«  EPA
                   United States
                   Environmental Protection
                   Agerfcy       	
                 Office of Health and
                 Environmental Assessment
                 Washington, DC 20460
                   Research and Development
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
 600FP93002

March 1994
External Review Draft
Review
Draft
(Do Not Cite
or Quote)
                                 NOTICE
                  This document is a preliminary draft. It has not been formally
                  released by EPA and should not at this stage be construed to
                  represent Agency policy. It is being circulated for comment on
                  its technical accuracy and policy implications.

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DRAFT-DO NOT QUOTE OR CITE                                  EPA/600/AP-93/OOS!
                                                                  March 199*
                                                           External Review Draft
        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
                                   NOTICE
                  This document is a preliminary draft. It has not been formally
                  released by EPA and should not at this stage be construed to
                  represent Agency policy. It is being circulated for comment on
                  its technical accuracy and policy implications.
                    Environmental Criteria and Assessment Office
                    Office of Health and Environmental Assessment
                        Office of Research and Development
                       U.S. Environmental Protection Agency
                        Research Triangle Park, NC 27711

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                                 DISCLAIMER

     This document is an external draft for review purposes only and does not constitute
U.S. Environmental Protection Agency policy.  Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
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                                 LIST OF TABLES
Number                                                                    Page

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	       15

3         Comparison of Specific Airway Resistance and Forced
          Expiratory Volume in One Second Responses to Air and Sulfur
          Dioxide Exposure in Asthmatics 	       19

4         Estimates of Sulfur Dioxide Responses in Asthmatic
          Subjects  	       22

5         Comparative Responses of Asthmatic Subjects to Cold/Dry Air
          and Exercise:   Forced Expiratory Volume in One Second and
          Specific Airway Resistance	       26

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	       32

7         Medication Use After Sulfur Dioxide Exposure   	       37

8         Cooperative Indices of Severity of Respiratory Effects:
          Symptoms, Spirometry, and Resistance  	       42

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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                                LIST OF FIGURES
Number                                                                  Page

1        Distribution of individual airway sensitivity to sulfur dioxide ....       14

2        Specific airway resistance of 16 mild and 24 moderate asthmatic
         subjects exposed to 0.0, 0.4, and 0.6 ppm sulfur dioxide  	       20

3        Forced expiratory volume in one second responses to
         sulfur dioxide exposure in medication-dependent asthmatic
         subjects	       22
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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.
March 1994
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                                   REVIEWERS


     A preliminary draft version of the present 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 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 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
March 1994
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                               REVIEWERS (cont'd)


     In addition to the review of the early preliminary draft by the above individuals, an

External Review Draft of this Supplement was circulated by EPA for public comment and

peer-review by the Clean Air Scientific Advisory Committee (CASAC).  Revisions were then

incorporated into the present draft version of the Supplement in response to public comments

and recommendations made by the following CASAC members and Consultants at a public
review meeting held August 19, 1993 in Durham, NC.
                               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. Jean Ford
Harlem Hospital Center
Prevention Center
NNR-Room 524
506 Lenox Avenue
New York, NY 10037

Dr. Benjamin Y. H. Liu
University of Minnesota
125 Mechanical Engineering
111 Church Street, S.E.
Minneapolis, MN 55455-0111

Dr. Joe L. Mauderly
Inhalation Toxicology Research Inst.
Lovelance Biomedical and Env.
  Research Institute
P.O. Box 5890
Albuquerque, NM  87185
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
School for Public Health
Room 6010
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 Gustav L. Levy Place
Box 1232
New York, NY  10029
March 1994
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SAB Staff Personnel

Mr. Randall C. Bond
U.S. EPA
Science Advisory Board (A-101)
401 M. Street, SW
Washington, DC  20460
202/260-8414
FAX: 202/260-1889

Ms. Janice Jones
U.S. EPA
Science Advisory Board (A-101)
401 M. Street, SW
Washington, DC  20460
202/260-8414
FAX: 202/260-1889
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                                    ABSTRACT

     The present Supplement to the Second Addendum (1986) to the document Air Quality
Criteria for Paniculate 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 < 1-h SO2 NAAQS.
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 i      SUPPLEMENT TO THE SECOND ADDENDUM (1986)
 2       TO AIR QUALITY CRITERIA FOR PARTICIPATE
 3               MATTER AND SULFUR OXIDES (1982):
 4            Assessment of New Findings on Sulfur Dioxide
 5       Acute  Exposure Health Effects in Asthmatic  Individuals
 6
 7
 8    1.0   INTRODUCTION
 9         The United States Clean Air Act and its Amendments (1977, 1990)  mandate that the
10    U.S. Environmental Protection Agency (U.S. EPA) periodically review criteria for National
1 1    Ambient Air Quality Standards (NAAQS) and revise such standards as appropriate. Earlier
12    periodic review of the scientific bases underlying the NAAQS for paniculate matter (PM)
13    and sulfur oxides (SOX) culminated in the 1982 publication of the U.S. EPA document Air
14    Quality Criteria for Paniculate Matter and Sulfur Oxides (U.S. EPA, 1982a), an associated
15    PM staff paper (U.S. EPA, 1982b) that examined implications of the revised criteria for
16    review of the PM NAAQS, an addendum to the criteria document assessing further
17    information on health effects (U.S. EPA, 1982c), and another staff paper relating the revised
18    scientific criteria to the review of the SOX NAAQS (U.S. EPA,  1982d).  Based on the
19    criteria document, addendum, and staff papers, revised 24-h and annual-average standards for
20    PM were proposed (Federal Register, 1984a) and public comments on the proposed revisions
21    received both in written form and orally at public  hearings (Federal Register, 1984b).
22    Subsequently, a Second Addendum to the 1982 PM/SOX Criteria Document was prepared and
23    published in 1986.  The Second Addendum (U.S.  EPA, 1986) included evaluation of
24    numerous new studies that had become available since completion of the  earlier PM/SOX
25    criteria document, its addendum,  and a _.jciated staff papers (U.S. EPA,  1982a,b,c,d),
26    emphasizing assessment of those key new studies likely to have important bearing on
27    development of criteria to support decisionmaking on PM or SOX NAAQS revisions.
28         The evaluations contained in the foregoing criteria document, addenda, and staff papers
29    ultimately provided the scientific  bases for establishment (Federal Register,  1987) of new
30    24-h and annual average PM NAAQS. More specifically, new PM standards were set at
31    150 /ig/m  (24 h) and 50 /ig/m3 (annual) for paniculate matter less than 10 pm aerometric
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 1     diameter (PM10). In addition, U.S. EPA published a proposal (Federal Register, 1988) to
 2     retain the current primary NAAQS for sulfur dioxide (SO2) (i.e., 365 ng/m3 [24 h] and
 3     80 /ig/m  [annual]) along with a call for public comment on possibly adding an even shorter
 4     term (1-h) SO2 NAAQS to protect against health effects in asthmatic individuals associated
 5     with very acute exposures to SO2.  The most crucial information supporting consideration of
 6     possible setting of an acute exposure standard cited by the 1988 proposal were recent
 7     findings from controlled human exposure studies concerning:  (1) exposure-response
 8     relationships for SO2-induced bronchoconstriction and respiratory symptoms in asthmatic
 9     subjects; (2) the severity of such effects, which might vary in intensity as a function of the
10     preexisting disease severity  (mild to severe asthma); and (3) other factors (e.g., medication
1 1     use) that might alter such SO2-induced responses.
12          Since the Second Addendum (1986) was completed, several new controlled human
13     exposure studies have become available that further evaluate acute (< 1-h) SO2 exposure
14     effects on asthmatic individuals and provide pertinent additional information useful in
15     supporting U.S. EPA decisionmaking on whether a new short-term SO2 NAAQS is needed
16     and, if so, the appropriate form and level of such a standard.  Accordingly, the present
17     supplement: (1) incorporates by reference  and  summarizes the most important key findings
18     from the above previous criteria reviews (U.S.  EPA, 1982a,c, 1986) as they pertain to
19     derivation of health-related criteria for a possible new "acute exposure" (< 1-h) primary
20     SO2 NAAQS;  and (2) provides an updated  assessment of newly available information of
21     potential importance for derivation of health criteria for any such new short-term SO2
22     standard.
23          This document is intended to be considered in conjunction with the extensive 1982
24     Criteria Document (U.S. EPA, 1982a) and its earlier Addenda (U.S. EPA, 1982c, 1986).
25     Much background material was presented in these ~revious documents and is not repeated in
26     this supplement; the reader  is therefore encouraged to read  such background material to
27     become more fully informed.  The material presented here focuses mainly on the assessment
28     of selected new information regarding controlled exposure of asthmatic subjects to SO^
29     along with concise summarization and discussion of certain information on the "natural
30     history" of asthma in  order to place the SO2 effects in context in relation to variations in
31     respiratory responses  otherwise often experienced by asthmatic subjects.

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 1     2.0   BACKGROUND INFORMATION ON ASTHMA
 2          The information discussed below on the health effects of SO2 in asthmatic individuals is
 3     derived from controlled human exposure studies which are often used to study the effects of
 4     single (or multiple) inhaled pollutants such as SO2.  Such studies may be performed in
 5     environmental chambers where the subjects are free to breathe as they would in the ambient
 6     environment or studies may be conducted using mouthpiece or facemask systems where the
 7     subjects are required to breathe through the mouthpiece or facemask. In addition to the
 8     concentration of SO2, these studies also permit accurate determination  of the duration of
 9     exposure and the volume of inspired air containing SO2.  Other factors  such as exercise and
10     air temperature and humidity, which can alter responses, can also be controlled.
11          Exercise alone may have some important confounding effects, particularly in the case of
12     exercise-induced bronchoconstriction in asthmatic individuals, which can be indexed by
13     significant decrements in spirometric variables or increments in  airway resistance.  Exercise-
14     induced bronchoconstriction is followed by a refractory period of several hours during which
15     asthmatic individuals are less  susceptible to bronchoconstriction  (Edmunds et al.,  1978).
16     This period of refractoriness can alter the subject's responsiveness to SO2 or other inhaled
17     substances.  The major external determinants of the exposure "dose" of a pollutant are the
18     concentration of pollutant, the duration of the exposure, and the volume of air breathed
19     (specifically,  the route, depth, and frequency of breathing) during the exposure.  Further
20     information is necessary to determine the actual  dose delivered to  the various "target" regions
21     of the respiratory tract (i.e., total respiratory uptake) and is not  discussed in this document.
22          In controlled human exposure studies, the methods used for assessment of respiratory
23     effects primarily involve "noninvasive" procedures.  Lung function tests such as spirometric
24     measures of lung volumes, measures of resistance of lung or nasal airways, ventilation
25     volume (volume of air inhaled into the lung), breathing pattern  "-equency and depth of
26     breathing), and numerous other "breathing" tests have been utilized (Bouhuys, 1974). These
27     tests provide  useful information about some of the basic physiological functions of the lung.
28     Dynamic spirometry tests (forced expiratory tests such as forced expiratory volume in 1 s
29     [FEVj], maximal and partial flow-volume curves, peak flow measurements, etc.) and specific
30     airway resistance/conductance measurements  (SR,^, SGaw) provide information primarily
31     about large airway function.  These "standard pulmonary function" tests are relatively simple

