EPA-600/FP-93/002
August 1994
SUPPLEMENT TO THE SECOND ADDENDUM (1986)
TO AIR QUALITY CRITERIA FOR PARTICULATE
MATTER AND SULFUR OXIDES (1982):
Assessment of New Findings on Sulfur Dioxide
Acute Exposure Health Effects
in Asthmatic Individuals
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Printed on Recycled Paper
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental Protection
Agency policy and approved for publication. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
11
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TABLE OF CONTENTS
Page
LIST OF TABLES v
LIST OF FIGURES vi
AUTHORS ...,. -.,,,, :..-, ..... vii
REVIEWERS • viii
ABSTRACT ....:.... xi
1.0 INTRODUCTION • • • • 1
2.0 BACKGROUND INFORMATION ON ASTHMA 3
2.1 DEFINITION AND INCIDENCE OF ASTHMA 5
2.2 MEDICATION USE BY ASTHMATIC INDIVIDUALS 9
3.0 SUMMARY OF PREVIOUS FINDINGS ON SULFUR
DIOXIDE EFFECTS 10
4.0 KEY NEW FINDINGS ON FACTORS AFFECTING RESPIRATORY
RESPONSES TO SULFUR DIOXIDE IN ASTHMATIC
SUBJECTS 15
4.1 EXPOSURE DURATION/HISTORY AS SULFUR DIOXIDE
DOSE-RESPONSE DETERMINANTS 15
4.2 SULFUR DIOXIDE RESPONSES AND ASTHMA
SEVERITY • 19
4.3 RANGE OF SEVERITY OF SULFUR DIOXIDE
RESPONSES 27
4.3.1 Severity of Sulfur Dioxide Respiratory
Function Responses 30
4.3.2 Severity of Respiratory Symptom Responses to
Sulfur Dioxide 32
4.4 MODIFICATION OF SULFUR DIOXIDE RESPONSE BY
ASTHMA MEDICATIONS 34
4.5 MODIFICATION OF SULFUR DIOXIDE RESPONSIVENESS
BY OTHER AIR POLLUTANTS 41
5.0 SUMMARY AND CONCLUSIONS 43
5.1 EXPOSURE DURATION/HISTORY AS SULFUR DIOXIDE
RESPONSE DETERMINANTS 43
5.2 SULFUR DIOXIDE RESPONSES AND ASTHMA
SEVERITY 44
5.3 RANGE OF SEVERITY OF SULFUR DIOXIDE
RESPONSES 44
5.4 MODIFICATION OF SULFUR DIOXIDE RESPONSE BY
ASTHMA MEDICATIONS . . .' , 46
m
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TABLE OF CONTENTS
5.5 MODIFICATION OF SULFUR DIOXIDE RESPONSIVENESS
BY OTHER AIR POLLUTANTS
5.6 HEALTH RISK IMPLICATIONS
•5.7 POPULATION GROUPS AT RISK
REFERENCES
APPENDIX A
APPENDIX B
47
48,
52
54
A-l
B-l
IV
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LIST OF TABLES
Number
1 Classification of Asthma by Severity of Disease 6
2 Summary of Key New Study Results from Controlled Human
Exposure Studies of Acute Sulfur Dioxide Exposure Effects!
in Asthmatic Subjects . 16
3 Comparison of Specific Airway Resistance and Forced
Expiratory Volume in One Second Responses to Air and Sulfur
Dioxide Exposure in Asthmatic Subjects 20
4 Estimates of Sulfur Dioxide Responses in Asthmatic
Subjects 23
5 . Comparative Responses of Asthmatic Subjects to Cold/Dry Air
and Exercise: Forced Expiratory Volume in One Second and
Specific Airway Resistance 28
6 Summary of Results from Controlled Human Exposure
Studies of Effects of Medications on Pulmonary Function
Effects Associated with Exposure of Asthmatic Subjects
to Sulfur Dioxide 35
7 Medication Use After Sulfur Dioxide Exposure 40
8 Comparative Indices of Severity of Respiratory Effects
Symptoms, Spirometry, and Resistance 46
A-l Summary of Key Controlled Human Exposure Studies of
Pulmonary Function Effects Due to Exposure of Asthmatics
to Sulfur Dioxide • • • • • A"2
B-l Average Magnitudes of Lung Function Changes at Tested
Sulfur Dioxide Exposure Levels and Percentages of Subjects
Exhibiting Changes of Increasing Severity at Moderate to
High Exercise Levels, Based on U.S. Environmental Protection
Agency Evaluation of Data from Selected Recent Controlled
Human Studies • B-2
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Number
1
2
LIST OF FIGURES
Distribution of individual airway sensitivity to sulfur dioxide
Specific airway resistance of 16 mild and 24 moderate asthmatic
subjects exposed to 0.0, 0.4, and 0.6 ppm sulfur dioxide
Forced expiratory volume in one second responses to
sulfur dioxide exposure in medication-dependent asthmatic
subjects
14
22
24
VI
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AUTHORS
Dr. Lawrence J. Folinsbee
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Chapel Hill, NC 27514
Dr. Lester D. Grant, Director
Environmental Criteria and Assessment
Office
Office of Health and Environmental
Assessment
U.S. Environmental Protection Agency
Research Triangle Park, NC 27514
Dr. James J. McGrath*
Environmental Criteria and Assessment
Office
Office of Health and Environmental
Assessment
U.S. Environmental Protection Agency
Research Triangle Park, NC 27514
"On Intergovernmental Personnel Agreement (IPA) assignment to U.S. EPA from the School of Medicine,
Department of Physiology, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock,
Texas 79430.
Vll
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REVIEWERS
A preliminary draft version of this supplement was circulated for internal and external
review. Written and/or oral comments were received from the following individuals/and
revisions were made in response to their peer-review of that preliminary draft.
Internal EPA Reviewers
Dr. Donald H. Horstman
Health Effects Research Laboratory
U.S. Environmental Protection Agency
(MD-58)
Chapel Hill, NC 27514
Dr. William Pepelko
Human Health Assessment Group
Office of Health and Environmental
Assessment
U.S. Environmental Protection Agency
(RD-689)
401 M Street, S.W.
Washington, DC 20460
Dr. Jeannette Wiltse, Deputy Director
Office of Health and Environmental
Assessment
U.S. Environmental Protection Agency
(RD-689)
401 M Street, S.W.
Washington, DC 20460
Dr. Howard Kehrl
Health Effects Research Laboratory
U.S. Environmental Protection Agency
(MD-58)
Chapel Hill, NC 27514
External Non-EPA Reviewers
Dr. Jane Koenig
Department of Environmental Health
Mail Stop SC-34
University of Washington
Seattle, WA 98195
Mr. William S. Linn
Rancho Los Amigos Medical Center
51 Medical Science Building
7601 East Imperial Highway
Downey, CA 90242
In addition to review of the preliminary draft by the above individuals, External Review
Drafts of this Supplement were circulated by EPA for public comment and peer-review by
the Clean Air Scientific Advisory Committee (CASAC) of EPA's Science Advisory Board
(SAB). Revisions have been incorporated into the present final version of the Supplement in
response to public comments and recommendations made by the following CASAC members
and consultants as the result of public review meetings held in Durham, NC, August 19,
1993 and April 12, 1994.
vm
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REVIEWERS (corit'd)
Science Advisory Board
Clean Air Scientific Advisory Committee
Sulfur Dioxide Review Roster
Chair
Dr. George Wolff
General Motors Research Labs
Environmental Science Dept.
Warren, MI 48090
Members
Dr. Stephen Ay res
Deans Office, School of Medicine
Virginia Commonwealth University
Medical College of Virginia, Box 565
Richmond, VA 23298
Dr. Jean Ford
Columbia University
School of Public Health
Division of Environmental Sciences
60 Haven Avenue
New York, NY 10032
Dr. Benjamin Y. H. Liu
University of Minnesota
130-A Mechanical Engineering Bldg.
Ill Church Street, S.E.
Minneapolis, MN 55455
Dr. Joe L. Mauderly
Inhalation Toxicology Research Inst.
Lovelance Biomedical and Env.
Research Institute
P.O. Box 5890
Albuquerque, NM 87185
Dr. Paulette Middleton
University Cooperation for Atmospheric
Research
P.O. Box 3000
Boulder, CO 80307
Dr. James H. Price, Jr.
Manager, Research Section
Texas Natural Resources Conservation
Commission
P.O. Box 13087
Austin, TX 78711
Dr. Mark Utell
Pulmonary Disease United Box 692
University of Rochester Med. Ctr.
601 Elm wood Avenue
Rochester, NY 14642
Consultants
Dr. Nedd Robert Frank
Johns Hopkins University
School of Public Health
615 N. Wolfe Street
Baltimore, MD 21205
Dr. Roger O. McClellan
Chemical Industry Institute
of Toxicology
P.O. Box 12137
Research Triangle Park, NC 27709
Dr. Neil Schachter
Mt. Sinai Medical Center
1 Grustav L. Levy Place
Box 1232
New York, NY 10029
IX
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REVIEWERS (cont'd)
SAB Staff Personnel
Mr. Randall C. Bond
U.S. EPA
Science Advisory Board (A-101)
401 M. Street, SW
Washington, DC 20460
Ms. Janice Jones
U.S. EPA
Science Advisory Board (A-101)
401 M. Street, SW
Washington, DC 20460
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ABSTRACT
The present Supplement to the Second Addendum (1986) to the document Air Quality
Criteria for Particulate Matter and Sulfur Oxides (1982) focuses on evaluation of newly
available controlled human exposure studies of acute (< 1 h) sulfur dioxide (SO2) exposure
effects on pulmonary function and respiratory symptoms in asthmatic subjects. The
Supplement more specifically: (1) incorporates by reference and concisely summarizes the
most important key findings on the same topic from the previous criteria reviews in the 1982
Criteria Document and its 1986 Second Addendum, as they pertain to derivation of health
criteria for a possible new "acute exposure" (< 1 h) primary SO2 National Ambient Air
Quality Standard (NAAQS); and (2) provides an updated assessment of new information that
has become available since completion of the 1986 Second Addendum and is of likely
importance for derivation of health criteria for any such short-term SO2 NAAQS. Thus, this
Supplement is not intended as a comprehensive detailed review of all new information on
SO2 effects, but rather is targeted explicitly on those human studies thought to provide key
information useful to U.S. EPA decision making regarding a
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SUPPLEMENT TO THE SECOND ADDENDUM (1986)
TO AIR QUALITY CRITERIA FOR PARTICIPATE
MATTER AND SULFUR OXIDES (1982):
Assessment of New Findings on Sulfur Dioxide
Acute Exposure Health Effects in Asthmatic Individuals
1.0 INTRODUCTION
The United States Clean Air Act and its Amendments (1977, 1990) 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. Earlier
periodic review of the scientific bases underlying the NAAQS for particulate matter (PM)
and sulfur oxides (SOX) culminated in the 1982 publication of the U.S. EPA document Air
Quality Criteria for Particulate Matter and Sulfur Oxides (U.S. EPA, 1982a), an associated
PM staff paper (U.S. EPA, 1982b) that examined implications of the revised criteria for.
'• ^
review of the PM NAAQS, an addendum to the criteria document assessing further
information on health effects (U.S. EPA, 1982c), and another staff paper relating the revised
scientific criteria to the review of the SOX NAAQS (U.S. EPA, 19,82d). Based on the
criteria document, addendum, and staff papers, revised 24-h and annual-average standards for
PM were proposed (Federal Register, 1984a) and public comments on the proposed revisions
received both in written form and orally at public hearings (Federal Register, 1984b).
Subsequently, a Second Addendum to the 1982 PM/SOX Criteria Document was prepared and
published in 1986. The Second Addendum (U.S. EPA, 1986) included evaluation of
numerous new studies that had become available since completion of the earlier PM/SOX
criteria document, its addendum, and associated staff papers (U.S. EPA, 1982a,b,c,d),
emphasizing assessment of those key new studies likely to have important bearing on
development of criteria to support decisionmaking on PM or SOX NAAQS revisions.
The evaluations contained in the foregoing criteria document, addenda, and staff papers
ultimately provided scientific bases for establishment (Federal Register, 1987) of new 24-h
and annual average PM NAAQS set at: 150 /zg/m3 (24 h) and 50 /zg/m3 (annual) for
particulate matter less than 10 /zm aerodynamic diameter (PM10). In addition, U.S. EPA
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published a proposal (Federal Register, 1988) to retain the current primary NAAQS for
sulfur dioxide (SO2) (i.e., 365 ^g/m3 [24 h] and 80 Atg/m3 [annual]) along with a call for
public comment on possibly adding an even shorter term (1-h) SO2 NAAQS to protect
against health effects in asthmatic individuals associated with very acute exposures to SO2.
The most crucial information supporting consideration of possible setting of an acute
exposure standard cited by the 1988 proposal were recent findings from controlled human
exposure studies concerning: (1) exposure-response relationships for SO2-induced
bronchoconstriction and respiratory symptoms in asthmatic subjects; (2) the severity of such
effects, which might vary in intensity as a function of the preexisting disease severity (mild
to severe asthma); and (3) other factors (e.g., medication use) that might alter such
S02-induced responses.
Since the Second Addendum (1986) was completed, several new controlled human
exposure studies have become available that further evaluate acute (< 1-h) SO2 exposure
effects on asthmatic individuals and provide pertinent additional information useful in
supporting U.S. EPA decisionmaking on whether a new short-term SO2 NAAQS is needed
and, if so, the appropriate form and level of such a standard. Accordingly, the present
supplement: (1) incorporates by reference and summarizes the most important key findings
from the above previous criteria reviews (U.S. EPA, 1982a,c, 1986) as they pertain to
derivation of health-related criteria for a possible new "acute exposure" (< 1-h) primary
SO2 NAAQS; and (2) provides an updated assessment of newly available information of
potential importance for derivation of health criteria for any such new short-term SO2
standard.
This document is intended to be considered in conjunction with the extensive 1982
Criteria Document (U.S. EPA, 1982a) and its earlier Addenda (U.S. EPA, 1982c, 1986).
Much background material was presented in these previous documents and is not repeated in
this supplement; the reader is therefore encouraged to read such background material to
become more fully informed. The material presented here focuses mainly on the assessment
of selected new information regarding controlled exposure of asthmatic subjects to SO2,
along with concise summarization and discussion of certain information on the "natural
history" of asthma in order to place the SO2 effects in context in relation to variations in
respiratory responses otherwise often experienced by asthmatic subjects.
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2.0 BACKGROUND INFORMATION ON ASTHMA
The information discussed below on the health effects of SO2 in asthmatic individuals is
derived from controlled human exposure studies which are often used to study the effects of
single (or multiple) inhaled pollutants such as SO2. Such studies may be performed in
environmental chambers where the subjects are free to breathe as they would in the ambient
environment or studies may be conducted using mouthpiece or facemask systems where the
subjects are required to breathe through the mouthpiece or facemask. In addition to the
concentration of SO2, these studies also permit accurate determination of the duration of
exposure and the volume of inspired air containing S02. Other factors such as exercise and
air temperature and humidity, which can alter responses, can also be controlled.
Exercise alone may have some important confounding effects, particularly in the case of
exercise-induced bronchoconstriction in asthmatic individuals, which can be indexed by
significant decrements in spirometric variables or increments in airway resistance. Exercise-
induced bronchoconstriction is followed by a refractory period of several hours during which
asthmatic individuals are less susceptible to bronchoconstriction (Edmunds et al., 1978).
This period of refractoriness can alter the subject's responsiveness to SO2 or other inhaled
substances. The major external determinants of the exposure "dose" of a pollutant are the
concentration of pollutant, the duration of the exposure, and the volume of air breathed
(specifically, the route, depth, and frequency of breathing) during the exposure. . Further
information is necessary to determine the actual dose delivered to the various "target" regions
of the respiratory tract (i.e., total respiratory uptake) and is not discussed in this document.
In controlled human exposure studies, the methods used for assessment of respiratory
effects primarily involve "noninvasive" procedures. Lung function tests such as spirometric
measures of lung volumes, measures of resistance of lung or nasal airways, ventilation
volume (volume of air inhaled into the lung), breathing pattern (frequency and depth of
breathing), and numerous other "breathing" tests have; been utilized (Bouhuys, 1974). These
tests provide useful information about some of the baisic physiological functions of the lung.
Dynamic spirometry tests (forced expiratory tests such as forced expiratory volume in 1 s
[FEVJ, maximal and partial flow-volume curves, peak flow measurements, etc.) and specific
airway resistance/conductance measurements (SRaw, SGaw) provide information primarily
about large airway function. These "standard pulmonary function" tests are relatively simple
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to administer, provide a good overall index of lung function, and have a relatively low
coefficient of variation (CV). For FEVlt the CV is about 3% and for SRaw, the CV is about
10 to 20% for normal healthy subjects1.
Measurements of spirometry (FEVls etc.) and peak flow are also commonly used in
clinical practice to assess lung function, especially in patients with respiratory disease such as
asthma. Measurements of airway resistance with a body plethysmograph may be used in
clinical evaluations but, because of the cost, complexity, and size of the equipment required,
they are more often conducted in research laboratories or major medical centers. The
coefficient of variation for SRaw measurements tends to be somewhat higher in patients with
lung disease than in healthy individuals (Skoogh, 1973; Pelzer and Thompson, 1966). Both
asthmatic and healthy patients experience a circadian variation in lung function, with the
poorest function (i.e., lowest FEVj and highest SRaw) being experienced in the early
morning hours (4 to 6 AM) and the best function (i.e., highest FEV, and lowest SR )
•*• 3.W'
occurring in the mid-afternoon (2 to 4 PM). The oscillations can vary by ±5 to 10% about
the daily mean in asthmatic subjects (this means that FEVj could be as much as 20% higher
at mid-afternoon as opposed to early morning although the typical range is about 10%), but
are typically smaller in healthy subjects. Similar variations in SRaw may result in SRaw
being about 40% higher in early morning than at mid-afternoon in asthmatic subjects
(Smolensky et al., 1986).
Circadian variations in lung function in asthmatic individuals have been reviewed by
Smolensky et al. (1986). They discuss that the chronobiology of asthma is, in part,
associated with other body rhythms having a circadian periodicity, such as cortisol,
catecholamines, vagal tone, etc. Daily variability of lung function is a typical feature of
asthma and has been used as a predictor of airway hyperresponsiveness (Higgins et al.,
1992). For a group of subjects selected because they had ever experienced wheezing, the
90th percentile for variability in peak flow (expressed as the [lowest PEF - highest PEF] -^
mean PEF) was 17.6%. The mean amplitude of variability for those who had wheezed in
the past week was 10%.
ave"g^ C°f fi,cient of variation for a number of subjects tested multiple times. CV = S.D
calculated for tests
x
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2.1 DEFINITION AND INCIDENCE OF ASTHMA
The Expert Panel Report from the National Asthma Education Program of the National
Heart Lung and Blood Institute (NIH, 1991) has recently defined asthma as:
Asthma is a lung disease with the following characteristics: (1) airway obstruction that is
reversible (but not completely so in some patients) either spontaneously or with treatment,
(2) airway inflammation, and (3) increased airway responsiveness to a variety of stimuli.
