted for age, nonwhite population, poverty and cigarette
smoking. Results obtained with use of additional explanatory variables and
varying model specifications were very mixed: (1) sulfate coefficients were
quite unstable, ranging from near 0.0 to 0.049 (highly significant and corres-
ponding to an elasticity of 6 percent); (2) TSP coefficients were similarly
variable, with similar maximum elasticity; (3) in no case were TSP and sulfate
variables significant in the same regression; and (4) when the full set of
explanatory variables were used with the dummy pollution variables, the coeffi-
cients for the pollution variables became more significant. Lipfert (1984),
based on these total mortality analyses, concluded that: (1) the Lave-Seskin
specification is inadequate and provides misleading results; (2) using addi-
tional explanatory variables improves the fit; (3) the existence of thresholds
for the air pollution variables can neither be proved nor disproved; (4)
although difficult to separate S04 effects from TSP effects, the TSP coeffi-
cients displayed slightly more consistent behavior across all the data sets
considered; and (5) effects for drinking water, ozone, and (to a lesser extent)
coal and wood heat warrant further investigation.
Results obtained by Lipfert (1984) with further age- and sex-specific
regression analyses for <65 yr old subjects, using all other variables as
defined in the above total mortality regressions, produced similar results as
for the total mortality analyses. That is, as explanatory variables are added,
the pollution variables tend to lose significance and the r values are con-
siderably higher than those of Lave and Seskin (1978), even when using the same
specifications. Based on the age- and sex-specific analyses: (1) sulfate was
never significant for males (except for Lave-Seskin specifications) and only
occasionally significant for females; and (2) TSP was more often significant
3-22
-------
for both males and females, especially with threshold specifications. Analo-
gous sex-specific analyses for persons > 65 yr old revealed further interesting
results: (1) the migration variable was the single most important variable and
the age variable was negative; (2) sulfate was significant only with the
Lave-Seskin specification (both sexes) or with other variables suppressed
(females); and (3) TSP was never significant.
In sum, it is quite evident from the above results that the air pollution
regression results for the U.S. data sets analyzed by Upfert (1984) are
extremely sensitive to variations in the inclusion/exclusion of specific
observations (for central city versus SMSA's or different subsets of locations)
or additional explanatory variables beyond those used in the earlier Lave and
Seskin (1978) analyses. The results are also highly dependent upon the parti-
cular model specifications used, i.e. air pollution coefficients vary in
strength of association with total or age-/sex-specific mortality depending
upon the form of the specification and the range of explanatory variables
included in the analyses. Lipfert's overall conclusion was that; the sulfate
regression coefficients are not to be taken seriously and, since sulfate and •
TSP interact with each other in these regressions, caution is warranted for T§P
as well.
Ozkaynak and Speingler (1985) have also described recent results from
ongoing attempts of a Harvard University group to improve upon some of the
previous analyses of mortality and morbidity effects of air pollution in the
United States. Ozkaynak and Speingler (1985) present principal findings from a
cross-sectional analysis of the 1980 U.S. vital statistics and available air
pollution data bases for sulfates, and fine, inhalable and total suspended
particles. In these analyses, using multiple regression methods, the associa-
tion 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 autocorrelation 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 parti-
cular, 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)
3-23
1
-------
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
non-significant 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 non-significant 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
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, 1986) may at least partly explain
their contrasting results, but there is at present no basis by which to deter-
mine if this is the case or which set of findings may or may not most accurate-
ly characterize associations between mortality and chronic PM or SOX exposures
in the United States.
Selvin et al. (1984) also used regression analyses applied to ecologic
data to study the influence of air quality in the U.S. on mortality. The
analyses used 1968-72 mortality data aggregated by county (3082) or by groups
of counties comprising 410 1970 Census Public Use Sample (PUS) areas (some of
which may be a single heavily populated urban county, e.g. Los Angeles, or
several sparsely populated rural counties grouped together). Total mortality,
rather than cause-specific, rates were calculated for sex-, race, and
age-specific categories and were then evaluated by regression analyses in rela-
tion to air quality values (for TSP, S02, and N02) extracted from data collected
at 6625 monitoring stations during 1974-76. County level aerometric estimates
were interpolated from average values at individual monitoring stations, and
air pollution estimates for the 410 PUS areas were population-weighted averages
of the county level value. Overall, various regression analyses (taking into
3-24
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account numerous control variables) for county-wide or PUS areas in all of the
U.S. or broken down into regions (West, South, etc.) yielded extremely mixed
results, with both positive and negative coefficients being obtained in various
analyses for mortality in relation to TSP, SOp, and N02- The authors: (1)
concluded that their results provided no persuasive evidence for links between
air cjuality and general mortality levels; (2) noted that their results were
inconsistent with previously published work; and (3) opined that linear regres-
sion analyses applied to nationally collected ecologic data cannot be usefully
employed to infer causal relationships between air quality and mortality.
However, the manner in which the Selvin et al. (1984) study was conducted
provides little basis for assigning any credibility to the results obtained,
especially in view of: (1) use of 1974-76 air quality data to estimate retro-
spectively exposures against which to compare 1968-74 mortality data and; (2)
use of mortality data aggregated by county or by groups of counties with highly
variable relationships between air monitoring locations and the population
groups from which the mortality data were drawn.
Turning from ecological or macroepidemiological studies of mortality
relationships to chronic air pollution exposures in the U.S., Imai et al.
(1986) have recently published analyses of associations between mortality from
asthma and chronic bronchitis and air pollution variables in Yokkaichi, Japan.
An industrial city on Ise Bay several hundred miles south of Tokyo, Yokkaichi's
industrial base and harbor facilities were largely destroyed during World War
II. They were later rebuilt to include the establishment in 1957 of a petro-
leum complex that contained the largest oil-fired power plant in Japan, which
burned high-sulfur oil that resulted in large SC^ emissions and consequent high
SO concentrations in immediate residential/commercial areas around the harbor.
This continued until stringent emission controls were put in place and resulted
in dramatic decreases in SO concentrations in the highly polluted area around
*\
the harbor from 1972 to 1973 and thereafter. Mortality rates for the popula-
tion in that high pollution area were compared against analogous rates '(for
bronchial asthma or chronic bronchitis including emphysema, determined from
death certificates issued during 1963-83) for people living in less-polluted
areas of Yokkaichi. Sulfur oxides levels (measured by the lead peroxide
method) averaged across several monitoring sites in the polluted harbor area
ranged .from around 1.0 to 2.0 mg/day (annual average) during 1964-72 and then
steadily declined from somewhat less than 1.0 mg/day in 1973 to less than 0.5
3-25
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rag/day in 1982. This is in contrast to SOX levels consistently below 0.3
mg/day (annual average) at 3 monitoring sites in the low pollution areas of the
city throughout 1967 to 1982. Annual average levels for other pollutants
(N02, TSP, Oxidants) monitored in the high pollution area were also consistent-
ly low, i.e. <0.02 ppm (N02), <0.05 mg/m3 (TSP), and <0.05 ppm (oxidants, daily
max hourly values) from 1974 to 1982. Results obtained indicated significant
differences between chronic bronchitis mortality for persons > 60 yr old in the
high pollution area compared against rates for the same age group from the
low-pollution control area for 1967-70 and extending into 1971^74, somewhat
beyond the point where marked declines became evident in SO levels after
J\
control measures were implemented. Lagged correlations showed large signifi-
cant associations between SO levels and chronic bronchitis mortality occur-
f\
ring >1 yr later in the high pollution area (the largest correlations were
found for 4-5 yr lags). In contrast, bronchial asthma mortality became rela-
tively higher in the polluted area during the 1967-70 period, and began to
decrease thereafter in more immediate response to the improvement in air
quality.
These findings, overall, are quite interesting in that they relate mortal-
ity changes in populations in circumscribed urban neighborhoods to air pollu-
tion indices obtained from monitoring sites spatially located in close proxi-
mity to the residences of the population groups for whom mortality rates were
determined. Further, consistently elevated mortality for the elderly in the
high-pollution area (relative to the control area) was evident across many
years while the SO concentrations were high, but then declined following
A
reductions in the SO levels, thus enhancing the likelihood of a causal rela-
J\
tionship between sulfur-containing air pollution and mortality having been
detected in the study. However, it is not possible to quantitate with any
precision the relative contributions to the observed mortality increases of
SOp versus sulfates or other sulfur agents (e.g., possibly H2S04 aerosols
likely formed in the moist air of the coastal city).
The 1982 EPA document (U.S. EPA, 1982a) also noted that, other epidenrio-
logical studies have more specifically attempted to relate lung cancer mor-
tality to chronic exposures to sulfur oxides, PM undifferentiated by chemi-
cal composition, or specific PM chemical species. However, the 1982 document
concluded that little or no clear epidemiological evidence advanced to date
substantiates hypothesized links between S02 or other sulfur oxides and cancer;
3-26
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nor does there now exist credible epidemiologies! evidence linking increased
cancer rates to elevations in PM as a class, i.e., uncHfferentiated as to
chemical content.
3.2.2. Morbidity Effects of Long-Term Exposures
Impairment of pulmonary function is likely to be one of the effects of
long-term exposures to air pollution, since the respiratory system includes
tissues that receive the initial impact when toxic materials are inhaled.
Acute and chronic changes in pulmonary function may be significant biological
responses to air pollution exposure, A number of studies have been conducted
in an effort to relate pulmonary function changes to the presence of air
pollutants in European, Japanese, and American communities. However, few
provide more than qualitative evidence relating pulmonary function changes to
airborne particles. The few elevated earlier by U.S. EPA (1982a) as providing
quantitative evidence for lung function effects due to long-'teTm PM and/or SOX
exposure are. summarized in Table 2.
One series of studies, reported on from the early 1960s to the mid-1970s,
was conducted by Ferris, Anderson, and others (Fern's and Andersen, 1962;
Kenline, 1962; Andersen et al., 1964; Ferris et al., 1967, 1971, 1976). The
initial study involved comparison of three areas within a pulp-mill town
(Berlin, New Hampshire). Kenline (1962) reported average 24-h SQ2 levels
(estimated from sulfation rates) during a limited summer sampling period
(August-September, 1960) to be only 16 ppb and average 24-h TSP levels for the
two-month period to be 183 jjg/m . In the original prevalence study (Ferris
and Anderson, 1962; Anderson et al., 1964), no association was found between
questionnaire-determined symptoms and lung function tests assessed in the
winter and spring of 1961 in the three areas with differing pollution levels,
after standardizing for cigarette smoking. The authors discuss why residence
is a limited indicator for exposure (Anderson et al., 1964). The study was
later extended to compare Berlin, New Hampshire, with the cleaner city of
Chilliwack, British Columbia in Canada (Anderson and Ferris, 1965). Sulfation
rates (lead 'candle method) and dustfall rates were higher in Berlin than in
Chilliwack. The prevalence of chronic respiratory disease was greater in
Berlin, but the authors concluded that this difference was due to interactions
between age and smoking habits within the respective populations.
3-27
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3-28
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The Berlin, New Hampshire, population was followed up in 1967 and again in
1973 (Ferris et a!., 1971, 1976). During the period between 1961 and 1967, all
o
measured indicators of air pollution fell, e.g., TSP from about 180 ug/m in
1961 to 131 ug/m3 in 1967. In the 1973 follow-up, sulfation rates nearly
doubled from the 1967 level (0.469 to 0.901 mg SOVlOO/cm2 day) while TSP
3
values fell from 131 to 80 ug/m . Only limited S02 data were available (the
mean of a series of 8-h samples for selected weeks). During the 1961 to 1967
period, standardized respiratory symptom rates decreased and, there was an in-
dication that lung function also improved. Between 1967 to 1973, age-sex
standardized respiratory symptom rates and age-sex-height standardized pulmonary
function levels were unchanged. Although some of the testing was done during
the spring versus the summer in the different comparison years, Ferris and co-
workers attempted to rule out likely seasonal effects by retesting some sub-
jects in both seasons during one year and found no significant differences in
test results. Given that the same set of investigators, using the same
standardized procedures, conducted the symptom surveys and pulmonary function
tests over the entire course of these studies, it is unlikely that the observed
health endpoint improvements in the Berlin study population were due to varia-
tions in measurement procedures, but rather appear to have been associated with
o
decreases in TSP levels from 180 to 131 ug/m . The relatively small changes
observed and limited aerometric data available, however, argue for caution in
placing much weight on these findings as quantitative indicators of effect or
no-effect levels for health changes in adults associated with chronic exposures
to PM measured as TSP.
The earlier criteria review (U.S. EPA, 1982a) also noted that one other
American study provided potentially useful qualitative or quantitative informa-
tion regarding association of morbidity effects in adults with ambient exposures
to S02 or particulate matter. A cross-sectional study was conducted by Bouhuys
(1978) in two Connecticut communities in which differences in respiratory and
pulmonary function were examined in 3056 subjects (adults and children).
Hosein (1977a) reported on aerometric data used in the study, which were
obtained at three sites in Ansonia (urban) and four sites in Lebanon (rural)
near the residences of study subjects. The TSP levels during the period of the
o
study in Lebanon and Ansonia were 39.5 and 63.1 ug/m and S09 levels were 10.9
o *•
and 13.5 ug/m , respectively. Site-to-site variations on the same day were
frequently significant in Ansonia and also occurred in Lebanon. During the
3-29
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years 1966-72, annual average TSP levels in Ansonia ranged from 88 to 152
ug/m3. No historical data for SOp or TSP in Lebanon were provided. Size
fractionation (Hosein, 1977b) of a limited number of TSP samples in Ansonia
showed that 81 percent of the TSP sample was 9.4 urn or less in diameter.
Binder et al. (1976) obtained for 20 subjects in Ansonia one 24-hour measure of
personal air pollution exposure for particles (<7 urn diameter), St^, and N02-
Subjects with smokers in the home were exposed to significantly higher levels
than those without such exposure. Personal exposure and outdoor exposures were
also significantly different. The mean personal respiratory level was 114
n 2
ug/m as compared to the outdoor TSP level of 58.4 ug/m .
An extended version of the MRC Questionnaire was administered via a
computer data-acquisition terminal (Mitchell, 1976) between October 1972 and
January 1973 in Lebanon and from mid-April through July 1973 in Ansonia. For
children 7 to 14 yrs) the response rate varied from 91 to 96 percent for boys
and girls. For adults (25 to 64 years) the response rate was 56 percent in
Ansonia and 80 percent in Lebanon. After analysis of non-responder versus
responder differences, the responders were considered to be representative of
the total population, although some significant differences were noted between
responders and non-responders for some symptom reporting and current smoking in
some age groups.
Bouhuys (1978) found no differences between Ansonia and Lebanon for
chronic bronchitis prevalence rates but did note that a history of bronchial
asthma was highly significant for male residents of Lebanon (the cleaner town)
as compared to Ansonia (the higher-pollution area). No differences were
observed between the communities for pulmonary function tests adjusted for sex,
age, height and smoking habits. However, three out of five symptoms (cough,
phlegm, and plus one dyspnea) prevalences were significantly higher for adult
non-smokers in Ansonia (p <0.001). The mix of both positive and negative
health effect results obtained in this cross-sectional study make it difficult
to interpret. Although the study generally found few air pollution effects,
the statistically significantly increased symptom rates raise questions as to
whether some-impact on health (due to prior PM exposures, for example) might
have occurred. A follow-up longitudinal examination could have determined
whether the effects persisted. Also, it may be that the reported effects
related, more to historical rather than current pollutant levels or to occupa-
tional exposures which were not examined.