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 1     to administer, provide a good overall index of lung function, and have a relatively low
 2     coefficient of variation (CV).  For ¥EV1, the CV is about 3%  and for SRaw, the CV is about
 3     10 to 20% for normal healthy subjects.
 4          Measurements of spirometry (FEV^ etc.) and peak flow  are also commonly used in
 5     clinical practice to assess lung function, especially in patients with respiratory disease such as
 6     asthma. Measurements of airway resistance with a body plethysmograph may be used in
 7     clinical evaluations but, because of the cost, complexity, and size of the equipment required,
 8     they are more often conducted in research laboratories or major medical centers.  The
 9     coefficient of variation for SRaw measurements tends to be somewhat higher in patients with
10     lung disease than in healthy individuals  (Skoogh,  1973; Pelzer and Thompson, 1966). Both
11     asthmatic and healthy patients experience a  circadian variation  in lung function, with the
12     poorest function (i.e., lowest FEVj and highest SRaw) being experienced in the early
13     morning hours (4 to 6 AM) and the best function (i.e., highest FEVj and lowest SR^)
14     occurring in the mid-afternoon (2 to 4 PM). The oscillations can vary by +5 to 10% about
15     the daily mean in asthmatic  subjects (this means that FEVi could be as  much as 20%  higher
16     at mid-afternoon as opposed to early morning although the typical range is about 10%), but
17     are typically smaller in healthy subjects. Similar variations in  SR^ may result in  SR^,
18     being about 40% higher in early morning than at mid-afternoon in asthmatic subjects
19     (Smolensky etal.,  1986).
20          Circadian variations in lung function in asthmatic individuals have been reviewed by
21     Smolensky et al. (1986).  They discuss that the chronobiology  of asthma is, in part,
22     associated with other body rhythms having a circadian periodicity, such as  cortisol,
23     catecholamines, vagal tone,  etc.  Daily variability in lung function measurements is a typical
24     feature of asthma and has been used as an indicator of airway  hyperresponsiveness (Higgins
25     et al., 1992).  For a group of subjects selected because they had ever experienced  wheezing,
26     the 90th percentile for variability in peak flow (expressed as the [lowest PEF  - highest PEF]
27     -r mean PEF) was 17.6%.  The mean amplitude of variability for those who had wheezed in
28     the past week was 10%.
29
30
31

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 1     2.1   DEFINITION AND INCIDENCE OF ASTHMA
 2          The Expert Panel Report from the National Asthma Education Program of the National
 3     Heart Lung and Blood Institute (NIH, 1991) has recently defined asthma as:
 4
 5     Asthma is a lung disease with the following characteristics: (1) airway obstruction that is
 6     reversible  (but not completely so in some patients) either spontaneously or with treatment,
 1     (2) airway inflammation, and (3) increased airway responsiveness to a variety of stimuli.
 8
 9          About  10 million people or 4% of the population of the United States are estimated to
10     have asthma (NIH,  1991).  The prevalence is higher among African Americans, older (8- to
11     11-year-old) children, and urban residents (Schwartz et al.,  1990). The true prevalence of
12     asthma may  be somewhat higher than determined by epidemiologic surveys since some
13     individuals with mild asthma who have never been treated by a physician may be unaware of
14     the fact that  they have asthma (Voy, 1984). Depending upon the definition of asthma, some
15     estimates of  prevalence may be as high as 7 to 10% of the U.S. population (Evans et al.,
16     1987).
17          There is a broad range of severity of asthma ranging from mild to severe (see Table 1,
18     reproduced from NIH, 1991). Common symptoms include cough, wheezing,  shortness of
19     breath, chest tightness, and sputum production.  A positive response (skin test) to common
20     inhalant allergens and an increased serum immunoglobulin E are common features of asthma.
21     However,  not all asthmatic individuals have allergies (although estimates range as high as
22     80%) and a  large number of healthy individuals who have allergies (approximately 30 to
23     40% of healthy individuals) do not develop asthma (Weiss and Speizer, 1993). Asthma is
24     characterized by an exaggerated bronchoconstrictor response to many physical challenges
25     (e.g., cold or dry air; exercise) and chemical and pharmacologic agents (e.g., histamine or
 1     methacholine).  Notably, however, bronchial hyperresponsiveness is not synonymous WiOi
 2     asthma (Weiss and Speizer,  1993).  Asthma is typically associated with airway inflammation
 3     and epithelial injury (NIH, 1991; Beasley et al., 1989; Laitinen et al., 1985; Wardlaw et al.,
 4     1988).  Based on laboratory findings (Deal et al., 1980) asthma symptoms are expected to be
 5     exacerbated  by cold dry weather, although such an effect of ambient cold on asthma
 6     morbidity  has not been clearly demonstrated.  Approximately 50% of childhood asthmatic


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       TABLE 1.   CLASSIFICATION  OF ASTHMA BY SEVERITY OF DISEASE3
Characteristics
                                Mild
                                                           Moderate
                                                                                                  Severe
A. Pretreatment
Frequency of
exacerbations
Frequency of
symptoms

Degree of exercise
tolerance
Frequency of
nocturnal asthma

School or work
attendance
Pulmonary function
• Peak Expiratory
  Flow Rate (PEFR)
• Spirometry
                     Exacerbations of cough and
                     wheezing no more often than
                     1-2 times/week.
                     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.
 1 Methacholine
  sensitivity
                     PEFR > 80% predicted.
                     Variability1" <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 PC2Q
                     > 20 mg/mL.c
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.
Cough and low grade wheezing
between acute exacerbations often
present.
Exercise tolerance diminished.
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.
Symptoms of nocturnal asthma
present 2-3 times/week.

School or work attendance may be
affected.
PEFR 60-80% predicted.
Variability 20-30%.
Signs of airway obstruction on
spirometry are evident.  Flow
volume curve shows reduced
expiratory flow at low lung
volumes. Lung volumes often
increased. Usually a >15%
response to acute aerosol
bronchodilator administration.
Methacholine PCjo between 2 and
20 mg/mL.
Considerable, almost nightly sleep interruption
due to asthma. Chest tight in early morning.

Poor school or work attendance.
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 PC2Q < 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
 into 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.
CAlthough the degree of methacholine/histamine sensitivity generally correlates with severity of symptoms and medication requirements,
 there are exceptions.

Source:  National Institutes of Health (1991).
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 1     individuals later experience remission of their disease as adults, although, an early age of
 2     onset and the presence of atopy make this less likely (Weiss and Speizer, 1993).
 3          In a group of child and adolescent moderate asthmatics studied over a period of 22 mo
 4     (Van Essen-Zandvliet et al., 1992), approximately half of those on beta-agonist therapy alone
 5     experienced one or more exacerbations of their asthma requiring treatment with prednisolone.
 6     The incidence of exacerbations was much less (about 15%) for those on a combined regimen
 7     of inhaled corticosteroids and beta-agonist.  Weitzman et al. (1992) reported that 10% of a
 8     national sample of children (< 18 years) with asthma (U.S. National Health Interview
 9     Survey, 1988; total n =  17,100; asthmatic n = 735) were hospitalized within the past year.
10     Based on  a total of 450,000 hospitalizations for asthma and an estimated U.S. population of
11     10,000,000 asthmatics, the incidence of hospitalization for all asthmatic subjects is about
12     45 per 1,000 asthmatics (NIH, 1991).  Attendance at hospital emergency rooms for asthma in
13     Vancouver, Canada,  averaged 350 per 100,000 population (or 350 per 4,000 asthmatics
14     based on an estimated prevalence of 4%) and accounted for 1.2% of all emergency room
15     visits.
16          For  asthmatic individuals who experienced an asthma attack causing them to seek
17     treatment  by a physician, the rate of hospitalization based on the National Asthma Attack
18     Audit in the United Kingdom (1991 to 1992) was 12% (Neville et al., 1993).  Asthma attack
19     rates in general practice in the United Kingdom suggest an incidence of asthma attacks
20     (requiring medical intervention) of < I/asthmatic patient-year (Ayres,  1986).  Although
21     asthma attacks occurred throughout the year, there was a tendency for the highest rates to
22     follow the seasonal elevation of grass pollen.  Schwartz et al. (1993) found fall and spring
23     peaks for  hospital admissions for asthma in Seattle.  However, rates did not differ for
24     summer and winter, as also shown by Bates and Siszto (1986) in Ontario, Canada.  Based on
25     the Los Angeles asthma panel data (EPRI,  1988), only 15% of mild asthmatics see a
26     physician  annually for their asthma compared to about 67% of the moderate asthmatics.  The
27     United Kingdom national asthma attack audit reported an attack rate of 14 per 1,000 patients
28     (or 14 per 40 asthmatics), suggesting an attack rate of < 1 asthmatic patient/year (Nevill
29     et al., 1993).  A similar attack incidence was estimated by Van Essen-Zandvliet et al. (1992)
30     and  Lebowitz et al. (1985) for U.S. asthma patients.
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 1           Schoettlin and Landau (1961) reported an asthma attack frequency among a group of
 2     asthmatic patients currently under a physician's care for asthma.  The daily asthma attack
 3     rate was 25 % of all person-days.  However, 95 % of all attacks were classified as mild, and
 4     40 of 137 patients had fewer than 4 attacks in 14 weeks.  Only 4% of all attacks were
 5     attributed to exertion.  Zeidberg et al. (1961) also reported that, for 85 asthmatic patients
 6     followed for  43  days, the mean asthma attack rate was 0.133 per patient day or an average of
 7     just less than once a week.
 8           Death due  to asthma is a rare event; about two to four deaths annually occur per
 9     1,000,000 population or about one per 10,000 asthmatic individuals.  Mortality rates are
10     higher among males and  are at least 100% higher among nonwhites.  Indeed, in two large
11     urban centers (New York and  Chicago) mortality rates from asthma among nonwhites may
12     exceed the city average by up  to five-fold and exceed the  national average by an even larger
13     factor (Sly, 1988; Evans  et al., 1987; Nffl, 1991; Weiss and Wagener,  1990;  Carr et al.,
14     1992).  For example the  mortality rate from asthma in the neighborhood of East Harlem in
15     Manhattan (49 per million population) was approximately  10-fold greater than the national
16     average.
17           The economic impact of  asthma is substantial. McFadden (1988) estimates that asthma
18     results in 27  million patient visits, 134,000 hospital admissions, 6 million lost work days,
19     and 90 million days of restricted activity.  In 1975, a cost of $292 million was estimated for
20     medication alone.  In 1987, there were 450,000 hospital admissions for asthma, a rate of
21     approximately 45 per 1,000 asthmatics (Nffl, 1991).
22           Asthmatic  persons who participate in controlled human exposure studies typically have
23     mild allergic asthma. In many cases, these individuals can go without medication altogether
24     or can discontinue medication  for brief periods of time if  exposures are conducted outside
25     their normal  allergy season. The most common participants are young adult white male and
26     female college and high school students.  Black and Hispanic adolescents and young adults
27     have not been studied systematically.  The extent to which groups of asthmatic individuals
28     who participate  in controlled exposure studies reflect the characteristics  of the asthmatic
29     population at large is not known.  Subjects who participate in controlled exposure studies are
30     generally self-selected and this could conceivably introduce some bias.  However, the high
31     degree of consistency among studies suggests that the subjects are generally representative of