About 10 million people or 4% of the U.S. population are estimated to have asthma
(NIH, 1991). The prevalence is higher among African Americans, older (8- to 11-year-old)
children, and urban residents (Schwartz et al., 1990). The true prevalence of asthma may be
somewhat higher than determined by epidemiologic surveys since some individuals with mild
asthma who have never been treated by a physician may be unaware of the fact that they
have asthma (Voy, 1984). Depending upon the definition of asthma,, some estimates of
prevalence may be as high as 7 to 10% of the U.S. population (Evans et al., 1987).
There is a broad range of severity of asthma ranging from mild to severe (see Table 1,
reproduced from NIH, 1991). Common symptoms include cough, wheezing, shortness of
breath, chest tightness, and sputum production. A positive response (skin test) to common
inhalant allergens and an increased serum immunoglobulin E are common features of asthma.
However, not all asthmatic individuals have allergies (although estimates range as high as
80%) and a large number of healthy individuals who have allergies (approximately 30 to
40% of healthy individuals) do not develop asthma (Weiss and Speizer, 1993). Asthma is
characterized by an exaggerated bronchoconstrictor response to many physical challenges
(e.g., cold or dry air; exercise) and chemical and pharmacologic agents (e.g., histamine or
methacholine). Notably, however, bronchial hyperresponsiveness is not synonymous with
asthma (Weiss and Speizer, 1993). Asthma is typically associated with airway inflammation
and epithelial injury (NIH, 1991; Beasley et al., 1989; Laitinen et al., 1985; Wardlaw et al.,
1988). Based on laboratory findings (Deal et al., 1980) asthma symptoms are expected to be
exacerbated by cold dry weather, although such an effect of ambient cold on asthma
morbidity has not been clearly demonstrated. Approximately 50% of childhood asthmatic
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TABLE 1. CLASSIFICATION OF ASTHMA BY SEVERITY OF DISEASE8
Characteristics
Mild
Moderate
Severe
A. Pretrearmem
Frequency of
exacerbations
Exacerbations of cough and
wheezing no more often than
1-2 times/week.
Exacerbation of cough and
wheezing on a more frequent basis
than 1-2 times/week. Could have
history of severe exacerbations, but
infrequent. Urgent care treatment
in hospital emergency department
or doctor's office < 3 times/year.
Frequency of
symptoms
Degree of exercise
tolerance
Frequency of
nocturnal asthma
School or work
attendance
Pulmonary function
• Peak Expiratory
Flow Rate (PEFR)
• Spirometry
1 Methacholine
sensitivity
Few clinical signs or
symptoms of asthma between
exacerbations.
Good exercise tolerance but
may not tolerate vigorous
exercise, especially prolonged
running.
Symptoms of nocturnal
asthma occur no more often
than 1-2 times/month.
Good school or work
attendance.
PEFR > 80% predicted.
Variability <20%.
Minimal or no evidence of
airway obstruction on
spirometry. Normal
expiratory flow volume
curve; lung volumes not
increased. Usually a >15%
response to acute aerosol
bronchodilator administration,
even though baseline near
normal.
Methacholine PC2o
> 20 mg/mL.c
Cough and low grade wheezing
between acute exacerbations often
present.
Exercise tolerance diminished.
Symptoms of nocturnal asthma
present 2-3 times/week.
School or work attendance may be
affected.
Virtually daily wheezing. Exacerbations
frequent, often severe. Tendency to have
sudden severe exacerbations. Urgent visits to
hospital emergency departments or doctor's
office >3 times/year. Hospitalization
>2 times/year, perhaps with respiratory
insufficiency or, rarely, respiratory failure and
history of intubation. May have had cough
syncope or hypoxic seizures.
Continuous albeit low-grade cough and
wheezing almost always present.
Very poor exercise tolerance with marked
limitation of activity.
Considerable, almost nightly sleep interruption
due to asthma. Chest tight in early morning.
Poor school or work attendance.
PEFR 60-80% predicted.
Variability 20-30%.
Signs of airway obstruction on
spirometry are evident. Flow
volume cui ve shows reduced
expiratory flow at low lung
volumes. Lung volumes often
increased. Usually a >15%
response to acute aerosol
bronchodilator administration.
Methacholine PC20 between 2 and
20 mg/mL.
PEFR < 60% predicted.
Variability > 30%.
Substantial degree of airway obstruction on
spirometry. Flow volume curve shows marked
concavity. Spirometry may not be normalized
even with high dose steroids. May have
substantial increase in lung volumes and marked
unevenness of ventilation. Incomplete
reversibility to acute aerosol bronchodilator
administration.
Methacholine PC20 < 2 mg/mL.
12-24 h. Regular drug
therapy not usually required
except for short periods of .
time.
B. After optimal treatment is established
Response to and Exacerbations respond to Periodic use of bronchodilators Requires continuous, multiple around-the-clock
duration of therapy broncodilators without the use required during exacerbations for drug therapy including daily corticosteroids,
of systemic corticosteroids in a week or more. Systemic steroids either aerosol or systemic, often in high doses.
usually required for exacerbations
as well. Continuous around-the-
clock drug therapy required.
Regular use of anti-inflammatory
agents may be required for
prolonged periods of time.
'Characteristics are general; because asthma is highly variable, these characteristics may overlap. Furthermore, an individual may switch
Jnto different categories over time.
Variability means the difference either between a morning and evening measure or among morning peak flow measurements each day for a
week.
Although the degree of methachoiine/histamine sensitivity generally correlates with severity of symptoms and medication requirements
there are exceptions. • •
Source: National Institutes of Health (1991).
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individuals later experience remission of their disease as adults, although, an early age of
onset and the presence of atopy make this less likely (Weiss and Speizer, 1993).
In a group of child and adolescent moderate asthmatics studied over a period of 22 mo
(Van Essen-Zandvliet et al., 1992), approximately hall' of those on beta-agonist therapy alone
experienced one or more exacerbations of their asthma requiring treatment with prednisolone.
The incidence of exacerbations was much less (about 15%) for those on a combined regimen
of inhaled corticosteroids and beta-agonist. Weitzman et al. (1992) reported that 10% of a
national sample of children (< 18 years) with asthma (U.S. National Health Interview
Survey, 1988; total n = 17,100; asthmatic n = 735) were hospitalized within the past year.
Based on a total of 450,000 hospitalizations for asthma and an estimated U.S. population of
10,000,000 asthmatics, the incidence of hospitalization for all asthmatic subjects is about
45 per 1,000 asthmatics ( = 4.5%/year) (NIH, 1991). Attendance at hospital emergency
rooms for asthma in Vancouver, Canada, averaged 350 per 100,000 population or 350 per
4,000 asthmatics ( = 8.9%/year) based on an estimated prevalence of 4% and accounted for
1.2% of all emergency room visits. :
For asthmatic individuals who experienced an asthma attack causing them to seek
treatment by a physician, the rate of hospitalization based on the National Asthma Attack
Audit in the United Kingdom (1991 to 1992) was 12% (Neville et al., 1993). Asthma attack
rates in general practice in the United Kingdom suggest an incidence of asthma attacks
(requiring medical intervention) of < 1/asthmatic patient-year (Ayres, 1986). Although
asthma attacks occurred throughout the year, there was a tendency for the highest rates to
follow the seasonal elevation of grass pollen. Schwartz et al. (1993) found fall and spring
peaks for hospital admissions for asthma in Seattle. However, rates did not differ for
summer and winter, as also shown by Bates and Siszto (1986) in Ontario, Canada. Based on
the Los Angeles asthma panel data (EPRI, 1988), only 15% of mild asthmatics see a
physician annually for their asthma compared to about 67% of the moderate asthmatics. The
United Kingdom national asthma attack audit reported an attack rate of 14 per 1,000 patients
(or 14 per 40 asthmatics), suggesting an attack rate of < 1 asthmatic patient/year (Nevill
et al., 1993). A similar attack incidence was estimated by Van Essen-Zandvliet et al. (1992)
and Lebowitz et al. (1985) for U.S. asthma patients.
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Schoettlin and Landau (1961) reported an asthma attack frequency among a group of
asthmatic patients currently under a physician's care for asthma. The daily asthma attack
rate was 25% of all person-days. However, 95% of all attacks were classified as mild, and
40 of 137 patients had fewer than 4 attacks in 14 weeks. Only 4% of all attacks were
attributed to exertion. Zeidberg et al. (1961) also reported that, for 85 asthmatic patients
followed for 43' days, the mean asthma attack rate was 0.133 per patient day or an average of
just less than once a week.
Death due to asthma is a rare event; about two to four deaths annually occur per
1,000,000 population or about one per 10,000 asthmatic individuals. Mortality rates are
higher among males and are at least 100% higher among nonwhites. Indeed, in two large
urban centers (New York and Chicago) mortality rates from asthma among nonwhites may
exceed the city average by up to five-fold and exceed the national average by an even larger
factor (Sly, 1988; Evans et al., 1987; NIH, 1991; Weiss and Wagener, 1990; Carr et al.,
1992). The mortality rate from asthma in the East Harlem neighborhood of Manhattan
(49 per million population) was approximately 10-fold greater than the national average.
The economic impact of asthma is substantial. McFadden (1988) estimates that asthma
results in 27 million patient visits, 134,000 hospital admissions, 6 million lost work days,
and 90 million days of restricted activity. In 1975, a cost of $292 million'was estimated for
medication alone. In 1987, there were 450,000 hospital admissions for asthma, a rate of
approximately 45 per 1,000 asthmatics (NIH, 1991).
Asthmatic persons who participate in controlled human exposure studies typically have
mild allergic asthma. In many cases, these individuals can go without medication altogether
or can discontinue medication for brief periods of time if exposures are conducted outside
their normal allergy season. The most common participants are young adult white male and
female college and high school students. Black and Hispanic adolescents and young adults
have not been studied systematically. The extent to which groups of asthmatic individuals
who participate in controlled exposure studies reflect the characteristics of the asthmatic
population at large is not known. Subjects who participate in controlled exposure studies are
generally self-selected and this could conceivably introduce some bias. However, the high
degree of consistency among studies suggests that the subjects are generally representative of
-------
the population at risk or that any selection bias is consistently present across a diverse group
of laboratories.
2.2 MEDICATION USE BY ASTHMATIC INDIVIDUALS
The extent to which asthmatic individuals, especially the mild asymptomatic individuals
who constitute the majority of asthmatics and who often serve as subjects in these studies,
may use prophylactic medication prior to exercising outdoors is unknown. Most mild
asthmatic persons only use medication when symptoms arise. National Heart Lung and
Blood Institute guidelines (NIH, 1991) for treatment of chronic mild asthma recommend use
of beta-agonists on an as needed (prn) basis. The results of an analysis of activity patterns,
symptoms, and medication use of a panel of 52 asthmatic subjects in Los Angeles are in
accord with these recommendations (Roth et al., 1988). One third of the mild asthmatic
patients studied had not used any asthma medication within the past year, and fewer than half
used an inhaled bronchodilator at least once during the past year. Furthermore, only 20% of
the moderate asthmatic patients studied used an inhaled bronchodilator on a regular basis.
Thus the frequency of use of beta-agonist bronchodilator medication varies widely among
asthmatic individuals and is related, at least in part, to the severity of their disease. For
example, in a rural community in Australia, Marks et al. (1992) reported that 12% of the
asthmatic residents had never used a beta-agonist and that only 38% had used a beta-agonist
at least once in the preceding week. Thus, for more than half the asthmatic individuals hi
the community, beta-agonist use was infrequent and would be unlikely to be used in temporal
proximity to an environmental exposure. Furthermore, NIH guidelines recommend
additional treatment if beta agonists are used on a daily basis.
Medication compliance for those on a regular medication regime varies considerably
among asthmatic patients (from none to full compliance). Average compliance figures are
reported to range from approximately 50 to 70% (Weinstein and Cuskey, 1985; Partridge,
1992; Smith et al., 1984; Smith et al., 1986), although Klingelhofer (1987) reports a range
of 2 to 83% among children with moderate to severe asthma, "based on his review of eleven
studies of medical compliance. Given the infrequent use of medication by many mild
asthmatic individuals and the poor medication compliance of 30% to 50% of the "regularly
medicated" asthmatic patients, it appears that a substantial proportion of asthmatic subjects
-------
would not likely be "protected" by medication use from impacts of environmental factors on
their respiratory health. However, the frequency of use of medication (bronchodilators)
specifically prior to engaging in outdoor activity cannot be confidently extrapolated from
epidemiologic data on medication compliance. Thus, the relative number of persons who
may be protected by medication prior to exercise is unclear.
3.0 SUMMARY OF PREVIOUS FINDINGS ON SO2 EFFECTS
Key controlled human exposure studies of SO2 respiratory effects published in the
scientific literature from 1982 to 1986, as reviewed in the Second Addendum (U.S. EPA,
1986), are summarized in Appendix Table A-l. Those studies were found to support and
extend many of the conclusions reached in the earlier PM/SOX Criteria Document (U.S.
EPA, 1982) and its previous Addendum (U.S. EPA, 1982c).
More specifically, the additional studies evaluated in U.S. EPA (1986) clearly showed
that asthmatic subjects are much more sensitive to SO2 as a group than are nonasthmatic
individuals. Nevertheless, it was clear that a broad range of sensitivity to SO2 existed among
asthmatic subjects exposed under similar conditions. Those studies also confirmed that
normal healthy subjects, even with moderate to heavy exercise, do not experience effects on
pulmonary function due to SO2 exposure in the range of 0 to 2 ppm. The minor exception
may be the annoyance of the unpleasant smell or taste associated with SO2. The suggestion'
that asthmatic individuals are about an order of magnitude more sensitive than healthy,
nonasthmatic persons was thus confirmed.
The studies reviewed in the Second Addendum (U.S. EPA, 1986) further substantiated
that normally breathing asthmatic individuals performing moderate to heavy exercise will
experience SO2-induced bronchoconstriction when breathing SO2 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 SO2 breathing depends on a variety of factors.
Exposures to less than 0.25 ppm were found not to evoke group mean changes in
responses. Although some individuals may appear to respond to SO2 concentrations less than
0.25 ppm, the frequency of these responses was not demonstrably greater than with clean air.
10
-------
The Second Addendum (U.S. EPA, 1986) also noted that, in the SO2 concentration
range from 0.2 to 0.3 ppm, six chamber exposure studies were performed with asthmatic
subjects performing moderate to heavy exercise. The evidence that SO2-induced
bronchoconstriction occurred at such concentrations 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 questionable quantitative relevance for criteria development purposes.
These findings are in accord with the observation that the most reactive subject in the
Horstman et al. (1986) study had a PCSO2 (SO2 concentration required to double SRaw) of
0.28 ppm.
The Second Addendum (U.S. EPA, 1986), however, went on to note that several
observations of significant group mean changes in specific airway resistance (SRaw) had then
recently been reported for asthmatic subjects exposed to 0.4 to 0.6 ppm SO2. Most, if not
all of the 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 SO2-induced bronchoconstriction at
/
0.5 ppm SO2. Exposures that included higher ventilations, mouthpiece breathing, and
inspired air with a low water content resulted in the greatest responses. Mean responses
ranged from 45% (Roger et al., 1985) to 280% (Bethel et al., 1983b) increases in SRaw.
At concentrations in the range of 0.6 to 1.0 ppm, marked increases in SRaw were observed
following exposure, and recovery was generally complete within approximately 1 h, although
the recovery period may be somewhat longer for subjects with the most severe responses.
It is now evident that for SO2-induced bronchoconstriction to occur in asthmatic
individuals at concentrations less than 0.75 ppm, the exposure must be accompanied by
hyperpnea (deep and rapid breathing). Ventilations in the range of 40 to 60 L/min have been
most effective; breathing at these levels typically involves oronasal ventilation (breathing
through mouth and nose). Oral breathing (especially via mouthpiece) clearly caused
exacerbation of SO2-induced bronchoconstriction. New studies reviewed in the Second
Addendum (U.S. EPA, 1986) reinforced the concept that the mode of breathing is an
important determinant of the intensity of SO2-induced bronchoconstriction in the following
order: oral > oronasal > nasal. A second exacerbating factor implicated in the
11
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then-reviewed new reports was the breathing of dry and/or cold air. It was not clearly
established whether exacerbation of SO2 effects was due to airway cooling, airway drying, or
some other mechanism.
The new studies reviewed in the Second Addendum (U.S. EPA, 1986), unfortunately,
did not provide sufficient additional information to establish whether the intensity of the
SO2-induced bronchoconstriction depended upon the severity of the disease. The studies
available at that time more specifically indicated that, across a broad clinical range from
"normal" to "moderate" asthmatic subjects, there clearly existed a relationship between the
presence of asthma and sensitivity to SO2. However, within the asthmatic population, the
relationship of SO2 sensitivity to the qualitative clinical severity of asthma had not been
systematically studied. It was noted that ethical considerations (i.e., continuation of
appropriate medical treatment) generally prevent the unmedicated exposure of "severe"
asthmatic individuals because of their dependence upon drugs for control of their asthma.
True determination of sensitivity requires that the interference with SO2 response caused by
such medication be removed. Because of these mutually exclusive requirements, it was
thought unlikely that the "true" SO2 sensitivity of severe asthmatic individuals could be
determined, although it was noted that more severe asthmatic patients should be studied if
possible. Alternative methods to those used with mild asthmatic individuals, not critically
dependant on regular medication, were noted as being required to assess asthmatic
individuals with severity of disease ranging to beyond the "mild to moderate" level (i.e.,
moderate to severe asthmatic persons).
Studies reviewed in the Second Addendum (U.S. EPA, 1986) also indicated that
consecutive SO2 exposures (repeated within 30 min or less) result in a diminished response
compared with the initial exposure. It was 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 were not yet clearly established, but the refractoriness did not appear to be related
to an overall decrease in bronchomotor responsiveness. These observations suggested that
the effects of SO2 on airway resistance and spirometry tend to be brief and do not tend to
become worse with continued or repeated exposure. Nevertheless, the issue of repeated or
chronic exposure to SO2 in asthmatic individuals remained to be more definitively addressed.
12
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Overall, then, based on the review of studies included in the Second Addendum, it was
clear that the magnitude of response (typically bronchoconstriction) induced by any given
SO2 concentration was highly variable among individual asthmatic subjects. Exposures to
SO2 concentrations of 0.25 ppm or less, which did not induce significant group mean
increases in airway resistance, also did not cause symptomatic bronchoconstriction in
individual asthmatic subjects. On the other hand, exposures to 0.40 ppm SO2 or greater
(combined with moderate to heavy exercise), which induced significant group mean increases
in airway resistance, did cause substantial bronchoconstriction in some individual asthmatic
subjects. This bronchoconstriction was often associated with wheezing and the perception of
respiratory distress. In a few instances it was necessary to discontinue the exposure and
provide medication. The significance of these observations was that some SO2-sensitive
asthmatic subjects appeared to be at risk of experiencing clinically significant (i.e.,
symptomatic) bronchoconstriction requiring termination of activity and/or medical
intervention when exposed to SO2 concentrations of 0.40 to 0.50 ppm or greater, when such
exposure is accompanied by at least moderate activity.