3-30
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The 1982 Criteria Document (U.S. EPA, 1982a) further indicated that
apparent quantitative relationships between air pollution and lower respiratory
tract illness in children were reported by Lunn et al. (1967), These investi-
gators studied respiratory illness in 5- and 6-year old school children living
in four areas of Sheffield, England. Air pollution concentrations showed a
gradient in 1964 across four study areas for mean 24-hour smoke (BS) concentra-
00
tions from 97 ug/m to 301 ug/m . During the following year, the annual
concentrations of smoke were about 20 percent lower and S02 about 10 percent
higher, but the gradient was preserved for each pollutant. In high-pollution
areas, individual 24-h mean smoke concentrations exceeded 500 ug/m 30 to 45
times in 1964 and 0 to 15 times in 1965 for the lowest and highest pollution
2
areas, respectively. Sulfur dioxide exceeded 500 ug/nT 11 to 32 times in 1964
and 0 to 23 times in 1965 for the lowest and highest pollution areas, respec-
tively. Information on respiratory symptoms and illness was obtained by
questionnaires completed by parents, by physical examination, and by tests of
pulmonary function (FEVQ 75 and FVC). Socioeconomic factors (SES) were con-
sidered in the analyses, but parental smoking and home-cheating systems were
not. Although some differences in SES between areas were noted, gradients
between areas existed even when the groups were divided by social class, number
of children in house, and so on. Positive associations were found between air
pollution concentrations and both upper and lower respiratory illness. Lower
respiratory illness was 33 to 56 percent more frequent in the higher pollution
areas than in the low-pollution area (p <0.005). Also, decrements in lung
function, measured by spirometry tests, were closely associated with respira-
tory disease symptom rates.
In a second report, Lunn et al. (1970) gave results for 11-year-old
children studied in 1963-64 that were similar to those found earlier for the
younger group. Upper and lower respiratory illness occurred more frequently in
children exposed to annual average 24-h mean smoke (BS) concentrations of 230
to 301 ug/m3 and 24-h mean S02 levels of 181-275 ug/m3 than in children exposed
to smoke (BS) at 97 ug/m3 and S02 at 123 ug/m3. This report also provided
. additional information obtained in 1968 on 68 percent of the children who were
5 and 6 years old in 1963-64. By 1968, the reported BS concentrations were
only about one-half those measured in 1964, S02 levels were about 10 to 15
percent below those of 1964, and the pollution gradient no longer existed; so
3-31
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the combined three higher pollution areas were compared with the single origi-
nal low-pollution area. Lower respiratory illness prevalence measured as
"colds going to chest" was 27.9 percent in the low-pollution area and 33.3
percent in the combined high-pollution areas, but the difference was not
statistically significant (p >0.05). Ventilatory function results were
similar. Also, the 9-year-old children had less respiratory illness than the
11-year-old group seen previously. Becuase 11-year-old children generally have
less respiratory illness than do 9-year olds, this represented an anomaly that
the authors suggested may be due to improved air quality.
It should be noted that these Lunn et al. (1967, 1970) findings have been
widely accepted (WHO, 1979; Holland et al., 1979; U.S. EPA, 1982a,b) as valid.
On the basis of the results reported, it appears that increased frequency of
lower respiratory symptoms and decreased lung function in children may occur
O
with long-term exposures to annual BS levels in the range of 230 to 301 ug/m
and SOp levels of 181 to 275 ug/m . However, these must be taken only as very
approximate observed-effect levels because of uncertainties associated with
estimating PM mass based on BS readings. Also, it cannot now be concluded,
based on the 1968 follow-up study, that no-effect levels were demonstrated for
BS levels in the range of 48 to 169 ug/m because of: (1) the likely insuffi-
cient power of the study to have detected small changes given the size of the
population cohorts studied, and (2) the lack of site-specific calibration of
the BS mass readings at the time of the later (1968) study. In summary, the
one study by Lunn et al. (1967) provided the clearest evidence cited in the
1982 EPA criteria document (U.S. EPA, 1982a) for associations between both
significant pulmonary function decrements and increased respiratory disease
illnesses in children and chronic exposure to specific ambient air levels of PM
and S02.
Since the earlier criteria review (U.S. EPA, 1982a), results of analyses
of data from the ongoing Harvard study of outdoor air pollution and respiratory
health status of children in six cities in the eastern and midwestern United
States have been reported recently by Ware et aV. (1986), 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 stan-
dardized, questionnaire regarding the child's health status and other important
background information. Most of the children (8,380) were seen for a second
3-32
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evaluation one year later. Measurements of TSP, the sulfate fraction of TSP
(ISO.), and SOp concentrations at study-affiliated outdoor stations were
combined with data from other public and private monitoring sites to create a
record of TSP, ISO., and SCL levels in each of 9 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.
Analyzing data across all six cities, Ware et al. (1985) found that fre-
quency of chronic cough (see Figure 5) was significantly associated (p <0.01)
with the average of 24-hr mean concentrations of all three air pollutants (TSP,
TSO., SOp) during the year preceding the health examination. Rates of bron-
chitis and a composite measure of lower respiratory illness were significantly
(p <0.05) associated with annual average particulate concentrations, as well as
being related to measures of lifetime TSP 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 (see Figure 6) or, for lifetime
residents, with lifetime average concentrations, although Ferris et al. (1986)
reported a small effect on lower airway function (MMEF) related to FP concen-
trations. ;
Overall, these results appear to suggest that risk may be increased for
bronchitis and some other respiratory disorders in preadolescent children at
moderately elevated TSP, TSO^ and SO^,, 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. For example, it might be argued that the non-significant
associations within cities but significant symptom increases in relation to air
pollutant gradients across the cities may reflect spurious correlations across
the cities. On the other hand, the within city variation in air pollutant
gradients and/or size of study populations within particular cities may not be
sufficiently large to detect associations between the health endpoints and air
pollutant variables included in the analyses. Also, the PM indices employed in
3-33
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CHRONIC COUGH
175-
150-
§125-1
o
cc
UJ
D-
LiJ
I—
d
100-
75
50
25
0
H
25 50 75
HERN TSP
100 125 150
Figure 5 Adjusted frequency of cough for the 27 region-cohorts from the
Six-Cities Study at the second examination plotted against mean
•TSP concentration during the previous year, with between-cities
regression equation. LEGEND: P=Portage, T=Topeka, W=Watertown,
C=Carondolet, L=0ther St. Louis, R=Steubenville Ridge, V=Steubemn1
Valley, K=Kinston, H=Harriman.
Source: Ware et al. (1985).
3-34 '
-------
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the analyses (e.g., TSP, etc.) may provide a "diluted" measure of exposure to
the most highly toxic PM components (e.g., FP or small coarse-mode particles).
In fact, the reported stronger associations between TSO^ levels and other
measures of ambient air FP concentrations are highly suggestive of possible
associations between health effects observed in the Ware et al. (1985) study
and exposure to small particles in contemporary U.S. atmospheres. Available
data (Spengler and Thurston, 1983) from air monitors sampling inhalable parti-
culates (IP; <15 urn) in the same cities included in the Harvard Six Cities
Study analyses discussed here indicate IP mass annually averaged from approxi-
mately 20 to 60 ug/m3. This suggests that the observed health effects noted
above may be associated with annual average IP (<15 urn) concentrations below 60
jig/m3. However, full interpretation of the strength and significance of these
findings is difficult at this point, in light of further follow-up of these
children still being in progress and the expectation that longitudinal analyses
will later be carried out which will relate health data to more extensive
aerometric data (including such data collected in later years).
In another new American study, by Schenker et al. (1983), respiratory
symptom questionnaires were administered to 5557 adult women in a rural area of
western Pennsylvania. Air pollution data (including S02 but not PM measure-
ments) were derived from 17 air monitoring sites and stratified in an effort to
define low, medium and high pollution areas. The means of 4-yr (1975-1978)
annual average S02 levels in each stratum were 62, 66, and 99 ug/m , respec-
tively. Risks for respiratory symptoms were assessed by a multiple logistic
model that controlled for several potentially confounding factors (e.g.,
smoking) and used estimated air pollution concentrations at population-weighted
centroids of 36 study districts (i.e., the concentrations were derived from
another model which weighted observed monitoring data for distance from the
district centroid and corrected for terrain effects). The risk of "wheeze most
days or night" in nonsmokers residing in the high- and medium-pollution areas
was 1.58 and 1.26 (p = 0.02), respectively, in relation to the low-pollution
area. For residents living in the same location for >5 yr, these relative
risks were 1.95 and 1.40 (p <0.01), and increased, risk of grade 3 dyspnea in
nonsmokers was associated with S02 levels at p <0.11. However, no significant
association was observed betv/een cough or phlegm and air pollution variables.
The results of this study, while suggesting that wheezin'g may be qualitatively
associated with ambient exposure to S02, are difficult to accept in light of:
3-36
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(1) the very limited gradient of annual-average S02 levels across which health
effects were reported to have been detected (associations with higher level
exposures versus distinctly lower S02 concentrations would be more credible);
(2) the very rough estimation of S02 exposure concentrations by means of model
calculations; and (3) the lack of evaluation of possible PM or short-term S02
peak contributions to the evaluated health effects.
Several other recent studies have been reported that evaluated PM and/or
SO effects in populations residing in the southwestern United States. In one,
Chapman et al. (1983) conducted a survey in early 1976 regarding the prevalence
of persistent cough and phlegm (PCP) among 5,623 young adults in four Utah
communities stratified to represent a gradient of sulfur oxides exposures.
Community-specific mean S02 levels had been 11, 18, 36 and 115 ug/m during the
5 years prior to the survey and corresponding mean sulfate levels were 5, 7, 8,
and 14 ug/m3. No gradients of TSP or suspended nitrates were observed across
the communities. Aerometric data were obtained from monitors sited at ground
level. Differences along the sulfur oxides gradient were tested by chi-square
statistics, and data were also analyzed by constructing .categorical'logistic
regression models that treated PCP as the dependent variable and controlled for
numerous potentially important factors (e.g. smoking, age, SES, etc.). For
nonsmoking mothers, PCP prevalence was 4.2 percent in the high-exposure com-
munity and ~2.0 percent in all other communities. For non-smoking fathers,
the PCP prevalence was 8.0 percent in the high pollution community and 3.0
percent elsewhere, while the PCP prevalence was less strongly associated with
ambient sulfur oxides exposures for smoking fathers. Overall, intercommunity
prevalence differences were significant at p <0.05 for all the above groups
except smoking fathers. The categorical logistic regression model yielded
similar results, providing evidence suggestive of increased cough and phlegm
O O
being associated with annual average 115 ug/m S02 levels and/or 14 ug/m
sulfate levels. There is much to argue for acceptance of the reported results
from this study, including use of aerometric data from monitors situated in
close proximity to study subjects' homes and nearly equivalent response rate?
on the health questionnaire across the communities sampled.
Dodge (1983) studied the respiratory health and lung function of Anglo-
American children (grades 3 to 5) residing in an Arizona smelter community
versus such children residing in another small Arizona community free of
smelter air pollution. Cough prevalence was 25.6 percent in the smelter town
3-37
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children and 14.3 percent in the non-smelter groups (p <0.05). Baseline
pulmonary function at the outset of the study was equal in the two groups, and
over the four years of the study, lung function growth (measured in terms of
FEV-, after 4 yr. of study minus predicted FEV-^) was also equal between,the two
groups. During the study, annual average S02 levels were 55 and 48 ug/m at
company and state monitoring sites, respectively (highest 24-hr S02 levels were
611 and 524 ug/m3, respectively, at the company and state sites). Annual
average TSP was 28 ug/m3 in the smelter community. These results suggest that
smelter community children had more cough than the control group children but
no evident differences in lung function. However, it is difficult to ascribe
the reported effects specifically to S02 or TSP (although the very low levels
,of the latter are unlikely to account for the effects).
Dodge et al. (1985) more recently reported on a longitudinal study of
children exposed to markedly different concentrations of S02 and moderately
different levels of particulate sulfate (SO]J) in Southwestern U.S. towns. Four
groups of subjects lived in two areas of one smelter town and in two other
towns, one of which was also a smelter town. In the highest pollution area,
the children were exposed intermittently to high S09 levels (peak 3-hr x
3
exceeded 2,500 ug/m or ~1.0 ppm) and moderate particulate SO^ levels (x = 10.1
ug/m3). When children were grouped by the four observed pollution gradients,
the prevalence of cough (measured by questionnaire) correlated significantly
with pollution levels (trend chi-square = 5.6; p = 0.02). No significant
differences occurred 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 exposures to S02, in
the presence of moderate particulate sulfate levels, produced evidence of
bronchial irritation (increased cough) but no chronic effect on lung function
or lung function growth. It is difficult to quantitate the S02 levels specifi-
cally associated with the observed effects, although the intermittent high
level exposures to ~1.0 ppm (3 hr averages) mentioned earlier are likely
implicated. Note that S02 levels for the higher polluted smelter town annually
averaged 103'± 282 (S.D.) ug/m3 (indicating wide variability in the one hr mean
levels) versus 14 ug/m3 in the lesser polluted town. Other measured air
pollutants, e.g. TSP, differed little between the high and low pollution areas
(24-hr TSP x = 52 and 58 ug/m3, respectively). The observation of increased
3-38
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cough but lack of lung function changes in children comports well with the
findings of Ware et al. (1986).
Lebowitz et al. (1982) studied 117 families in Tucson, Arizona, selected
from a stratified sample of families in geographical clusters from a represen-
tative community population included in an ongoing epidemiologic study. Both
asthmatic and non-asthmatic families were evaluated over a two year period,
using daily diaries; and the health data obtained were related to various in-
dices of environmental factors derived from simultaneous micro-indoor and out-
door monitoring in a representative sample of houses for air pollutants,
pollen, fungi, algae and climate. Macromonitoring of air pollutants and pollen
was carried out simultaneously. The data were mainly evaluated in terms of
statistical techniques employing contingency tables and frequency distributions
using SPSS programs. Two-month averages of indoor TSP ranged from 2.1 to 169.6
ug/m3. Cyclone measurements of respirable particulate (RSP) ranged from below
readable limits up to 28.8 ug/m3. CO and NOX measurements were also taken, but
no S02 monitoring was reported. Suspended particulate matter and pollen were
reported to be related to symptoms in both asthmatics and non-asthmatics, but
the authors reported that the statistical analyses used were all qualitative
(becase of low sample size) and statistical significance was not computed.
In a recently published Canadian study, Pengelly et al. (1986) reported
results for an ongoing study of associations between particle size and respira-
tory health in children of Hamilton, Ontario. From 1979 to 1982, a cohort of
approximately 3500 elementary school children was studied by determining each
child's health history and respiratory symptoms by means of a questionnaire
administered to their parents. Also, pulmonary function tests were conducted
on the children at school. Particle size and concentrations were determined by
using two networks distributed across the city, one consisting of 7 to 9
Anderson 2000 Cascade impactors and another of 27 hi-vol TSP samplers. Smoking,
use of gas for cooking, SES and other potentially confounding factors were
assessed by parental questionnaire and controlled for in statistical analyses,
i.e., stepwise multiple regression techniques (linear for continuous dependent
variables and logistic for binary dependent variables).
In the present report, Pengelly et al. (1986) focused on two indicators of
respiratory health (cough and bronchitis episodes) and two indicators of
pulmonary function (peak expiratory flow or PF and MEF?5), both adjusted for
body size. Logistic regression analyses found no significant associations
3-39
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between cough or bronchitis episodes and air pollution indices, 'correcting for
other factors. Both peak flow and MEFyg (adjusted for height) were reported to
be significantly associated with the presence of fine particles. However, the
fine fraction (FF) was estimated by adding results for samples collected by the
lower stages of a cascade impactor (nominally reflecting sizes <3.3 urn). Based
on particle bounce problems associated with this impactor (see discussion in
Chapter 1) and comparison measurements made by the authors in Hamilton between
dichotomous fine (<2.5 urn) and the cascade FF, additional coarse material >3.3
pm was probably also included in the FF measured by Pengelly et al. (1985).
Overall the FF mass was more than double the dichotomous sampler fine mass.