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 1     the population at risk or that any selection bias is consistently present across a diverse group
 2     of laboratories.
 3
 4     2.2   MEDICATION USE BY ASTHMATIC INDIVIDUALS
 5          The extent to which asthmatic individuals, especially the mild asymptomatic individuals
 6     who constitute the majority of asthmatics and who often serve as subjects in these studies,
 7     may use prophylactic medication prior to exercising outdoors is unknown.  Most mild
 8     asthmatic persons only use medication when symptoms arise.  National Heart Lung and
 9     Blood Institute guidelines (NIH, 1991) for treatment of chronic mild asthma recommend use
10     of beta-agonists on an as needed (prn) basis.  The results of an analysis of activity patterns,
11     symptoms, and medication use of a panel of 52 asthmatic subjects in Los Angeles are in
12     accord with these recommendations (Roth et al., 1988).  One third of the mild asthmatic
13     patients studied had not used any asthma medication within the past year, and fewer than half
14     used an inhaled bronchodilator at least once during the past year.  Furthermore, only 20%  of
15     the moderate asthmatic patients studied used an inhaled bronchodilator on a regular basis.
16     Thus the frequency of use of beta-agonist bronchodilator medication varies widely among
17     asthmatic individuals and is related, at least in part, to the severity of their disease. For
18     example, in a rural community in Australia, Marks et al. (1992) reported that 12% of the
19     asthmatic residents had never used a beta-agonist and that only 38% had used a beta-agonist
20     at least once in the preceding week.  Thus, for more than half the asthmatic individuals in
21     the community, beta-agonist use was infrequent and would be unlikely to be used in temporal
22     proximity to an environmental exposure. Furthermore, NIH guidelines recommend
23     additional treatment if beta agonists are used on a daily basis.
24          Medication compliance for those on a regular medication regime varies considerably
25     among asthmatic patients (from none to full compliance). Average compliance figures range
26     from approximately 50 to 70% (Weinstein  and Cuskey,  1985; Partridge, 1992; Smith et al.,
27     1984; Smith et al., 1986).  Given the infrequent use of medication by many mild asthmatic
28     individuals and the poor medication compliance of 30%  to 50% of the "regularly medicated"
29     asthmatic patients, a substantial proportion of asthmatic subjects would not likely be
30     "protected"  by medication use from impacts of environmental factors on their respiratory
31     health.

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 1     3.0   SUMMARY OF PREVIOUS FINDINGS ON SO2 EFFECTS
 2          Key controlled human exposure studies of SO2 respiratory effects published in the
 3     scientific literature from 1982 to 1986, as reviewed in the Second Addendum (U.S. EPA,
 4     1986), are summarized in Appendix Table A-l.  Those studies were found to support and
 5     extend many of the conclusions reached in the earlier PM/SOX Criteria Document (U.S.
 6     EPA, 1982) and its previous Addendum (U.S. EPA, 1982c).
 7          More specifically, the additional studies evaluated in U.S. EPA (1986) clearly showed
 8     that asthmatic subjects are much more sensitive to SO2 as a group than are nonasthmatic
 9     individuals.  Nevertheless,  it was clear that a broad range of sensitivity to S^ existed among
10     asthmatic subjects exposed under similar conditions. Those studies  also confirmed that
11     normal healthy subjects, even with moderate to heavy  exercise, do not experience effects on
12     pulmonary function due to  SO2 exposure in the range of 0 to 2 ppm.  The minor exception
13     may be the annoyance of the unpleasant smell or taste associated with SO2.  The suggestion
14     that asthmatic individuals are about an order of magnitude more sensitive than healthy,
15     nonasthmatic persons was thus confirmed.
16          The studies reviewed in the Second Addendum (U.S. EPA, 1986) further substantiated
17     that normally breathing asthmatic individuals performing moderate to heavy exercise will
18     experience SO2-induced bronchoconstriction when breathing SO2 for at least 5 min at
19     concentrations less than 1 ppm.  Durations beyond 10 min do not appear to cause substantial
20     worsening of the effect.  The lowest concentration at which bronchoconstriction is clearly
21     worsened by SO2 breathing depends on a variety of factors.
22          Exposures to less than 0.25 ppm were  found not to evoke group mean changes in
23     responses.  Although some individuals may appear to respond to SO2  concentrations less than
24     0.25 ppm, the frequency of these responses  was not demonstrably greater than with clean air.
25          The Second Addendum (U.S. EPA, 1986)  also noted that, in the SO2 concentration
26     range from 0.2  to 0.3 ppm, six chamber exposure studies were performed with asthmatic
27     subjects performing  moderate to heavy exercise. The evidence that SO2-induced
28     bronchoconstriction  occurred at such concentrations with natural breathing under a range of
29     ambient conditions was equivocal.  Only with oral mouthpiece breathing of dry air
30     (an unusual breathing mode under exceptional ambient conditions) were small effects
31     observed on a test of questionable quantitative relevance for criteria development purposes.

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 1     These findings are in accord with the observation that the most reactive subject in the
 2     Horstman et al. (1986) study had a PCSO2 (SO2 concentration required to double SR,,W) of
 3     0.28 ppm.
 4           The Second Addendum (U.S. EPA, 1986), however, went on to note that several
 5     observations of significant group mean changes in specific airway resistance (SRgW) had then
 6     recently been reported for asthmatic subjects exposed to 0.4 to 0.6 ppm SO2.  Most, if not
 7     all of the studies, using moderate to heavy exercise levels (>40 to 50 L/min), found
 8     evidence of bronchoconstriction at 0.5 ppm.  At a lower exercise rate, other studies (e.g.,
 9     Schachter et al., 1984) did not produce clear evidence of SO2-induced bronchoconstriction at
10     0.5 ppm SO2. Exposures that included higher ventilations, mouthpiece breathing, and
11     inspired air with a low water content resulted in the greatest responses.  Mean responses
12     ranged from 45% (Roger et  al.,  1985) to 280% (Bethel et al., 1983b) increases in SRaw.
13     At concentrations in the range of 0.6 to  1.0 ppm, marked increases in SRaw were observed
14     following exposure, and recovery was generally complete within approximately 1 h, although
15     the recovery period may  be somewhat longer for subjects with the most severe responses.
16           It is now evident that for SO2-induced bronchoconstriction to occur in asthmatic
17     individuals at concentrations less than 0.75 ppm, the exposure must be accompanied by
18     hyperpnea  (deep and rapid breathing). Ventilations in the range of 40 to 60 L/min have been
19     most effective; but such ventilations are  beyond the usual transition between nasal only and
20     oronasal ventilation. Oral breathing (especially via mouthpiece) clearly caused exacerbation
21     of SO2-induced bronchoconstriction.  New studies reviewed in the Second Addendum (U.S.
22     EPA, 1986) reinforced the concept that the mode of breathing is an important determinant of
23     the intensity of SO2-induced bronchoconstriction in the following order:   oral  >  oronasal >
24     nasal. A second exacerbating factor implicated in the then-reviewed  new reports was the
25     breat'^ng of dry and/or cold air.  It was not clearly established whether exacerbation of
26     SO2 effects was due to airway cooling, airway drying, or some other mechanism.
27           The new studies reviewed in the Second Addendum (U.S. EPA, 1986), unfortunately,
28     did not provide sufficient additional information to establish whether  the intensity of the
29     SO2-induced bronchoconstriction depended upon the severity of the disease.  The studies
30     available at that time more specifically indicated that, across a broad  clinical range from
31     "normal" to "moderate" asthmatic subjects, there clearly existed a relationship between the

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 1     presence of asthma and sensitivity to SO2.  However, within the asthmatic population, the
 2     relationship of SO2 sensitivity to the qualitative clinical severity of asthma had not been
 3     systematically studied.  It was noted that ethical considerations (i.e., continuation of
 4     appropriate medical treatment) generally prevent the unmedicated exposure of "severe"
 5     asthmatic individuals because of their dependence upon drugs for control of their asthma.
 6     True determination of sensitivity requires that the interference with SC^ response caused by
 7     such medication be removed.  Because of these mutually exclusive requirements, it was
 8     thought unlikely that the "true" SO2 sensitivity of severe asthmatic individuals could be
 9     determined, although it was noted that more severe asthmatic patients  should be studied if
10     possible.  Alternative methods to those used with mild asthmatic individuals, not critically
11     dependant on regular medication, were noted as being required to assess asthmatic
12     individuals with severity of disease ranging to beyond the "mild to moderate" level (i.e.,
13     moderate to severe asthmatic persons).
14           Studies reviewed in the Second Addendum (U.S. EPA,  1986) also indicated that
15     consecutive SO2 exposures (repeated within 30 min or less) result in a diminished response
16     compared with the initial exposure.  It was apparent that this  refractory  period lasts at least
17     30 min, but that normal reactivity returns within 5 h.  The mechanisms  and time course of
18     this effect were not yet clearly established, but the refractoriness did not appear to be related
19     to an overall decrease in bronchomotor responsiveness.  These observations suggested that
20     the effects of SO2 on airway resistance and spirometry tend to be brief and do not tend to
21     become worse with continued or repeated exposure. Nevertheless, the issue of repeated or
22     chronic exposure to SO2 in asthmatic individuals remained to be more definitively addressed.
23           Overall, then, based on the review of studies included in the  Second Addendum, it was
24     clear that the magnitude of response (typically bronchoconstriction) induced by any given
25     SO2 concentration was highly variable among individual asthmatic subjects.  Exposures to
26     SO2 concentrations of 0.25 ppm or less, which did not induce significant group mean
27     increases in airway resistance, also did not cause symptomatic bronchoconstriction in
28     individual asthmatic subjects.  On the other hand, exposures to 0.40 ppm SO2 or greater
            \
29     (combined with moderate to heavy exercise), which induced significant group mean increases
30     in airway resistance,  did cause substantial bronchoconstriction in some individual asthmatic
31     subjects.  This bronchoconstriction was often associated with wheezing and the perception of