The Second Addendum (U.S. EPA, 1986), therefore, clearly supported the premise that
asthmatic individuals are substantially more responsive to sulfur dioxide (SO2) exposure than
individuals without airways hyperresponsiveness. The extensive exposure-response
information presented in the Addendum indicated that: exercising asthmatic subjects may
respond to brief exposures to SO2 concentrations greater than 0.40 ppm, but little (if any)
response is observed with resting exposures at concentrations less than 1.0 ppm SO2.
Exposure durations of 5 to 10 min were found to be sufficient to stimulate a near maximal
bronchoconstrictive response. The median concentration, to which a large group of
asthmatic subjects responded by doubling their specific airway resistance (over and above
that caused by air exposure and exercise alone), was 0.75 ppm (Horstman et al., 1986) as
depicted in Figure 1. Responses to SO2 are amplified by oral breathing of SO2, by breathing
cold dry air in combination with SO2, and by the magnitude of either voluntary or exercise-
induced hyperpnea. However, repeated exposures to SO2 result in a period of diminished
responsiveness, also called a refractory period. In addition to SO2-induced changes in
respiratory function indicative of bronchoconstriction (namely increased airway resistance and
decreased FEVj) there were increased symptoms, most notably wheezing and a perception of
13
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100n
I
cr
I
>
is
3
O
75-
50-
25-
0
x
x
X
X
X
X
X
X
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X
{
)
0
X
X
X
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Figure 1. Distribution of individual airway sensitivity to SO2, (PC[SO2]). PC(SO2) is
the estimated SO2 concentration needed to produce doubling of SRaw in each
subject. For each subject, PC(SO2) is determined by plotting change in
SRaw, corrected for exercise-induced bronchoconstriction, against SO2
concentration. The SO2 concentration that caused a 100% increase in SRj,w is
determined by linear interpolation. Cumulative percentage of subjects is
plotted as a function of PC(SO2), and each data point represents PC(SO2) for
an individual subject (see also the discussion of PCCSOJ in Section 3.3).
Source: Horseman et al. (1986).
respiratory distress. A small number of studies noted increased medication usage among
SO2-exposed asthmatic subjects, although no studies were specifically designed to study
medication use. The effects of some asthma medications on response to SO2 were also
studied. It was shown that cromolyn sodium inhibited SO2-induced bronchoconstriction
(SIB) in a dose-related manner (Myers et al., 1986a). Also, albuterol, a j3-sympathomimetic
drug, was shown to inhibit the response to SO2 (Koenig et al., 1987).
14
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4.0 KEY NEW FINDINGS ON FACTORS AFFECTING RESPIRATORY
RESPONSES TO SULFUR DIOXIDE IN ASTHMATIC SUBJECTS
Since completion of the earlier Second Addendum (1986), a number of additional
studies have become available that provide further information with regard to various aspects
related to the induction by acute SO2 exposure of respiratory effects in asthmatic subjects,
and the most salient findings from such studies are concisely discussed below. Key new
studies yielding important new information on SC>2 exposure-response relationships for
asthmatic subjects and factors affecting such relationships are summarized in Table 2.
4.1 EXPOSURE DURATION/HISTORY AS SULFUR DIOXIDE
DOSE-RESPONSE DETERMINANTS
Previous studies reviewed in the Second Addendum (U.S. EPA, 1986) found that the
bronchoconstrictive response to SO2 has a rapid onset and reaches a peak response within
about 5 to 10 min. Two more recent studies have shown that significant responses can occur
in as little as 2 min. Horstman et al. (1988) showed, in a group of 12 SO2-responsive
asthmatic subjects, that with 2 and 5 min of exercise (VE = 40 L/rhin) exposure to 1.0 ppm
SO2, SRaw increased by 121 and 307%, respectively (percentages corrected for exercise-
induced responses during exercise in clean air). Balmes et al. (1987) demonstrated an even
more rapid onset of bronchoconstriction in eight asthmatic subjects exposed to 1.0 ppm SO2
during eucapnic hyperpnea ( = 60 L/min) by mouthpiece. At 1, 3, and 5 min, they reported
SRaw increases of 47, 349, and 534%, respectively. They also showed significant increases
in SRaw after 3 (127%) and 5 (188%) min of exposure to 0.5 ppm SO2. In each of these
two studies, several subjects requested a bronchodilator to alleviate symptoms induced by the
exposures; 7 of 8 subjects did so in the Balmes et al. (1987) study, as did 4 of 12 in the
Horstman et al. (1988) study. Additionally, two subjects were unable to complete the 5-min
exposures to 1.0 ppm in the Balmes et al. (1987) study.
Linn et al. (1987) concluded that exposure history to SO2 (over the course of several
weeks as opposed to hours) was largely irrelevant. They did, however, observe, as had
Kehrl et al. (1987), that bronchoconstriction responses to a first exercise period within an
hour-long SO2 exposure resulted in a diminished response in the second exercise period.
15
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SRaw increased with. exercise and SO2
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This observation is in support of the concept of a refractory period from repeated SO2
exposures accompanied by exercise or hyperpnea.
Torres and Magnussen (1990) examined the effect of 30 min of resting ventilation of
0.5 ppm SO2 on a subsequent SO2 ventilatory challenge. The SO2 challenge involved
breathing 0.5 ppm SO2 at progressively increasing levels of eucapnic hyperpnea. There was
no difference in response to the SO2 challenge when it was preceded by breathing of SO2
while at rest. This is not surprising since breathing of < 1.0 ppm SO2 while at rest does not
typically cause changes in lung function or symptoms.
Overall, the above new results provide further evidence for the rapid onset of
respiratory effects in exercising asthmatics in response to SO2, demonstrating that such
effects can occur within a few minutes (2 to 5 min) of initiation of SO2 exposure. The
results also further confirm a refractory period for SO2-induced respiratory effects, following
prior SO2 exposure within the immediately preceding few hours that resulted in a
physiologically significant increase in airway resistence. This means that repeated SO2
exposures during a short time period do not lead to any greater manifestation of effects
beyond those seen immediately after the first SO2 exposure. However, other evidence
indicates that much earlier SO2 exposures (days/weeks ago) do not prevent or dampen effects
of subsequent SO2 exposures.
4.2 SULFUR DIOXIDE RESPONSES AND ASTHMA SEVERITY
Another question left unresolved by studies evaluated in the 1986 Second Addendum
was the extent to which differential sensitivity might exist among SO2-sensitive asthmatic
individuals (with regard to lowest effective SO2 exposure levels evoking significantly
enhanced bronchoconstriction and/or respiratory symptoms or the magnitude of such effects
observed at a given SO2 exposure level), especially as a function of the severity of the
preexisting disease (from mild to severe asthma). Some newly available studies have
attempted to address this difficult issue.
Although in most studies of asthmatic individuals exposed to SO2, a change in specific
airway resistance (SR,^) has been used as a measure of response, in other studies, a change
in FEVj was the response measure. In a few studies, data for both response measures have
been obtained. In order to provide an estimate of the comparability of the two response
19
-------
measures, the data of Linn et al. (1987, 1990) were used (actual data were obtained from
two project reports [Hackney et al., 1987, 1988]). In Table 3, the preexposure and
postexposure measurements for FEVj and SRaw are shown for three different groups of
subjects after clean air exposure and after SO2 exposure. Using these data, the comparability
of SR.jW and FEVj as physiologic measures of response can be estimated. Based on simple
linear interpolation, a 100% increase in SRaw roughly corresponds to a 12 to 15% decrease
in FEV! and a 200% increase in SRaw corresponds to a 25 to 30% decrease in FEVj.
TABLE 3. COMPARISON OF MEAN SRAW AND FEV! RESPONSES TO AIR AND
SULFUR DIOXIDE EXPOSURE IN ASTHMATIC SUBJECTS
[S02]
Linn et al.. 1990a
low
normal
low
normal
Linn et al.. 1987b
mild
moderate
mild
moderate
0.0
0.0
0.6
0.6
0.0
0.0
0.6
0.6
Pre-FEVj
1,907
2,270
1,914
2,264
2,962
2,473
2,968
2,430
Post-FEVj
1,634
1,992
1,332
1,584
2,908
2,278
2,428
1,775
A% FEVjL
-14.3
-12.2
-30.0
-30.0
-1.8
-7.9
-18.2
-27.0
Pre-SRaw
16.0
7.9
13.3
7.9
5.4
7.8
5.4
8.1
Post-SRaw
26.8
14.0
40.9
27.6
6.9
13.5
13.7
24.4
A % SRaw
+68
+77
+208
+249
+29
+73
+ 153
+201
an = 21; low and normal refer to medication level.
bn = 16 (mild), n = 24 (moderate), [SO2] in ppm, FEVj in mL, SRaw in cm H2OL~ -s-L.
Hackney et al. (1987) studied both (a) concentration-response relationships of SO2 and
lung function, as well as (b) differences in response between normal, atopic, mild asthmatic
individuals and moderate/severe asthmatic individuals. All groups of subjects were exposed
to 0, 0.2, 0.4, and 0.6 ppm SO2. Each subject was exposed to each level on two different
occasions. These results were also reported in the published Linn et al. (1987) report. The
1-h exposures included three 10-min exercise periods. This study supported earlier
20
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investigations (Roger et al., 1985), in that the responses (especially of asthmatic subjects at
the highest concentration) tended to be greatest early in exposure (i.e., after the first
exercise) and were possibly greater on the first round of exposures than on the second.
When the mild asthmatic subjects were compared with the moderate/severe asthmatic
subjects, the 'FEV^ decrement caused by exercise was greater in the moderate/severe
asthmatic subjects, and the combined response to exercise and SO2 exposure resulted in a
greater overall decrease in FEV^ However, when the "exercise effect" was subtracted from
the overall FEVj response, the response to SO2 was similar in,the mild versus the
moderate/severe asthmatic subjects. Thus severity of asthma, as defined operationally in this
study (Hackney et al., 1987), did not influence the FEV^ response to SO2.
However, this conclusion must be tempered by the fact that the moderate/severe
asthmatic subjects started the exposure with compromised function compared to the mild
asthmatic subjects. Thus, it is not clear that similar functional declines beginning from a
different baseline have the same biological importance: (see Figure 2). Another possible
reason that the responses were not greater in the moderate/severe group is that there may
have been some persistence of medication, since this group was less able to withhold
medication and some of the medication normally used had effects that would persist beyond
the brief withholding period prescribed in this study.
Based on an analysis similar to that of Horstman et al. (1986) (i.e., an analysis of the
median concentration at which the SRaw was doubled, PC100 SRaw), Hackney et al. (1987)
estimated that the median PC100SRaw was greater than 0.6 ppm. Pooling the data for mild
and moderate/severe asthmatic subjects and using only the first round of exposures, only
15 of 40 subjects showed a doubling of SR,^ at <0.60 ppm SO2. Based on Horstman
et al.'s (1986) cumulative frequency plot of PC100SRaw against SO2 concentration,
approximately 35% of asthmatic subjects would be expected to reach the PC10oSRaw at a
concentration of 0.60 ppm. Thus the 37.5% incidence (15/40) observed by Linn et al.
(1987) is consistent with Horstman et al.'s observations (see Table 4), despite the fact that
Linn et al.'s subject group included asthmatic individuals with more severe disease.
In comparing responses to SO2 among asthmatic subjects of varying severity, the health
significance of the observed lung function responses would have been considered to be
greater had these responses persisted for several hours or days after exposure or if there had
21
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SO2 Increment
Exercise Increment
Baseline SR
0
0.6 0.0
SO2(PPM)
Figure 2. Redrawn from Linn et al. (1987). SRaw of 16 mild (10 M, 6 F) and
24 moderate (10 M, 14 F) asthmatic subjects exposed to 0.0, 0.4, and
0.6 ppm SO2. The bottom segment of the bar illustrates the baseline SRaw;
the middle segment, the response to exercise; and the upper segment, the™
increase in SR.^. due to SO2 exposure. Overall bar height indicates SR^
after SO^ exposure. At 0.6 ppm, after adjustment for SR,,W increase due to
exercise in 0.0 ppm, the percentage change in SR,^, as a result of SO2
exposure is 124% in mild asthmatic subjects and 128% in moderate asthmatic
subjects, expressed as:
SO2 increment
baseline SR
x 100%
been a persistent change in airway responsiveness. However, it was concluded in the
Hackney et al. (1987) report that there were no persistent functional or symptom effects and
that SC>2 did not alter airway responsiveness.
Linn and coworkers (1990) examined the effects of different levels of medication in a
group of moderate asthmatic individuals dependent on regular medication for normal lung
22
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TABLE 4. ESTIMATES OF SULFUR DIOXIDE RESPONSES
IN ASTHMATIC SUBJECTS
Horstman (1986)
Linn (1987)
Magnussen (1990)
Asthmaa
Mild
Mild/moderate
Mild/moderate
L/min
Chamber 40
Chamber 40
Mouth 30
Fraction0
14/27
15/40
16/45
PCS02d
0.75
0.60
0.50
aAsthma is the rating of asthma severity.
L/min is the ventilation and exposure method.
°Fraction is the number of subjects with 100% increase.
dPCSO2 is the [SO2] at which SRaw was doubled.
function. These subjects had a similar response to 0.6 ppm SO2 as observed in moderate
asthmatic subjects in a previous study (Linn et al., 1987). The somewhat greater increase in
SRaw (approximately fourfold versus approximately threefold) in the more recent study may
be due to the slightly higher exercise ventilation rate (about 50 L/min versus 40 L/min).
There was a weak correlation of the baseline SRaw with the response to SO2 (r = 0.35) when
the subjects from the 1987 and the 1990 studies were combined. Therefore, baseline
function may not be a good predictor of response to SO2. Subjects we're exposed to three
levels of SO2 in this study: 0.0, 0.3, and 0.06 ppm. These exposures occurred under three
different medication levels: (1) normal; (2) reduced or "low" medication (normal
medications withheld for 48 h for antihistamines, 24 h for oral bronchodilators, and 12 h for
inhaled bronchodilators), and (3) enhanced medication (an additional dose of metaproterenol
[i.e., 0.3 mL of 5% Alupent]). The responses are illustrated in Figure 3 and Table 3.
When medication was withheld, baseline lung function deteriorated (e.g., FEVj fell about
350 mL). Exercise alone caused slightly less than a 300 mL decrease in FEVr, and
0.6 ppm SO2 caused a significant further decline in FEVj. Although the absolute FEVj was
lower after SO2 exposure in the low medication condition, the decrement caused by SC^ was
similar to that seen in the normal medication state.2 The lower absolute level of FEVj in
2Based on a previously released project report [Hackney et al., 1988], baseline FEVj fell from about 2,270 mL
in the normal medication state to about 1,910 mL in the low medication state. The average decrease in FEVj
resulting from exercise in clean air was similar in the two conditions: —273 and —278 mL in the low and normal
states, respectively. The overall decrease in FEVj was -582 and -680 mL, respectively, in the two conditions,
leaving an SO2 effect (total FEV^ decrease - exercise in clean adr effect) of -309 and -402 mL, respectively.
23
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2 600
2 400
-J 2 200
rjj t,£X/W
••>" 2 000
UJ
| |
1 800
1 ROD
1 400
1.200
-
-
-
-
-
.._-.
_L
Pre
Post
I~~~~...
.....
i
— I
• i i
Low 0.0 Low 0.6 Norm 0.0 Norm 0.6 High 0.0 High 0.6
Medication Level
Figure 3. Redrawn from Linn et al. (1990). FEVl responses to SO2 (0.6 ppm) exposure
in medication-dependent asthmatic subjects. Horizontal dashed lines
represent preexposure FEVj and horizontal solid lines are postexposure. The
vertical bar indicates change with exercise or exercise plus SO2 exposure.
Three medication states were used: Low = withdrawal of all medication for
at least 12 h; normal = typical medication level (mostly theophylline and
inhaled beta-agonist but no steroids); high == supplemental inetaproterenol
before exposure. Exposures lasted 10 min. Standard error of the mean
change in FEVj due to exposure to SO2 and exercise was about 100 mL for
the SO2 exposures.
the unmedicated subjects would be cause for additional concern. However, with
supplementary metaproterenol, the effect of SO2 was greatly diminished (about 5% lower
postexercise FEVj for the 0.6-ppm SO2 exposure versus air-only exposure under
supplementary [high] metaproterenol conditions). In comparison to the normal medication
baseline, moderate/severe asthmatic subjects who withheld medication had an overall
As a percentage of the preexposure resting measurement, these reflect a decrease of 16.1 and 17.8. %, respectively,
that can be attributed to SO2. If expressed as a percentage of the response after exercise in clean air, these
percentages would be —18.9 and -20.2, respectively.
24
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reduction of FEVj of about 40% from the combined effects of exercise, SO2 exposure
(0.6 ppm), and the absence of their normal medication.
In comparing asthmatic individuals of different degrees of severity, the metric used in
this comparison can greatly influence the conclusion that is drawn. It is not clear whether
the most appropriate metric is (a) the absolute change in airway resistance or FEVj or (b) the
relative change. Small absolute increases around a low baseline SRaw (usually in a well
controlled or milder asthmatic) result in large relative (i.e., percentage) changes in function,
whereas a much larger absolute change in function around a higher baseline may result in a
smaller relative change in function. The SRaw data are particularly subject to this sort of
potential bias because of the larger range of baseline values, which may vary from 2 to
8 cm H2O-L"1-s"1-L in healthy people or mild asymptomatic asthmatic subjects.
The manner in which a percentage change is calculated can greatly influence the
apparent response. For example, the data of Linn et al. (1990) (see Table 3) for normally
medicated subjects gives a percent change in FEVl with clean air exposure of -12.2% and
for 0.6 ppm SO2 of -30.0% (calculated as [post-pre] + pre X 100%). If the response after
SO2 exposure is corrected for the effect of exercise in clean air ({2,264 — [1,584 +
(2,270 - 1,992)] -s- 2,264} x 100%), the "SO2" effect is -17.8% (the same as the
difference between -30% and -12.2%). However, it could be argued that the SO2 effect is
that additional change beyond the response in clean air and should be expressed relative to
post-clean air response. In this case, the result is ({2,264 - [1,584 + (2,270 - 1,992)] -s-
1,992} X 100%) or —20.2%. Corresponding calculations made for SRaw responses give
pre- to post-increases of +77 and +249% for clean air and SO2, respectively. Correcting
for the clean air response gives an SO2 response, as above, of+112%. The SR^ response,
if expressed relative to the post-clean air exercise response ({27.6 — [7.9 + (14.0 — 7.9)]
+ 14.0} X 100%) is +97%. Thus expressing the SO2 response relative to the post-clean air
exercise response results in an apparently larger relative FEVj response and smaller relative
SRaw response. In all cases cited in the main text of this document, the changes in FEV^
and SRaw, when expressed as percentages, are expressed relative to the baseline value, not
the post-exercise value.
Another approach to estimating responses would have been to express them in percent
predicted (e.g., FEY^). The advantage of such an approach would be that the functional
25
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level would be on a more "absolute" scale in terms of functional capacity, and thus would be
more relevant to the level of pulmonary disability than is a percent change from baseline.
The disadvantage is that the information necessary to determine the predicted level is not
always available. When the predicted levels are provided directly, additional variability is
introduced because there are a number of acceptable standards for prediction which vary
slightly from each other.