Also since preparation of the earlier criteria review (EPA, 1982a),
additional analyses of health effects relationships to PM and SO air pollution
J\
in European cities have emerged. Some of the new European work includes
longitudinal analyses reported by van der Lende et al. (1986) as being conduct-
ed in regard to evaluating relationships between prevalence of respiratory
symptoms and pulmonary function decline and variations in air pollution in two
areas of The Netherlands. That is, health measurements were obtained from
cohorts of approximately 2000 men and women (aged 15 to 64 years), residing in
a highly polluted area (Vlaardingen) or a non-polluted rural area (Vlagtweddej,
with subjects being followed and examined at intervals of three years. Over
the course of the study, air pollution levels (PM measured as British smoke,
SOg, etc.) remained consistently very low in the latter area, whereas pollution
levels declined over time in the former, highly polluted area. Van der Lende
et al. (1986) noted that in a previous publication, they reported both a
significantly higher prevalence of respiratory symptoms in the polluted area
and also a greater decline there in pulmonary function (based on four consec-
utive studies over a 9-year period). In the present update paper (van der
Lende et al., 1986), further findings are provided regarding associations
between respiratory symptoms and pulmonary function decline and air pollution
after six consecutive studies covering a 15-year period. The results, termed
"preliminary" by the authors, provide some indications of more respiratory
•symptoms and greater pulmonary function declines in the polluted area than the
control, non-polluted area. However, as currently available, the reported
results do not allow for any quantitative conclusions to be clearly drawn
regarding PM levels associated with observed health effects.
3-40
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In another study (PAARC, 1982a,b), relationships between atmospheric
pollution and chronic or recurrent respiratory diseases were evaluated from
1974 to 1976 as part of a French national survey in 28 areas of 7 cities and a
newly industrialized region. The following pollutants were measured: S0?
(specific-SP and acidimetric-AF methods); suspended particles (smoke and
modified OECD gravimetric methods); nitrogen oxides (NO and NOp measured by
modified Griess-Saltzmann method); and sulfates (measured by colorimetry after
reduction). Samples were obtained over 24 hr. periods, but for the gravimetric
measures (48 to 96 h), from 1974-76 except for one summer month each year and
except for the sulfates which were determined only during the last half of the
study and only in one part of the study zones. Twenty-eight study zones were
defined to include 2-4 groups of ~1000 people in different cities exposed to
pollution that differed as much as possible in quality and quantity (estimated
from earlier aerometric data from 1971-72). Zones included populations situ-
ated within 0.5 to 2.3 km (x = 1.3 km) of air monitoring stations located 2-4 m
above ground level in the center of each zone. National meteorological ser-
vices supplied climatic data (e.g., temperature and humidity) taken at a
station best characterizing each city (usually an airport, sometimes far from
the zones investigated), and laboratory analyses for the air pollutants mea-s-
ured were carried out by laboratories in each city studied but for sulfates
done at a single laboratory. Means for daily data for the pollutants studied
were calculated for 1974-76 (where values came from data accumulated over
several days, it was assumed the pollution was the same on each day). The
o
extreme mean daily concentrations from various zones were: 13 and 127 ug/m
for S02 (AF), 22 and 85 ug/m3 S02 (Sp); 18 and 152 ug/m3 (smoke); 45 and 243
ug/m3 (gravimetric), 7 and 145 ug/m3 (NO); and 12 to 61 ug/m3 (N02).
As for health evaluations, ventilatory function was measured in both men
and women aged 25 to 59 and children aged 6 to 10 and respiratory symptoms were
ascertained by standardized questionnaire. The results presented by PAARC
(1982a,b) were for ~20,300 subjects from 20 zones (response rates varied from
70 to >90 percent in the included zones). Analyses of covariance were used for
FEV results' and logistical regression for the analysis of symptoms scores,
taking into account control factors such as smoking and socioeconomic status.
It should be noted that efforts were made to standardize the health endpoint
measurements by common training of personnel carrying out testing in various
zones and use of standard protocols.
3-41
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The results of the study were reported by PAARC (19825) as follows: (1)
among both male and female adults, S0£ concentrations are significantly associ-
ated with the prevalence of lower respiratory disease (LRD) symptoms; (2) among
children, S02 is associated with the prevalence of upper respiratory disease
(URD) symptoms; (3) for both adults and children, FEV1<0 varied negatively in
relation to elevations in S02 levels; and (4) no other pollutants were associ-
ated with ventilatory function or the prevalence of respiratory symptoms. More
specifically, S0£ concentrations were significantly correlated (r >0.44) with
incidence of cough, expectoration, and LRD symptoms in men and with LRD inci-
dence in women (r = 0.49); and S02 correlated (r = 0.53) significantly with URD
in children. It was noted that, whereas the above results emerged from
analyses including data drawn from across cities, the gradient of S02 effects
on symptom rates was not always evident within the same city (an analogous
situation to findings reported by Ware et al., 1985, from data from six
American cities). Similarly, the gradients emerging from regressions across
cities for relationships between S02 and FEV-L Q measures for men (r = -0.52),
women (r = -0.67) and children (r = -0.70) were not always evident from data
within all individual cities. In contrast to the S02 results, very mixed
correlations (some positive and some negative, but none significant) were found
between symptoms and measures of PM (smoke or gravimetric) and nitrogen oxides
(NO, N02). Also, oddly, the correlations between FEV-,^ Q and PM or nitrogen
oxides measures were positive (some significantly so for NO or N02); i.e., they
implied improved lung function as airborne particle or nitrogen oxides levels
increased.
The results from the PAARC (1982a,b) study are interesting but challenging
in terms of interpretation. The study appears to have ensured that aerometric
data from the sampling stations used would be reasonably well representative of
the surrounding study populations in the various zones, a definite strong point
of the study. Similarly, efforts to standardize measurements of health end-
points across the different cities is another strong point. Also, in the case
of the S02 measurements, analytical techniques were used and periodic inter-
.comparisons made between laboratories such that the aerometric data and result-
ing correlations with symptoms and FEV decrements are probably credible. Much
less confidence can be placed in the data derived for particulate matter,
however,-in view of the use of smoke readings and/or gravimetric readings that
varied for 48 to 96 h periods as the basis for generating estimated particle
3-42
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concentrations to compare across cities. It is very dubious that an adequate
comparison could be made, then, across cities in terms of relationships between
either symptoms or pulmonary function measures and PM estimates; analyses
relating such health endpoints to PM measures within individual cities (not
reported in PAARC, 1982a,b) might be more credible, but this remains to be
evaluated. The very anomalous results obtained for nitrogen oxides are diffi-
cult to explain or understand without more in-depth evaluation of specific
aspects of the NO aerometric measurement methods as they were applied in the
/\
present study. Clearly, the results obtained for the nitrogen oxides are not
believable in light of other existing literature.
In another European study (CEC, 1983) reported since the 1982 EPA criteria
.document was prepared, various health endpoints in children (6-11 yrs old) were
evaluated in relation to air pollution in 19 geographic areas located in
several different European Community countries. Data were obtained on 22,337
children and included information on respiratory symptoms obtained by question-
naire and pulmonary function measurements (peak expiratory flow rate measured
by Wright peak flow meters). Efforts were made to standardize health measure-
ments and protocols across all study areas. S02 concentrations were determined
(using six different analytical methods) and particulate pollution was measured
by smoke methods in some countries and by unspecified gravimetric methods in a
few other ones. Side by side monitors were set up at 20 sites to help provide
a basis for calibration across sites; these 20 "comparison" monitoring stations
standardly used the British smoke method for PM and acidimetric method for
SOp. Significant associations emerged from analyses within some individual
countries, but differed greatly from one country to another. In three coun-
tries, a composition variable called chronic non-specific lung disease (CNSLD)
was highly significantly correlated positively with smoke, but the magnitude of
the effects differed by a factor of about seven. The range of annual smoke
levels was about the same in all three countries, about 15-40 ug/m . In four
countries, there were significant associations with S02, but two of these were
negative. In those with positive correlations annual median SO, levels were
3 3
60-160 ug/m, and for those with negative associations they were 20-120 ug/m ,
making it likely that the SOp results reflected chance variations rather than
actual pollution effects. However, no significant relationships between health
effects and particulate pollution were found when data from across countries
were pooled. The reported results are difficult to interpret. The CEC (1983)
3-43
-------
report noted that annual average levels of smoke greater than 140 |jg/m in the
presence of SO* at >180 ug/m have been found by other studies to be levels
above which consistent positive associations between health effects and air
pollution are detectable. These levels are higher than any measured in the
present study, and this might explain the lack of consistent effects observed
from city to city or when data were analyzed across all cities. The results of
analyses for data within a given city may warrant further, more detailed
evaluation and may yield useful information on quantitative exposure-effect
relationships. However, given the great difficulty noted by the CEC (1983)
report in deriving bases for comparing air quality measurements for PM and 50^
across different cities it is dubious that useful quantitative conclusions can
be drawn from analyses of data combined across cities. This is especially the
case in view of only limited calibration of smoke readings against gravimetric
measurements by collocated gravimetric devices in the various countries.
Muhling et al. (1985) also studied the relationship between croup and
obstructive bronchitis of German children taken to clinic versus the level of
air pollutants of their residential areas. They show in this retrospective
study that the incidence of these two diseases was greater in the area with
higher S02 and dustfall levels. Several important confounding factors were
examined (i.e., infection incidence, meteorological parameters, social status,
and distance from clinic). Quarterly average values of S02 and dustfall were
provided by the county of Nord Rhein in Westphalia. The authors state that
their results clearly show that the disease frequency depended on whether the
children lived in an area of high or low S02 and dustfall levels, but noted
that it cannot be clearly stated whether or not the measured emissions are the
actual cause of any increased morbidity.
Wojtyniak et al. (1984) using a multivariate analysis method showed that
among men reporting persistent cough or phlegm, the prevalence of exacerbation
of these symptoms was much greater in residents of more highly polluted parts
of Cracow, Poland. In women, the prevalence of exacerbation of symptoms was
associated with indoor air pollution resulting from coal combustion from coal
stoves. This extensive longitudinal survey used questions based on the MRC
questionnaire. An extensive monitoring network of 20 sampling stations covered
the entire area of the city. Most important confounding factors were examined.
3-44
-------
In summary, of the numerous new studies published on morbidity effects
associated with long-term exposures to PM or SOX, only a few provide
potentially useful results by which to derive quantitative conclusions
concerning exposure-effect relationships for the subject pollutants. The Ware
et al. (1985) study, for example, provides evidence of respiratory symptoms in
children being associated with particulate matter exposures in contemporary
U.S. cities without evident threshold across a range of TSP levels for -25 to
150 ug/m3. The increase in symptoms appear to occur without concomitant
decrements in lung function among the same children. The medical significance
the observed increased in symptoms unaccompanied'by decrements in lung
function remains to be fully evaluated but is of likely health concern.
Caution is warranted, however, in using these findings for risk assessment
purposes in view of the lack of significant associations for the same
variables when assessed from data within individual cities included in the
Ware et al. (1985) study.
Other new American studies provide evidence for: (1) increased
respiratory symptoms among young adults in association with annual-average S02
levels of -115 ug/m3 (Chapman et al., 1983); and (2) increased prevalence of
cough in children (but not lung function changes) being associated with
intermittent exposures to mean peak 3-hr S02 levels of -1.0 ppm or annual
average levels of -103 ug/m (Dodge et al., 1985).
Results from one European study (PAARC, 1982a,b) also suggest the
likelihood of lower respiratory disease symptoms and decrements in lung
function in adults (both male and female) being associated with annual average
S0? levels ranging without evident threshold from about 25 to 130 ug/m . In
addition that study suggests that upper respiratory disease and lung function
decrements in children may also be associated with annual-average S02 levels
across the above range. Further analyses would probably be necessary to
determine whether or not any thresholds for the health effects reported by
PAARC (1982a,b) exist within the stated range of annual-average S02 values.
3-45
-------
-------
CHAPTER 4. CONTROLLED HUMAN EXPOSURE STUDIES OF SULFUR DIOXIDE
HEALTH EFFECTS
Since the completion of the 1982 EPA criteria document (U.S. EPA, 1982a)
and the first addendum to it (U.S. EPA, 1982c), numerous scientific articles
have been published in the peer-reviewed literature or accepted for publication
in regard to controlled human exposure studies providing important additional
information pertinent to development of criteria for primary (health related)
NAAQS for S02. This chapter of the present addendum summarizes and evaluates
the newly available studies and discusses their relationship with certain other
key studies and conclusions from Chapter 13 of the 1982 criteria document and
the earlier addendum. Several of the key issues discussed in the previous
addendum have been further investigated. Those discussed here are
(1) Differences in subject characteristics, medication, and restriction
from medication which may have considerable impact upon the differ-
ences in results reported by different laboratories.
(2) Concentration (SOp^response relationships in sensitive individuals
under various conditions of exercise activity level or other form of
hyperpnea.
Possible enhancement of S02-induced bronchoconstriction by cold
and/or dry air and by mouthpiece breathing.
(3)
(4)
Mechanisms of action of SOp-induced bronchoconstriction in sensitive
(asthmatic) individuals.
The majority of subjects used in the studies summarized in this addendum
were asthmatic.' Asthma is a heterogeneous disease classification which in-
cludes a broad range of subjects. The least severe asthmatic may have had
asthma diagnosed by a physician during childhood (by an unknown set of
criteria) .and have been mainly symptom-free since childhood and rarely, if
ever, requires medication. On the other end of the spectrum are individuals who
4-1
-------
may be on chronic bronchodilator therapy (theophylline), who may use chromolyn
(disodium chromoglycate) prior to activity, and may also require steroids.
Pulmonary function tests (spirometry and airway resistance) are used to define
the clinical status of an asthmatic at the time the studies are performed.
Since airway obstruction in asthma is variable and often intermittent, and
given that the physiologic status is highly influenced by the quantity and type
of medication being used, tests of lung function cannot be used alone to
determine the severity of the disease at any one time.
In addition to the diversity of clinical status, there was a broad range
of selection criteria used to define asthma in various laboratories and from
study to study. In some of the early studies, a clinical definition of asthma
(i.e., diagnosed by a physician) was the selection criterion. In an effort to
provide more descriptive information about the subjects, other criteria such as
a positive response (i.e, much more reactive than "normal" subjects) to a
pharmacologic stimulus such as methacholine or histamine was used as a criteri-
on for selection. A positive (bronchoconstriction) response to an exercise
test (5 to 10 min at 85 percent of maximum) or to an SOp inhalation challenge
was also used to select subjects. The use of these descriptive criteria is
sometimes useful in comparing results between laboratories.
One further point which relates to severity of asthma is the ability of
the subjects to safely withhold their medication for a particular period of
time. There was considerable variation between laboratories in the duration of
time for which certain types or general classes of medication were restricted.
A number of the characteristics of the subjects who participated in
studies described in this addendum are summarized in Table 3 along with other
information on aspects of protocols employed in the studies.
4.1. NORMAL SUBJECTS EXPOSED TO SULFUR DIOXIDE
The pulmonary function effects of S02 in normal healthy adult volunteers
have usually been much less than those seen in SOp-exposed subjects with
clinically documented asthma. The newly available information supports this
conclusion in general but also suggests that some mild effects which are of
little if any acute health importance may be observed in normal subjects at
concentrations below 5.0 ppm. The 1982 criteria document presented the con-
clusion that the probable lowest-observable-effects level in normal healthy
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subjects is 5.0 ppm S02 at rest. The first addendum to the criteria document
further suggests that normal subjects are approximately one order of magnitude
(i.e., tenfold) less sensitive to S02 exposure than asthmatics.