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 1     respiratory distress.  In a few instances it was necessary to discontinue the exposure and
 2     provide medication.  The significance of these observations was that some SO2-sensitive
 3     asthmatic subjects appeared to be at risk of experiencing clinically significant (i.e.,
 4     symptomatic) bronchoconstriction requiring termination of activity and/or medical
 5     intervention when exposed to SO2 concentrations of 0.40 to 0.50 ppm or greater, when such
 6     exposure is accompanied by at least moderate activity.
 7          The Second Addendum (U.S. EPA, 1986), therefore, clearly supported the premise that
 8     asthmatic individuals are substantially more responsive to sulfur dioxide (SO2) exposure than
 9     individuals without airways hyperresponsiveness.  The extensive exposure-response
10     information presented in the Addendum  indicated that exercising asthmatic subjects may
11     respond to brief exposures to SO2 concentrations greater than 0.40 ppm, but little (if any)
12     response is observed with resting exposures at concentrations less than 1.0 ppm SO2.
13     Exposure durations of 5 to 10 min were found to be sufficient to stimulate a near maximal
14     bronchoconstrictive response.  The median concentration, to which a large group of
15     asthmatic subjects responded by  doubling their specific airway resistance (over and above
16     that caused by air exposure and exercise alone), was 0.75 ppm (Horstman et al., 1986) as
17     depicted in Figure 1.  Responses to SO2 are amplified by oral breathing of SO2, by breathing
18     cold dry air in combination with SO2, and by the magnitude of either voluntary or exercise-
19     induced hyperpnea.   However, repeated exposures to SO2 result in a period  of diminished
20     responsiveness, also  called a refractory period.  In addition to SO2-induced changes in
21     respiratory function indicative of bronchoconstriction (namely increased airway resistance and
22     decreased FEVj) there were increased symptoms,  most notably wheezing and a perception of
23     respiratory distress.  A small number of studies noted increased medication usage among
24     SO2-exposed asthmatic subjects,  although no studies were specifically designed to study
25     medication use.  The effects ' f some asthma medications on response to SO2 were also
26     studied.  It was shown that cromolyn sodium inhibited SO2-induced bronchoconstriction
27     (SIB) in a dose-related manner (Myers et al., 1986a).  Also,  albuterol, a /3-sympathomimetic
28     drug, was shown to inhibit the response to SO2  (Koenig et al.,  1987).
29
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          100-1
        I
        
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S TABLE 2. SUMMARY OF KEY NEW STUDY RESULTS FROM CONTROLLED HUMAN EXPOSURE
| STUDIES OF ACUTE SULFUR DIOXIDE EXPOSURE EFFECTS IN ASTHMATIC SUBJECTS
H- S02
^Q Concentration
0.1 ppm










0.0, 0.2, 0.4,
0.6 ppm




d




O

£
3
i
2 0.0, 0.25, 0.5,
Z, 1.0,2.0,
;=! 4.0 ppm
H

C3
0

tn
O
?*3
o
Number of
Duration Subjects
15 min SO2 13 adolescent
after 45 min asthmatic
03 subjects








1 h 85 (24 normals;
21 atopies;
16 mild asthmatic
subjects;
24 moderate/
severe asthmatic
subjects
medication
dependent)







4 min 9 asthmatic
subjects










Exposure Exposure
Mode Status
Oral Intermittent exercise
mouthpiece VE = 30 L/min
22 °C Exposure sequence:
75% RH (1) air followed by
0.1 ppmSO2;
(2) 0.12 ppm 03
followed by
0.12 ppm 03;
(3) 0.12 ppm 03
followed by 0.1 ppm
S02
Chamber Included three
21 °C 10-min periods
50% RH exercise; pulmonary
function tested after
first (10-min) and
third (50-min)
exercises
VE = 40 L/min
Exposure sequence:
each subject exposed
to all SO2
concentrations in
random order at
1-week intervals and
tested twice at each
concentration
Chamber Intermittent exercise
VE = 30 L/min
Exposure for 30 min
to 0.30 ppm NO2 or
clean air followed by
SO2 challenge that
consisted of
successive doubling
of SO% concentration
every 4 min during
isocapnic breathing
at VE = 20 L/min.
Observations
45-min prior exposure to 0.12 ppm 03 modified
response to 15-min exposure to 0.10 ppm SC>2
(FEVj decreased 8%; RT increased 19%;
Vmsx50 decreased 15%). Respiratory symptom
scores (57 for air-SO^ 60 for 03-03; 78 for
03-802) not significantly different.





Normals unresponsive; atopies minimally
responsive; asthmatic subjects developed
meaningful bronchoconstriction and associated
respiratory symptoms. Mild asthmatic subjects
showed slight SRaw response at 0.0 ppm
(exercise effect), which increased progressively
with SO2 concentrations. Moderate/severe
asthmatic subjects reacted more markedly to
exercise at 0.0 ppm but response to increasing
SO2 similar to minimal/mild asthmatic subjects.
FEVj decreased with exercise; decrease greatest
in moderate/severe asthmatic subjects. When
"exercise effect" subtracted out, response to SO2
similar in both mild and moderate/severe
asthmatic subjects.

No significant effects of NO2 on lung function
(single breath nitrogen washout, SR,,W, FVC,
FEVj) or respiratory symptoms. Cone, of SO2
to increase SRaw by 8 units was 1 .25 + 0.70
ppm after air exposure and 1.31 + 0.75 ppm
after NO2.






Comments References
Prior 03 exposure may increase Koenig et al.
bronchial hyperresponsiveness in (1990)
asthmatic subjects such that they
respond to an ordinarily subthreshold
SO2 concentration with pulmonary
function decrements but not
necessarily higher respiratory
symptom rates.



Severity of asthma did not influence Hackney et al.
FEVj response to SO^. Additional (1987),
drop in FEVj caused by SO2 (above Linn et al.
that caused by exercise) similar for (1987)
mild and moderate/severe asthmatic
subjects. Most subjects able to
maintain physical activity near own
normal levels even at 0.6 ppm SO^
Some atopic (i.e., nonasthmatic)
subjects responded to SO2. This
suggests that population at risk may
be larger than just the asthmatic
population.



Preexposure to NO2 did not appear to Rubinstein et al.
increase responsiveness to subsequent (1990)
SO2 exposure at either subthreshold
or superthreshold SOj levels.









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     TABLE 2 (cont'd).  SUMMARY OF KEY NEW STUDY RESULTS  FROM CONTROLLED HUMAN EXPOSURE
                 STUDD1S OF ACUTE SULFUR DIOXIDE EXPOSURE EFFECTS  IN ASTHMATIC SUBJECTS
1— »
VO
SO2
Concentration
0.5, 1.0 ppm
Number of
Duration Subjects
1,3, 8 adult
5 min asthmatic
subjects
Exposure
Mode
Oral
mouthpiece
Tl
Exposure
Status
Eucapnic hyperpnea
VE *> 60 L/min
Observations
Magnitude of bronchoconstrictor
response to SO2 progressively
increased with time. After 1,3, and
5 min with 1 .0 ppm SO2, SRaw
increased 47, 349, and 534%; after 3
and 5 min with 0.5 ppm SOj, SRaw
increased 127 and 188% .
Comments
Seven of eight subjects required
bronchodilator medication after SO2
exposure. Two subjects unable to
complete 5-min exposure to 1 .0 ppm
SO2 because of symptomatic
bronchoconstriction.
References
Balmes et al.
(1987)
0.5 ppm
20 min
0.5, 0.75 ppm   30 min
1.0 ppm
1.0 ppm
              60 min
46 adult
asthmatic
subjects
          14 adult
          mild
          asthmatic
          subjects
          10 young
          adult mild
          asthmatic
          subjects
0.0, 0.5,   12 young
1.0,2.0,   adult
5.0 min    asthmatic
          subjects
   Oral
mouthpiece
  23 °C
 92% RH
               Oral
             mouthpiece
              24.3 °C
             50.5% RH
             Chamber
              26 °C
              70% RH
              Chamber
               20 °C
              40% RH
Isocapnic hyperventilation
 VE = 30 L/min
Exposure sequence:  10 min
followed by 10 min isocapnic
hyperpnea
            VE = 45 L/min. Subjects
            breathed 0.25 ppm NO2 or
            0.5 ppm SO2 at rest followed
            by challenge with 0.75 ppm
            SC>2 during isocapnic
            hyperventilation. Ventilation
            increased in 15-L/min steps.
            each lasting 3 min.

            Intermittent exercise
             VE -  41 L/min
            10-min periods broken by
            15-min rest periods or 30 min
            continuous exercise
            Exercising Vg = 40 L/min
            Exposure sequence: each
            subject  exposed to all exposure
            durations in random order on
            separate days
Exposure to air increased SR,W 45%;
SO2 increased SR,W 131%.
                           No difference in response to SO2
                           challenge when it was proceeded by
                           breathing SO2 at rest. Enhanced
                           airway responsiveness to 0.75 ppm
                           SO2 during hyperventilation following
                           prior 30-min exposure to 0.25 ppm
                           NO2 at rest.
                           SO2 exposure; increase with
                           continuous exercise (233 %)
                           significantly greater than with
                           intermittent exercise (106%).
                           Postexposure SRaw and symptom
                           ratings increased with increased
                           exposure duration in SO2. Stat.
                           significant SO2-induced
                           bronchoconstriction observed at 2.0-
                           and 5.0-min exposures, SRaw
                           increased by 121 % and 307%.
Weak correlation between histamine    Magnussen
and SO2 responses indicates NSBR     et al. (1990)
response to histamine is a poor
predictor of response to SOj. Results
also indicate that large mean change is
driven by larger changes in small
group of subjects.
Prior exposure at rest to SO2          Jorres and
concentration not causing             Magnussen
bronchoconstriction did not alter       (1990)
subsequent magnitude of response to
suprathreshold SO2 exposure; but prior
subthreshold exposure to NO2 did
appear to enhance subsequent
suprathreshold response to SO2.

Asthmatic subjects show an attenuated   Kehrl et al.
response to repetitive exercise in       (1987)
1.0 ppm SO2 atmosphere.
                                Approximately half of subjects         Horstman et al.
                                perceived significant (mod. or severe)   (1988)
                                SO2-induced symptoms after 2- or
                                5-min exposure; 4 of 12 required
                                bronchodilator therapy after exposure.