Magnussen et al. (1990) also studied the responses of 45 asthmatic individuals
(46 subjects are included in the list but data for only 45 are given) to 0.5 ppm SO2 with
10 min of resting breathing followed by 10 min of eucapnic hyperpnea. Although this mode
of exposure has previously been shown to overestimate responses that would occur in natural
(oronasal breathing) exposure, it is interesting to note that the group mean response was an
increase of SRaw from 6.93 to 18.21 cm H2O-L'1-S-1-L (also referred to as SR^ "units").
After correcting for the increase in SR,^ due to hyperventilation, ( = 45%; from 6.27 to
9.10), the increase in SR,^ (8.65) as a percentage of the mean baseline (6.60) is 131%.
However, only 16 of the 45 subjects experienced at least a doubling of SR^, indicating that
the large mean change is driven by much larger changes in a small group of subjects. Based
on the cumulative frequency distribution of PC100SRaw versus SO2 concentration of
Hortsman et al. (1986), approximately 25% of the subjects would be expected to have a
doubling of their SRaw at an SO2 concentration of 0.50 ppm. The somewhat larger fraction
(36%) in this group of subjects (see Table 4) may be due to the fact that SO2 was inhaled via
a mouthpiece, which is known to increase SO2 responses. Also 16 subjects w&re on inhaled
or oral steroid medication (only 6 of the 16 who doubled SR,^ used steroids). These
subjects would likely be considered to have more severe asthma than those studied by either
Linn et al. (1987) or Horstman et al. (1986).
Magnussen et al. (1990) also found only a weak correlation (r = 0.47; R2 = 0.22)
between histamine response and SO2 response to changes in SRaw. They concluded that
nonspecific bronchial responsiveness (NSBR) to histamine is a poor predictor of response to
S02. A number of investigators (Roger et al., 1985; Linn et al., 1983b; Witek and
Schachter, 1985) have reported a weak correlation between histamine or methacholine
responsiveness and functional responses to SO2. In these studies, it has generally been
26
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concluded that histamine or methacholine response is not a good predictor of responsiveness
to SO2 among asthmatic subjects.
4.3 RANGE OF SEVERITY OF SULFUR DIOXIDE RESPONSES
In order to place the changes in FEVj and SRaw that result from SC>2 exposure into
broader perspective, responses to exercise and/or cold air breathing were compared under a
variety of conditions. The extent of exercise-induced bronchoconstriction is in part
dependant upon the intensity of the exercise (Table 5). As seen in this review and the
Second Addendum (U.S. Environmental Protection Agency, 1986), mild exercise alone under
normal indoor conditions results in small, if any change in FEVj or SRaw. For example,
after 10 min exercise at 40 L/min ( = 35% max), SR,,W increased 29% and FEVj decreased
by only 1.8% in one study (Linn et al., 1987); and, after 5 min exercise at a similar level,
SRaw increased 67% in another study (Horstman et al., 1988). These are modest changes,
typically not accompanied by symptoms. NIH guidelines (1991) suggest that a decline of
15% in FEV1 indicates the presence of exercise-induced bronchoconstriction. At higher
exercise intensities (60 to 85% of maximum), FEVj decreases range from 10 to 30%
(Anderson and Schoeffel, 1982; Anderson et al., 1982; Fitch and Morton, 1971; Strauss
et al., 1977). With the combination of exercise and inhalation of dry subfreezing air, the
decrease in FEVl may reach 35 to 40% (Strauss et al., 1977; Smith et al., 1989). Inhalation
of warm humid air during exercise markedly reduces or eliminates exercise-induced
decreases in FEVj (Anderson et al., 1982) or increases in SRaw (Linn et al., 1984, 1985).
Balmes et al. (1987) stated that the responses to 5-min exposures to 1 ppm SO2 were
qualitatively similar, in terms of symptoms and function changes, to "maximal acute
bronchoconstrictor responses" from other nonimmunologic stimuli (i.e., cold/dry air,
hypertonic saline, histamine, or methacholine). This opinion is based on the responses of a
small number of subjects who had striking responses to SO2. This study was not designed to
evaluate maximal responses.
The magnitude of functional responses of asthmatics to a variety of physical, chemical,
biological, and environmental stimuli varies widely. Mild exercise in mild asthmatics may
produce modest changes in pulmonary function (< 10%> decrease in FEVj) in the absence of
symptoms or breathing difficulty. On the other hand, functional responses of patients
27
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TABLE 5. COMPARATIVE RESPONSES OF ASTHMATIC SUBJECTS TO
COLD/DRY AIR AND EXERCISE: FORCED EXPIRATORY VOLUME IN ONE
SECOND (FEV) AND SPECIFIC AIRWAY RESISTANCE
Author
Moderate exercise typical of chamber studies
Conditions
Linn et al. (1985)
Exercise 5 min at
VE = 50 L/min
(a) 21 °C, dry
(b) 38 °C, humid
Response
(a)SRaw+21%
(b) SRaw -4%
Linn et al. (1984b)
Exercise 5 min at
VE = 50 L/min
(a) -6 °C
(b) 7 °C
(c) 21 °C, humid
(a) SRaw +94%
(b) SRaw +59%
(c) SRaw +28%
Bethel et al. (1984)
Eucapnic hyperpnea
VE = 30-50 L/min for 3 min
(a) ambient humid
(b) cold/dry
(a) SRaw +3%
(b)SRaw +18%
Linn et al. (1987)
10 min at 40 L/min
(a) SRaw +29%
-1.8%
Horstman et al. (1988) 5 min = 40 L/min
(mean of two trials)
Mild asthmatics
Maximum exercise-induced bronchoconstrictor challenge
Anderson and Schoeffel (1982) 60-85% VO2 peak (predicted) for
6-8 min (exercise)
Anderson et al. (1982) 70% predicted max. exercise 6-8
min: (a) 23 °C (b) 31 °C, humid
SRaw +67%
20-25% decline in FEV
(a) FEV! -35% +13%
-10% ±9%
Fitch and Morton (1971)
Strauss et al. (1977)
Exercise 80-85% max.
=75% predicted
max exercise
900 kpm 3-5 min
VE = 90 L/min
(a) ambient
(b) sub-freezing air
FEVj -28 to -31%
(a) FEVj -20%
(b) FEV! -40%
Smith et al. (1989)
75% max exercise 5-10 min
VE = 42 L/min
-5 °C air, dry
Children and adolescents (median
age 14 years)
-20 to -25%
NIH guidelines suggest a decrease of > 15% in FEVj as a diagnostic criteria for exercise-induced asthma.
28
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seeking emergency treatment for asthma are striking (Lim et al., 1989; Fanta et al., 1982;
Hilman et al., 1986). The average FEVl in a group of 16 subjects treated in a hospital
emergency room was 41 ±9% predicted. In another study of subjects with acute severe
asthma, the average FEV! when first measured was 21+5% predicted. Fanta et al. (1982)
reported a mean FEV^ of 38% predicted for a group of 102 asthmatic patients treated in a
hospital emergency room. Although none of these groups constituted a clearly representative
population sample, they do illustrate the severity of functional responses (i.e., FEVi
decrements of -60 to -80% of predicted) observed in asthmatic patients seeking emergency
medical treatment.
One diagnostic procedure used in evaluation of asthma is measurement of airway
, responsiveness. Airway inhalation challenges to histamine or methacholine are typically used
to determine the inhaled dose of these drugs which causes a 20% decline in FEVj (Cropp
et al., 1980; Chatham et al., 1982; Chai et al., 1975). Responses are rapidly induced
(within 1 to 2 min), recovery is typically complete within an hour or so, and there are no
sequelae. Asthmatics are much more responsive to these nonspecific (i.e., non-allergenic)
stimuli; the concentration required to evoke a response is typically 1/10 to 1/100 that
required in a healthy non-asthmatic person. The responses to histamine, methacholine, and
cold dry air are well correlated in asthmatics (Cockcroft et al., 1977; O'Byrne et al., 1982).
Airway responses to these non-specific stimuli can vary widely over time (i.e., many
months). Significant circadian or daily variations also occur. Other factors which can alter
airway responsiveness include occupational exposures to chemicals such as toluene
diisocyanate or plicatic acid, exposure to allergens such as ragweed or dust mites, or viral
respiratory tract infections (Clough and Holgate, 1989). In contrast to non-specific stimuli,
airway challenge with specific allergens to which the patient is sensitized cause both an acute
response, and in many cases, a delayed or "late phase" response. The acute response is
somewhat slower to develop (10 to 20 min) and slower to resolve (1 to 2 h) than for the non-
specific stimuli. A late phase response, which occurs in 30 to 50% of allergic asthmatics,
can be of even greater magnitude than the acute response and resolves with a variable and
often prolonged time course (Cockcroft, 1987).
In terms of its behavior as an airway stimulant, SO2 acts similarly to other non-specific
stimuli. It induces a response within a few minutes and the response resolves spontaneously
29
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within an hour or so. There is no reported late phase response to SO2, and SO2 exposure
does not induce' a change in non-specific bronchial responsiveness. Because of the rapid
onset and recovery, the responses to non-specific stimuli are thought to be due to constriction
of airway smooth muscle. Unlike histamine and methacholine inhalation challenges which
are not followed by a refractory period (Beckett et al., 1992), there is a refractory period
after SO2-induced bronchoconstriction. Similarly, exercise or hyperventilation (cold air)
challenges are followed by a refractory period (Bar-Yishay et al., 1983; Haas et al., 1986).
A 20% reduction in FEVj is typically associated with symptomatic complaints of chest
tightness and/or wheeze as well as other complaints associated with dyspnea. Killian et al.
(1993) showed that there is a wide range of perception of dyspnea after a 20% decrease in
FEVj, rated from 0 to 9 on a 10 point scale. Breathing difficulty at this level of FEV1
reduction corresponded to that at about 60 to 70% of maximum exercise level. Furthermore,
perception of dyspnea is not a good index of functional status. Some patients with near-fatal
asthma attacks had a poor perception of their breathing difficulty and were thus unable to
perceive an attack of severe bronchospasm (Kikuchi et al., 1994).
4.3.1 Severity of Sulfur Dioxide Respiratory Function Responses
As with all biological responses, there is a range of response to SO2 in asthmatic
individuals irrespective of the other factors that influence response magnitude such as
concentration, duration, ventilation, exercise, air temperature, air dryness, etc. Some
subjects experienced small or minimal functional responses to SO2 exposure especially at
relatively low S02 concentrations. Four studies presented sufficient published individual data
to estimate the range of responses in terms of post exposure SRaw in the most responsive
quartile of subjects. The most responsive subjects (3 of 12) in Horstman et al. (1988)
exposed for 5 min to 1.0 ppm had SR^'s ranging from 55 to 71 cmH2Os. In the Linn
et al. (1988) study, the most responsive subjects (5 of 20) had SRaw's ranging from +18 to
+ 122 cm H2O • s, when exposed in the untreated condition to 0.6 ppm SO2 for 10 min.
In the Linn et al. (1990) study (10 min at 0.6 ppm), the most responsive subjects (5 of 21)
on normal medication had a range of response from 46 to 76 cmH2Os representing an
increase of 420 to 1,090%. When normal medication was withheld, this range increased to
66 to 95 cmH20-s. In the Linn et al. (1987) study of mild and moderate asthmatic subjects
30
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(0.6 ppm for 10 min), the range of response for the most responsive quartile (10 of 40) was
21 to 118 cmH2O-s. This represents an increase of SRaw ranging from 390 to 1,600%.
Additional, more detailed information is presented in Appendix B (Table B-l) with
regard to the range of severity of respiratory function changes observed among asthmatic
subjects exposed to SO2 in selected recent controlled exposure studies, i.e., those by Roger
et al. (1985) and Linn et al. (1987, 1988, 1990). Of most interest are Table B-l entries
concerning: (1) average magnitudes of pulmonary function changes (SR^; FEV^ measured
at different tested SO2 exposure concentrations under moderate exercise conditions, and
(2) percentages of asthmatic subjects exceeding cutpoints for defining ranges of effects of
increasing severity (magnitude) and potential medical concern as a function of SO2 exposure
levels.
The data presented in Table B-l indicate that the average magnitudes of responses
(FEV^ decreases; SRaw increases) due to SO2 at 0.4 and 0.5 ppm are not distinguishable, for
either mild or moderate asthmatic subjects, from the range of normal variation often
experienced by asthmatic persons during a given day, i.e., up to 10 to 20% lower FEVl in
early morning versus the afternoor and up to 40% higher SR.^ (see discussion on page 4).
Nor are the average changes due to SO2 at 0.4 or 0.5 ppm particularly distinguishable from
the range of analogous average pulmonary function changes observed among asthmatic
persons in response to cold/dry air or moderate exercise levels (see Table 5). Even taking
the combined effects of exercise and SO2 exposure at 0.4 and 0.5 ppm, the average total
lung function changes generally do not reach magnitudes identified as being of much medical
concern. Similarly, at 0.4 and 0.5 ppm, only relatively small percentages (generally <10 to
25%) of tested subjects exhibited marked responses to SO2 (after correction for exercise) that
both (a) very markedly exceeded typical daily variations for lung function measures for
asthmatic persons or functional changes displayed by them in response to cold/dry air or
moderate exercise levels and (b) reached magnitudes falling in a range of likely clinical
concern (i.e., SRaw increases >200% and FEV1>0 decreases >20%). However, as
discussed in U.S. EPA (1986), it should be noted that Bethel et al. (1984) reported a
significant interaction between oral hyperventilation of cold dry air and 0.5 ppm SO2 via
mouthpiece that resulted in a >200% increase in SR^,, whereas breathing SO2 in warm
humid air or breathing cold dry air alone resulted in a <40% change in SRaw. This
31
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suggests that airway cooling and drying may exacerbate SO2-induced airway constriction in
hyperventilating asthmatic subjects, but insufficient data exist by which to estimate the
magnitude of any combined effects of joint SO2 and cold, dry air exposure under more
natural free-breathing conditions during exercise.
In contrast to the patterns seen at 0.4 and 0.5 ppm, distinctly larger average lung
function changes were observed at SO2 exposures of 0.6 ppm and higher. Of particular
importance is that the average total changes due to combined effects of exercise and SO2 are
at the upper end of or exceed (a) the range of typical daily variations in FEVj, and SRaw and
(b) average magnitudes of changes seen in such measures in response to cold/dry air and
moderate exercise levels. Also, at 0.6 ppm or higher SO2 concentrations, substantially
higher percentages of tested subjects exhibited lung function changes due to SO2 that
approach or reach levels of medical concern. For example, in response to 0.6 or 1.0 ppm
SO2 exposure under moderate (40 to 50 L/min) exercise conditions, 25 to 55% of both mild
and moderate asthmatic subjects exhibited FEV decrements in excess of -20% and SRaw
increases that exceeded 200% after correction for exercise. Changes of this magnitude
clearly exceed the maximum 20% FEV1 and 40% SRaw variations often experienced by
asthmatic subjects during a given day. Similarly, approximately 15 to 35% of moderate
asthmatics exposed at 0.6 or 1.0 ppm SO2 experienced FEV1 decrements in excess of -30%
and SRaw increases above 300% due to SO2, after correction for exercise. Respiratory
function changes of such magnitude in response to SO2 clearly fall into a range of medical
concern, especially if accompanied by increased respiratory symptoms (e.g., wheezing, chest
tightness, shortness of breath, etc.) rated as more severe than due to exercise alone.
4.3.2 Severity of Respiratory Symptom Responses to Sulfur Dioxide
The symptoms associated with responses to SO2 are typical of those experienced by
asthmatic individuals when bronchoconstriction occurs in response to any one of a number of
nonimmunologic provocative stimuli. Unfortunately, in most published reports, the
quantitative or qualitative description of symptoms is often insufficient for the purpose of
comparison between studies. Linnet al. (1987) presented a total score for the sum of
12 symptoms in subjects exposed to 0.2 to 0.6 ppm SO2. Symptoms were higher in the
moderate than in the mild asthmatic subjects, as would be anticipated. In addition, there was
32
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a trend for symptoms to increase with increasing SO2 concentration. About 25 % of
asthmatic subjects rated their lower respiratory symptoms (wheeze, dyspnea, etc.) 20 points
higher (on a 40 point scale) after exposure to 0.6 pprn SO2. A 20-point increase represents a
change of a previously "mild" symptom to "severe" or the new appearance of "moderate"
symptom. Four of 24 moderate/severe asthmatic subjects required a reduced exercise level
because of asthma symptoms at 0.6 ppm SO2. This happened only once at each of the other
(lower) concentrations. Analogous findings of distinctly higher and more serious
symptomatic response at 0.6 ppm SO2 than at lower concentrations (0.2 or 0.4 ppm) were
reported by Freudenthal et al. (1989), based on comparisons of respiratory symptoms and
lung function changes of varying magnitudes derived from detailed evaluation of raw data
(N = 23) from an earlier Linn et al. (1983) study. Freudenthal et al. (1989) grouped absent,
minimal, and mild symptom levels (as designated by Linn et al.) into an "insignificant"
category, and defined two symptomatic response categories as follows: (1) annoying (going
from a pre-exposure symptom level of "insignificant" to a post-exposure symptom level of
"moderate" or "severe"); and (2) performance-limiting (going from a pre-exposure symptom
level of "insignificant" or "moderate" to post-exposure level of "severe"). The subjective
symptom responses were labeled according to the symptom score descriptions given by Linn
et al. (1983). Distinctly higher numbers of subjects reported annoying symptoms at 0.6 ppm
SO2 during exercise ( = 50 L/min) than at 0.2 or 0.4 ppm SO2 exposure (none at 0.2 ppm)
regardless of the associated level (25%, 100%, 200%) of SR^ increase in response to SO2.
Even more indicative of 0.6 ppm SO2 being a concentration of likely concern was the fact
that none of the subjects reported performance-limiting symptoms at 0.2 or 0.4 ppm SO2
(regardless of associated level of SR.^ increase), whereas at least one subject reported
performance-limiting symptoms in association with SO2-induced SRaw increases of 25, 100,
and 200%, respectively.
Horstman et al. (1988) presented data for two individual symptom categories, wheezing
and shortness of breath-chest discomfort for subjects exposed to 1.0 ppm SO2 for 2 and
5 min. Wheezing was strongly associated with an increase in SR^ (r > 0.80) and the
severity of wheezing increased with increased duration of exposure. The four most
responsive subjects (n = 12) rated their wheezing at either three or four on a four-point scale
(severe or intolerable wheezing was rated as four). Balmes et al. (1987) indicated all
33
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but one of their eight subjects developed wheezing, chest tightness, and dyspnea after 3 min
at 1.0 ppm SO2 that was of sufficient magnitude in two subjects that they were unwilling to
undergo a subsequent 5-min exposure.
In addition to the above published information, more detailed analyses by U.S. EPA
staff of data from recent studies of SO2 effects in asthmatic individuals presented in
Appendix B (Smith 1994 memo) also show that substantially greater percentages of moderate
and mild asthmatics experienced moderate to severe respiratory symptoms at 0.6 or 1.0 ppm
SO2 exposure during moderate (40 to 50 L/min) exercise than occurred in response to
comparable exercise alone. Similarly, much greater percentages of asthmatic subjects
experienced combinations of large lung function changes and severe symptoms in response to
SO2 exposures than with exercise alone. In addition, up to 15% of mild or moderate
asthmatic subjects required reduced workload or termination of exposure at 0.6 ppm or
1.0 ppm SO2, whereas none exhibited diminished exercise tolerance with comparable
exercise alone.