Bedi et al (1984) studied subjects exposed to 1.0 and 2.0 ppm S02 in an
environmental chamber (22°C, 40 percent RH) for 2h (V£ = 40 L/min for 3 to 30
min exercise periods with intervening 10 min rest). In the initial 9 subjects
tested at both 1.0 ppm and 2.0 ppm S02, these investigators reported a modest
(10.3 percent) but significant increase in SRaw following both exposure
concentrations. Further investigation with a total of 22 subjects at 1.0 ppm
using the same protocol failed to substantiate this finding. Given the trivial
increase in SRaw (well within daily variations), the finding in the initial
group probably occurred by chance. Folinsbee et al. (1985) also reported
exposure of normal subjects to 1.0 ppm S02 in a study in which the effects of
combined exposure to ozone and S02 were examined. The exposure protocol for
this study was the same as the Bedi et al. (1984) study and included many of
the same subjects. There were no significant changes in forced expiratory
spirometry or airway resistance as a result of 1.0 ppm S02 exposure reported
for these subjects.
Stacy et al. (1983) exposed subjects to 0.75 ppm S02 alone and in combina-
tion with several particulate pollutants. During the 4-h exposures, subjects
walked on a treadmill on two occasions (VV approximately 55 L/min). There were
no significant effects of this S02 (or S02 plus particulate) exposure on either
forced expiratory spirometry or airway resistance.
Schachter et al. (1984) compared the responses of asthmatics and normals
(4M, 6F) to SOp. Three of the normals were reportedly atopic (i.e., they
probably had some history of allergy). There were no significant effects in
normal subjects at any of the concentrations tested (0.25, 0.50, 0.75, and 1.0
ppm S02). Measurements were made for 60 min following a 10-min bicycle exercise
period (vV estimated at 35 L/min by measurement at the same workload on another
occasion) in S02; the S02 level was maintained for the first 30 min post-
exercise. At the higher SOp concentrations (0.75 and 1.0 ppm) the subjects did
experience upper respiratory symptoms (these included unpleasant taste and odor
and sore throat, symptoms associated with extrathoracic airways).
Koenig and Pierson (1985) in a review of several studies from their
laboratory .reported a decline (6 percent) in FEV1 Q following exposure to 1.0
ppm S09 in 8 healthy normal adolescents. These subjects were exposed via
4-7
-------
mouthpiece to either 1 ppm S02, 1 mg/m NaCl aerosol, or their combination.
Resting exposure of 30 min was followed by 10 min of exercise (V^ = 39.9
L/min). The apparent decrease in FEV-j^ Q occurred 2 to 3 min following the
exercise period in S02. However, the FEV-j^ Q decrease following saline aerosol
was 4 percent and the absolute post-exposure FEV1 Q values were identical
(i.e., 2.89 liters). Furthermore, the authors used repeated pair t-tests in
their analysis without correction for multiple comparisons (e.g., Bonferroni).
These data should be subjected to a more rigorous statistical analysis to
ascertain their significance. Even if these FEV-j^ 0 data were statistically
significant, the differences between the air exposure and S02 exposure are so
small that they are of no clinical importance.
Exposure to a mixture of S02 (1 ppm) and ammonium sulfate (528 ug/mO was
studied in 20 normal subjects by Kulle and associates (1984). The subjects
were young adult nonsmokers (10M, 10F) with normal spirometry and no allergic
or respiratory disease history. Four hour exposures occurred in an environmen-
tal chamber (22°C, 60 percent RH) and included two 15-min exercise periods
(mild-100 watts, v"E estimated 40 L/min [4 to 5 times rest]). There were no
significant effects on spirometry or airway resistance after exposure to either
S02 alone, ammonium sulfate alone, or their combination. There was no change .
in the response to a methacholine inhalation challenge following any of the
exposures. There were reports of upper respiratory symptoms which were most
prevalent with the combination exposure. This study further supports the
absence of pulmonary function effects of S02 at 1.0 ppm in normal subjects.
Wolff et al. (1984) exposed nine steel workers, two of whom were classi-
fied as asthmatic, to 5 ppm S02 or S02 plus carbon dust for 2.5 h in an
environmental chamber (22°C, 50 percent RH). The exposure included five 4-min
exercise periods (vV not reported). Mucociliary clearance measurement
exhibited no consistent pattern of change. Histamine reactivity (percent drop
in FEV, Q at threshold dose) showed a tendency to increase slightly (37
percent; 28 percent excluding asthmatics). There were no notable changes in
pulmonary function among the normal subjects. Symptomatically the subjects
found the S02 p-lus carbon dust exposure more unpleasant than S02 alone.
In summary, these studies of S02 exposure in normal healthy adults and
adolescents demonstrate minimal, if any, significant pulmonary function effects
of S0? exposure at 0.25 to 2.0 ppm with exposure durations ranging from 10
minutes to four hours including exercise periods, with work outputs sufficient
4-8
-------
to increase ventilation to 35 to 55 L/min. The only effect of any consequence
was the increase in upper respiratory symptoms, which was chiefly the result of
the unpleasant taste/odor of sulfur dioxide.
4.2 CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS EXPOSED TO S02
In addition to studies of asthmatics, Linn et al. (1985b) have studied 15
patients (ages 49 to 68) with COPD (mild to severe — airway reactivity and
reversibility not characterized) exposed to S02 (0.4, 0.8 ppm). One-hour
exposures in an environmental chamber (22.5°C, 86 percent RH) included two
15-min exercise periods (v"E = 18 L/min). In contrast to many previous studies
of mild asthmatics, most of these patients regularly used bronchodilators and
were permitted their use up to 4 h prior to study. There were no effects of
S02 exposure in this subject group and no trends indicative of change in any of
the measured functions (including SRaw, spirometry, and arterial oxygen satura-
tion). It should be noted that little if any effect would be anticipated in
asthmatics under these exposure conditions. The authors suggested that these
COPD patients may be less reactive to S02 than younger asthmatics, although, as
the authors discuss, given the low dose rate of exposure and the marked
differences in medication status, this conclusion may be premature. The
ventilations achievable by COPD patients are limited by the severity of their
disease. It is conceivable that patients with less severe COPD able to
exercise at a higher intensity and able to withhold medication may demonstrate
responses to S02 which are similar to or even greater than those of young
asthmatics.
4.3 FACTORS AFFECTING THE PULMONARY RESPONSE TO S02 EXPOSURE IN ASTHMATICS
4.3.1 Dose-Response Relationships
Important considerations in assessing the response to any inhaled gas or
aerosol include the concentration of the substance in the inspired air, the
rate of exchange of ambient air with the lung (ventilation), and the duration
of exposure. The concentrations to which asthmatics have been exposed in more
recent studies (since 1981) range from 0.10 to 2.0 ppm S02 although interest
has focused on the range from 0.2 to 1.0 ppm. A broad range of exposure
durations has been utilized ranging from 3 min to 6 h, although the primary
4-9
-------
focus has been on 5 to 10-min exposures which incorporate hyperpnea.
Ventilation rates have ranged from 8 to 10 L/min at rest to 60 to 70 L/min
(exercise or voluntary eucapnic hyperpnea), although most interest has centered
on moderate (VE = 35 to 50 L/min) to heavy (V, > 50 L/min) exercise levels
which in warm humid environments provoke, at most, only mild to moderate
exercise-induced bronchoconstriction. Results from the recently published
studies are summarized in Table 4.
Schachter et al. (1984) performed a concentration-response study in a
group of 10 normal subjects (see Section 4.1 above) and a group of 10 asthmatic
subjects exposed in an environmental chamber (23°C, 70 percent RH) to 0, 0 25,
0 50 and 1.0 PPm S0?. Subjects rested briefly and then exercised for 10
rinuU. at 450 kpm (V, = 35 L/min). In addition, subjects were exposed to 1.0
ppm SO, at rest. A significant decline in FEV1>0 followed both the 0.75 ( 8.3
percent) and 1.0 (-13 percent) ppm exercise exposures in these asthmatics ^
This was accompanied by a significant increase (54 to 68 percent at 1.0 ppm) in
airway resistance (interrupter method). There were also some changes (these
did not occur consistently at all concentrations or time -Intervals after
exposure) in maximum expiratory flow which mainly occurred at the two highest
concentrations. The recovery was rapid and pulmonary function was within 5
percent of baseline (and no longer significantly different) by 10 mm
postexercise even though S02 exposure continued. As other investigators have
reported, there was a considerable range of response among these subjects, with
3 or 4 subjects demonstrating no appreciable response to S02 at any
concentration while some others showed trends indicative of a dose-response
(SO,-FEV, n) relationship beginning as early as 0.25 ppm. The responses of
asthmatics'seen in this study may appear less severe than those seen by o her
investigators at similar S02 concentrations, although comparisons are difficult
because of the different measurements made; the relatively small changes in Raw
may be partially due to the use of the interrupter method. However, a number
of other factors could account for the discrepancies between this and other
recent studies of asthmatics. First, the subjects were not P^selected for
' the presence of'airway hyperreactivity to SO,, cold air, exercise hi stamina or
methacholine, an approach frequently used by others. Second the moderate
workload and unencumbered oronasal ventilation probably resulted in a lower SO,
delivery io the reactive airways than would occur with mouth breathing.
4-10
-------
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In a subsequent paper, Witek et al. (1985b) described the symptoms experi-
enced by the subjects in the Schachter et al. (1984) study. Both asthmatics
and normal subjects experienced increased respiratory symptoms following S02
exposure. Normal subjects complained chiefly of upper airway (nose and mouth)
symptoms of odor or unpleasant taste; these symptoms were not increased by
exercise. Normals experienced no significant lower respiratory symptoms.
There was an increase in lower respiratory symptoms in asthmatics at 0.75 and
1 0 ppm S09, although the significance of this trend is not clear (p = 0.09).
Upper airway symptoms tended to be elevated in both asthmatics and normals, but
more consistently in normals. The lower respiratory symptoms increased with
exercise in the asthmatics and were significantly correlated (r = 0.67, p <.05)
with the decrease in FEV, Q. In contrast, exercise did not affect symptoms in
normals. The authors stated that even the asthmatics' symptoms were generally
mild and required no therapy.
Linn and coworkers (1983D) also evaluated the responses of naturally
breathing asthmatics exposed to S02 in an environmental chamber (23°C, 85
percent RH) while performing 5 min of moderately heavy exercise (V£ = 48
L/min) Twenty-three mild asthmatics (some of whom were hyperreactive to
methacholine and all of whom were reactive to 0.75 ppm S02) were exposed four
times, once each to 0, 0.20, 0.40, and 0.60 ppm. Significant increases in SRaw
occurred after clean air exposure due to exercise-induced bronchoconstriction.
The SRaw increase after 0.20 ppm was not significantly larger than after clean
air, but the SRaw following exposure to the two higher concentrations was
significantly elevated. SRaw demonstrated a significant trend to increase with
increasing SO, concentration but this trend was not linear; the mean increases
in SRaw after 0.2, 0.4 and 0.6 ppm S02, over those seen with clean air, were
0 54, 2.03, and 6.77 cm H-O-sec. The response data are suggestive of a
threshold concentration for response to SO,,. There is a strong possibility of
a concentration threshold for S02 at low concentrations and ventilations since
the scrubbing of SO, by the upper airway mucosal surfaces may be so efficient
that only a relatively small quantity of SO, reaches the reactive portions of
6 ^Roglfet al. (1985) studied 27 mild asthmatics (methacholine sensitive,
not using cromolyn or steroid medication). Exposures were to 0.0, 0.25, 0.50,
and 1.0 ppm SO, in an environmental chamber (26°C, 70 percent RH) utilizing
natural breathing while performing treadmill exercise (V£ = 41 L/min) The
increases in SRaw post-exercise associated with these exposures were 48, 63,
4-20
-------
93, and 191 percent respectively; the increases at the two highest
concentrations were significantly greater than with air. The data reported by
Roger et al. (1985) were further analyzed (Horstman et al., 1986) in order to
determine individual S02-SRaw dose-response relationships. This analysis
included previously unreported data on exposure to 2 ppm in subjects who were
non-responsive to lower concentrations. From interpolation of the
dose-response plots, the concentration of S02 which provoked a 100 percent
increase in SRaw (PCS02) was determined for each subject. All S02 responses
were corrected for the response observed with clean air, i.e., exercise-induced
bronchoconstriction. For the most reactive 80 percent of the subjects the
PCSOp ranged from 0.28 to 1.38 ppm; it was greater than 1.95 ppm (and therefore
.basically indeterminate) in the remaining 20 percent of subjects. (This
percentage of SOg-insensitive asthmatics is in general agreement with Linn et
al.s 1984b) The median PCS02 in all subjects and under these conditions was
0.75 ppm; 25 percent (i.e., 6) of the subjects had a PCS02 less than 0.50 ppm,
the lowest being 0.28 ppm. The dose-response relationships relate only to the
level of exercise used in this study. Different dose-response relationships
would be expected for different exercise levels or different exposure
durations.
4.3.2 SO^-Induced Versus Non-Specific Airway Reactivity
It is well established that most asthmatics are highly reactive to bron-
chial inhalation challenge with histaminergic (histamine) and cholinergic
(acetylcholine, carbachol, methacholine) agents. Clear evidence has also
emerged that asthmatics are substantially more reactive to S02. The relation-
ship between S02-induced bronchoconstriction and non-specific airway reactivity
has been examined or alluded to in a number of studies (Horstman et al., 1986;
Witek et al., 1985a; Sheppard et al., 1983). Airway reactivity to methacholine
and to histamine are well correlated (r = 0.70) (Chatham et al., 1982). Metha-
choline reactivity was more highly correlated with exercise-induced bronchocon-
striction and was better able to distinguish between normals and asthmatics
. (Chatham et al., 1982).
Witek et al. (1985a) reported that the methacholine reactivity of a group
of 8 asthmatics was highly (r = 0.86, p <0.05) correlated with their reactivity
to S02. The subjects were a subgroup of 8 of the 10 subjects used in the
Schachter et al. (1984) study (see Schachter et al., 1984, for protocol
details). The dose of methacholine required to produce a 20 percent drop in
4-21
-------
the maximal expiratory flow at 40 percent VC above RV on a partial expiatory
maneuver (MEF40 percent-P) was determined. From the MEF40 percnet-P vs. SO,
response relationship, the S02 concentration required to produce a 20 percent
drop was determined. The relationship between the methacholine provocative
dose and the SO, provocative concentration was determined by rank Correlation.
This study suggests that there is a relationship between methacholine
reactivity and severity of S02-induced bronchospasm.
On the other hand, Koenig and Pierson (1985) concluded in their recent
review article that the response to a methacholine challenge was not a good
predictor of the degree of S02-induced bronchoconstriction in asthmatics They
suggested that a positive response to an exercise challenge was more likely to
predict a positive response to SO,. Linn et al. (1983b) present subject data
(their Table 1) for methacholine reactivity, exercise response (SRaw change),
and SO, response (SRaw change), which are sufficient to allow calculation of
correlation coefficients between these three variables. The rank-order cor-
relation coefficient between methacholine reactivity and SO, response was 0.38,
between exercise response and SO, response was 0.46, and between exercise and
methacholine response was 0.47 (these calculations by the authors of the
addendum). The latter two-correlation coefficients were significant p <05)
and this observation supports the suggestion of Koenig and Pierson (1985)
Horstman et al. (1986) have compared the methacholine reactivity (interpolated
dose causing a doubling of SRaw) with the SO, response (PCSO,; see previous
section). The methacholine and S02 responses were significantly but weakly
correlated (r = 0.31).
The relationship of histamine reactivity to S02-induced bronchoconstric-
tion is less well described. "Tolerance" to SO, exposure reported by Sheppard
et al (1983) was not accompanied by any decrease in histamine reactivity.
However, this does not necessarily indicate the absence of an overall relation-
ship between histamine reactivity and S02 responsiveness.