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 1     4.1   EXPOSURE DURATION/HISTORY AS SULFUR DIOXIDE
 2           DOSE-RESPONSE DETERMINANTS
 3          Previous studies reviewed in the Second Addendum (U.S. EPA,  1986) found that the
 4     bronchoconstrictive response to SO2 has a rapid onset and reaches a peak response within
 5     about 5 to 10 min. Two more recent studies have shown that significant responses can occur
 6     in as little as 2 min.  Horstman et al. (1988) showed, in a group of 12 SO^responsive
 7     asthmatic subjects, that with 2 and 5 min of exercise (VE = 40 L/min) exposure to  1.0 ppm
 8     SO2, SRaW increased by 121 and 307%, respectively (percentages corrected for exercise-
 9     induced responses during exercise in clean air). Balmes et al. (1987)  demonstrated an even
10     more rapid onset of bronchoconstriction in eight asthmatic subjects exposed to 1.0 ppm SO2
11     during eucapnic hyperpnea ( = 60 L/min) by mouthpiece. At 1, 3, and 5 min, they reported
12     SRaW increases of 47, 349, and 534%, respectively.  They also showed significant increases
13     in SRaW after 3 (127%) and 5 (188%) min of exposure to 0.5 ppm SO2. In each  of these
14     two studies, several subjects requested a bronchodilator to alleviate symptoms induced by the
15     exposures; 7 of 8 subjects did so in the Balmes et al. (1987) study, as did 4 of 12 in the
16     Horstman et al. (1988) study.  Additionally, two subjects were unable to complete the 5-min
17     exposures to 1.0 ppm in the Balmes et al. (1987) study.
18          Linn et al.  (1987) concluded that exposure history to SO2 (over the course of several
19     weeks as opposed to hours) was largely irrelevant.  They did, however, observe,  as had
20     Kehrl et al.  (1987), that bronchoconstriction responses to a first exercise period within an
21     hour-long SO2 exposure resulted in a diminished response in the second exercise period.
22     This observation is in support of the concept of a refractory period from repeated SO2
23     exposures accompanied by exercise or hyperpnea.
24          Torres and Magnussen (1990) examined the effect of 30 min of resting ventilation of
25     0.5 ppm SO2 on a subsequent SO2 ventilatory challenge. The SO2 challenge Evolved
26     breathing 0.5 ppm SO2 at progressively increasing levels of isocapnic  hyperpnea.  There was
27     no difference in response to the SO2 challenge when it was preceded by breathing of SO2
28     while at rest.  This is not surprising since breathing of < 1.0 ppm SO2 while at rest does not
29     typically cause changes in lung function or symptoms.
30          Overall, the above new results provide further evidence for the rapid onset of
31     respiratory effects in exercising asthmatics in response to SO2, demonstrating that such

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 1     effects can occur within a few minutes (2 to 5 min) of initiation of SO2 exposure.  The
 2     results also further confirm a refractory period for SO2-induced respiratory effects, following
 3     prior SO2 exposure within the immediately preceding few hours. This means that repeated
 4     SO2 exposures during a short time period do not lead to any greater manifestation of effects
 5     beyond those seen immediately after the first SO2 exposure.  However, other evidence
 6     indicates that much earlier SO2 exposures (days/weeks ago) do not prevent or dampen effects
 7     of subsequent SO2 exposures.
 8
 9     4.2   SULFUR DIOXIDE RESPONSES AND ASTHMA SEVERITY
10          Another question left unresolved by studies evaluated in the 1986 Second Addendum
11     was the  extent to which differential sensitivity might exist among SO2-sensitive asthmatic
12     individuals (with regard to lowest effective SO2  exposure levels evoking significantly
13     enhanced bronchoconstriction and/or respiratory symptoms or the magnitude of such effects
14     observed at a given SO2 exposure level), especially as a function of the severity of the
15     preexisting disease (from mild to severe asthma).  Some newly available studies have
16     attempted to address this difficult issue.
17          Although in most studies of asthmatic individuals exposed to SO2, a change in  specific
18     airway resistance (SR^) has been used as a measure of response, in other studies, a change
19     in FEV! was the response  measure.  In a few studies, data for both response measures have
20     been obtained. In order to provide an estimate of the comparability of the two response
21     measures, the data of Linn et al. (1987, 1990) were used (actual data were obtained  from
22     two project reports [Hackney et al., 1987, 1988b]).  In Table 3, the preexposure and
23     postexposure measurements for FEV^ and SRaw are shown for three different groups of
24     subjects after clean air exposure and after SO2 exposure. Using these data, the comparability
25     of SRj,w and  •1EVl as physiologic measures of response can be estimated.  A 100%  increase
26     in SRaw roughly  corresponds to a 12 to 15% decrease in FEVj and a 200% increase in  SRaw
27     corresponds to a 25 to 30% decrease in FEVj.
28          Hackney et al. (1987) studied both (a) concentration-response relationships of SO2 and
29     lung function,  as well as (b) differences in response between normal, atopic, mild asthmatic
30     individuals and moderate/severe asthmatic individuals.  All groups of subjects were exposed
31     to 0, 0.2, 0.4, and 0.6 ppm SO2.  Each subject was exposed to each level on two different

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            TABLE 3. COMPARISON OF SRAW AND FEVj RESPONSES TO AIR AND
                   SULFUR DIOXIDE EXPOSURE IN ASTHMATIC SUBJECTS
[S02] Pre-FEV!
Linnet al., 1990ft
low
normal
low
normal
Linnetal.. 1987b
mild
moderate
mild
moderate
0.0
0.0
0.6
0.6
0.0
0.0
0.6
0.6
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% FEV!
-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), [SQJ in ppm, FEVj in mL, SRaw in cm H2O-L"1-s-L.
 1     occasions.  These results were also reported in the published Linn et al. (1987) report. The
 2     1-h exposures included three 10-min exercise periods.  This study supported earlier
 3     investigations (Roger et al., 1985), in that the responses (especially of asthmatic subjects at
 4     the highest concentration) tended to be greatest early in exposure (i.e.,  after the first
 5     exercise) and were possibly greater on the first round of exposures than on the second.
 6     When the mild asthmatic subjects were compared with the moderate/severe asthmatic
 7     subjects, the FEV^ decrement caused by exercise was greater in the moderate/severe
 8     asthmatic subjects, and the combined response to exercise and SO2 exposure resulted in a
 9     greater overall decrease in FEV^ However, when the "exercise effect" was subtracted from
10     the overall FEVj response, the response to SO2 was similar in the mild versus the
11     moderate/severe asthmatic subjects.  Thus severity of asthma, as defined operationally in this
12     study (Hackney et al., 1987), did not influence the FEVl  response to SO2.
13          However, this conclusion must be tempered by the fact that the moderate/severe
14     asthmatic subjects started the exposure with compromised function compared to the mild
15     asthmatic subjects.  Thus, it is not clear that similar functional declines beginning from a
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1
2
3
4
5
6
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.
            25
            20
         3
         &
          CM
         DC
         CO
            15
            10
                                           0.6         0.0
                                             SO2(PPM)
                                                                         0.6
      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 SO2 exposure. At 0.6 ppm, after adjustment for SRaw increase due to
                exercise in 0.0 ppm, the percentage change in SRj,w as a result of SO2
                exposure is 124% in mild asthmatic subjects and 128% hi moderate asthmatic
                subjects, expressed as:
                                 SO2 increment
                                  baseline SR.m,
x  100%
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 1          Based on an analysis similar to that of Horstman et al. (1986) (i.e., an analysis of the
 2     median concentration at which the SRaw was doubled, PC100 SR^), Hackney et al.  (1987)
 3     estimated that the median PC100SRaw was greater than 0.6 ppm.  Pooling the data for mild
 4     and moderate/severe asthmatic subjects and using only the first round of exposures,  only
 5     15 of 40 subjects showed a doubling of SR^ at  ^0.60 ppm SO2. Based on Horstman
 6     et al.'s (1986) cumulative frequency plot of PC100SRaw against SO2  concentration,
 7     approximately 35%  of asthmatic subjects would be expected to reach the PC100SRaw at a
 8     concentration of 0.60 ppm. Thus the 37.5% incidence (15/40) observed by Linn et  al.
 9     (1987) is consistent  with Horstman et al.'s observations (see Table 4), despite the fact that
10     Linn et al.'s subject group included asthmatic individuals with more severe disease.  In
11     comparing responses to SO2 among asthmatic subjects of varying severity, the health
12     significance of the observed lung function responses would have been considered to  be
13     greater had these responses persisted for  several  hours or days after exposure or if there had
14     been a persistent change in airway responsiveness.  However, it was concluded in the
15     Hackney et al. (1987) report that there were no persistent functional or symptom effects and
16     that SO2 did not alter airway responsiveness.
17          Linn and coworkers (1990)  examined the effects of different levels of medication in  a
18     group of moderate asthmatic individuals dependent on regular medication for normal lung
19     function. These subjects had a similar response  to 0.6 ppm SC>2 as observed in moderate
20     asthmatic subjects in a previous study (Linn et al.,  1987).  The somewhat greater increase in
21     SRaw (approximately fourfold versus approximately threefold) in the more recent study may
22     be due to the slightly higher exercise ventilation  rate  (about 50 L/min versus 40 L/min).
23     There was a weak correlation of the baseline SRaW with the response to SO2 (r = 0.35) when
24     the subjects from the 1987 and the 1990  studies  were combined.  Nevertheless baseline
25     function may not be a good predictor of response to SO2.  Subjects were exposed to three
26     (normal medications withheld for 48 h for antihistamines, 24 h for oral bronchodilators, and
27     12 h for inhaled bronchodilators), and (3) enhanced medication (an additional dose of
28     metaproterenol [i.e., 0.3 mL of 5% Alupent]).  The responses are illustrated in Figure 3 and
29     Table 3.  When medication was withheld, baseline lung function deteriorated (e.g., FEVj fell
30     about 350 mL).  Exercise  alone caused slightly  less than a 300 mL decrease in FEV1( and
31     0.6 ppm SO2 caused a  significant further decline in FEVj. Although the absolute FEVj was

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           TABLE 4.  ESTIMATES OF SULFUR DIOXIDE RESPONSES
                           IN ASTHMATIC SUBJECTS
                      Asthma*
                  L/min
    Fraction0
PCSO2
Horstman (1986)
Linn (1987)
Magnussen (1990)
Mild
Mild/moderate
Mild/moderate
Chamber 40
Chamber 40
Mouth 30
14/27
15/40
16/45
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.
 PCSO2 is the [SO2] at which SR^ was doubled.
         2,800