4.4 MODIFICATION OF SULFUR DIOXIDE RESPONSE BY ASTHMA
MEDICATIONS
It was shown in the Second Addendum (U.S. EPA, 1986), and has been substantiated
more recently, that common asthma medications such as cromolyn sodium and various beta2
adrenergic receptor agonists either reduce or abolish SO2-induced lung function responses in
asthmatic subjects. Since completion of that earlier Addendum, a number of medications
have been evaluated in various newly available studies for their efficacy in altering responses
to SO2 exposure, as summarized in Table 6. Some of these medications are routinely used to
treat asthma such as inhaled betaragonists (metaproterenol and albuterol), oral theophylline,
and inhaled steroids such as beclomethasone. Inhaled bronchodilator medications such as
metaproterenol and albuterol are the most widely used asthma medications (Kesten et al.,
1993). Information on the effects of some other less widely used medications (e.g.,
ipratropium bromide, antihistamines, cromolyn sodium) are of interest from the point of view
that they may provide insight into mechanisms of response to SO2.
34
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Authors concluded no protective Koenig et ;
effect of chronic theophylline use (1989)
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36
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Theophylline. Koenig et al. (1992) examined the effect of theophylline, an airway
smooth muscle relaxant, on SO2 induced bronchoconstriction in a group of eight allergic mild
asthmatic subjects. There was a trend for the FEVj response to be smaller when the subjects
took theophylline, but because of the small sample size and the variability of the responses,
the trend did not reach statistical significance. However, total respiratory resistance was
significantly less in the theophylline than in the placebo group after SO2 exposure. The
mean decrease in FEVl in the placebo group (medication withheld for 1 week) was
approximately 0.5 L or about 16% and, in the theophylline group, was about 7%. Linn
et al. (1990) noted that subjects normally medicated with theophylline had similar responses
to SO2 whether they had high or low blood levels of theophylline. This suggests that, with
typical medication levels, theophylline did not afford much protection from the effects of
so2.
Koenig et al. (1989) examined the effects of 1 ppm SO2 on a group of 12 moderate
asthmatic individuals who were on chronic theophylline: therapy. Subjects were exercised in
the morning 3 to 4 h after drug administration and on a different day in the afternoon, 8 to
10 h after drug, with no inhaler use within 4 h of exposure. Mean theophylline levels were
similar in the morning and the afternoon. There were no differences in FEVj response to
SO2 between morning and afternoon exposures. The change in FEVj, about —14%, was
similar to other studies where a placebo was evaluated under the same conditions. There was
no correlation between theophylline levels in the blood and FEV1 decrements in response to
SO2 exposure. The authors concluded that there was mo protective effect of chronic
theophylline use on response to SO2.
Ipratropium Bromide. McManus et al. (1989) examined the effects of ipratropium
bromide (IB) (a muscarinic receptor [cholinergic] blocking agent) on a group of nonallergic
("intrinsic") asthmatic subjects (age > 55 years). Although IB improved baseline lung
function, the fall in FEY} after exposure to 0.5 and 1.0 ppm SO2 was similar to the response
with placebo. These subjects experienced an approximate 15% reduction in FEVi after
20 min of rest and 10 min of mild exercise (VE = 26 L/min) at 1 ppm SO2. They
experienced about an 8.5% drop in FEV1 from the resting exposure alone. Typically,
resting exposure has not produced appreciable responses, even with mouthpiece exposure
37
-------
systems, suggesting that these subjects could be more responsive to SO2 than younger
allergic asthmatic subjects studied under similar conditions (Koenig et al., 1983).
Inhaled Steroids. Wiebicke et al. (1990) recently examined the effects of regular
treatment over a 5-week period with an inhaled steroid (beclomethasone) and a beta-agonist
(salbutamol/albuterol) on nonspecific bronchial responsiveness to histamine, methacholine,
hyperventilation, and SO2. All medications were withheld for at least 6 h prior to any
challenge. Salbutamol treatment alone had no effect on responsiveness to standard challenges
with histamine or methacholine. The eucapnic hyperpnea challenge involved a progressive
increase (steps of 15 L/min) in target ventilation (maintained for 3 min) until the SRaw
increased by 75% above baseline. Breathing was performed via a mouthpiece with or
without SO2 added to the airstream. Salbutamol treatment did not change the responses to
hyperventilation with air or with 0.75 ppm SO2. Combined treatment with salbutamol and
beclomethasone caused a reduction in baseline SRaw and also reduced airway responsiveness
to methacholine, histamine, and hyperpnea with air. However, treatment with salbutamol
plus beclomethasone did not cause a significantly decreased response to SO2, although the
SO2 response did tend to be less. The absence of an effect of salbutamol in this study is in
contrast to the significant reduction in SO2 response with metaproterenol (Linn et al., 1988)
and albuterol (i.e., same drug as salbutamol) (Koenig et al., 1987) seen in other studies.
The suspension of drug treatment at least 6 h prior to any challenge exceeds the duration
(~2 to 3 h) of the peak therapeutic effect for salbutamol (Oilman et al., 1990). Any
persistent effect of salbutamol was apparently insufficient to alter SO2 responses.
Beta Agonists. Linn et al. (1988) examined effects of metaproterenol on responses of
asthmatic subjects to 0.3 and 0.6 ppm SO2. Pretreatment with metaproterenol (dose
administered 5 min prior to pretesting) caused an improvement in baseline lung function
(increased FEV1 and decreased SRaw) and a reduced response to SO2 exposure in an
environmental chamber. The estimated average SRaw SO2 response, adjusted for exercise-
induced bronchospasm (EIB), of no treatment and placebo treatment was a 66 or 166%
increase in SRaw at 0.3 and 0.6 ppm, respectively. These percentages were derived by
taking the average ASRaw reported by Linn et al. (1988) for untreated and placebo groups at
0.0 ([8.8 + 6.1] 12 = 7.45), 0.3 ([12.8 + 9.9] 12 = 11.95), and 0.6 ppm ([17.5 + 17.1] 12
= 17.3) as a percentage of the average baseline (5.94) and then subtracting the 0.0 ppm
38
-------
from the 0.3 and 0.6 ppm responses (125, 191, and 291%, respectively). Metaproterenol
given prior to exposure blocked the responses to SO2. Symptoms were markedly reduced
but not eliminated. Following the 0.6-ppm SO2 exposure with either the no-treatment or
placebo treatment condition, 9 out of 20 subjects needed medication to treat symptoms caused
by at least one of the exposures.
Koenig et al. (1987) studied a group of allergic adolescents with exercise-induced
bronchospasm but who were not classified as asthmatic (never wheezed except with exercise,
never used beta-agonist). These subjects exhibited a 14% decrease, from post-placebo
baseline, in FEVl after 10 min of moderate exercise (34 L/min) at 0.75 ppm SO2. Albuterol
markedly attenuated the drop in FEVj caused by SO2, although it caused a modest (7%) but
significant improvement in baseline FEVj. These observations in a group of subjects not
previously identified as asthmatic suggest that the population at risk may be slightly larger
than suggested earlier. However, by the objective criteria presented in this paper, many
would classify these subjects as asthmatic.
Cromolyn Sodium. Koenig et al. (1988a) examined the effects of four different dose
levels of cromolyn sodium (a nonspecific mast cell degranulation inhibitor) on subjects
exposed to 1.0 ppm SO2 for 10 min with exercise (VE ~ 35 L/min). Subjects received
either 0, 20, 40, or 60 mg cromolyn 20 min prior to exposure to SO2. The SO2 response
with the 20-mg dose was not significantly different than the response with the placebo.
However, the 40-mg dose caused a partial blockade, and 60 mg almost completely obliterated
the response to SO2. These observations support the previous observations of Myers et al.
(1986a) that cromolyn sodium reduced responses to SO2 in asthmatic individuals in a dose-
dependant manner. However, the Koenig et al. (1988) data are more relevant to clinically
acceptable doses of cromolyn.
Chlorpheniramine Maleate. Koenig et al. (1988b) evaluated the effect of an oral
antihistamine, chlorpheniramine maleate, on SO2 responses in a group of allergic adolescents
with exercise-induced bronchoconstriction (but who had never been treated for or diagnosed
with asthma). Subjects were exposed to 1.0 ppm SO2 via mouthpiece while exercising with
a ventilation of about 34 L/min. Medication was taken 12 h prior to exposure and included
placebo or 4 or 12 mg chlorpheniramine. The FEVl responses were similar under the three
conditions, with decrements of -11, -12.6, and -12.3%, respectively. The authors
39
-------
concluded that this oral antihistamine did not provide any protective effect from SO2-induced
bronchoconstriction in these allergic adolescent subjects. However, changes in nasal function
induced by SO2 were blocked by antihistamine.
In the Second Addendum (U.S. EPA, 1986), medication usage after SO2 exposure was
cited as an adverse outcome that could be quantified, as summarized in Table 7 based on
information reported hi pertinent published studies. In the more recent studies, medication
use following exposure has been carefully noted. After 2- to 5-min exposures to 1.0 ppm
SC>2, 7 of 8 subjects in one study (Balmes et al., 1987) and 4 of 12 in another (Horstman
et al., 1988) required bronchodilator medication after exposure. Two of the subjects in
Balmes et al. (1987) were unable to complete the 5-min exposure in addition to requiring
medication. Linn et al. (1988) found that 7 of 20 mild asthmatic subjects exposed to
0.6 ppm SO2 needed medication to treat their symptoms following exposure, whereas only
2 of 20 did so after 0.3 ppm SO2 exposure or after exposure to clean air at comparable
exercise rates.
TABLE 7. MEDICATION USE AFTER SULFUR DIOXIDE EXPOSURE3
Reference
Bethel et al. (1984)
Koenig et al. (1985)
Linn et al. (1984a)
Linn et al. (1984b)
Linn et al. (1988)
Linn et al. (1990)
Balmes et al. (1987)
Horstman et al. (1988)b
Type of Medication After
Exposure Exercise in Clean Air
Mouthpiece
Facemask
Chamber
Chamber
Chamber
Chamber
Mouthpiece
Chamber
-0-
-0-
-0-
-0-
2/20
13/21 (low)
3/21 (norm)
—
Proportion of Subjects Tested
Using Medication After SO2
Exposure (in ppm)
2/7 d
2/10 d
1/24 <<
3/24 d
2/20 0.3 ppm (low med)
^0.3 ppm (norm med)
^0.6 ppm (low med)c
^0.6 ppm (norm med)c
g 1.0 ppm
g 1.0 ppm
aMedication use indicates that the subject either took their own medication or else requested medication from the
investigators conducting the study.
Subjects prescreened as earlier having at least 100% increase in SRaw in response to SO2 at 1.0 ppm.
"Tvfedication use data obtained from Hackney et al. (1988) may not agree with independently provided
individual data.
40
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Many asthmatic subjects take medication to relieve the symptoms and functional
responses associated with exacerbations of the disease. The most commonly used of these
medications (beta agonists) also inhibit responses to SO2. Thus, there have been suggestions
that asthmatic persons may be protected from responses to SO2 because of medication that
they would have used in any case. However, several lines of evidence suggest that this is
not likely the case.
Mild asthmatic persons who constitute the majority of asthmatic individuals, use beta
agonists on an as needed basis. Even once a week use exceeds the norm for such
individuals, as discussed in Section 2.2. Only about 20% of moderate asthmatic persons
regularly use inhaled bronchodilators, the most effective medication in minimizing SO2
responses. Even among moderate asthmatic persons on regular bronchodilator therapy (oral
and inhaled), compliance with medication use ranges from 50% to 70%. Thus one third to
one half of regularly medicated asthmatics do not take all prescribed medication. National
Heart Lung and Blood Institute guidelines indicate that daily bronchodilator use suggests the
need for additional therapy. Indeed there is some suggestion that excessive use of beta-
agonists leads to a worsening of asthma status (Sears et al., 1990b; van Schuyk et al., 1991).
The frequency of use of medication prior to outdoor exercise is unknown. Furthermore
there are a substantial number of individuals with EIB who are not aware of the need for or
benefits of treatment (Voy, 1984).
4.5 MODIFICATION OF SULFUR DIOXIDE RESPONSIVENESS BY
OTHER AIR POLLUTANTS
The effect of prior ozone exposure on response to SO2 was examined by Koenig et al.
(1990) in 13 allergic adolescent asthmatic individuals. A 45-min exposure to 0.12 ppm
ozone caused a modest and transient exacerbation (from a 3% decrease to an 8% decrease) of
FEVj response to 0.1 ppm SO2. Ozone does produce an increase in nonspecific bronchial
responsiveness (NSBR); these observations may reflect a change in NSBR due to ozone or an
additive effect of ozone, SO2, and exercise. The importance of these observations, from a
risk assessment point of view, depends upon the prevalence in the ambient environment of
the sequential occurrence of elevated levels of ozone followed by SO2 peaks. However, the
possibility that stimuli such as ozone that may cause changes in NSBR and may also alter
41
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responses to SO2 is important because other non-specific stimuli (e.g., cold air, exercise,
etc.) may occur in temporal and spatial proximity to increased levels of SO2.
The effects of prior NO2 exposure on SO2-induced bronchoconstriction has been
examined in two other studies (Torres and Magnussen, 1990; Rubinstein et al., 1990). Jorres
and Magnussen (1990) exposed 14 mild to moderate asthmatic subjects to 0.25 ppm NO2 for
30 min while breathing through a mouthpiece at rest. There were no changes in SR^ as a
result of the exposure. After the exposure, airways responsiveness to SO2 was assessed by
eucapnic hyperpnea of 0.75 ppm SO2 using stepwise increases in ventilation; the initial level
was 15 L/min with subsequent increases to 30, 45 L/min, and so forth. After each 3-min
period of hyperpnea, SRaw was determined. The ventilation of SO2 required to produce a
100% increase in SRaw (PV100SRaw[SO2]) was estimated using interpolation of ventilation
versus SRaw (dose-response) curves. The PV100SRaw(SO2) was significantly reduced after
NO2 exposure compared to after filtered air exposure, suggesting that the airways were more
responsive to SO2 as a result of the prior NO2 exposure. However, this response is not
specific to SO2 as other studies have suggested increased nonspecific bronchial
-esponsiveness in subjects exposed to NO2 (Folinsbee, 1992).
Rubinstein et al. (1990) exposed nine asthmatic subjects to 0.30 ppm NO2 for 30 min
(including 20 min light exercise). There were no significant effects of NO2 exposure on lung
function (single breath nitrogen washout, SRaw, FVC, FEV^ or respiratory symptoms,
although a slight increase in SRaw was observed as a result of exercise. After exercise,
an SO2-bronchoprovocation test was administered, but using a different technique than Jorres
and Magnussen (1990). Increasing amounts of SO2 were administered by successive
doubling of the SO2 concentration (0.25, 0.5, 1.0, 2.0, 4.0 ppm) at a constant, eucapnic
hyperpnea of 20 L/min, maintained for 4 min. Specific airway resistance was measured after
each step increase in SO2 concentration. The concentration of SO2 required to increase SRa
by 8 units (PD8uSO2) -was interpolated from a dose-response curve of SO2 concentration
versus SRaw. The PD8uSO2 was 1.25 ± 0.70 ppm after air exposure and 1.31 + 0.75 after
NO2 exposure, indicating no mean change in responsiveness to SO2. Only one subject
showed a tendency toward increased responsiveness to SO2 after NO2 exposure.
The contrasting findings in these two studies are somewhat puzzling because the
subjects of Rubinstein et al. (1990) were exposed to a higher NO2 concentration and
w
42
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exercised during exposure. However, Torres and Magnussen's subjects appeared to have had
slightly more severe asthma and were somewhat older. The modest increase in SRaw
induced by exercise in the Rubinstein et al. study may have interfered with the response to
SO2 (i.e., the subjects may have been in a refractory state). Finally, the different method of
administering the SO2 bronchoprovocation test (i.e., increased VE at constant SO2 versus
increasing SO2 at constant VE) may produce a different response, because hyperpnea alone
could contribute to the increase in SRaw (Deal et al., 1979; Eschenbacher and Sheppard,
1985). Thus, although similar, the two SO2 challenges are not necessarily comparable.
5.0 SUMMARY AND CONCLUSIONS
In general, the conclusions reached in the 1986 Second Addendum have been supported
by subsequent research. Those conclusions were restated at the beginning of the present
supplement, and there is little point in repeating them here. However, the newer studies
reviewed in this supplement provide further information useful in drawing conclusions of
relevance to developing criteria for a possible short-term (< 1 h) SO2 NAAQS.
5.1 EXPOSURE DURATION/HISTORY AS SULFUR DIOXIDE
RESPONSE DETERMINANTS
Two new studies (Balmes et al., 1987; Horstman et al., 1988) have shown that airways
resistance changes resulting from SO2 exposure can occur with as little as 2 min exposure at
SO2 levels ranging from 0.5 to 1.0 ppm. Significant changes were seen with 2 min exposure
at 1.0 ppm and with 3 min exposure at 0.5 ppm. These observations clearly indicate that
brief exposures to high concentrations, which may be masked by ambient SO2 monitoring
procedures using averaging times of 1 h or greater, can have detectable health consequences.
Other studies (e.g., Linn et al., 1987; Roger et al., 1985) evaluated the effects of prior
exposure to SO2 on the magnitude of bronchoconstriction responses to subsequent SO2
exposures. Prior exposure history to SO2 over the course of several weeks (as opposed to
several hours) was found to be largely irrelevant in determining responsiveness to later SO2
exposures. However, the response to a second exercise period was diminished in comparison
to initial bronchoconstriction observed in response to a first exercise period within a 1-h SO2
43
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exposure, thus further confirming a likely refractory period to SO2 exposures accompanied
by exercise or hyperpnea repeated within a span of a few hours.
5.2 SULFUR DIOXIDE RESPONSES AND ASTHMA SEVERITY
Several new studies have evaluated responses to SO2 among asthmatic individuals with
moderate or severe disease. One new study (McManus et al., 1989) of older (>55 years)
"intrinsic" asthmatic individuals suggests that they may experience bronchoconstriction with
mouthpiece SO2 exposure while resting. Another study (Linn et al., 1987), while indicating
similar relative responses to SO2 among mild and moderate asthmatic subjects, demonstrated
larger absolute increases in airway resistance among the moderate to severe asthmatic
subjects. While current studies are suggestive of greater SO2 responsiveness among those
asthmatic patients with more severe disease, this issue cannot be unequivocally resolved.
However, because of the lower baseline function in moderate and severe asthmatic persons,
especially those lacking optimal medication, any effect of SO2 would further reduce their
lung function toward levels that may become cause for medical concern.