One problem in establishing the strength of the relationship between
non-specific airway reactivity and SO, response is the restricted range of the
. observations in these studies which deal only with the most reactive segment of
the population, namely asthmatics. Inclusion of data from normal objects
would undoubtedly result in a higher correlation. Nevertheless it is app.re.it
that increased SO, responsiveness in asthmatics cannot simply be ascribed to
elevated non-specific airway reactivity.
4-22
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4.3.3 Oral, Nasal, and Oronasal Ventilation
For S02 in particular, but also for many other gases and aerosols, the
inhalation route is an important factor in delivery of the substance to the
lung. Since 1982, a number of studies have been reported which specifically
address this issue. There are important interactions between the inhalation
route, which in many cases is simultaneous oral and nasal breathing (oronasal)
(Proctor, 1981), and the ventilation rate is such that the efficiency of the
oral or nasal mucosa in absorbing S02 declines as the air flow increases. As
noted in the previous addendum (U.S. EPA, 1982c) the studies of Kirkpatrick et
al. (1982) and Linn et al. (1982b in the earlier Addendum I; 1983b in the
present reference list) indicated the importance of oronasal airway scrubbing
of S02 in mitigating the effects of S02 during nasal or oronasal breathing.
In.an effort to further resolve the interaction between exercise ventila-
tion and route of inhalation in asthmatics, Bethel et al. (1983b) studied 9
mild asthmatics breathing humidified air (23°C, 80 percent RH) through either a
mouthpiece or a divided facemask (ventilation could be measured separately in
nasal and oral chambers). Subjects worked at 250 (V£ = 26 L/min), 500 (V£ = 53
L/min), or 750 kpm (VE, 62 L/min) and breathed either clean air or 0.50 ppm S02
for 5 min. Mouthpiece inhalation of S02 resulted in increased SRaw at moderate
(231 percent) and heavy (306 percent) workloads, but with facemask breathing,
the SRaw only increased at the heavy workload (219 workload). The oral
component of ventilation during mask breathing was approximately 38 L/min at
the heavy workload, similar to the oral ventilation of 41 L/min with mouthpiece
breathing at the moderate workload; the similarity of SRaw responses in these
two cases is noteworthy. From these studies it is apparent that oronasal
breathing ameliorates some of the effect of S02 breathing in asthmatics, but
this effect becomes less important as the exercise workload increases and both
the overall ventilation rises and the relative contribution of oral ventilation
to total ventilation increases.
Kleinman (1984) has modeled the bronchoconstriction response to S02 in
relation to ventilation, oral/nasal partitioning of ventilation, and differ-
ences in S02 -scrubbing capability of the two upper airways. This model
suggests that differences in response to S02 can be quantitatively accounted
for by differences in penetration of S02 to target sites within the lower or
thoracic, airways (defined as structures at or just below the laryngopharynx).
4-23
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Because of the possible interference with oral breathing during the face-
mask exposures, Bethel et al. (1983a) studied 10 mild asthmatics exposed to
0.50 ppm S02 in an exposure chamber (23°C, 80 percent RH) to determine if
freely breathing subjects would develop bronchoconstriction at this
concentration. Following 5 min exercise at 750 kpm (tf£ unreported,
approximately 50 to 60 L/min), SRaw increased 39 percent in clean air but
increased 238 percent in 0.50 ppm S02 similar to that previously observed with
facemask breathing. Thus mild asthmatics performing moderate to heavy exercise
exhibited clear evidence of bronchoconstriction after 5 min exposure to 0.50
ppm S02 while breathing unencumbered.
In a subsequent study (Bethel et al., 1985), the effects of 0.25 ppm S02
were studied in 19 mild to moderate asthmatics using a similar protocol (23°C,
36 percent RH with 5 min exercise at 750 kpm). SRaw increased from 6.38 to
11.32 post-exercise in clean air and from 5.70 to 13.33 post-exercise in 0.25
ppm S02. The slightly greater response following S02 exposure was apparently
significant (p <0.05, Wilcoxon one-tailed sign test). The application of a
signed rank test, preferable in this case, would not confirm this significance.
However, when the workload was increased to 1000 kpm in 9 of the 19 subjects,
the increase in SRaw after clean air exercise was slightly, but not signifi-
cantly, greater than that after exercise with 0.25 ppm S02. The authors
suggested that the threshold concentration of S02 which may cause broncho-
constriction in mild asthmatics under conditions of moderate to heavy exercise
appears close to 0.25 ppm. However, the very small rise in SRaw at only one
work output indicates that the additional effect of 0.25 ppm S0£ (over that
produced by exercise) is of minor, if any, clinical significance. Neverthe-
less, it must be stressed that these asthmatics had relatively mild disease.
Voenig et al. (1983b) examined the effects of exposure to 0.5 and 1.0 ppm
S02 combined with a sodium chloride droplet aerosol in nine extrinsic adoles-
cent asthmatics. Judging from their medication requirements, this group of
asthmatics would have to be considered more severe than the adult asthmatics
studied by several other investigators. The exposures were delivered via
mouthpiece (22°C, 75+ percent RH) for 10 min during moderate treadmill exercise
(30 min rest exposures were followed by 10 min exercise). The responses ranged
from a 15 percent decrease in FEV1>0 at 0.5 ppm to a 61 percent decrease in
i . _... I ll.l^^l_~.wu«*iK*it^At/tl*Vll^TH'1C
at 1.0 ppm. The response to 1.0 ppm tended to be greater but this
difference between S02 concentrations did not attain overall statistical
significance. Nevertheless, the effects of S0£ on lung function persisted
4-24
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longer after the higher concentration exposure. FEV-j^ Q, Vmax50 and Vmax?5
(partial flow volume curves) were significantly reduced and total respiratory
resistance (forced oscillation) was significantly increased following
mouthpiece breathing of 0.5 or 1.0 ppm S02. Seven of nine subjects were also
exposed to 0.5 ppm S02 plus aerosol delivered via a facemask (ventilation 5 to
6 times rest or 30 to 50 L/min). The pulmonary function changes after
breathing 0.50 ppm S02 plus aerosol via facemask were not significantly dif-
ferent from baseline. However, some of the subjects intentionally breathed
through their nose rather than oronasally therefore the comparison of the
results of this study with those of Bethel et al. (1983a) would not be
appropriate. '-"'
Previous studies (Andersen et al., 1974) cited in the criteria document
have suggested that nasal resistance increases following S02 exposure. Because
this could have an important impact on the route of inhalation and/or the
oronasal ventilation switch point, Koenig and associates (1985) examined the
effects of 0.50 ppm S0£ on the work of nasal breathing in a group of moderate
adolescent asthmatics (7/10 were theophylline users). Subjects were exposed
to S02 (and H2S04 aerosol - 100 ug/m3) either via mouthpiece or oronasal
facemask (22°C, 75 percent RH). Thirty min resting exposure was followed by 20
min of moderate exercise on a treadmill (V£ = 43 L/min). Exposure to S02 via
mouthpiece or facemask resulted in an approximate 30 percent increase in nasal
work of breathing (measured with a divided diving mask containing two pressure
transducers which measured the pressure drop across the nasal passages). Due
to marked inter- and intra-individual variability in these nasal measurements,
only the increase in nasal work of breathing after facemask exposure was found
to be statistically significant. No increase occurred with clean air or
sulfuric acid aerosol exposure. The decreases in FEV-,^ n and Vmax5Q were
significantly greater with mouthpiece than with facemask exposure to 0.50 ppm
SO
The implications of this finding may be of considerable importance.
A
rise in nasal work of breathing could provoke a switch to predominantly oral
breathing during exercise at a lower ventilation, thus causing more inspired
air to traverse the oropharynx rather than the nasopharynx. Since oral
inhalation of S02 results in greater increases in airway resistance and larger
declines in spirometric tests, an increase in the proportion of oral
ventilation due to nasal congestion could result in S02-induced
bronchoconstriction at lower concentrations in freely breathing exercising
asthmatics.
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4.3.4 Time Course of Response to SOo In Asthmatics
Early studies of SCL exposure in normal healthy subjects indicated that
the peak response occurred early in exposure and was reduced with continued
exposure. The effect of prolonged or repeated exposure has recently been
addressed in asthmatics.
Sheppard and associates (1983) reported the responses of mild to moderate
asthmatics (n = 8) exposed three consecutive times to 0.51 ppm SOg. The
subjects performed voluntary eucapnic hyperpnea with 0.5 ppm S02 for 3 min at a
ventilation which had previously caused bronchoconstriction (air temperature =
22.6°C, RH = 82 percent). Three subjects failed to reach the target of a 60
percent increase in SRaw above baseline and consequently performed additional
hyperpnea to produce increased SRaw. Twice more, at 30-min intervals, the S02
hyperpnea was repeated. SRaw was measured before and after each S02 exposure.
A single bout of S02 hyperpnea was performed on the following day and again one
week later. The first exposure to S02 caused a doubling of SRaw (104 percent
increase). The second and third S02 exposures elicited only modest increases
in SRaw (35 percent, 30 percent respectively). However, 1-day and 7 days
later, the response to S02 was similar (+89, +129 percent) to that on the first
exposure.
In this study, the relationship of S02 tolerance to histamine-induced
bronchoconstriction was examined in a subgroup of four subjects. A baseline
histamine challenge test was followed 30 min later by two 3-min periods of S02
breathing separated by 30 min (as in the initial part of the study). When the
histamine challenge was repeated after a further 30 min, the histamine
dose-response relationship was unchanged despite the blunted response to S02
inhalation. This study demonstrated that repeated exposure of asthmatics to
0.5 ppm S0£ by mouthpiece at 30-min intervals resulted in a blunted S02 re-
sponse (tolerance) which persisted for at least 30 min but was absent after 24
h and was not associated with any change in airway reactivity to histamine.
The implications of this study for response mechanisms are discussed in
Section 4.3.
Linn et al.' (1984c) also studied the effect of repeated S02 inhalation in
14 mild to moderate asthmatics who were exposed to 0.6 ppm S02 for 6 h on each
of two consecutive days. These were compared with similar clean air exposures.
They performed two 5-min bouts of exercise (V"E = 50 L/min), one immediately
upon entering the exposure chamber (22°C and 85 percent RH) and a second bout 5
h later. SRaw was measured immediately post-exercise and at hourly intervals
4-26 . . •'.
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between exercise periods. With S02 exposure, SRaw was approximately doubled
following each exercise bout. Small increases in SRaw also occurred following
exercise in clean air. There were no differences in response between early and
. i
late exercise challenges and no significant differences in SRaw response
between exposure days. SGaw, but not SRaw, responses indicated smaller
decreases on the second S02 exposure day (-0.091 sec-cm H20) than the first
(-0.119 sec-cm H20). This difference was of only marginal statistical
significance and not of any clinical importance. The results of this study
indicate that S02~exercise challenges separated by 5 h (between exercise
periods) produce essentially similar responses and that the responses are not
appreciably different on two consecutive days. The Linn et al. (1984c) and
Sheppard et al. (1983) studies had several methodological differences;
respectively, these were free breathing vs. mouthpiece, exercise vs. eucapnic
hyperpnea, 4.5 h vs. 30 min interexposure interval, 5 min vs. 3 min exposure
duration, and 0.6 ppm vs. 0.5 ppm S02 concentration. Nevertheless, in each
study, an initial S02 exposure which produced at least a doubling of SRaw was
followed later by a second exposure. With the shorter 30-min interval in the
Sheppard study, the response to S02 was blunted. However, with the longer 5-h
interval in the Linn study, the SO,, response was unchanged from the initial
exposure. Evidence from the exercise-induced bronchoconstriction literature
(Edmunds et al., 1978; Stearns et al., 1981) indicates that the refractory
period following exercise induced bronchoconstriction persists for 2 to 4 h.
The refractory period following S02-induced bronchoconstriction lasts at least
30 min but less than 5 h.
Snashall and Baldwin (1982) studied the effect of exposures to 8 ppm S02
repeated at 4 h and 24 h in 4 normal and 1 asthmatic subjects. Compared to the
initial exposures, S02~induced bronchoconstriction was reduced 42 percent at 4
h while no difference was observed at 24 h.
In a more comprehensive examination of repeated exercise during continuous
S02 exposure in a large subject population (n~28) exposed to 3 different S02
levels with repeated exercise, Roger et al. (1985) also observed attenuation of
S02-induced bronchoconstriction. The subjects worked at a moderate workload
(VV = 42 L/min) and breathed freely (except for 2 min at the end of exercise
periods 2 and 3). They were not selected for S02 sensitivity, were sensitive to
methacholine challenge, and used no cromolyn or steroids. Each subject was
exposed, on three different days, to three S02 concentrations (0.25, 0.50, and
1.0). During each exposure, the subject exercised three times for 10 min each
4-27
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separated by 15-min intervals between exercise bouts. SRaw was measured pre-
exposure and following each exercise period. After the first exercise, SRaw
increased significantly over that seen with clean air (48 percent), with
exposure to both 0.5 (+93 percent) and 1.0 ppm S02 (+191 percent). With
subsequent exercise bouts in both 0.5 and 1.0 ppm S0£, the SRaw increased only
about half as much (third exercise SRaw increase was 52 percent and 116 percent
in 0.5 and 1.0 ppm, respectively). This attenuation of response was less than
that seen by Sheppard et al. (1983). Nevertheless, there were several
differences between the two studies (exposure duration 3 min vs. 10 min,
inter-exposure interval 30 min vs. 15 min, mouthpiece eucapnic hyperpnea vs.
free breathing exercise, S02 sensitive vs. methacholine sensitive selection
criterion). The subjects in this study demonstrated a refractoriness to both
exercise in clean air and to exercise in S02; the latter was of greater
absolute magnitude in terms of less increase in SRaw but the relative reduction
in response from first to last exercise periods was similar for repeated
exercise in either clean air or S02.
A subset of 10 subjects from the Roger et al. (1985) study were further
studied by Kehrl and coworkers (1986, in press). The subjects were selected
for moderate S02 sensitivity (i.e., no subjects non-responsive to S02 were used
and the most reactive subjects were not studied). In addition to the three
10-min exercise periods performed previously, these subjects exercised continu-
ously for 30 min at the same exercise intensity (v"£ = 41 L/min) in an environ-
mental chamber (26°C, 70 percent RH) while exposed to 1,0 ppm S0r The SRaw
data for the original intermittent exercise exposures were similar to those of
the original larger subject group (SRaw: baseline 5.4, postexercise-1 14.7,
postexercise-2 12.8, postexercise-3 11.1). After 30 min continuous exercise in
1.0 ppm S02, SRaw significantly increased from 5.2 to 17.3 cm H20-sec. The
SRaw change was not significantly different than that seen after the first 10
minute exercise period of the intermittent exercise exposure. This study
demonstrated that SOg-induced bronchoconstriction is elicited by 10-min
exposures but a further 20 min of continuous exercise resulted in only a
slightly greater increase in SRaw which did not attain statistical
significance.
In order to examine the time course of recovery from S02-induced broncho-
constriction in asthmatics, Hackney et al. (1984) exposed 17 mild to moderate,
nonsmoking, S02-sensitive asthmatics (not using cromolyn or steroid medication)
to 0.75 ppm S02 for 3 h. A secondary objective of 'this study was to determine
4-28
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the usefulness of spirometric testing as an adjunct or alternative to
plethysmography under such exposure conditions. The exposure consisted of 3 h
in an environmental chamber with a 10-min exercise period (VE = 45 L/min) at
the beginning of the exposure followed by post-exercise and hourly SRaw mea-
surements. SRaw was approximately quadrupled (+263 percent) after exercise,
returned almost to baseline at one hour (+34 percent, not significant) and was
unquestionably back to baseline after 2 h recovery. In an otherwise identical
exposure sequence which included spirometric testing, the FEV1 Q was
significantly reduced (-20 percent) post-exercise. The correlation between the
FEV, Q and SRaw changes was significant (r = 0.60) but accounted for
considerably less than half the variance, indicating that the two measures did
not track each other closely in all subjects. This study demonstrated that
moderate S02/exercise-induced bronchoconstriction will be relieved during rest
(over a 1 to 2 h period) even if a low-level S02 exposure is continued. Second
the authors demonstrated that changes in FEV^ Q are also useful indicators of
S02 exposure in asthmatics, although it is not clear that significant changes
in FEV, 0 would occur with less severe exposure more typical of the ambient
environment.