         2,
      gj 2,200

      ^2,000
      u_
         1,800

         1,
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). FEVj 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 metaproterenol
          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.
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 1      lower after SO2 exposure in the low medication condition, the decrement caused by SO^ was
 2      similar to that seen in the normal medication state.1  However, with supplementary
 3      metaproterenol, the effect of SO2 was greatly diminished (about 5% lower postexercise FEVj
 4      for the 0.6-ppm SO2 exposure versus air-only exposure under supplementary [high]
 5      metaproterenol conditions).  In comparison to the normal medication baseline,
 6      moderate/severe asthmatic subjects who withheld medication had an overall reduction of
 7      FEVj of about 40% from the combined effects of exercise, SO2 exposure (0.6 ppm), and the
 8      absence of their normal medication.
 9           In comparing asthmatic individuals of different degrees of severity,  the metric used in
10      this comparison can greatly influence the conclusion that is drawn.  It is not clear whether
11      the most appropriate metric is (a) the absolute change in airway resistance or FEVj or (b) the
12      relative change.  Small absolute increases around a low baseline SRaw (usually in a well
13      controlled or milder asthmatic) result in large relative (i.e., percentage) changes in function,
14      whereas a much larger absolute change in function around a higher baseline may result in a
15      smaller relative change in function.  The SR^ data are particularly  subject to this sort of
16      potential bias  because of the larger range of baseline values, which may vary from 2 to
17      8 cm H2O-L"  -s" -L in healthy people or mild asymptomatic asthmatic subjects.
18           The manner in which a percentage  change is calculated can greatly influence the
19      apparent response.  For example, the data of Linn et al. (1990) (see Table 3) for normally
20      medicated subjects gives a percent change in FEVj with clean air exposure of  —12.2% and
21      for 0.6 ppm SO2 of -30.0% (calculated as fpost-pre]  •*- pre  x 100%).   If the response after
22      SO2 exposure is corrected for the effect of exercise in clean air ({2,264  -  [1,584 +
23      (2,270 - 1,992)]  -=- 2,264} x  100%), the "SO2" effect is -17.8% (the same as the
24      difference between -30% and  -12.2%).  However, it could be argued  that the SO2 effect is
25      that additional change beyond the response in clean air and should be expressed relative to
26      post-clean air response.   In this case, the result is ({2,264 - [1,584 + (2,270 - 1,992)] •*•
27       Based on a previously released project report [Hackney et al., 1988b], baseline FEVj fell from about 2,270 mL
28       in the normal medication state to about 1,910 mL in the low medication state. The average decrease in FEV,
29       resulting from exercise in clean air was similar in the two conditions:  —273 and —278 mL in the low and normal
30       states, respectively. The overall decrease in FEV] was —582 and —680 mL, respectively, in the two conditions,
31       leaving an SC>2 effect (total FEVj decrease — exercise in clean air effect) of —309 and —402 mL, respectively.
32       As a percentage of the preexposure resting measurement, these reflect a decrease of 16.1 and 17.8. %, respectively,
33       that can be attributed to SO2.  If expressed as a percentage of the response after exercise in clean air, these
34       percentages would be  —18.9 and  —20.2, respectively.

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 1      1,992}  x 100%) or -20.2%.  Corresponding calculations made for SRaw responses give
 2      pre- to post-increases of +77 and +249% for clean air and SO2, respectively.  Correcting
 3      for the clean air response gives an SO2 response, as above, of +172%.  The SR^ response,
 4      if expressed relative to the post-clean air exercise response ({27.6 - [7.9 + (14.0 - 7.9)]
 5      -f- 14.0} x  100%) is  +97%.  Thus expressing the SO2 response relative to the post-clean air
 6      exercise response results in an  apparently larger relative FEVj response and smaller relative
 7      SRaW response.  In all cases cited in the main text of this document, the  changes in FEVj
 8      and SRaw, when expressed as percentages, are expressed relative to the baseline value, not
 9      the post-exercise value.
10          Magnussen et al.  (1990) also studied the responses of 45 asthmatic  individuals
11      (46 subjects are included in the list but data for only 45 are given) to 0.5 ppm  SC^ with
12      10 min  of resting breathing followed by 10 min  of isocapnic hyperpnea.  Although this mode
13      of exposure has previously been shown to overestimate responses that would occur in natural
14      (oronasal breathing) exposure,  it is interesting to note that the group mean response was an
15      increase of SR^ from 6.93 to  18.21 cm H2O-L" -s" -L.  After correcting for the increase in
16     SRaW due to hyperventilation, («45%; from 6.27 to 9.10), the increase in SR^ (8.65) as a
17     percentage of the mean baseline (6.60) is 131 %.  However, only 16 of the 45 subjects
18     experienced at least a doubling of SR^, indicating that the large mean change is driven by
19     much larger changes in a small group of subjects.  Based on the cumulative frequency
20     distribution of PC100SRaw versus SO2 concentration of Hortsman et al. (1986), approximately
21     25% of the subjects would be expected to have a doubling of their SRaw at an SO2
22     concentration of 0.50 ppm.  The somewhat larger fraction (36%) in this group of subjects
23     (see Table 4) may be due to the fact that SO2 was inhaled via a mouthpiece, which is known
24     to increase SO2 responses.  Also 16 subjects were on inhaled or oral steroid medication (only
25     6 of the 16 who doubled SRaw used steroids). These subjects would  likely be considered to
26     have more severe asthma than those studied by either Linn et al. (1987) or Horstman et al.
27     (1986).
28          Magnussen et al. (1990) also found only a weak correlation (r = 0.47; R2 = 0.22)
29     between histamine response and SO2 response to changes in SRaw. They concluded that
30     nonspecific bronchial responsiveness  (NSBR) to histamine is a poor predictor of response to
31     SO2. A number of investigators (Roger et al., 1985; Linn et al.,  1983b;  Witek and

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 1     Schachter, 1985) have reported a weak correlation between histamine or methacholine
 2     responsiveness and functional responses to SO2.  In these studies, it has generally been
 3     concluded that histamine or methacholine response is not a good predictor of responsiveness
 4     to SO2 among asthmatic subjects.
 5
 6     4.3   RANGE OF SEVERITY OF SULFUR DIOXIDE RESPONSES
 7          In order to put the changes in FEV{ and SRaw that result from  SO2 exposure into
 8     perspective, responses to exercise and/or cold air breathing were compared under a variety of
 9     conditions. The extent  of exercise-induced bronchoconstriction is in  part dependant upon the
10     intensity of the exercise (Table 5). As seen in this review and the Second Addendum (U.S.
11     Environmental Protection Agency, 1986), mild exercise alone under  normal indoor conditions
12     results in small, if any change in FEVl or SRaw.  For example,  after 10 min exercise at
13     40 L/min (»35% max), SRaw increased 29% and FEVj decreased by only 1.8% in one
14     study (Linn et al., 1987); and, after 5 min exercise at a similar level, SRaw increased 67%  in
15     another study (Horstman et al., 1988).  These are modest changes, typically not accompanied
16     by symptoms. NIH guidelines (1991) suggest that a decline of 15%  in FEV^ is an acceptable
17     response to exercise challenge. At higher exercise intensities  (60 to  85% of maximum),
18     FEVj decreases range from  10 to 30% (Anderson and Schoeffel, 1982; Anderson et al.,
19     1982; Fitch and Morton, 1971; Strauss et al., 1977).  With the combination of exercise and
20     inhalation of dry subfreezing air, the decrease in FEV^ may reach 35 to 40% (Strauss et al.,
21     1977; Smith et al., 1989). Inhalation of warm humid air during exercise markedly reduces
22     or eliminates  exercise-induced decreases in FEVj (Anderson  et  al.,  1982) or increases in
23     SRaw (Linn et al., 1984, 1985). Balmes et al. (1987) stated that the  responses  to 5-min
24     exposures to  1 ppm SO2 were qualitatively similar, in terms of symptoms and function
25     changes, to "maxr ' u acute bronchoconstrictor responses" from  other nonimmunologic
26     stimuli (i.e., cold/dry air, hypertonic saline, histamine, or methacholine).  This opinion is
27     based on the  responses  of a  small number of subjects who had striking responses to SO^.
28     This study was not designed to evaluate maximal responses.
29          The magnitude of functional responses of asthmatics to a variety of physical, chemical,
30     biological, and environmental  stimuli varies widely.  Mild exercise in mild asthmatics may
31     produce modest changes in pulmonary function (< 10% decrease in FEVj) in the absence of

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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                                 Conditions
Moderate exercise typical of chamber studies
Linn et al. (1985)               Exercise 5 min at
                             VE = 50 L/min
                             (a) 21 °C, dry
                             1 (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) SR^ +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%
              +18%
Linn et al. (1987)
                             10 min at 40 L/min
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
      (a) SRaW +29%
      (b)FEVj -1.8%

      SRaw +67%
                                                          20-25% decline in FEVj

                                                          (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)
              -20%
              -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)
      FEV, -20 to -25%
 NIH guidelines suggest a decrease of > 15% in FEVj as a diagnostic criteria for exercise-induced asthma.
March 1994
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 1     symptoms or breathing difficulty.  On the other hand, functional responses of patients
 2     seeking emergency treatment for asthma are striking (Lim et al., 1989; Fanta et al.,  1982;
 3     Hilman et al., 1986).  The average FEVl in a group of 16 subjects treated in a hospital
 4     emergency room was 41 ±9% predicted.  In another study of subjects with acute severe
 5     asthma, the average FEVl when first measured was 21 ±5% predicted. Fanta et al.  (1982)
 6     reported a mean FEVj  of 38% predicted for a group of 102 asthmatic patients treated in a
 7     hospital emergency room. Although none of these groups constituted a clearly representative
 8     population sample, they do illustrate the severity of functional responses (i.e., FEVl
 9     decrements of —60 to  —80% of predicted) observed in asthmatic patients seeking emergency
10     medical treatment.
11          One of the diagnostic procedures used in the evaluation of asthma is a measurement of
12     airway responsiveness.   Airway inhalation challenges to histamine or methacholine are
13     typically used to determine the dose of these drugs which cause a 20% decline in FEVj.
14     (Cropp et al., 1980; Chatham et al.,  1982; Chai et al., 1975). This level of reduction in
15     FEVj is typically associated  with symptomatic complaints of chest tightness and/or wheeze as
16     well as other complaints associated with dyspnea.  Killian et al. (1993) showed that there is a
17     wide range of perception of  dyspnea after a 20%  decrease in FEVl5 rated from 0 to 9 on a
18     10 point scale.  Breathing difficulty at this level of FEVj reduction corresponded to that at
19     about 60 to 70% of maximum exercise level.  These responses and symptoms typically
20     resolve spontaneously within an hour, although a bronchodilator may be used to reverse the
21     induced bronchoconstriction. Allergen inhalation challenges have been used, although much
22     less  frequently, to produce similar functional responses.  The acute response is less rapid
23     (10 to 20 min) and may take somewhat longer (1  to 2 h) to spontaneously return to baseline
24     (Cockcroft, 1987).
25
26     4.3.1    Severity of Sulfur  Dioxide Respiratory Function Responses
27          As with all biological responses, there is a range of response to SO2 in asthmatic
28     individuals irrespective of the other factors that influence response magnitude such as
29     concentration, duration, ventilation, exercise, air  temperature, air dryness, etc.  Some
30     subjects experienced small or minimal functional  responses to SO2 exposure  especially at
31     relatively low SO2 concentrations.  Four studies presented sufficient published individual data