5.3 RANGE OF SEVERITY OF SULFUR DIOXIDE RESPONSES
Efforts have been made to help characterize the range of severity of respiratory effects
exhibited by asthmatic subjects in response to SO2 exposure, and some of these were
discussed in earlier sections of this Supplement. Many of the newly available studies provide
substantial additional information that is helpful in delineating the range of severity of SO2-
induced respiratory responses. For example, two additional studies support the concept
advanced by Horstman et al. (1986) of the estimation of a median response to SO2 among
asthmatic individuals. Results from the studies by Linn et al. (1987) and Torres and
Magnussen (1990), using relatively large groups of subjects, are consistent with the
estimation of Horstman et al. (1986). These data suggest that the average asthmatic
individual will experience increased airway resistance (i.e., at least a doubling of baseline
resistance) with exposure to 0.75 ppm SO2 for 10 min while performing moderate exercise.
Numerous factors can modify these responses, as noted previously in the Second Addendum
(U.S. EPA, 1986), and there is a broad range of response among asthmatic individuals.
44
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In the earlier Second Addendum (U.S. EPA, 198(5), a table was presented which
defines a continuum of responses of increasing severity and concern in asthmatic subjects.
A modification of this table is presented below as Table 8. In Section 4.2 of this
supplement, the range of responses among asthmatic subjects exposed to SO2 was discussed.
Although most asthmatic subjects tested in studies reviewed here had only relatively mild
responses at low SO2 concentrations (0.2 to 0.5 ppm), some of the more responsive
asthmatic subjects had responses to SO2 exposures at 0.6 ppm or higher that included SRaw
increases exceeding 50 units, FEVl decreases (corrected for exercise response) exceeding
20%, the presence of marked wheezing and breathing discomfort, and the need for
medication to resolve these symptoms. Such responses, in the most sensitive subjects, which
would be considered to be severe or incapacitating according to definitions of increasing
severity in Table 8, likely constitute adverse health effects. Also, tables contained in
Appendix B materials provide further detailed, quantitative analyses of combinations of
respiratory function effects, severity of symptoms and post-SO2 exposure medication use, by
which to estimate percentages of mild or moderate asthmatic subjects that experience SO2-
induced responses that meet Table 8 criteria for moderate, severe or incapacitating
respiratory effects. Based on the Appendix B analyses, it is clear that (a) substantial
percentages of mild and moderate asthmatic subjects experience combinations of lung
function changes and respiratory symptoms at 0.6 or 1.0 ppm SO2 that meet the criteria in
Table 8 for severe or incapacitating effects and (b) the magnitude of the observed SO2
responses for such individuals clearly exceed the range of daily average variations in lung
function or responses to other stimuli (i.e., cold air, exercise) often experienced by them.
It is also notable that up to 15% of mild or moderate asthmatics experienced sufficiently
severe lung function changes and/or respiratory symptoms at 0.6 or 1.0 ppm SO2 so as not
to be able to continue to maintain moderate exercise workload levels under the SO2 exposure
conditions or to have to terminate SO2 exposure entirely—in contrast to none requiring
reduced workloads in response to comparable exercise alone.
45
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TABLE 8. COMPARATIVE INDICES OF SEVERITY OF RESPIRATORY EFFECTS
SYMPTOMS, SPIROMETRY, AND RESISTANCE
Type of Response
Change in SRaw
Change in
spirometry
(FEV,.0, FVC)
Duration of effect/
treatment needs
Symptoms
Gradation of Response Severity
None
No change
No change
NA
No
respiratory
symptoms
Mild
Increase <100%
<10%
Spontaneous
recovery
<30 min
Mild respiratory
symptoms,
no wheeze or
chest tightness
Moderate
Increase up to
200% or up to
15 units
Decrease of
10 to 20%
Spontaneous
recovery < 1 h
Some wheeze
or chest
tightness
Severe
Increases more
than 200%,
or more than
15 units3
Decrease >20%
Bronchodilator
required to resolve
symptoms
Obvious wheeze,
marked chest
tightness, breathing
distress
Incapacitating
Increases much
greater than 300%
or total SRaw
exceeds 50 units3
Decrease much
greater than 20%
or <50%
predicted.
Possible emergency
treatment required
if persistent
Severe breathing
distress
aSRaw units are cm H20 • L"1 • S"1 • L
Source: Modified from Figure 7 on page 4-7 of U.S. EPA (1986).
5.4 MODIFICATION OF SULFUR DIOXIDE RESPONSE BY ASTHMA
MEDICATIONS
Asthma medications can reduce or eliminate the airway resistance increase in response
to SO2 exposure. The most effective medications appear to be beta2 sympathomimetic
medications, such as albuterol or metaproterenol. Cromolyn sodium, a nonspecific mast cell
degranulation inhibitor, given in therapeutic doses will partially or completely prevent
bronchoconstriction in response to SO2 exposure. Other standard asthma medications such as
inhaled steroids or methylxanthine medications appear to be less effective. Withdrawal of
normal asthma medication causes degradation of baseline lung function but does not
necessarily increase the response to SO2, although this has not been studied extensively.
In the two investigations where patients on "normal medication" (mainly theophylline) were
exposed to SO2, there did not appear to be any protective effect (Koenig et al., 1989; Linn
et al., 1990). Specifically, the SO2 responses were similar whether the patients were using
medication or not, although baseline function was depressed by the absence of regular
medication.
46
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Only anecdotal information on medication use after SO2 exposures was mainly available
from studies earlier reviewed in the Second Addendum (U.S. EPA, 1986). That information
indicated that a few of the most sensitive asthmatic individuals exposed at 0.5 or 0.6 ppm
SO2 during moderate exercise required medication after such SO2 exposure, but not after
comparable exercise levels in clean air (see Table 7). Newer studies reviewed in this
supplement have more systematically evaluated medication use as a response endpoint of
clinical significance. Two of the newer studies Linn et al. (1988, 1990) found no greater
proportions of subjects to require medication use after' 0.3 ppm SO2 exposure than after clean
air exposure at comparable exercise levels. On the other hand, additional new information
presented from recent studies conducted by three different laboratories (Balmes et al., 1987;
Horstman et al., 1988; Linn et al., 1988, 1990) indicates that many asthmatic individuals
(who either withheld medication prior to SO2 exposure or did not normally require
medication) did need medication due to severity of responses after exposure to SO2 at 0.6 or
1.0 ppm. However, in some cases, a substantial number of asthmatic subjects also needed
medication following clean air exercise exposure as well (Linn et al., 1990); in the study
reported by Hackney et al. (1988) and Linn et al. (1990), for example, approximately half of
the asthmatic subjects used medication after 0.6-ppm SO2 exposure, but among those on a
reduced (low) medication regime, approximately the same number used medication following
the exercise-alone exposure. Overall, the available published findings point toward more
substantial percentages of individuals likely requiring medication use after SO2 exposure
>0.6 ppm than at exposure concentrations of 0.5 ppm or below (as is also indicated by the
more detailed Appendix B Smith memo analyses of raw data from the 1988 and 1990 Linn
et al. studies).
5.5 MODIFICATION OF SULFUR DIOXIDE RESPONSIVENESS BY
OTHER AIR POLLUTANTS
One new study by Koenig et al. (1990) reported that prior exposure to ozone at the
current NAAQS level (0.12 ppm, 1 h) causes a transient moderate exacerbation of lung
function decrements due to a later exposure to 0.1 pprn SO2. However, the particular results
make it difficult to separate out clearly the degree of nonspecific bronchial responsiveness
due to O3 alone or to combined effects of O3, SO2, and exercise.
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Other pollutants may also modify the response to SO2 exposure, although currently
available evidence is still inconclusive. More specifically, NO2 may also possibly increase
responses to SO2 in asthmatic individuals. One study by Torres et al. (1990) appears to
provide indications of increased responsiveness to SO2 after prior NO2 exposure, whereas a
second study by Rubenstein et al. (1990) failed to find analogous NO2 exacerbation of SO2
effects. This may have been due to somewhat older and slightly more severe asthmatic
subjects being exposed in the first study. It appears that a pollutant that increases nonspecific
bronchial responsiveness may also increase airway responses to SO2.
5.6 HEALTH RISK IMPLICATIONS
Based both on earlier criteria evaluations (U.S. EPA, 1982a,b,c,d, 1986) and the
present supplemental assessment of more recent findings on SO2 respiratory effects, several
salient points can be made with regard to implications of the reviewed findings for assessing
health risks associated with ambient S02 exposures. First, it is now clear that, whereas
healthy nonasthmatic individuals are essentially unaffected by acute (< 1 h) exposures to SO2
at concentrations of 0 to 2 ppm, even very brief (2 to 10 min) exposures of asthmatic
subjects to SO2 concentrations at or below 1.0 ppm can cause detectable respiratory function
changes and/or symptoms—if such exposures occur while the subjects are sufficiently active
to achieve breathing rates typical of at least moderate exercise (i.e., 30 to 50 L/min). Given
this fact, mild to moderate asthmatic persons are much more likely to be at risk for
experiencing respiratory effects in response to ambient SO2 exposures than are those with
chronically severe asthma. The individuals with severe asthma, by definition (NIH, 1991;
see Table 1), have very poor exercise tolerance with marked limitation of activity and,
therefore, are less likely to engage in sufficiently vigorous activity (exercise) so as to achieve
requisite breathing rates for notable SO2 respiratory effects to occur.
Of key importance, then, for criteria development purposes is the characterization of
exposure-response relationships for the induction by SO2 of respiratory function changes and
symptoms in mild to moderate asthmatic subjects and to provide a framework which will
assist in determining which SO2 responses may be of sufficient magnitude and severity so as
to be of significant health concern. ^ The health significance of SO2 respiratory effects can be
evaluated in terms of several criteria, such as: (1) the point at which substantial percentages
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of SO2 exposed asthmatic subjects experience respirator/ function changes or symptoms that
exceed usual daily variations or responses to other commonly encountered stimuli (e.g.,
exercise, cold/dry air, etc.) that trigger bronchoconstriction and other asthma symptoms;
(2) whether the responses evoked by SO2 are sufficient to require reductions in exercise
workloads, termination of the SO2 exposure entirely, use of asthma medication after the SO2
exposure, and/or seeking of medical attention; and (3) the persistence of the observed acute
SO2 exposure effects and/or their relationship to any other more serious chronic health
impacts.
Collectively, the foregoing analyses of exposure-response relationships and severity of
acute (<10 min) SO2 exposure effects in asthmatic subjects suggest the following:
(1) Overall, the responses to SO2 demonstrated by controlled laboratory studies of
exercising asthmatic subjects are similar in many ways to effects evoked by other
commonly encountered non-specific stimuli (such as exercise, cold/dry air,
psychological stress, etc.). That is, bronchoconstriction and/or respiratory
symptoms occur with rapid onset after exposure (within 5 to 10 min.), but
typically the acute-phase bronchoconstriction and any accompanying symptoms
reverse on their own within 1 to 2 h and are not followed by additional late-phase
responses (often much more severe and dangerous) that typify asthmatic reactions
to more specific stimuli (e.g., pollen, dust mites, or other biocontaminants).
Moreover, the acute-phase responses to SO2 are followed by a short-lived
refractory period and can be prevented or ameliorated by inhalation of beta-
agonist aerosol medications. On the other hand, it has been well documented in
numerous studies that SO2 may interact with weather factors (e.g., cold/dry air)
and/or exercise to cause exaggerated bronchonstriction and accompanying
symptoms when asthmatic individuals are exposed to sufficiently high SO2
concentrations while engaged in exercise of sufficient intensity to require oronasal
breathing. Of particular concern are a subset of asthmatic individuals that appear
to be hyperresponsive to SO2 in displaying dramatically greater-than-average
bronchoconstriction and more marked symptomatic responses at given SO2
concentrations than do most other potentially affected asthmatic persons.
Quantitative estimation of SO2 concentrations at which notable numbers
(percentages) of such SO2-sensitive asthmatic subjects display bronchocontriction
responses and symptoms of sufficient magnitude or severity to be of health
concern is discussed below.
(2) At most, only about 10 to 20% of mild or moderate asthmatic individuals are
likely to exhibit lung function decrements in response to SO2 exposures of 0.2 to
0.5 ppm during moderate exercise that would be of distinctly larger magnitude
than typical daily variations in their lung function or average changes in lung
function experienced by them in response to other often encountered stimuli, e.g.,
comparable exercise levels alone and/or cold/dry air. Furthermore, it appears
that only the most sensitive responders might experience sufficiently large lung
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function changes and/or respiratory symptoms of such severity as to be of
potential health concern, leading to disruption of ongoing activities (e.g.,
reduction or termination of physical exertion), the need for bronchodilator
medication, or seeking of medical attention. If so affected, however, it is also
likely that use of bronchodilator medication would be effective in rapidly
ameliorating the affected individual's distress or that the SO2-induced effects
would be short-lived (i.e., less than a few hours; usually less than 1 h). Further,
although the persons' symptoms, however brief, may be perceived by some as an
"asthma attack", it is unlikely that many would seek emergency medical treatment
(i.e., physician or hospital visit), given the rarity with which such individuals
normally respond in such a fashion to other "asthma" events (as discussed in
Section 2.1). Also, given the refractory period found to exist after SO2
exposures, it would be less likely for the individual to experience notable
responses upon reexposure to SO2 within the next several hours after the initial
exposure, should they choose to resume physical exertion after amelioration or
cessation of any initial SO2-induced distress.
(3) In contrast to the above projected likely consequences of ambient exposures to
0.2 to 0.5 ppm SO2 of mild or moderate asthmatic persons, considerably larger
lung function changes and respiratory symptoms of notably greater severity would
be expected to occur due to exposure of such individuals to SO2 concentrations of
0.6 to 1.0 ppm while physically active. That is, substantial percentages (>20 to
25%) of mild or moderate asthmatic individuals exposed to 0.6 to 1.0 ppm SO2
during moderate exercise would be expected to have respiratory function changes
and severity of respiratory symptoms that distinctly exceed those experienced as
typical daily variation in lung function or in response to other stimuli, e.g.,
moderate exercise or cold/dry air. The severity of the effects for many of'the
responders, furthermore, are likely to be sufficient to be of concern, i.e., to cause
disruption of ongoing activities, use of bronchodilator medication, and/or possible
seeking of medical attention. Again, however, for those thusly affected,
bronchodilator treatment would likely lead to rapid amelioration of the distress or
it would be relatively transient (not more than a few hours) and unlikely to
reoccur if reexposure to SO2 occurred within the next several hours after initial
exposure. Also, the intensity of distress is much more likely to be perceived as
an "asthma attack" than would be the case for most 0.2 to 0.5 ppm SO2 effects,
although it still would appear to be relatively unlikely that the short-lived
symptoms would be sufficient to cause many to seek emergency medical attention
for reasons noted above.
(4) The relative health significance of the above types of responses is difficult to
judge. However, the degree of concern for effects of the magnitude and severity
expected at 0.6 to 1.0 ppm SO2 exceeds that for those responses likely to be seen
with 0.2 to 0.5 ppm exposures of physically active asthmatic individuals. For
most mild to moderate asthmatic persons, effects induced by acute, brief (2 to
10 min) exposures to SO2 at such concentrations (<0.5 ppm) would generally be
barely perceptible (if perceived at all) and not of any medical concern. For a few
others among the most sensitive responders, responses may be of such magnitude
50
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and severity to be viewed as more than a mild annoyance—although the resulting
distress would probably be short-lived even if not treated with medication and has
not been demonstrated to be a harbinger of any more serious, chronic health
sequelae. At 0.6 to 1.0 ppm SO2, on the other hand, the effects per se are more
likely to be of sufficient magnitude and severity for >20 to 25% of mild or
moderate asthmatic individuals to be both perceptible and thought of as being of
some immediate health concern. If such effects were to be experienced often in
response to ambient SO2 exposures, then the degree of concern would increase.
Therefore, the likely frequency of occurrence of such SO2-induced effects is one
of the factors that should be considered in determining the public health
significance of ambient SO2 exposures.
(5) The possibility exists that bronchodilator medication use before engaging in
physical exercise might prophylactically protect against the above types of effects
due to SO2 exposure during physical exertion. This may be true for some
asthmatic individuals, but given relatively low medication usage compliance rates
for many mild or moderate asthma patients (see Section 4.4 and Appendix B
Smith memo), pre-exercise bronchodilator use may not occur (and, therefore,
offer protection) for many potentially affected sensitive individuals. For a large
number of mild asthmatics with normal baseline lung function or well controlled
moderate asthmatics on a regular regimen of medication, SO2 probably represents
a limited public health concern, in that exposure is unlikely to reduce their lung
function below a critical level that would be of immediate medical concern.
However, many moderate asthmatics who come from families with lower
socioeconomic status may not have adequate access to the health care system,
may have poor compliance for medication use (possibly based on limited
availability of medication) and may thus be prone to frequent deterioration of
their lung function. Such individuals would be at increased risk from SO2
exposure because of their potentially poorer baseline level of lung function in
addition to the likelihood of exposure to additional airway irritants (e.g., NO2,
cockroach antigen, and dust mite antigen). Exposure of unmedicated moderate
asthmatics to SO2 could cause additional deterioration of lung function that could
be cause for medical concern. In evaluating the possible frequency with which
mild to moderate asthmatic persons may be sufficiently affected by SO2 exposures
so as to disrupt their normal daily activities, attention should be focussed on
estimation of the frequency of occurence of SO2 exposures (at 0.6 to 1.0 ppm or
higher) in combination with increased physical activity (moderate or greater
exercise levels). Greater concern would exist for SO2 effects in that fraction of
adolescent or adult mild or moderate asthmatic population segments who regularly
exercise outdoors (e.g., jogging, tennis, etc.), are involved with outdoor athletics
(e.g., high school sports), or are employed in occupations requiring frequent
increased physical exertion. Similarly, children with mild to moderate asthma
may also be of concern, given the tendency for children to generally be much
more physically active than adults.
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5.7 POPULATION GROUPS AT RISK
As highlighted above, mild or moderate asthmatic children and physically active
adolescents or adults with mild or moderate asthma clearly represent population segments
likely to be at special risk for potential SO2 exposure effects.
In addition, certain minority group (e.g., Black, Hispanic) individuals might be
hypothesized as being at increased potential risk for SO2 respiratory effects, given distinctly
higher asthma mortality rates reported among non-white individuals in large urban centers
such as Chicago and New York, as discussed in Section 2.1. However, no specific evidence
has been brought forward to date that specifically implicates SO2 as contributing to the
increased asthma mortality rates observed among non-white population groups. Nor have
epidemiologic evaluations of possible SO2 effects on asthma rates in New York City's
"asthma alley" areas (Brooklyn, Harlem) found evidence of significant associations between
either 24 h average SO2 concentrations or briefer 1 h SO2 excursions above 0.1 ppm and
increased visits to hospital emergency rooms for asthma (Goldstein and Block, 1974;
Goldstein and Arthur, 1978; Goldstein and Weinstein, 1986). Lastly, Heath et al. (1984)
found no significant differences between respiratory function changes of 10 African
American and 12 Caucasian methacholine positive asthmatic male subjects in response to
controlled exposure to 1.0 ppm SO2 while exercising, although both groups showed
significant (p < 0.04) increases in total respiratory resistance following the SO2 exposure.
Another population group that could be hypothesized as being at increased risk for SO2
effects are atopic allergic individuals, based on reports (e.g., by Koenig et al., 1987, 1988)
of allergic adolescent subjects showing similar responses to SO2 as mild asthmatic subjects.