4.3,5 Exacerbation of the Responses of Asthmatics to SO., by Cold/Dry Air
It has been well established that both cold air and dry air can exacerbate
bronchoconstriction in asthmatics (Deal et al., 1979a; Strauss et al., 1977).
The precise mechanism(s) for the effect are not universally agreed upon
(Anderson, 1985). Although direct convective cooling of the airway plays a
minor role, the major avenue of heat loss is due to evaporation to humidify the
inspired air. Evaporation of airway surface liquid may also lead to other
changes discussed in section 4.4. The potential for evaporative cooling by
inhaled air can be most readily appreciated from the determination of the
absolute humidity of the inspired air. Absolute humidity (AH) expresses the
water content of the air in mg/L (g/m3). The lower the AH, the greater the
potential for evaporative cooling. AH is listed, for each study, in Table 4.
F6r reference, the AH of saturated air at 37°C (i.e. BTPS) is 44 mg/liter.
Therefore, in order to bring inspired air at 0°C, AH = 1 mg/L to BTPS, the
temperature of each liter of air must be increased to 37°C (0.011 kcal) and 43
mg of water must be evaporated (0.025 kcal) (calculated from the respiratory
heat exchange equation of Deal et al., 1979b).
4^29
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Sulfur dioxide exposure can occur during the winter months when the
ambient air temperature is low, and consequently the water vapor content is
reduced. Accordingly, Bethel and coworkers (1984) examined the separate and
combined effects of sulfur dioxide and cold dry air in seven asthmatics (mil^
to moderate asthma) breathing via mouthpiece. In this study and the following
study by Sheppard and coworkers (1984), a series of bronchpprovocation tests
were used. The methods are as follows:
The subjects breathed a test gas mixture for 3 min, then SRaw was deter-
mined every 30 s for 2 min. This cycle of 3 min exposure and 2 min SRaw
testing was repeated until the desired response was achieved. The
vantnatorv bronchoprovocation test consisted of performing voluntary
eucapnic hyperventilation at increasing ventilation levels (20, 30, 40,
50 60 etc. L/min) while breathing a single test gas mixture. The SO^
h,nnrhnprovocation test consisted of breathing (eucapnic hyperventilation)
at some fixed ventilation and gas temperature and humidity with succes-
sively doubling levels of sulfur dioxide (e.g. 0, 0.125, 0.25, 0.50, 1.0,
2.0 ppm S02) used as the stimulus.
Bethel's subjects performed ventilatory bronchoprovocation tests with both 0.50
ppm SO, in warm humid air and with no S0£ in cold-dry air (-ll'C, dew point
-15oC) until an increase in SRaw was observed in order to determine the venti-
lation which caused "little or no bronchoconstriction" with either stimulus.
At the selected ventilation, subjects breathed on a mouthpiece for 3 min one of
the following mixtures: (1) warm-humid (23°C, dew point = 18.4'C) fir, {2) warm
humid air with 0.50 ppm S02, (3)cold dry air, (4) cold dry air with 0.50 pp.
SO Modest but non-significant increases in SRaw followed each of the first
three conditions [(1) +3 percent, (2) +38 percent, (3) +18 percent]. However,
the combination of 0.50 ppm S0£ and cold dry air caused a striking increase in
SRaw (from 6.94 to 22.35, or a 222 percent increase). In this study, the
combined effect of breathing cold dry air and 0.50 ppm S02 via mouthpiece was
"clearly larger than the sum of the individual response to either S02 or cold
dry ^Sheppard and coworkers (1984) further explored the interaction of breath-
ing cold dry air and SO- via mouthpiece in a group of 8 mild asthmatics. The
purpose of the study was' to determine the relative contributions of Screwed
air temperature (-20°C) and reduced water vapor content (0 percent RH). Using
4-30
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a ventilatory bronchoprovocation test with cold dry air, the highest ventila-
tion which did not cause increased SRaw was determined. The study consisted of
having the subjects perform eucapnic voluntary hyperpnea, at the selected
ventilation, 6 consecutive times for 3 min at a time with 2 min intervals
between efforts. This was done on four separate occasions (different days)
ordered randomly. On one occasion, the subject breathed cold-dry air only;
this did not cause an increase in SRaw. The three other tests consisted of S02
bronchoprovocation tests at the selected ventilation with successive doubling
S02 concentrations (starting at 0.125 ppm), one with cold dry air, one with
warm-dry (22°C, 0 percent RH) air, and one with warm-humid (22°C, 70 percent
RH) air. The S02 concentration required to produce a doubling of baseline SRaw
(PC100) was interpolated from the dose-response curve. The PC100 for cold dry
air (0.51 ppm) and for warm dry air (0.60 ppm) were not significantly different
but both were less than the PC100 for warm humid air (0.87 ppm). The PC100
measured in this study may not be a useful effects index because the response
may be a function of the cumulative effect of all S02 concentrations breathed,
as noted by the authors. In addition, the authors considered the possible
mitigating effect of repeated exposure - tolerance, but the importance of this
is unclear. Further studies were performed using a ventilatory
bronchoprovocation test while breathing either 0.0, 0.1, or 0.25 ppm S0£ in
warm-dry air. From the ventilation-SRaw dose-response plots at each S02
concentration, the ventilation producing an 80 percent increase in SRaw (PV80)
was determined. The PV80 at 0.0, 0.1, and 0.25 ppm S02 were 54.9, 51.1, and
49.3 L/min, respectively. The differences in PV80 between 0.1 or 0.25 and
clean air (0.0 ppm) reportedly reached significance although it was not clear
how these data were analyzed (presumably repeated measures analysis of
variance). Regardless of whether or not the difference in PV80 between clean
air and 0.1 and 0.25 ppm S02 was statistically significant, the magnitude of
this difference is small and of no established or obvious clinical importance.
Nevertheless, the first part of this study did confirm that breathing dry air
and cold air potentiates sulfur dioxide-induced bronchoconstriction. This
'potentiation could be an additive effect since both cooling (convective and
evaporative) and drying of the airway may act as direct bronchoconstrictive
stimuli, per se (Sheppard et al., 1984). In addition, the drying of the upper
airway also reduces the ability of the oropharynx to scrub S02 from the inhaled
air and may also cause a concentrating effect of the remaining airway surface
liquid (see Mechanism section).
4-31 • •'-
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Concurrent studies by Linn and coworkers (1984a) also were directed at the
possible interaction of inhalation of sulfur dioxide and cold air. They
studied a group of 24 mild to moderate SOg-sensitive asthmatics. A preliminary
study to determine the effects of humidity at cold ambient temperatures in-
cluded eight subjects exposed to 0.0, 0.2, 0.4, and 0.6 ppm S02 at 5°C under
two humidity conditions (81 percent and 54 percent). The subjects exercised
for 5 min in an environmental chamber at a workload selected to elicit a
ventilation of approximately 50 L/min (range 37 to 60) and breathed naturally.
SRaw showed a tendency to increase more from pre- to post-exposure with
increased S0£ concentration. The post-hoc analyses for changes at each
concentration were not presented, presumably because of the small sample size
and the non-randomized experimental design. No effect of ambient humidity on
response to S02 was seen at the 5°C air temperature. However, the difference
in water vapor content at the low and high humidities was approximately 1.84
mg/L, approximately 1/20 of the difference in water vapor pressure between
ambient and BTPS, and thus the absence of a difference should have been
expected. A second • study in this same series compared responses of 24
asthmatic subjects exposed to 0.6 ppm S02 under warm-humid (22°C, 85 percent
RH, AH = 16.5) and cold humid (5°C, 85 percent RH, AH = 3.4) conditions. The
same exercise and natural breathing procedures as above were followed.
Breathing 0.0 ppm S02, subjects had small non-significant increases in SRaw
under warm (27 percent) and cold (38 percent) conditions. 0.6 ppm S02 exposure
under these temperature-humidity conditions produced significant increases in
SRaw in both warm (132 percent) and cold (182 percent) conditions. However,
the temperature effect, unlike in the Sheppard et al. (1984) and Bethel et al.
(1984) studies, was not significant although the trend was in the direction of
an increased response at the lower temperature. The temperature difference
between cold and warm air was larger in the Sheppard et al. and Bethel et al.
studies (42°C and 34°C, respectively) compared to the Linn et al. study (17°C).
However the cold-warm difference in inspired air water content (AH) were
similar for the three studies (14.8, 12.6, 13.1 respectively). Nevertheless,
ft is apparent that the exacerbation of S02-induced bronchoconstriction by cold
air, containing small quantities of water vapor, is minimal in freely breathing
asthmatics exposed during moderately heavy exercise at 5°C air temperature.
In order to determine the possible effects of even colder ambient air
temperatures, Linn et al. (1984b) exposed 24 mild S02-sensitive asthmatic?
(including 11 subjects from Linn, 1984a) to 0.0, 0.'3, and 0.6 ppm S02 at +21,
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+7, and -6°C (RH approximately 78 percent). The exposure duration was 5 min.
The authors noted that "only 10-20 percent of clinically asthmatic prospective
subjects had to be rejected as non-responsive to S02" (10 min exercise at 40
L/min breathing 0.75 ppm S02). There was a significant effect of decreasing
air temperature and of increasing S02 concentration on the post-exercise SRaw.
However, the authors reported that there was no statistically significant
interaction of air temperature and S02 concentration for SRaw although the
interaction was apparently significant for SGaw. The effect of cold air (in
increasing SRaw or decreasing SGaw) was most pronounced with the 0.0 ppm S02
exposures and minimal with 0.6 ppm exposures. The results of this study do not
support the hypothesis that S02 acts synergistically with cold air in freely
breathing, exercising, mild to moderate asthmatics. The authors concluded that
the cold air and S02 effects "acted additively at most." The results for the
7°C and 21°C 0.6 ppm S02 exposures (+207 percent, +150 percent SRaw) were
similar to those seen in their previous (1984a) study (+182 percent, +132
percent SRaw), thus demonstrating the reproducibility of these studies.
In order to study the full range of S02-temperature-humidity interactions,
Linn et al. (1985a) also examined the effects of warm-dry (38°C, 20 percent RH)
and warm-humid (38°C, 85 percent RH) conditions on 22 SOg-exposed (Q.(5 ppm)
asthmatics. The exposure protocol was similar to the two 1984 studies with a 5
min chamber exercise period and ventilation of approximately 50 L/min. The
experimental design was a three-factor (S02-0.0 and 0.6 ppm; temperature-21 and
38°C; and humidity-20 percent and 80 percent) factorial design with repeated
measures across all factors. In this study, the major differences would be
anticipated to occur between the warm humid (38°C, 85 percent RH) condition and
the cooler dryer condition (21°C, 20 percent RH). There were significant
effects of temperature, S02 and humidity on the delta-SRaw (pre to
post-exercise) response and significant temperature-S02 and humidity-S02
interactions. The largest clean air increase in SRaw (20 percent) occurred
with cool-dry air and the smallest with warm-humid. The largest S02 induced
increase in SRaw (204 percent) occurred under cool-dry conditions and again the
smallest change (35 percent) occurred under warm-humid conditions. Symptoms
showed a similar pattern of response after S02 exposures with lower symptoms
scores under warm-humid than cool-dry conditions. SRaw responses to 0.6 ppm
S0? under 21°C-humid conditions were similar for all three Linn et al. studies
(1984a, 132 percent; 1984b, 150 percent; 1985a, 157 percent). The response
under warm humid conditions was considerably less. The authors discussed the
4-33
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possibility that they observed a synergism between S02 exposure and airway
drying/cooling due to reduced temperature or humidity of inspired air.
4.4 MECHANISM(S)
4.4.1 Mode of Action
A single unequivocal definition of asthma is not realistic on the basis of
existing knowledge and the heterogeneity of the disease. The single condition
that is common to all definitions of asthma is the reversibility of slowed
forced expiration presumably due to airway narrowing (smooth muscle
contraction, excess mucous secretion, mucosal edema). Most current definitions
of asthma also include the concept of nonspecific airway hyperreactivity (e.g.,
methacholine, histamine). The present American Thoracic Society definition of
asthma is:
A disease characterized by an increased responsiveness of the airways to
various stimuli and manifested by slowing of forced expiration which
changes in severity either spontaneously or with treatment.
It is noteworthy that the data summarized in this addendum indicate that asth-
matics experience substantial, but transient, bronchoconstriction (slowed
forced expiration) when exposed to low S02 concentrations (i.e. increased
responsiveness).
Because of its relatively rapid reversibility, SOg-induced bronchocon-
striction in asthmatics is likely the result of decreased airway caliber caused
by contraction of airway smooth muscle. The study of Roger et al. (1985) in-
dicated the largest S02-induced increases in airway resistance measured by
plethysmography were associated with increases in the low frequency component
of respiratory system impedance measured by the forced random oscillation
(noise) technique. The interpretation of this finding was an elevated peri-
pheral resistance associated with constriction of anatomically peripheral or
small airways. However, narrowing of central upper airway structures such ,as
the larynx and glottis may accompany increased airway resistance (Cole, 1982)
and it is possible that some of the increase in airway resistance may be due to
elevated laryngeal or glottal resistance.
Contraction of airway smooth muscle in response to environmental stimuli
can be evoked by intrinsic chemical and/or physical stimuli acting via neural
4-34 • '
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and/or humoral pathways. S02 may either act directly on smooth muscle or may
cause the release of chemical mediators from tissue, especially the release of
histamine from mast cells. It is beyond the scope of this document to provide
even a brief review of the mechanism of action of all the possible pharmaco-
logic mediators of SOp-induced bronchoconstriction. However, some plausible
candidates include histamine, slow-reacting substance of anaphylaxis, leuko-
trienes, and prostaglandin F2-alpha, all of which are released in the airways
and can cause smooth muscle contraction.
As reported in the previous addendum (U.S. EPA, 1982c), both activation of
parasympathetically mediated reflexes (Nadel et al., 1965; Sheppard et al.,
1980) and mast cell degranulation (Sheppard et al., 1981) with consequent re-
lease of chemical mediator (most likely histamine) play a significant role in
S02-induced bronchoconstriction. While the specific mechanism whereby S02 in-
teracts with the airways to induce bronchoconstriction has not been elucidated,
two reports of studies relevant to the mechanism(s) have appeared since the
previous addendum. These studies assessed the inhibitory effects on SOVinduced
bronchoconstriction of a variety of receptor antagonists (drugs that bind ^he
receptors but do not stimulate the receptor-induced response). Results from
these studies suggest that mechanisms in addition to reflex bronchoconstriction
and mast cell degranulation may play a significant part in the responses of the
asthmatic airway to S02.
Snashall and Baldwin (1982) studied the effects of atropine and cromolyn
on relatively mild bronchoconstriction (Raw increased <100 percent above
baseline) induced by breathing 8 ppm S02 at rest. Both atropine and cromolyn at
least partially blocked S02-induced bronchoconstriction in all but one of 11
normal subjects. The degree of atropine blockade was inversely related to the
magnitude of the SOy-induced response (r = -0.75), i,e., small responses were
completely blocked, while there was little blockade of large responses. For
asthmatics, atropine enhanced S02-induced bronchoconstriction in three of four
subjects tested; minimal blockade was observed in the remaining subject.
Cromolyn blocked the S02-induced response in three of the four asthmatic
subjects.