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 1     to estimate the range of responses in terms of post exposure SRaw in the most responsive
 2     quartile of subjects.  The most responsive subjects (3 of 12) in Horstman et al. (1988)
 3     exposed for 5 min to 1.0 ppm had SRaw's ranging from 55 to 71 cmH2O-s. In the Linn
 4     et al. (1988) study, the most responsive subjects (5 of 20) had SRaw's ranging from +18 to
 5     +122, when exposed in the untreated condition to 0.6 ppm SO2 for 10 min.  In the Linn
 6     et al. (1990) study (10 min at 0.6 ppm), the most responsive subjects (5 of 21) on normal
 7     medication had a range of response from 46 to 76 cmH2O-s representing an increase of
 8     420 to 1,090%.  When normal medication was withheld, this range increased to 66 to
 9     95 cmH2O-s.  In the Linn et al. (1987) study of mild and moderate asthmatic subjects
10     (0.6 ppm for 10 min), the range of response for the most responsive quartile  (10 of 40) was
11     21 to 118 cmH2Os.  This represents an increase of SR^ ranging from 390 to 1,600%.
12          Additional, more detailed information is presented in Appendix B (Table B-l) with
13     regard to the range of severity of respiratory function changes observed among asthmatic
14     subjects exposed to SO2 in selected recent controlled exposure studies, i.e., those by Roger
15     et al. (1985) and Linn et al.  (1987, 1988, 1990). Of most interest are Table  B-l entries
16     concerning: (1) average magnitudes of pulmonary function changes (SR,^; FEV^) measured
17     at different tested SO2 exposure concentrations under moderate exercise conditions, and
18     (2) percentages of asthmatic  subjects exceeding cutpoints for defining ranges of effects of
19     increasing severity (magnitude) and potential medical concern as a function of SO2 exposure
20     levels.
21          The data presented in Table B-l indicates that the average  magnitudes of responses
22     (FEVl decreases; SRaw increases) due to SO2 at 0.4 and 0.5 ppm are not distinguishable, for
23     either mild or moderate asthmatic subjects, from the range of normal variations often
24     experienced by asthmatic persons during a given day, i.e., up to 10 to 20% lower FEVj in
25     early morning versus the afternoon and up to 40% higher SR,^  (see discussion on page 4).
26     Nor are the average changes due to SO2 at 0.4 or 0.5 ppm particularly distinguishable from
27     the range of analogous pulmonary function changes observed among asthmatic persons in
28     response to cold/dry  air or moderate exercise levels (see Table 5). Even taking the
29     combined effects of exercise and SO2 exposure at 0.4 and 0.5 ppm, the average total lung
30     function changes generally do not reach magnitudes identified as being of medical concern.
31     Similarly, at 0.4 and 0.5 ppm, only relatively small percentages (generally  <10 to 25%) of

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 1     tested subjects exhibited marked responses to SO2 (after correction for exercise) that both
 2     (a) very markedly exceeded typical daily variations for lung function measures for asthmatic
 3     persons or functional changes displayed by them in response to cold/dry air or moderate
 4     exercise levels and (b) reached magnitudes falling in a range of likely clinical concern (i.e.,
 5     SRaW increases ^200% and FEV10 decreases  ^20%).
 6          In contrast to the patterns seen at 0.4 and 0.5 ppm, distinctly larger average lung
 7     function changes were observed  at SO2 exposures of 0.6 ppm and higher.   Of particular
 8     importance is that the average total changes due to combined effects of exercise and SC^ are
 9     at the upper end of or exceed (a) the range of typical daily variations in FEVl5 and SRaw and
10     (b) the magnitudes of changes seen in such measures in response to cold/dry air and
11     moderate exercise levels.  Also,  at 0.6 ppm or higher SO2 concentrations, substantially
12     higher percentages of tested subjects exhibited lung function changes due to SO2 that
13     approach or reach levels of medical concern.  For example, in response to 0.6 or 1.0 ppm
14     SO2 exposure under moderate (40 to 50 L/min) exercise conditions, 25 to 55% of both mild
15     and moderate asthmatic subjects  exhibited FEV decrements in excess of -20% and  SR^
16     increases that exceeded 200% after correction for exercise. Changes of this magnitude
17     clearly exceed the maximum 20% FEVj and 40% SR^, variations often experienced by
18     asthmatic subjects during a given day.  Similarly, approximately  15 to 40% of moderate
19     asthmatics exposed at 0.6 or 1.0 ppm SO2 experienced FEVj decrements in excess of —30%
20     and SRaw increases above 300% due to SO2, after correction for exercise.  Respiratory
21     function changes of such magnitude in response to SO2 clearly fall into a range of medical
22     concern, especially if accompanied by increased respiratory symptoms (e.g., wheezing, chest
23     tightness, shortness of breath, etc.) rated as more severe than due to exercise alone.
24
25     4.3.2   Severity of Respiratory Symptom Responses to "'-jlfur Dioxide
26          The symptoms associated with responses to SO2 are  typical of those experienced by
27     asthmatic individuals when bronchoconstriction occurs in response to any one of a number of
28     nonimmunologic provocative stimuli.  Unfortunately, in most published reports, the
29     quantitative or qualitative description of symptoms is often insufficient for the purpose of
30     comparison between studies. Linn et al. (1987) presented a total score for the sum of
31     12 symptoms in subjects exposed to 0.2 to 0.6 ppm SO2.  Symptoms were higher in the

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 1     moderate than in the mild asthmatic subjects, as would be anticipated.  In addition, there was
 2     a trend for symptoms to increase with increasing SO2 concentration.  About 25% of
 3     asthmatic subjects rated their lower respiratory symptoms (wheeze, dyspnea, etc.) 20 points
 4     higher (on a 40 point scale) after exposure to 0.6 ppm SO2.  A 20 point increase represents a
 5     change of a previously  "mild" symptom to "severe" or the new appearance of "moderate"
 6     symptom. Four of 24 moderate/severe asthmatic subjects required a reduced exercise level
 7     because of asthma symptoms at 0.6 ppm SO2.  This happened only once at each of the other
 8     (lower) concentrations.  Horstman et al. (1988) presented data for two individual symptom
 9     categories, wheezing and shortness of breath-chest discomfort for subjects exposed to
10     1.0 ppm SO2 for 2 and 5 min.  Wheezing was strongly associated with an increase in SRaw
11     (r > 0.80) and the severity of wheezing increased with increased duration of exposure.  The
12     four most responsive subjects (n = 12) rated their wheezing at either three or four on a four-
13     point scale (severe or intolerable wheezing was rated as four).  Balmes et al. (1987) indicated
14     all but one of their eight subjects developed wheezing, chest tightness, and dyspnea after
15     3 min at  1.0 ppm SO2 that was of sufficient magnitude in two subjects that they were
16     unwilling to undergo a  subsequent 5-min exposure.
17          In addition to the  above published information, more detailed analyses by U.S. EPA
18     staff of data from recent studies of SO2 effects in asthmatic individuals presented in
19     Appendix B (Smith 1994 memo) show that substantially greater percentages of moderate and
20     mild asthmatics experienced moderate to severe respiratory  symptoms at 0.6 or 1.0 ppm SO2
21     exposure during moderate (40 to 50 L/min) exercise than occurred in response to comparable
22     exercise alone.  Similarly,  much greater percentages of asthmatic subjects experienced
23     combinations of large lung function changes and severe symptoms in response to SO2
24     exposures than with exercise alone.  In addition, up to 15% of mild  or moderate asthmatic
25     subjects required redu^d workload or termination of exposure at 0.6 ppm or 1.0 ppm SO2,
26     whereas none exhibited diminished exercise tolerance with comparable exercise alone.
27
28     4.4   MODIFICATION OF SULFUR DIOXIDE RESPONSE BY ASTHMA
29           MEDICATIONS
30          It was shown in the Second Addendum (U.S. EPA, 1986), and has been substantiated
31     more recently, that common asthma medications such as cromolyn sodium and various beta2