However, the allergic adolescent subjects with exercise-induced bronchospasm (EIB) shown
by Koenig et al. to have a similar response to SO2 as mild asthmatics would be considered
by many experts to fall into the diagnostic category of mild allergic exercise-induced
asthmatics (see Clean Air Scientific Advisory Committee, 1993, transcript). In the clinic
population from which Koenig et al. (1987, 1988) drew these subjects, the incidence of EIB
among allergic adolescents is reported to be approximately 40% (Kawabori et al., 1976).
However, Custovic et al. (1994) found no EIB among children with allergic rhinitis and
atopic dermatitis. The difference in incidence of EIB in these two groups of allergic subjects
is most likely due to criteria used for diagnostic classification rather than a real population
52
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difference in incidence of EIB. As noted in Section 2.1, there may be a number of
undiagnosed asthmatics and a number of subjects without asthma who have exercise-induced
bronchospasm. In the process of estimating the number of persons potentially at risk to be
affected by ambient SO2 exposure, this uncertainty regarding the incidence of SO2 sensitivity
in the population should be considered.
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61
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-------
APPENDIX A
SUMMARY OF STUDIES (1982 TO 1986) AS EARLIER REVIEWED
IN SECOND ADDENDUM (U.S. EPA, 1986) WITH REGARD TO ACUTE
EXPOSURE EFFECTS OF SULFUR DIOXIDE ON LUNG FUNCTION
IN ASTHMATICS
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APPENDIX B
U.S. EPA STAFF ANALYSES OF SEVERITY OF
SULFUR DIOXIDE-INDUCED RESPIRATORY FUNCTION
CHANGES AND SYMPTOMS IN ASTHMATIC SUBJECTS
BASED ON DATA FROM RECENT CONTROLLED HUMAN
EXPOSURE STUDIES
B-l
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June 30, 1994
MEMORANDUM
SUBJECT: Assessment of data from recent chamber studies pertaining to the severity of
effects experienced at 0.6 to 1.0 ppm SO2 by asthmatic subjects
FROM: Eric Smith
Ambient Standards Branch, OAQPS
TO: Dr. Lester D. Grant, Director
Environmental Criteria and Assessment Office, RTF (MD-52)
This memorandum evaluates responses seen among asthmatic subjects to the highest
SO2 concentrations administered (0.6 and 1.0 ppm SO2) in four recent clinical chamber
studies. Extensive data on individual subjects made available to U.S. EPA by the
responsible investigators has allowed detailed assessment of the range and combination, of
responses seen in individual asthmatic subjects in response to SO2 exposure. As per requests
by the Clean Air Scientific Advisory Committee (CASAC) to portray the responses of
asthmatics to SO2 in the context of other responses an asthmatic individual may frequently
experience (CASAC Meeting, August 19, 1993), information is also presented for many of
the subjects concerning their typical circadian variation in lung function, frequency of
symptoms and perceived asthma attacks, and frequency of medication usage. The detailed
evaluations provided here are intended to assist judgements concerning the adversity of
effects that result from 0.6 to 1.0 ppm SO2 exposures and, as such, augment the analyses of
published findings contained in the main body of the present Supplement (CDA Supplement)
to the Second Addendum (1986) to the U.S. EPA document Air Quality Criteria for
Particulate Matter and Sulfur Oxides (1982).
The Studies .
Data from four recent large-scale clinical studies are summarized and discussed below.
These studies examine the effects of SO2 on mild asthmatic subjects (Linn et al., 1987, 1988;
Roger et al., 1985) and moderate asthmatic subjects (Linn et al., 1987, 1990) at exercise.
Details on classification are provided in Smith (1994). The Roger et al. (1985) subjects
(referred to in general as the "1985 mild asthmatic subjects") were exposed to 1.0 ppm SO2
while at exercise, while all the Linn et al. subjects (from the 1987, 1988 and 1990 studies,
B-3
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generally referred to as "the 1987 mild asthmatic subjects," "the 1987 moderate asthmatic
subjects," "the 1988 mild asthmatic subjects," and "the 1990 moderate asthmatic subjects")
were exposed to 0.6 ppm SO2. The 1987 and 1990 moderate asthmatic groups are fairly
similar, but the 1987 and 1988 mild groups are distinguished by the fact that a number of the
1988 subjects used medication at least once a week (Hackney et al., 1988a), while no 1987
mild asthmatic subjects used medication that frequently (Hackney et al., 1987).
For the 1985 and 1987 studies, which involved an 1-h exposure to SO2 with three
10-min exercise periods interspersed with rest, only data gathered immediately following the
first exercise period is used (and for the 1987 study, only the first round of the two identical
rounds of exposure was used). This more accurately reflects the likely ambient conditions
(brief peaks resulting in high concentrations of SOj) and allows the results to be more easily
compared with those from the single 10-min exposures used in the 1988 and 1990 studies.
The 1988 and 1990 studies were designed in part to assess the effect of supplementary use of
an inhaled bronchodilator just prior to SO2 exposure. For this analysis, the "untreated" case
was used for the 1988 mild asthmatic subjects and the "normal medication" case was used
for the 1990 moderate asthmatic subjects. No supplementary bronchodilator was
administered in either case.
Assessment of Responses
For the assessment of the four studies shown in Table 1, data on each individual subject
was obtained and responses were scored according to Table 8 of the Criteria Document
Addendum Supplement (CDA Supplement). Each study was assessed in terms of the lung
function and symptomatic responses observed, and, when available (the 1988 and 1990
studies), duration of response and medication use post-exposure as well. Four indices of
severity of response were examined, with the data presented as the percentage of subjects
experiencing: (1) a severe effect in at least one category of response (lung function,
symptoms, and for the 1988 and 1990 studies, medication use); (2) a moderate response in
both or all three of these categories; (3) a severe lung function response accompanied by a
moderate symptom response; and (4) a severe response in both or all three categories. These
varying indices permit those making judgments on the adversity of effects to select a point
where they believe the effects become adverse and determine the number of subjects
B-4
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Table 1. COMPARISON OF VARIOUS INDICES OF SEVERITY OF RESPONSE
AT 0.6 TO 1.0PPMSO2
0.6 ppm SO2 Single
Exposure Studies
Exposure
SEV for any 1 category
(FEVj Chg, SYM,
MEDUSE)
MOD for all 3 categories
SEV FEVj + MOD SYM
SEV for all 3 cat.
1990 Mod Asth -50 L/min
Normal Meds
SO2
81%
52%
43%
10%
EXC
33%
10%
5%
0
1988 Mild Asth -50 L/min
Untreated
SO2
55%
35%
35%
' 30%
EXC
10%
0
0
0
0.6 ppm SO2
First Exercise Period
Exposure
SEV for FEV! Chg or SYM
MOD for FEVj + SYM
SEV FEVj + MOD SYM
SEV for both cat.
1987 Mod Asth
44 L/min Round 1
SO2
58%
33%
33%
8%
EXC
8%
0
0
0
1987 Mild Asth
44 L/min Round 1
SO2
50%
13%
6%
0
EXC
0
0
0
0
1.0ppmSO2
First Exercise Period
Exposure
SEV for SRaw Chg or
SYM
MOD for SRaw + SYM
SEV SRaw, MOD SYM
SEV for SRaw and SYM
1985 Mild Asth
42 L/min
S02
43%
18%
18%
4%
EXC
0
0
0
0
*Responses rated as per Table 8 in Section 5.3 of CDA Supplement (1994), using Total Lung Function change,
the maximum symptom for chest tightness, shortness of breath, and wheeze, and, for the 1988 and 1990
studies, medication usage. (Duration of response > 1/2 h, [a "moderate" response] was able to be considered
for only one subject in the 1990 study. All the rest of the subjects with at least moderate lung function change
and symptoms took medication [a "severe" response]).
B-5
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experiencing that level of response. Further details on how responses were scored are
provided with Table 1. Supplementary information on the data and the judgments entering
into this analysis is also provided in Smith (1994) for all sections of this memorandum.
One choice made in scoring responses should be highlighted: change in total lung
function was used rather than change in lung function attributable to SO2. The change from
SO2 alone has often been emphasized in the past, and with good reason: since asthmatic
individuals can have considerable bronchoconstriction from exercise alone, subtracting out
the exercise effect from the total response to determine the lung function change due to SO2
allows for a clearer picture of the specific effects of the pollutant. However, for this
analysis, the symptom and medication use categories of response intrinsically reflect the
combined effect of SO2 and exercise. For consistency with these indicators, coupled with the
fact that the subject actually experiences the total change in lung function, not just the SO2-
specific change (thus total lung function change correlates better with severity of symptoms
and medication use post-exposure), the total change in lung function was used. A sense of
the magnitude of the exercise effects can be obtained from the prevalence of responses given
for exercise alone. To compare the present results with results using only the lung function
change attributable to SO2, see Smith (1994). More information about each category of
response can be obtained in Sections 3, 4, and 5 of this memorandum and from the
spreadsheets in Smith (1994).
One point distinctly stands out from Table 1: 10-min exposure of moderately
exercising asthmatic subjects (42 to 50 L/min) to 0.6 ppm to 1.0 ppm SO2 clearly causes
substantially more subjects to experience responses of greater than mild severity than does
exercise alone. Such an observation is not wholly unexpected, given that the responses to the
SO2 exposure represent the sum of exercise and SO2 effects, but the differences can be
dramatic; that is, in each study a sizeable number of subjects after exercise in 0.6 to 1.0 ppm
SO2 experienced responses that none of the subjects experienced from exercise alone at the
same ventilation rate.
The results are fairly consistent when compared across studies. The most recent single
exposure studies of moderate (1990) and mild (1988) asthmatic subjects at the highest
ventilation rate (-50 L/min, compared to the 42 to 44 L/min for the 1985 and 1987 studies)
have the highest prevalence of responses exceeding mild severity. This is likely due in part
B-6
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to the higher rates of ventilation, as indicated by the greater prevalence of responses from
exercise alone, plus the fact subjects in these studies were given complete discretion over
medication use post-exposure, thus being more likely to medicate post-exposure, a response
automatically scored as a "severe effect." The largest: differences are between the 1988 and
1987 studies of mild asthmatic subjects, making it important to consider the possible effects
of including 9 out of 20 subjects using medication fairly regularly (at least once a week) in
the 1988 group. Five of the 1988 subjects taking medication comprised the most sensitive
subjects in the group in terms of lung function responses to SO2. These subjects also
accounted for the bulk of severe symptoms reported (although one non-medication-using
subject had severe symptoms as well, and several had pronounced lung function changes,
especially when changes due to SO2 alone were considered).
The 1985 study of mild asthmatic subjects exposed to 1.0 ppm shows a prevalence of
responses that fall between the 1988 mild group and 1987 mild group. One might expect a
study at 1.0 ppm to show greater responses than studies at 0.6 ppm because of the increased
oral dose rate (approximately 30% greater [EPA, 1986b, p. A-2]). Symptom prevalence for
this study may be somewhat reduced by the fact that recording of symptoms was not given
much emphasis for the 1985 study, with symptoms being recorded only after all lung
function testing was complete (Dr. Don Horstman, personal communication). This may
explain why no subject in the Roger et al., 1985 study reported any wheeze symptoms, while
subjects in the Linn et al. studies often reported wheeze symptoms. A more recent study
from the same laboratory (Horstman et al., 1988) found more prevalent and pronounced
symptom responses, including wheeze symptoms, among a second group of mild asthmatics,
even after correction for the fact that this study involved only subjects who experienced at
least a 100% increase in SRaw due to SO2 at 1 ppm (Smith, 1994). However, SRaw
responses are also lower for the 1985 subjects compared to the 1987 and 1988, mild asthmatic
subjects at 0.6 ppm SO2 (Table B-l). Possible explanations for this difference include simple
variation between studies, potential differences in the sensitivity of asthmatic individuals from
the two geographic areas in which the studies were conducted (Raleigh-Durham and Los
Angeles), and special caution in choosing asthmatic subjects for the 1985 study (see Smith,
1994).
B-7
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Within the expected variation between studies, the four most recent studies are
relatively consistent in the effects observed. However, the earliest study (Roger et al., 1985)
does not show greater responses even though it was conducted at a higher concentration
(1.0 ppm versus 0.6 ppm), possibly due to one of the reasons discussed above.
The next three sections provide further information on the separate distributions of lung
function, symptoms, and medication use responses that, when combined, form the basis of
the assessment of responses in Table 1. In addition, information is included that provides a
context that allows the severity of these responses to be judged in relation to the responses
typically experienced for these asthmatic subjects.
Distribution of Lung Function Changes
Table 2 shows the distribution of lung function changes, as indicated by the 50th and
75th percentile responses, observed at 0.6 and 1.0 ppm. The 50th percentile response
designates the minimum change in lung function seen by the most sensitive 50% of the
subject group, while the 75th percentile response designates the minimum change in lung
function experienced by the most sensitive 25% of the group. Results for 0.6 ppm are given
as changes in FEV! for the Linn et al. studies (the top two rows). For the Roger et al.,
1985 study at 1.0 ppm (bottom row), only SRaw values are available and are given in
Table 1. The changes for mild asthmatic subjects at 0.6 ppm are the average of the results
from the 1987 and 1988 mild asthmatic groups, while the changes for moderate asthmatic
subjects are an average of results from the 1987 and 1990 moderate asthmatic groups.
Results for each study individually are given in Smith (1994).
The values for typical daily change (in FEY^ for mild and moderate asthmatic
individuals were obtained from a field study of Los Angeles asthmatic individuals (Linn,
1991). The study included a substantial number of the subjects in the 1987, 1988, and 1990
clinical studies, but was not restricted to these subjects.
Table 2 shows that sensitivity to SO2 varies considerably across mild and moderate
asthmatic subjects, as indicated by the noticeably larger responses for the most sensitive 25%
of subjects versus the most sensitive 50%. SO2 at these concentrations (0.6 and 1.0 ppm)
produces some rather marked changes in lung function, at least for the most sensitive 25% of
the subjects. Furthermore, since the 50th and 75th percentile results represent the minimum
B-8
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Table 2 LUNG FUNCTION CHANGES IN RESPONSE TO 0.6 AND 1 PPM SO2
COMPARED TO TYPICAL CIRCADIAN CHANGE AND RESPONSES TO EXERCISE
Asthmatic
Severity
MILD
(87+88 Avg)
FEVj
n=16;20
MODERATE
(87+90 Avg)
FEVj
n=24;21
MILD (1985)
SRaw
n=28
Daily
Change
-8%
-13%
?
Percentile of Test
Subjects
50th
75th
50th
75th
50th
75th
Moderate
Exercise
-2%
-7%
-8%
-14%
+46%
+59%
SO2 Change
(corrected
for exc.)
-21%
-26%
-10%
-31%
+ 118%
+230%
Total
Change
-21%
-30%
-25%
-39%
+ 164%
+249%
Changes due to SO2, exercise, and total change figures for the Mild (87+88) and Moderate (87+90) groups are
averages of the 50th and 75th percentile values for the two studies at 0.6 ppm involving that classification of
asthmatic subject. The 1985 Mild group was exposed to 1.0 ppm SO2. Changes are determined by subtracting
the changes seen due to exercise alone from the total change in lung function seen after SO2 exposure at
exercise for each subject: SO2 Chg = Total - Exercise. However, the 50th and 75th percentile Exercise and
SO2 changes do not sum to the 50th and 75th percentile of total change, because percentiles are determined by
separate ranking of exercise changes, SO2-attributable changes (Total-Exercise), and Total changes. Thus,
different subjects are accounting for the 75th percentile change in exercise versus the 75th percentile change due
to SO2. All lung function figures are changes in FEY^ except for the 1985 mild asthmatic subjects, for whom
the changes are in SRaw.
lung function change for that fraction of subjects, every individual in that fraction
experienced a response equaling or exceeding that minimum change. Comparing across a
given percentile, the effect of exercise is much less than the total change or change
attributable to SO2! seen in response to 0.6 ppm for both groups, except for the 50th
percentile SO2 change for moderate asthmatic subjects, which is only slightly larger than the
50th percentile exercise response.
The average circadian change is also substantially smaller than the total and SO2
changes except for the 50th percentile SO2 change for the moderate asthmatic subjects, which
!In this memo, the term "change attributable to SO2" or "due to SO2" is used to indicate the amount of change
determined by correcting total changes in lung function in response to SO2 for the effects of exercise (Total-
Exercise). The difference is the "change attributable to SO2." "Total Change," "Total FEVj," or "Total SRaw"
are used when the total change in lung function, representing both the change due to exercise and the change due
to SO2, is given.
B-9
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is slightly smaller than the average circadian change. For the 1985 study, no direct
information on circadian changes in SRaw is available, but given the magnitude of changes
seen in the Linn et al. mild subjects and the information presented in the CDA Supplement
(EPA, 1994, p. 4), it seems the 50th and 75th percentile changes are well in excess of the
typical daily change for these subjects.
It is possible that those who respond the most to SO2 also have the largest circadian
changes, thus the circadian changes of the 50th or 75th percentile responders may not be
captured by the average circadian changes used for the group. To provide some insight into
this question, the circadian changes for those subjects common to both the field study and the
chamber studies were compared to the changes post-SO2 exposure. Fifty-nine percent of the
subjects had FE^ changes attributable to SO2 in excess of their individual circadian change,
while 74% had total changes after SO2 exposure in excess of their circadian change. The
proportions increase substantially (to 74% and 89%, respectively) when only those subjects
showing at least a moderate FEVj response attributable to SO2 were examined. (Of course,
one would expect the proportion to increase. A focus on those subjects responding to SO2
can be considered appropriate because it is arguably more relevant than determining whether
small changes in response to SO2 exceed or do not exceed circadian change).
These findings are limited by the fact that the subset of subjects for whom circadian
information is available is not a representative sample of all of the Linn et al. subjects
(Smith, 1994). Nevertheless, the findings do provide support for the findings of Table 2 that
a large proportion of subjects, especially those responsive to SO2, have changes that exceed
their circadian change.
A related approach to examining the magnitude of lung function changes is to examine
the change in percent predicted lung function (FEVJ. An analysis of the 1987 subjects
revealed that, after exposure to 0.6 ppm SO2 at exercise, the lung function of 54% of the
moderate asthmatic subjects and one quarter of the mild asthmatic subjects was less than 50%
of their predicted FEVj. (After exercise alone, 17% of the moderate asthmatic subjects and
0% of the mild asthmatic subjects experienced predicted FEV1 of less than 50%). Some of
the moderate asthmatic subjects had even more pronounced changes, with the lung function
of 29% of the subjects being less than 40% of their predicted FEVj after SO2 exposure
(versus 8% after exercise alone), and 8% had less than 30% of predicted FEY} (versus 0%
B-10
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at exercise alone). For the moderate asthmatics especially, it should be noted that a number
of subjects began the exposure with a somewhat reduced predicted FEVl (half the moderate
subjects had less than 70% of their predicted lung function prior to exposure, with one
subject having a starting predicted lung function of slightly below 50%).