Tan et al. (1982) exposed resting normal and atopic subjects to 20 ppm and
asthmatics to 10 ppm S02 to induce bronchoconstriction. Both ipratropium
bromide (IB, an anticholinergic agent similar to atropine) afid cromolyn par-
tially inhibited the S02~induced response in all normal and atopic subjects
tested. For asthmatics, IB had little effect on S02-induced bronchoconstriction
4-35 . •'. •
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in five of nine subjects and afforded only partial blockade in the remaining
four subjects. Cromolyn at least partially inhibited S02-induced bronchocon- ^
striction in all 18 asthmatics tested. Clemastine (a selective HI receptor
antagonist without anticholinergic or antiserotinergic activity) effectively
blocked the SOg-induced response in five of seven asthmatic subjects tested.
4.4.2 Breathing Mode and Interaction With Dry Air
There is no question that the magnitude of SOg-induced bronchoconstriction
is significantly greater with oral than with oronasal or nasal breathing
(Kirkpatrick et al., 1982). When S02 is inhaled by mouth more S02 penetrates
beyond the pharynx to sites involved in the induction of bronchoconstriction
(Bethel et al., 1983b; Kleinman, 1984). It is assumed that because of their
geometry and greater relative surface area, the nasal passages are capable of
effectively removing most S02 breathed at rest and a large percentage during
conditions of increased ventilation (exercise, isocapnic hyperpnea). While
there is certainly less relative surface area available for S02 scrubbing in
the oral cavity, other factors may also influence increased .bronchoconstriction
associated with mouth breathing of S02, especially at higher ventilation rates.
Increased oral ventilation may result in substantial drying of both upper
(oral and pharyngeal area) and lower (larynx and trachea) airways. The extent
of airway surface drying will depend upon the ventilation (air flow rate) and
water content of inhaled air. Airway drying could lead to alterations in both
the quantity and properties of surface liquid in the airways. Decreased volume
of and/or surface area of liquid in the upper airway may result in decreased
efficiency of S02 absorption, allowing deeper penetration of the gas to sites
in the intrathoracic airway more likely involved in the induction of
bronchoconstriction. Decreased quantity of surface liquid in the lower airway
may result in a reduced volume in which soluble gases such as S02 can forip
solutions. The chemical interactions of S02 and S02-generated ionic species
could be altered by reduced fluid volume or by changes In concentrations of
other substances in surface liquid, which could alter the equilibria between
the SO- ionic species. Another factor which is altered by drying of airway
surface liquid is its osmolarity. Hyperosmolar solutions can induce
bronchoconstriction (Anderson, 1985) and could be associated with enhancement
of S09-induced bronchoconstriction.
Two laboratories (Cardiovascular Research Institute, UCSF, and Rancho Los
Amigos Hospital) have performed the bulk of the wofk on the interaction of S02
4-36
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breathing and inhaled air temperature and humidity. Although the results of
the two labs have been qualitatively similar, the mouthpiece breathing studies
(e.g. Bethel et al., 1983b) have typically yielded more pronounced increases in
airway resistance. In S02 exposures using oronasal ventilation, interlabora-
tory differences have been smaller. The use of mouthpiece breathing results in
a more direct airflow path of lower resistance than does unencumbered oronasal
breathing (Proctor, 1981; Cole, 1982). Under situations of unencumbered
oronasal breathing, the mouth may act as an effective organ of air modification
(i.e. warming, humidifying, scrubbing of particles and soluble gases). During
mouthpiece breathing, this effectiveness is reduced because of the alteration'
in oral airway geometry. Thus some of the difference between laboratories may
be due to differences in the amount of airway drying and the volume of nasal
ventilation, both of which would favor greater upper airway SO« scrubbing in
studies using oronasal ventilation. Undoubtedly subject selection criteria and
medication also play an important role in the magnitude of response but such
differences between study series are not obvious (see subject table). Another
possibility, noted incidentally by Koenig et al. (1985), is'that subjects may
deliberately breathe via the nasal airway, despite the higher resistance, in
order to alleviate both the drying effect due to cold (and/or dry) air and the
effect of S02 which may be associated with the distinctive odor or taste.
Cole (1982) notes that approximately 85 percent of adults are preferential
nose breathers who only resort to oral or oronasal breathing under the
demanding conditions of exercise, nasal obstruction, or speech. This occurs
despite the fact that upper airway resistance via the nasal airway is about
twice that via a mouthpiece. However, Bethel et al. (1983b) suggest more
asthmatics may breath oronasally and that asthmatics switch from nasal to
oronasal breathing at a lower ventilation than normals; this is due to the
greater prevalence of rhinitis in the asthmatic population.
4.4.3 Tolerance (Attenuation of Response) to SOg With Repeated Exposure
Attenuation of SOn-induced bronchoconstriction with repeated S0« exposure
(With eucapnic hyperpnea) was not associated with a decrease in airway respon-
siveness to histamine (Sheppard et al., 1983). This indicates that this
attenuation of response was not related to decreased responsiveness of airway
smooth muscle or decreased responsiveness of vagal reflex pathways. These
authors did suggest that depletion of mediators or a selective inhibition of
S02-sensitive afferents might be involved in this phenomenon. For equivalent
4-37 - •'
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total exercise time, Kehrl et al. (1986) observed greater SO^-induced
bronchoconstriction with continuous as compared to intermittent exercise during
SO* exposure. These findings suggest that mediator depletion or selective
inhibition of afferents, as well as exercise-induced release of endogenous
bronchodilators (epinephrine) are probably not related to the attenuation of
response with repeated exposure (or repeated intermittent exercise during
exposure).
The results obtained by Kehrl et al. (1986) are highly suggestive that the
attenuation of SC^-induced bronchoconstriction is related to events that occur
during the post-exposure/post-exercise recovery periods rather than events
occurring during the exposure per se. It is likely that during the recovery
periods, there is some mechanism that first helps alleviate bronchoconstriction
and may then prepare the subject for subsequent challenge. Without the
recovery period, the continuing stimuli of high ventilatory rates and S02
exposure overwhelm any attenuating process resulting in unremitting or in-
creasing bronchoconstriction. Since drying of the upper airways with resultant
changes in surface liquid quantities and properties has been strongly impli-
cated in the positive interactions between ventilation and SCL exposure, per
haps a corollary mechanism may account for the attenuation of SO^-induced
response.
It is clear that increased evaporation of water from airway mucosal sur-
faces must occur during exercise or hyperventilation (Anderson, 1985). The
continuance of increased production and/or secretion of airway surface liquid
during recovery periods may result in decreased delivery of SOy during subse-
quent inhalation of SOp. Whether or not SOp has any effect on surface liquid
quantity is unknown. Increased liquid in the lower airways would prevent
severe alterations in surface liquid properties postulated to occur when SOp is
dissolved in this liquid. Protection from subsequent challenges would be a
time-dependent phenomenon and would resolve as the factors governing airway
surface liquid homeostasis gradually return to normal.
Attenuation of bronchoconstriction has been reported for exercise (Stearns
et al., 1981) and hyperpnea of cold, dry air (Bar-Yishay et al. 1983, Wilson et
al., 1982) repeated at short time intervals, suggesting that the attenuation of
S09-induced bronchoconstriction may be secondary to this decline in respons
•
4-38
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4.5 CONCLUSIONS
Studies which have been published in the scientific literature since 1982
support many of the conclusions reached in the criteria document and th'e pre-
vious addendum.
The new studies clearly demonstrate that asthmatics are much more sensi-
tive to S0« as a group. Nevertheless, it is clear that there is a broad range
of sensitivity to SO* among asthmatics exposed under simiTar conditions. Re-
cent studies also confirm that normal healthy subjects, even with moderate to
heavy, exercise, do not experience effects on pulmonary function due to S02
exposure in the range of 0 to 2 ppm. The minor exception may be the annoyance
of the unpleasant smell or taste associated with S02. The suggestion that
asthmatics are about an order of magnitude more sensitive than normals is thus
confirmed.
There is no longer any question that normally breathing asthmatics per-
forming moderate to heavy exercise will experience S02-Induced bronchoeon-
striction when breathing SOg for at least 5 min at concentrations less than 1
ppm. Durations beyond 10 min do not appear to cause substantial worsening of
the effect. The lowest concentration at which bronchoconstriction is clearly
worsened by SO* breathing depends on a variety of factors.
Exposure to less than 0.25 ppm has not evoked group mean changes in
responses. Although some individuals may appear to respond to Sp2
concentrations less than 0.25 ppm, the frequency of these responses is npt
demonstrably greater than with clean air. Thus individual responses cannot be
relied upon for response estimates, even in the most reactive segment of the
population.
In the S02 concentration range from 0.2 to 0.3 ppm, six chamber exposure
studies were performed with asthmatics performing moderate to heavy exercise.
The evidence that S02~induced bronchoconstriction occurred at this concentra-
tion with natural breathing under a range of ambient conditions was equivocal.
Only with oral mouthpiece breathing of dry air (an unusual breathing mode under
exceptional ambient conditions) were small effects observed on a test of ques-
tionable quantitative relevance for criteria development purposes. These find-
ings are in accord with the observation that the most reactive subject in the
Horstman et al. (1986) study had a PCS02 (S02 concentration required to double
SRaw) of 0.28 ppm.
Several observations of significant group mean changes in SRaw have
recently been reported for asthmatics exposed to 0.4 to 0.6 ppm SO,,. Most if
4-39
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not all studies, using moderate to heavy exercise levels (>40 to 50 L/min),
found evidence of bronchoconstriction at 0.5 ppm. At a lower exercise rate,
other studies (e.g., Schachter et al., 1984) did not produce clear evidence of
SQp-induced bronchoconstriction at 0.5 ppm S02. Exposures which included
higher ventilations, mouthpiece breathing, and inspired air with a low water
content resulted in the greatest responses. Mean responses ranged from 45
percent (Roger et al., 1985) to 280 percent (Bethel et al., 1983b) increase in
SRaw. At concentrations in the range of 0.6 to 1.0 ppm, marked increases in
SRaw are observed following exposure. Recovery is generally complete within
approximately 1 h although the recovery period may be longer for subjects with
the most severe responses.
It is now evident that for S02-induced bronchoconstriction to occur in1
asthmatics at concentrations less than 0.75 ppm, the exposure must be
accompanied by hyperpnea. Ventilations in the range of 40 to 60 L/min have
been most successful; such ventilations are beyond the usual oronasal
ventilatory switchpoint.
There is no longer any question that oral breathing (especially via mouth-
piece) causes exacerbation of S02~induced bronchoconstriction. New studies
reinforce the concept that the mode of breathing is an important determinant of
the intensity of S02-induced bronchoconstriction in the following order: oral
> oronasal > nasal.
A second exacerbating factor strongly implicated in recent reports is the
breathing of dry and/or cold air with S02- It has been suggested that the
reduced water content and not cold, per se, could be responsible for much of
this effect. Airway drying may contribute to the S02 effect by decreasing the
efficacy of S02 scrubbing by the surface liquid of the oral and nasal airway.
Drying of airways peripheral to the 1aryngopharynx may result in decreased
surface liquid volume to buffer the effects of S02-
The new studies do not provide sufficient additional information to estab-
lish whether the intensity of the S02-induced bronchoconstriction depends upon
the severity of the disease. Across a broad clinical range from "normal" to
moderate asthmatic there is clearly a relationship between the presence of
asthma and sensitivity to S02. Within the asthmatic population, the relation-
ship of S02 sensitivity to the qualitative clinical severity of asthma has not
been studied systematically. Ethical considerations (i.e., continuation of
appropriate medical treatment) prevent the unmedicated exposure of the "severe"
asthmatic because of his dependence upon drugs for control of his asthma. True
4-40 • •'
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determination of sensitivity requires that the interference with S02 response
caused by such medication be removed. Because of these mutually exclusive
requirements, it is unlikely that the true S02 sensitivity of severe asthmatics
will be determined. Nevertheless, more severe asthmatics should be studied.
Alternative methods to those used with mild asthmatics, not critically
dependant on regular medication, will be required. The studies to date have
only addressed the "mild to moderate" asthmatic.
Consecutive S02 exposures (repeated within 30 min or less) result in a
diminished response compared with the initial exposure. It is apparent that
this refractory period lasts at least 30 min but that normal reactivity returns
within 5 h. The mechanisms and time course of this effect are not clearly
established but refractoriness does not appear to be related to an overall
decrease in bronchomotor responsiveness.
From the review of studies included in this addendum, it is clear that the
magnitude of response (typically bronchoconstriction) induced by any given SD2
concentration was variable among individual asthmatics. Exposures to S02
concentrations of 0.25 ppm or less, which did not induce significant group mean
increases in airway resistance also did not cause symptomatic bronchoconstric-
tion in individual asthmatics. On the other hand, exposures to 0.40 ppm S02 or
greater (combined with moderate to heavy exercise) which induced significant
group mean increases in airway resistance,also caused substantial bron-
choconstriction in some invididual asthmatics. This bronchoconstriction was
associated with wheezing and the perception of respiratory distress. In
several instances it was necessary to discontinue the exposure and provide
medication. The significance of these observations is that some S02-sensitive
asthmatics are at risk of experiencing clinically significant (i.e., symptoma-
tic) bronchoconstriction requiring termination of activity and/or medical
intervention when exposed to S02 concentrations of 0.40 ppm or greater when
this exposure is accompanied by at least moderate activity.
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CHAPTER 5. EXECUTIVE SUMMARY
In general, studies published in the scientific literature since 1981-82
support many of the conclusions reached in the earlier criteria review (U.S.
EPA, 1982a,c). Some of the key findings emerging from the present evaluation
of the newly available information on health effects associated with exposure
to PM and SO are summarized here.
f\
5.1 RESPIRATORY TRACT DEPOSITION AND FATE
Studies published since preparation of the earlier criteria document (U.S.
EPA, 1982a) and the previous addendum (U.S. EPA, 1982c) support the conclusions
reached at that time and provide clarification of several issues. In light of
previously available data, new literature was reviewed with a focus towards (1)
the thoracic deposition and clearance of Targe particles, (2) assessment of
deposition during oronasal breathing, (3) deposition in possibly susceptible
subpopulations, such, as children, and (4) information that would relate the
data to refinement or interpretation of ancillary issues, such as inter- and
intrasubject variability in deposition, deposition of monodisperse versus
polydisperse aerosols, etc.
The thoracic deposition of particles >10 urn D_Q and their distribution in
""" 36
the TB and P regions has been studied by a number of investigators (Svartengren,
1986; Heyder, 1986; Emmett et al., 1982). Depending upon the breathing regimen
used, TB deposition ranged from 0.14 to 0.36 for 10-um D3a particles, while the
36
range for 12-jjm D30 particles was 0.09 to 0.27. For particles 16.4 urn D=Q, a
36 3.6
maximally deep inhalation pattern resulted in TB deposition of 0.12. While the
magnitude of deposition in various regions depends heavily upon minute ventila-
tion, there is, in general, a gradual decline in thoracic deposition for large
particle sizes, and there can be significant deposition of particles greater
than 10 urn D_. particularly for individuals who habitually breathe through
36 *
their mouth. Thus, the deposition experiments wherein subjects inhale througb
5-1
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a mouthpiece are relevant to examining the potential of particles to penetrate
to the lower respiratory tract and pose a potentially increased risk. In-
creased risk may be due to increased localized dose or to the exceedingly long
half-times for clearance of larger particles (Gerrity et al., 1983).
Although experimental data are not currently available for deposition of
particles in the lungs of children, some trends are evident from the modeling
results of Phalen et al. (1985). Phalen and co-workers made morphometric •'
measurements in replica lung casts of people aged 11 days to 21 years and
modeled deposition during inspiration as a function of activity level. They
found that, in general, increasing age is associated with decreasing particu-
late deposition efficiency. However, very high flow rates and large particu-
late sizes do not exhibit consistent age-dependent differences. Since minute
ventilation at a given state of activity is approximately linearly related to
body mass, children receive a higher TB dose of particles than do adults and
would appear to be at a greater risk, other factors (i.e., mucociliary clear-
ance, particulate losses in the head, tissue sensitivity, etc.) being equal.