Symptoms
Table 3 compares the proportion of each subject group at 0.6 ppm reporting symptoms
of moderate severity or worse in response to the chamber exposures to 0.6 ppm SO2 or
exercise alone versus the frequency (the proportion of the weeks2) that subject group
reported symptoms of moderate or greater severity at all other times during the study period
(8-9 weeks). The information on frequency of weeks with symptoms was obtained from
information available on symptoms for the day and week post-exposure for each subject in
the 1987, 1988, and 1990 studies. This information was made available in the form of
maximum symptoms experienced during the day and week post-exposure. Although it would
be even more desirable to specifically determine the number of days with symptoms of a
given severity, the information provided only reports whether the maximum symptom in the
week achieved a certain level. Thus it is impossible to determine the number of days within
the week those symptoms were experienced. Although these subjects are being exposed to
varying concentrations of SO2 at regular times during the 8-9 week experimental period, such
exposure is viewed as being unlikely to confound these reports of typical symptoms, since
Linn et al. (1987) reported that, using some of this data, there was little or no noticeable
effect of SO2 on symptoms in the week post-exposure.
The frequency of symptoms in response to 0.6 ppm SO2 shown in Table 3 indicates
that the lung function changes presented in Table 2 do not go unperceived by the subjects.
As pointed out in the CDA Supplement (p. 27), perceived symptoms resulting from a given
lung function change can vary markedly from subject to subject, thus it is possible to have
symptoms without a large change in lung function. Efowever, by comparing the figures from
2To be precise, the "percentage of weeks with symptoms" (of a given severity) referred to in this section
actually designates the percentage of subject-weeks, i.e., when 32% of the weeks are designated as having maximum
symptoms of moderate or worse, this means that when all the weeks with available data are pooled, 32% of these
subject-weeks have maximum symptoms of moderate or worse. Some subjects have higher individual rates of weeks
with maximum symptoms and some have lower.
B-ll
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Table 3. COMPARISON OF SYMPTOMS POST-EXPOSURE WITH SYMPTOMS
DURING STUDY PERIOD
1990 Moderate
Asthmatic Subjects
Normal Medication
1987 Moderate
Asthmatic Subjects
1988 Mild
Asthmatic Subjects
1987 Mild
Asthmatic Subjects
% of weeks
MAX SYMP =
MOD or worse
32%
40%
17%
12%
% of Subjects
SO2 SYMP =
MOD or worse
62%
33%
40%
13%
% of Subjects
EXC SYMP =
MOD or worse
19%
4%
10%
6%
Table 3 on the incidence of moderate symptoms post-SO2 exposure with the proportion of
subjects in Table 1 experiencing severe lung function changes coupled with moderate
symptoms post-SO2, one can determine that most (but not all) of the subjects are
experiencing the moderate or worse symptoms after SO2 exposure in conjunction with greater
than a 20% decrease in FEVl.
Table 3 shows that the subjects of the 1988 and 1990 studies experienced the highest
prevalence of symptoms after SO2 exposure, with roughly half of the subjects (40 to 62%)
reporting at least moderate symptoms. A proportion of these asthmatic subjects (10 to 19%)
also experienced such symptoms simply from exercise alone. However, these asthmatic
groups did not experience symptoms of this severity with great frequency during the study
period. For 68% of the weeks the moderate asthmatic subjects of the 1990 study reported no
worse than mild symptoms (i.e., approximately 43 or more of the 63 days of the study).
The 1988 mild asthmatic subjects reported no worse than mild symptoms for approximately
83% of the weeks, or approximately 52 or more of the 63 days in this study. Furthermore,
the actual prevalence in terms of days with these symptoms may be substantially lower, since
the number of days with symptoms within any week that these symptoms were reported is
unknown (they may be reported only 1 out of 7 days, for instance).
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In addition, although not shown in Table 3, 19% of the 1990 moderate asthmatic
subjects and 30% of the 1988 mild asthmatic subjects experienced severe symptoms in
response to 0.6 ppm SO2, a response even less likely to be equaled during the study period
(severe symptoms being reported for only 9% of the weeks for the 1990 moderate asthmatic
subjects and only 5% of the weeks for the 1988 mild asthmatic subjects).
In the 1987 studies at slightly lower ventilation (44 L/min), somewhat fewer subjects
(approximately 13 to 33%) reported moderate or worse symptoms. The moderate asthmatic
subjects reported a greater frequency of moderate or worse symptoms (40%) than in the
more recent studies (although this frequency was still considerably less than half the weeks).
The 1987 mild asthmatic subjects had a very low frequency of moderate or worse symptoms
(12% of weeks), although a relatively small percentage of subjects experienced moderate or
worse symptoms in response to SO2 (13%). Very few 1987 subjects (4 to 6%) reported
moderate or worse symptoms after exercise at this ventilation.
It should be pointed out that the data presented above on frequency of symptoms is
unavoidably less precise than the data taken in the clinical setting. Although the Linn et al.
studies did feature daily logging of symptoms (later collated into weekly statistics), a recall
problem still exists. Subjects may rate symptoms higher when queried immediately after
exposure, as they were after SO2 or exercise exposures, than when recalling symptoms over
a full day.
The use of medication may also complicate comparisons of symptoms experienced
during the study period to symptoms during exposure. Some of the moderate asthmatic or
1988 mild asthmatic subjects who used medication may have medicated themselves to
ameliorate symptoms, and thus the symptom rating may tend to be lower than if they had not
used a bronchodilator in addition to their usual medication.
However, a related approach that may provide a separate, rough estimate of the general
prevalence of symptomatic responses also indicates that pronounced symptom responses for
these asthmatic individuals may be infrequent. The Linn et al. subjects kept records of the
occurrence of what they perceived to be asthma attacks. The frequency of these perceived
asthma attacks during the 9-week 1988 and 1990 studies is given in Table 4 below.
As can be seen, a majority of both moderate and mild asthmatic subjects experienced
episodes that they perceived as asthma attacks during the study period, but most of these
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Table 4. FREQUENCY OF ASTHMA ATTACKS DURING STUDY PERIOD (9 WEEKS)
HAD ATTACKS
HAD MORE THAN 1
ATTACK PER WEEK
HAD MORE THAN 5
ATTACKS PER WEEK
1990 Moderate Asthmatics
81%
38%
14%
1988 Mild Asthmatics
65%
15%
0
subjects did not experience attacks as frequently as even once a week. Some moderate
asthmatic subjects did experience 5 or more attacks a week. This comparison could also be
confounded by the use of medication by medication-using asthmatic subjects allowing them to
avert altogether an episode they might otherwise perceive as an asthma attack.
Perception of what constitutes an "asthma attack" would be likely to vaiy considerably
from subject to subject. Whether these asthmatics would rate their response to SO2 as an
asthma attack is also unclear, although at least seme subjects recorded events of very brief
duration as asthma attacks.
Because of these caveats, caution must be exercised, but the available information on
perceived asthma attacks is consistent with the data on symptom frequency. This data
indicates that the symptoms experienced by those subjects experiencing substantial symptoms
after 0.6 ppm SO2 are generally worse than the symptoms they otherwise typically
experience. For most of these adult asthmatic subjects, including many of the more
moderate subjects, asthmatic episodes may be an infrequent experience.
Medication Usage
Table 5 presents the prevalence of medication (bronchodilator) use post-exposure in the
1988 and 1990 studies. For all subjects, medication use included an inhaled bronchodilator
except for one 1990 subject who took the bronchodilator Alupent in tablet rather than inhaled
form. The 1987 moderate and mild groups also had a very few subjects who took
medication while in the chamber. Medication use by the 1987 subjects was not considered
for the assessment of responses in Table 1, but is indicated on spreadsheets in Smith (1994).
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Table 5. USE OF BRONCHODILATORS POST-EXPOSURE
Study
1990 Moderate Asthmatics
1988 Mild Asthmatics
SO2
71%
40%
EXC
29%
10%
Medication use has previously been considered as a fairly severe response to an
exposure to an environmental pollutant. The 1988 arid 1990 Linn et al. studies, in which
subjects were given complete discretion over the decision whether or not they needed
medications, show much higher prevalence of medication use than did previous studies (e.g.,
see Table 8 in EPA, 1986a). Given the discretionary nature of medication use for these two
Linn et al. studies, it would be interesting to determine how frequently these subjects use
bronchodilators in response to other stimuli.
Unfortunately, direct information on medication use is only available for the 1987
study, not the 1988 or 1990 studies. This information indicates that less than one-third of the
1987 mild asthmatic subjects used inhaled bronchodilators at all during the 8 weeks of the
study, and none of them used inhaled bronchodilators as often as once a week. Assessing the
medication use of the moderate asthmatic subjects was more difficult. Occasionally multiple
types of inhaled bronchodilators were used by these subjects in a week, creating ambiguity
over whether these medications were taken together or separately, and hi some instances it
was ambiguous whether inhalation was the means by which a drug was being administered
(e.g., Alupent spray versus Alupent tablets). However, it appears that approximately 85% of
the moderate asthmatic subjects in the 1987 study took inhaled bronchodilators at least once a
week, and slightly less than half of the moderate astlimatic subjects used inhaled
bronchodilators at least five times a week, on average. About one-quarter of the moderate
asthmatic subjects may use inhaled bronchodilators very frequently (apparently greater than
15 times a week).
The large dichotomy in medication use between the mild and moderate asthmatic
subjects is likely a result of the fact that, for this study, classification as being a mild or
moderate asthmatic subject was determined to a large extent on the basis of medication use
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(Hackney et al., 1987), with those subjects not using medications being classified as mild and
those using medication being classified as moderate asthmatic individuals.
Of particular interest would be the medication use patterns of the 1988 mild subjects
who used medication regularly, because the 1988 subjects in general, and a subset of these
medication-using subjects in particular, showed a considerably pronounced response to SO2.
While direct information is not available, 6 of the 9 subjects using medication regularly were
subjects in the 1987 study and had logged their medication use then. Although medication
use may vary over time and season, the available data from the previous year indicated that
4 of these 6 subjects used inhaled bronchodilators approximately once per week on average.
Included in this group of infrequent medication users is one of the five most responsive
subjects of the study. However, two of the five most responsive subjects in the 1988 study
used inhaled bronchodilators approximately 4 and 10 times a week on average during the
1987 study period. The other two responsive medication-using subjects were not part of the
1987 study, so no inferences about their medication use can be drawn. For the 1990 study,
less information is available, but the three subjects in this study who participated in the 1987
study all used bronchodilators with great frequency (approximately 15 or more times per
week).
Medication use by subjects in these studies is of interest for several reasons. Consistent
with the symptoms data, medication use post-exposure clearly shows that subjects are"
perceiving the effects of SO2 to which they are being exposed. Such information on
bronchodilator use also allows the probability of medication use prior to exercise to be
roughly estimated. The available data on medication use suggests that few mild asthmatic
individuals in these studies would have been expected to use a bronchodilator routinely
before exercise. The 1987 asthmatic subjects reported infrequent use of bronchodilators, and
the 1988 mild asthmatic subjects who used medications reported using them to relieve
symptoms or in anticipation of respiratory stress (allergens or irritants), with few citing
exercise specifically as a respiratory stress (Hackney et al., 1988a). Thus, it seems unlikely
that a significant portion of these mild asthmatic individuals would routinely use
bronchodilators prior to exercise in daily life.
Among the moderate asthmatic subjects, some of the 1987 moderate subjects
(approximately 15%) used inhaled bronchodilators only infrequently during the study period
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(<2 times per week on average). A few of these subjects responded markedly to SO2.
However, the large majority of moderate subjects used inhaled bronchodilators more
frequently and about half used bronchodilators 5 or more times per week on average. The
frequency with which these subjects would be expected to premedicate before exercise is
uncertain, but seems likely that a sizeable percentage of these subjects frequently using
bronchodilators would generally use medication prior to any planned, lengthy exercise.
Third, in contrast to the symptoms frequency and asthma attacks results, in which
baseline responses similar to those seen with SO2 are relatively infrequent, a substantial
portion of medication-using asthmatic subjects used inhaled bronchodilators fairly frequently.
This complicates assessment of the severity of medication use post-exposure. While for any
individual subject, taking medication is clearly a more serious response than not taking
medication (e.g., even though the 1990 moderate asthmatic subjects were prone to take
medication post-exercise, more than twice as many took medication after SO2 than after
exercise alone), comparison across subjects is more difficult. Taking an inhaled
bronchodilator may be a fairly atypical action for some subjects, and a fairly routine step for
others. (This is one reason why an index of simply "Severe lung function + Moderate
symptoms" was included in Table 1: comparisons across all the studies can be made without
having to interpret the significance of the medication use data).
In addition, if the subjects that are administering bronchodilators frequently are doing
so in response to environmental stimuli, then the bronchodilator use data suggests that this
subset of asthmatic individuals are experiencing a number of responses that are at least
sufficiently bothersome to motivate them to administer medication. However, the symptoms
and asthma attack data for these subjects in general suggest that significant episodes may be
infrequent. The resolution between these different indicators of typical asthmatic health for
the subjects in these studies remains uncertain.
Diminished Workload
Another indicator traditionally used to judge the effects of a pollutant is the degree to
which subjects in clinical trials have felt compelled to diminish their workload or terminate
exposure to a pollutant. Such changes in activity an; not expressly considered in the criteria
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used to judge the effects of SO2, but have been used to evaluate the effects of other
pollutants such as ozone (Table VII-5 in EPA, 1989).
Despite the fact that clinical exposures to SO2 in these studies are fairly brief (one or
several 10-min periods at exercise), a small number (2-3) of subjects in every subject group
except the 1987 mild asthmatic subjects felt compelled to alter their activity or terminate
exposure. The fraction of subjects diminishing workload or terminating exposure is given
below in Table 6.
Table 6. FRACTION OF SUBJECTS REQUIRING DIMINISHED WORKLOAD OR
TERMINATING EXPOSURE IN RESPONSE TO 0.6 OR 1.0 PPM SO2 EXPOSURE*
1990 Mod Asthmatics
(Norm Meds)
1988 Mild Asthmatics
1987 Mod Asthmatics
1987 Mild Asthmatics
1985 Mild Asthmatics
SO2
9.5%
15%
12.5%
0%
7%
term. exp. by 1.0 ppm
EXC
0
0
0
0
0
m
All results given for 0.6 ppm except the 1985 asthmatic subjects at 1.0 ppm.
In the multiple exposure studies (1987 moderate and 1985 mild asthmatic subjects) at
slightly lower ventilation rates, however, all subjects except 1 (4%) moderate asthmatic
individual were able to complete the first 10-min exposure without reducing workload or
terminating exposure. The percentages given for those two groups indicate the number of
subjects who had to alter activity or terminate exposure during the first, second, or third
exercise period. In general, protocols for these studies were not designed to elicit changes in
workload or termination of exposure, and such changes were probably actively discouraged
by the investigators conducting the studies, since changes in activity and ventilation rate
complicate the assessment of the effects of SO2 at a given ventilation rate.
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Conclusions
Several conclusions can be reached:
1. When responses of asthmatic subjects are assessed relative to the cutpoints
given in Table 8 of the CDA Supplement, a much higher percentage of
subjects exposed to 0.6 to 1.0 ppm SO2 while at moderate exercise
experience responses of moderate or greater severity than while exercising
in clean air alone. .
2. After correction for the effect of exercise, the changes in lung function
due to SO2 in a sizeable subset of asthmatic individuals (at least 25 % for
moderate asthmatic subjects and 50% for mild asthmatic subjects) at
0.6 ppm are considerably larger than the effects of exercise alone. These
changes in response to SO2 are also well in excess of average circadian
change for mild or moderate asthmatic persons as a group. In addition, a
subject-by-subject comparison indicates that for most subjects showing at
least a moderate FEVj response (attributable to SO2 alone), this response
exceeds their average circadian change.
3. The total FEVj decrease after SO2 exposure for the most responsive 25%
of mild and moderate asthmatic subjects equals or exceeds 30%.
4. Calculations of percent predicted FEVl indicate that slightly more than
half of the 1987 moderate asthmatic subjects and one quarter of the 1987
mild asthmatic subjects have an FEVj that is less than 50% of predicted
after 0.6 ppm SO2 exposure. None of the mild asthmatic subjects and a
smaller percentage (17%) of the moderate asthmatic subjects had such a
response after exercise alone, although it ishould be noted that, among
moderate asthmatics, FEVj may be significantly less than predicted even
prior to exposure.
5. Moderate symptoms are much more prevalent after 0.6 ppm SO2 exposure
at exercise than after exercise alone. The prevalence of these symptoms
shows that subjects are perceiving the change in lung function caused by
SO2.
6. During the majority of the weeks for each of the Linn et al. studies,
subjects on average did not experience even one day of moderate
symptoms. One reservation is that medication-using subjects may be
medicating in a manner to diminish their symptomatic response. The
relatively low incidence of reported asthma attacks also suggests that
asthmatic episodes are relatively infrequent for these subjects. However,
data on bronchodilator use suggest that, for at least some moderate
asthmatic subjects, asthmatic episodes may be a routine occurrence. This
possible contradiction is currently unresolved.
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7. Medication use is more prevalent after 0.6 ppm SO2 exposure than
exercise alone, for both mild and moderate asthmatic subjects. Such
medication use also indicates subjects are perceiving their change in lung
function caused by SO2.
8. For most or all of the mild asthmatic subjects in the Linn et al. studies,
bronchodilator use prior to exercise appears to be rare. For the moderate
asthmatic subjects, approximately three-quarters took inhaled
bronchodilators at least once a week, and one-half took bronchodilators at
least 5 times a week, with some subjects taking bronchodilators
considerably more frequently. Thus many of the moderate asthmatic
individuals might be likely to medicate prior to engaging in planned
exercise.
9. Some subjects are unable to maintain their assigned workload, even
during a 10-min exposure to 0.6 ppm SO2.
In summary, it appears that SO2 concentrations of 0.6 ppm or greater cause lung
function changes in a substantial proportion of subjects which exceed their typical circadian
variation or response to moderate exercise. A greater proportion of subjects also reported
symptoms (moderate or worse) in response to 0.6 ppm SO2 than from exercise alone, and,
for many of these subjects, these SO2-induced symptoms may exceed the symptoms that they
routinely experience. More subjects also took bronchodilators after SO2 exposure than after
exercise alone; however, some moderate asthmatic subjects may routinely administer
bronchodilators. Finally, in several of the studies, some subjects diminished workload or
terminated exposure in response to exercise plus SO2 but not in response to exercise alone.
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REFERENCES
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Oxides. Environmental Criteria and Assessment Office. Research Triangle Park, N.C. EPA-600/8-82-
029. Available from NTIS, Springfield, VA; PB 54-156801/REB.
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and Sulfur Oxides (1982: Assessment of Newly Available Health Effects Information. Environmental
Criteria and Assessment Office, Office of Research and Development, Research Triangle Park, N.C.
EPA-600/8-86-020F.
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Hackney, J.D.; Linn, W.S.; Avol, E.L. (1987) Replicated dose-response study of sulfur dioxide effects in
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Hackney, J.D.; Linn, W.S.; Avol, E.L. (1988a) Effect of metaproterenol sulfate on asthmatics' response to
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Research Institute; research project 1225-2.
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Linn, W.S.; Shamoo, D.A.; Peng, R.C.; Clark, K.W.; Avol. E.L.; Hackney, J.D. (1990) Responses to sulfur
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Linn, W. S. (1991) Short-term patterns of activity and respiratory status in adult asthmatics: their relationship to
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