5 2 SUMMARY OF EPIDEMIOLOGIC FINDINGS ON HEALTH EFFECTS ASSOCIATED WITH
EXPOSURE TO AIRBORNE PARTICLES AND SOX
Newly available reanalyses of data relating mortality in London to short-
term (24-h) exposures to PM (measured as smoke) and S02 were evaluated and
their results compared with earlier findings and conclusions discussed in U.S.
EPA (1982a). Varying strengths and weaknesses were evident in relation to the
different individual reanalyses evaluated and certain questions remain un-
resolved concerning most. Regardless of the above considerations, the following
conclusions appear warranted based on the earlier criteria review (U.S. EPA,
1982a) and present evaluation of newly available analyses of the London mortal-
ity experience: (1) markedly increased mortality occurred, mainly among the
elderly and chronically ill, in association with BS and S02 concentrations
above 1000 ug/m3, especially during episodes when such pollutant elevations
occurred for.several consecutive days; (2) the relative contributions of BS and
S02 cannot be clearly distinguished from those of each other, nor can the
effects of other factors be clearly delineated, although it appears likely that
coincident high humidity (fog) was also important (possibly in providing
5-2
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conditions leading to formation of H2$04 or other acidic aerosols); (3) in-
creased risk of mortality is associated with exposure to BS and S02 levels in
the range of 500 to 1000 ug/m3, clearly at concentrations in excess of ~700 to
750 ug/m ; and (4) less certain evidence suggests possible slight increases in
the risk of mortality at BS levels below 500 ug/m3, with no specific threshold
levels having yet been demonstrated or ruled out at lower concentrations of BS
(e.g., at 150 ug/m ) nor potential contribution of other plausibly confounding
variables having yet been fully evaluated.
In addition to the reanalyses of London mortality data, reanalyses of
mortality data from New York City in relation to air pollution reported by
Ozkaynak and Spengler (1985) were evaluated. Time-series analyses were carried
out on a subset of New York City data included in a prior analysis by Schimmel
(1978) which was critiqued during the earlier criteria review (U.S. EPA,
1982a). The reanalyses by Ozkaynak and Spengler (1985) evaluated 14 years
(1963-76) of daily measurements of mortality (the sum of heart, other circula-
tory, respiratory, and cancer mortality), COH, S02, and temperature. In
summary, the newly available reanalyses of New York City data raise possibili-
ties that, with additional work, further insights may emerge regarding
mortality-air pollution relationships in a large U.S. urban area. However, the
interim results reported thus far do not now permit definitive determination of
their usefulness for defining exposure-effect relationships, given the above-
noted types of caveats and limitations.
Similarly, it is presently difficult to accept findings reported in
another new study of mortality associated with relatively low levels of S0?
pollution in Athens, given questions regarding representativeness of the
monitoring data and the statistical soundness of using deviations of mortality
from an earlier baseline relatively distant in time. Lastly, a newly reported
analyses of mortality-air pollution relationships in Pittsburgh (Allegheny
County, PA) was evaluated as having utilized inadequate exposure characteriza-
tion and the results contain sufficient internal inconsistencies, so that the
analyses are not useful for delineating mortality relationships with either S0?
or PM. Z
Of the newly-reported analyses of short-term PM/SOX exposure-morbidity
relationships discussed in this Addendum, the Dockery et al. (1982) study
provides the best-substantiated and most readily interpretable results. Those
results, specifically, point toward decrements in lung function occurring in
5-3
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association with acute, short-term increases in PM and S02 air pollution. The
small, reversible decrements appear to persist for 1-2 wks after episodic
exposures to these pollutants across a wide range, with no clear delineation of
threshold yet being evident. In some study periods effects may have been due
to TSP and S02 levels ranging up to 422 and 455 ug/m3, respectively. Notably
larger decrements in lung function were discernable for a subset of children
(responders) than for others. The precise medical significance of the observed
decrements per se or any consequent long-term sequalae remain to be determined.
The nature and magnitude of lung function decrements found by Dockery et al.
(1982), it should be noted, are also consistent with: observations of Stebbings
and Fogelman (1979) of gradual recovery in lung function of children during
seven days following a high PM episode in Pittsburgh, PA (max 1-hr TSP esti-
mated at 700 ug/m3); and a report by Saric et al. (1981) of 5 percent average
declines in FEV-j^ Q being associated with high S02 days (89-235 ug/m3).
In regard to evaluation of long-term exposure effects, the 1982 U.S. EPA
criteria document (1982a) noted that certain large-scale "macroepidemiological"
(or "ecologic" studies as termed by some) have attracted attention on the basis
of reported demonstrations of associations between mortality and various
indices of air pollution, e.g., PM or SOV levels. U.S. EPA (1982a) also noted
x\
that various criticisms of then-available ecologic studies made it impossible
to ascertain which findings may be more valid than others. Thus, although many
of the studies qualitatively suggested positive associations between mortality
and chronic exposure to certain air pollutants in the United States, many key
issues remained unresolved concerning reported associations and whether they
were causal or not.
Since preparation of the earlier Criteria Document (U.S. EPA, 1982a)
additional ecological analyses have been reported regarding efforts to assess
relationships between mortality and long-term exposure to particulate matter
and other air pollutants. For example, Lipfert (1984) conducted a series of
cross-sectional multiple regression analyses of 1969 and 1970 mortality rates
for up to 112 U.S. SMSA's, using the same basic data set as Lave and Seskin
(1978) for 1969 and taking into account various demographic, environmental and
lifestyle variables (e.g., socioeconomic status and smoking). Also, the
Lipfert (1984) reanalysis included several additional independent variables:
diet; drinking water variables; use of residential heating fuels; migration;
and SMSA growth. New dependent variables included age-specific mortality rates
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with their accompanying sex-specific age variables. Both linear and several
nonlinear (e.g., quadratic or linear splines testing for possible threshold
model specifications) were evaluated.
It became quite evident from the results obtained that the air pollution
regression results for the U.S. data sets analyzed by Lipfert (1984) are
extremely sensitive to variations in the inclusion/exclusion of specific
observations (for central city versus SMSA's or different subsets of locations)
or additional explanatory variables beyond those used in the earlier Lave and
Seskin analyses. The results are also highly dependent upon the particular
model specifications used, i.e. air pollution coefficients vary in strength of
association with total or age-/sex-specific mortality depending upon the form
of the specification and the range of explanatory variables included in the '
analyses. Lipfert1s overall conclusion was that the sulfate regression coeffir
cients are not credible and, since sulfate and TSP interact with each other in
these regressions, caution is warranted for TSP coefficients as well.
Ozkaynak and Spengler (1985) have also newly described results from
ongoing attempts to improve upon previous analyses of mortality and morbidity
effects of air pollution in the United States. Ozkaynak and Spengler (1985)
present principal findings from a cross-sectional analysis of the 1980 U.§.
vital statistics and available 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 misspecifica-
tion and spatial autocorrelation of the residuals were also investigated.
The Ozkaynak and Spengler (1985) results for 1980 U.S. mortality provide
an interesting overall contrast to the findings of Lipfert (1984) for 1969-70
U.S. mortality data. Whereas Lipfert found TSP coefficients to be most con-
sistently 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 non-significant 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 particle exposure measures
5-5
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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, 1986) may at least partly explain their contrast-
ing 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 SO exposures in the United
/\
States. Thus conclusions stated in U.S EPA (1982a) concerning ecologic
analyses still largely apply here in regard to mortality PM/SO relationships.
The present Addendum also evaluated a growing body of new literature on
morbidity effects associated with chronic exposures to airborne particles and
sulfur oxides. In summary, of the numerous new studies published on morbidity
effects associated with long-term exposures to PM or SO , only a few may
J\
provide potentially useful results by which to derive quantitative conclusions
concerning exposure-effect relationships for the subject pollutants. A study
by Ware et al. (1986), for example, provides evidence of'respiratory symptoms
in children being associated with particulate matter exposures in contemporary
U.S. cities without evident threshold across a range of TSP levels of ~25 to
o
150 ug/m . The increase in symptoms appears to occur without concomitant
decrements in lung function among the same children. The medical significance
the observed increased in symptoms unaccompanied by decrements in lung of
function renjains to be fully evaluated but is of likely health concern.
Caution is warranted, however, in using these findings for risk assessment
purposes in view of the lack of significant associations for the same variables
when assessed from data within individual cities included in the Ware et al.
(1985) study.
Other new American studies provide evidence for: (1) increased respira-
tory symptoms among young adults in association with annual-average SO, levels
3
of ~115 ug/m (Chapman et al., 1983); and (2) increased prevalence of cough in
children (but not lung function changes) being associated with intermittent
exposures to mean peak 3-hr S02 levels of ~1.0 ppm or annual average S02 levels
of ~103 ug/m3 (Dodge et al., 1985).
Results from one European study (PAARC, 1982a,b) also suggest the likeli-
hood of lower respiratory disease symptoms and decrements in lung function in
5-6
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adults (both male and female) being associated with annual average S02 levels
ranging without evident threshold from about 25 to 130 ug/m3. in addition that
study suggests that upper respiratory disease and lung function decrements in
children may also be associated with annual-average S02 levels across the above
range. Further analyses would probably be necessary to determine whether or
not any thresholds for the health effects reported by PAARC (1982a,b) exist
within the stated range of annual-average S02 values.
5.3 SUMMARY OF CONTROLLED HUMAN EXPOSURE STUDIES OF SULFUR DIOXIDE HEALTH
tr r tv> I o
The new studies clearly demonstrate that asthmatics are much more sensi-
tive to S02 as a group. Nevertheless, it is clear that there is a broad range
of sensitivity to S02 among asthmatics exposed under similar conditions. Re-
cent studies also confirm that normal healthy subjects, even with moderate to
heavy exercise, do not experience effects on pulmonary function due to S0?
exposure in the range of 0 to 2 ppm. The minor exception may be the annoyance
of the unpleasant smell or taste associated with S02> The suggestion that
asthmatics are about an order of magnitude more sensitive than normals is thus
confirmed.
There is no longer any question that normally breathing asthmatics per-
forming moderate to heavy exercise will experience S02~induced bronchocon-
striction when breathing S02 for at least 5 min at concentrations less than 1
ppm. Durations beyond 10 min do not appear to cause substantial worsening of
the effect. The lowest concentration at which bronchoconstriction is clearly
worsened by S02 breathing depends on a variety of factors.
Exposure to less than 0.25 ppm has not evoked group mean changes in
responses. Although some individuals may appear to respond to S02 concentra-
tions less than 0.25 ppm, the frequency of these responses is not demonstrably
greater than with clean air. Thus individual responses cannot be relied upon
for response estimates, even in the most reactive segment of the population.
In the S02 concentration range from 0.2 to 0.3 ppm, six chamber exposure
studies were performed with asthmatics performing moderate to heavy exercise.
The evidence that S02-induced bronchoconstriction occurred at this concentra-
tion with natural breathing under a range of ambient conditions was equivocal.
Only with oral mouthpiece breathing of dry air (an unusual breathing mode under
5-7
-------
exceptional ambient conditions) were small effects observed on a test of ques-
tionable quantitative relevance for criteria development purposes. These find-
ings are in accord with the observation that the most reactive subject in the
Horstman et al. (1986) study had a PCS02 (S02 concentration required to double
SRaw) of 0.28 ppm.
Several observations of significant group mean changes in SRaw have
recently been reported for asthmatics exposed to 0.4 to 0.6 ppm S02- Most if
not all studies, using moderate to heavy exercise levels (>40 to 50 L/min),
found evidence of bronchoconstriction at 0.5 ppm. At a lower exercise rate,
other studies (e.g., Schachter et al., 1984) did not produce clear evidence of
S02-induced bronchoconstriction at 0.5 ppm S02. Exposures which included
higher ventilations, mouthpiece breathing, and inspired air with a low water
content resulted in the greatest responses. Mean responses ranged from 45
percent (Roger et al., 1985) to 280 percent (Bethel et al., 1983b) increase in
SRaw. At concentrations in the range of 0.6 to 1.0 ppm, marked increases in
SRaw are observed following exposure. Recovery is generally complete within
approximately 1 h although the recovery period may be longer for subjects with
the most severe responses.
It is now evident that for S02~induced bronchoconstriction to occur in
asthmatics at concentrations less than 0.75 ppm, the exposure must be accom-
panied by hyperpnea. Ventilations in the range of 40 to 60 L/min have been
most successful; such ventilations are beyond the usual oronasai ventilatory
switchpoint.
There is no longer any question that oral breathing (especially via mouth-
piece) causes exacerbation of S02-induced bronchoconstriction. New studies
reinforce the concept that the mode of breathing is an important determinant of
the intensity of S02-induced bronchoconstriction in the following order: oral
> oronasai > nasal.
A second exacerbating factor strongly implicated in recent reports is the
breathing of dry and/or cold air with S02. It has been suggested that the
reduced water content and not cold, per se, could be responsible for much of
this effect. -Airway drying may contribute to the S02 effect by decreasing the
efficacy of S02 scrubbing by the surface liquid of the oral and nasal airway.
Drying of airways peripheral to the laryngopharynx may result in decreased
surface liquid volume to buffer the effects of SOg.
5-8
-------
The new studies do not provide sufficient additional information to estab-
lish whether the intensity of the S02-induced bronchoconstriction depends upon
the severity of the disease. Across a broad clinical range from "normal" to
moderate asthmatic there is clearly a relationship between the presence of
asthma and sensitivity to S02< Within the asthmatic population, the relation-
ship of S02 sensitivity to the qualitative clinical severity of asthma has not
been studied systematically. Ethical considerations (i.e., continuation of
appropriate medical treatment) prevent the unmedicated exposure of the "severe"
asthmatic because of his dependence upon drugs for control of his asthma. True
determination of sensitivity requires that the interference with SO^ response
caused by such medication be removed. Because of these mutually exclusive
requirements, it is unlikely that the true S02 sensitivity of severe asthmatics
will be determined. Nevertheless, more severe asthmatics should be studied.
Alternative methods to those used with mild asthmatics, not critically
dependant on regular medication, will be required. The studies to date have
only addressed the "mild to moderate" asthmatic.
Consecutive S02 exposures (repeated within 30 min or less) result in a
diminished response compared with the initial exposure. 'It is apparent that
this refractory period lasts at least 30 min but that normal reactivity returns
within 5 h. The mechanisms and time course of this effect are not clearly
established but refractoriness does not appear to be related to an overall
decrease in bronchomotor responsiveness.
From the review of studies included in this addendum, it is clear that the
magnitude of response (typically bronchoconstriction) induced by any given SO,,
concentration was variable among individual asthmatics. Exposures to S0?
concentrations of 0.25 ppm or less, which did not induce significant group mean
increases in airway resistance also did not cause symptomatic bronchoconstric-
tion in individual asthmatics. On the other hand, exposures to 0.40 ppm S02 or
greater (combined with moderate to heavy exercise) which induced significant
group mean increases in airway resistance,also caused substantial bron-
choconstriction in some invididual asthmatics. This bronchoconstriction was
associated with wheezing and the perception of respiratory distress. In
several instances it was necessary to discontinue the exposure and provide
medication. The significance of these observations is that some S02-sensitive
asthmatics are at risk of experiencing clinically significant (i.e., symptoma-
tic) bronchoconstriction requiring termination of activity and/or medical
5-9
-------
intervention when exposed to S02 concentrations of 0.40 ppm or greater when
this exposure is accompanied by at least moderate activity.
5-10
-------
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U.S. GOVERNMENT PRINTING OFFICE: 1986 - 646-014/40014
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