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 1     adrenergic receptor agonists either reduce or abolish SO2-induced lung function responses in
 2     asthmatic subjects.  Since completion of that earlier Addendum, a number of medications
 3     have been evaluated in various newly available studies for their efficacy in altering responses
 4     to SO2 exposure, as summarized in Table 6.  Some of these medications are routinely used to
 5     treat asthma such as inhaled beta2-agonists (metaproterenol and albuterol), oral theophylline,
 6     and inhaled steroids such as beclomethasone.  Inhaled bronchodilator medications such as
 7     metaproterenol and albuterol are the most widely used asthma medications (Kesten et al.,
 8     1993).  Information on the effects of some other less widely used medications (e.g.,
 9     ipratropium bromide,  antihistamines, cromolyn sodium) are of interest from the point of view
10     that they may provide insight into mechanisms of response to  SO2.
11          Theophylline. Koenig et al. (1992) examined the effect of theophylline, an airway
12     smooth muscle relaxant, on SO2 induced bronchoconstriction in a group of eight allergic mild
13     asthmatic subjects.  There was a trend for the FEV^ response to be smaller when the subjects
14     took theophylline, but because of the small sample size and the variability of the responses,
15     the trend did not reach statistical significance.  However, total respiratory resistance was
16     significantly less in the theophylline than in the placebo group after SO2 exposure. The
17     mean decrease in FEVj in the placebo group (medication withheld for 1 week) was
18     approximately 0.5 L or about 16% and, in the theophylline group, was about 7%. Linn
19     et al. (1990) noted that subjects normally medicated with theophylline had similar responses
20     to SO2 whether they had high or low blood levels of theophylline.  This suggests that, with
21     typical medication levels, theophylline did not afford much protection from the effects of
22     SO2.
23          Koenig et al. (1989) examined the effects of 1 ppm SO2 on a group of 12 moderate
24     asthmatic individuals who were on chronic theophylline therapy.  Subjects were exercised in
25     the morning 3 to 4 h after drug administration and on a different day in the afternoon, 8 to
26     10 h after drug, with  no inhaler use within 4 h of exposure.  Mean theophylline levels were
27     similar in the morning and the afternoon.  There were no differences in FEVj response to
28     SO2 between morning and afternoon exposures.  The change in FEVl5 about -14%, was
29     similar to other studies where a placebo was evaluated under the same conditions. There was
30     no correlation between theophylline levels in the blood and FEVj decrements in response to
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                       TABLE 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
      Concentration
                       Duration
              Number of
               Subjects
  Exposure
    Mode
                                                                    Exposure
                                                                     Status
                                                                                                  Observations
                                                                                                                                    Comments
                                                                                                                                                      References
      0.0, 0.3, 0.6 ppm 10 min
             20 adult mild  Chamber
               asthmatic    23 °C
                subjects    85% RH
      0.0, 0.3, 0.6 ppm 10 min
                                       21
S>
      0, 0.5, 1.0 ppm  30 min
      0.75 ppm
Minutes
until SR,,,,
increased
75% above
baseline
                                      25
                          Chamber
                          21 °C
                          50% RH
                          Oral
                          mouthpiece
                          22 °C
                          75%RH
Oral
mouthpiece
24 "C
50% RH
             Exercising VE « 50 L/min
             Three pretreatment
             conditions: drug
             (metaproterenal); placebo
             (saline); no pretreatment
                                       Exercise
                                                                         50 L/min
            Three medication states:
            reduced (medication
            withheld); normal (usual
            medication schedule);
            enhanced (usual medication
            supplemented by inhaled
            metaproterenal before each
            exposure)
20 min rest followed by
10 min light-moderate
exercise Y£ * 26 L/min
Two medication states:
placebo; ipratropium bromide
(IB) (60 jig aerosol)
Isocapic hyperventilation
(started at  15 L/min; then
increased in 3 min. steps by
15 L/min).
Two medication states:
beclomethasone; salbutamol
With no pretreatment, typical exercise-
induced bronchospasm occurred at 0.0 ppm;
slightly increased at 0.3 ppm; markedly
increased at 0.6 ppm. Similar effects were
seen with placebo.  Drug pretreatment
improved lung function, prevented
bronchoconstrictiveeffect at 0.0 and
0.3 ppm, and greatly mitigated  responses at
0.6 ppm SO2.
With normal medication, typical
bronchoconstriction occurred with exercise
and exacerbated by 0.6 ppm SOj. With low
medication both baseline and postexposure
lung function noticeably worse (FEVj fell
from 2,350 to 1,900 mL; exercise alone
decreased FEVj by  300 mL and 0.6 ppm
SO2 decreased further) but decrement caused
by SC>2 similar to low medication state.  With
supplementary metaproterenal, SC>2 effect
greatly diminished (=5% decrease in FEVj).
Moderate/severe asthmatic subjects with
medication withheld had decrease of 40%
from combined effects of exercise, SC>2
(0.6 ppm) and absence of normal medication.
Significant dose-response effect of 1.0 ppm
S02onFEV1,SRT, Vmax50,  V^j.  IB
resulted in improvements in all baseline
measures of pulmonary function, but did not
alter the proportionate change in pulmonary
function caused by SO2.
Regular treatment with salbutamol alone or in
combination with heclomethasone did not
change responses to hyperventilation with air
or SO2. Medication withheld for at least 6 h
prior to challenge.
                                                               Nine of 20 subjects from the no- Linn et a). (1988)
                                                               treatment or placebo group
                                                               exposed to either 0.3 or 0.6 ppm
                                                               SO2 needed medication to treat
                                                               symptoms following exposure.
                                                               High medication appeared to
                                                               improve baseline lung function
                                                               and prevented most
                                                               bronchoconstrictive effects of
                                                               SC>2 and exercise.
                                                                                                      Linnet al. (1990)
Conclude that IB causes
significant bronchodilation but
does not completely protect
nonallergic asthmatic subjects
from the effect of SO2
inhalation.
Absence of salbutamol effect is
in contrast to other studies.
Peak response to salbutamol
occurs in 2-3 h, although some
effect may persist for up to 8 h.
                                                                                                      McManus et al.
                                                                                                      (1989)
Wiebicke et al.
(1990)

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s
s-
Oi
                 TABLE 6 (cont'd).  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
Concentration
Duration
Number of
Subjects
Exposure
Mode
Exposure
Status
Observations
Comments
References
      0.75 ppm        10 min
                                     10
      1.0 ppm
      1.0 ppm
                    10 min
                    10 min
13 Allergic
adolescents
12-19 years
      1.0 ppm
                    10 min
12 moderate
 asthmatic
 subjects
12-39 years
            Oral mouthpiece  Exercise VE « 34 L/min
                                              22 °C
                                              75% RH
                                           After SO2, FEVj decreased 14%   Suggests involvement of
            Oral mouthpiece
            22 "C
            75% RH
Oral mouthpiece
22 °C
75% RH
Oral mouthpiece
22 "C
75% RH
                                                            Two medication states: placebo;   and Rj increased 50% with        adrenergic nervous system or
                                                            albuterol (180/tg aerosol). Each  placebo; albuterol eliminated drop   mast cell degranulation in
                                                            subject exposed to four different   in FEVi and increase in RT caused  SO2-induced bronchoconstriction.
                                                            exposures (albuterol, air; placebo,  by SO2-
                                                            air; albuterol, SOj; placebo,
                                                            SOj).
                                                                                    Koenig et al.
                                                                                    (1987)
 Treadmill exercise
 VE » 35 L/min
 Medicated with cromolyn sodium
 (CS) 0, 20, 40, or 60 mg by
 turbinhaler.
 Treadmill exercise
VE = 33.9 L/min
 Three conditions: placebo, 4 mg
 or 12 mg  chlorpheniramine
 maleate (CM).
 Exercise
 VE = 31.6 L/min (AM)
 VE = 30.6 L/min (PM)
 Four conditions AM: Air or SO2
 3-4 h post theophylline.
 PM: Air or SO2 8-10 h post
 theophylline.
20 mg CS had no effect on SO2
response; 40 mg CS significantly
inhibited response; 60 mg
completely inhibited response.

In allergic adolescents (never used
inhaler or hospitalized) positive for
exercise-induced
bronchoconstriction, FEVj
decreased 11, 12.6, and 12.3%
under placebo, 4 mg CM, and
12 mg CM conditions, respectively,
from pre- to post SO2 exposure.
No differences between conditions
for respiratory symptoms 0-, 6-, or
24-h post SO2-
No differences in FEVj response to
SOj between morning (AM) or
afternoon (PM) exposures. Change
in FEVj (about —14%) was similar
to other studies where placebo
evaluated under similar conditions.
                                                                        Cromolyn sodium reduced       Koenig et al.
                                                                        bronchorestrictor response to SC>2  (1988a)
                                                                        in a dose-dependent manner.
No effect of an oral antihistamine Koenig et al.
on airway response to SOj      (1988b)
exposure. SO2 did increase nasal
work of breathing that was
blocked by antihistamine.
Authors concluded no protective  Koenig et al.
effect of chronic theophylline use (1989)
on response to SO2-
      1.0 ppm
                    10 min
            Oral mouthpiece
            22 °C
            65% RH
               Light exercise
                VE » 13-31 L/min
               Two medication states: placebo;
               theophylline (400 mg) daily for
               1 week.
                            After SO2 FEVj dropped 16% with Conclude that sustained release
                            placebo and 7% with theophylline,  theophylline tablets taken for
                            RT increased 37% with placebo and 1 week mitigate SC^-induced
                            7% with theophylline.            bronchoconstriction.
                                                        Koenig et al.
                                                        (1992)

-------
 1     SO2 exposure.  The authors concluded that there was no protective effect of chronic
 2     theophylline use on response to SO2.
 3          Ipratropium Bromide. McManus et al. (1989) examined the effects of ipratropium
 4     bromide (IB) (a muscarinic receptor [cholinergic] blocking agent) on a group of nonallergic
 5     ("intrinsic") asthmatic subjects (age > 55  years).  Although IB improved baseline lung
 6     function, the fall in FEVl after exposure to 0.5 and 1.0 ppm SO2 was similar to the response
 7     with placebo. These subjects experienced  an approximate  15% reduction in FEV! after
 8     20 min of rest and 10 min of mild exercise (VE =  26 L/min) at 1 ppm SO2. They
 9     experienced about an 8.5% drop in FEVj from the resting exposure alone. Typically,
10     resting exposure has not produced appreciable responses, even with mouthpiece exposure
11     systems, suggesting that these subjects could be more responsive to SO2 than younger
12     allergic asthmatic subjects studied under similar conditions (Koenig et al., 1983).
13          Inhaled Steroids. Wiebicke et al. (1990) recently examined the effects of regular
14     treatment over a 5-week period with an inhaled steroid (beclomethasone) and a beta-agonist
15     (salbutamol/albuterol) on nonspecific bronchial responsiveness to histamine, methacholine,
16     hyperventilation, and SO2. All medications were withheld for at least 6 h prior to any
17     challenge.  Salbutamol treatment alone had no effect on responsiveness to standard challenges
18     with histamine or methacholine. The isocapnic hyperventilation challenge involved a
19     progressive increase (steps of 15 L/min) in target ventilation (maintained for 3 min) until the
20     SRaw increased by 75 % above baseline. Hyperventilation was performed on a mouthpiece
21     with or without SO2 added to the airstream.   Salbutamol treatment did not change the
22     responses to  hyperventilation with air or with 0.75  ppm SO2.  Combined treatment with
23     salbutamol and beclomethasone caused a reduction  in baseline SR^ and also reduced airway
24     beclomethasone responsiveness  to methacholine, histamine, and hyperventilation with air.
25     However, treatment with salbutamol plus beclomethasone did not cause a  significantly
26     decreased response to SO2, although the SO2 response did tend to be less.  The absence of
27     an effect of salbutamol in this study is in contrast to the significant reduction in SC^ response
28     with metaproterenol (Linn et al.,  1988) and albuterol (i.e., same drug as salbutamol) (Koenig
29     et al., 1987) seen in other studies. The suspension of drug treatment at least 6 h prior to any
30     challenge exceeds the duration (» 2 to 3 h) of the peak therapeutic effect for salbutamol
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 1     (Oilman et al., 1990). Any persistent effect of salbutamol was apparently insufficient to alter
 2     SO2 responses.
 3          Beta Agonists. Linn et al.  (1988) examined effects of metaproterenol on responses of
 4     asthmatic subjects to 0.3 and 0.6 ppm SO2.  Pretreatment with metaproterenol (dose
 5     administered 5 min prior to pretesting) caused an improvement in baseline lung function
 6     (increased ¥EVl and decreased SRaw) and a reduced response to SO2 exposure in an
 7     environmental chamber.  The estimated average SRaw SO2 response, adjusted for exercise-
 8     induced bronchospasm (ElB), of no treatment and placebo treatment was a 66 or 166%
 9     increase in SR^ at 0.3 and 0.6 ppm, respectively.  These percentages were derived by
10     taking the average ^SR^ reported by Linn et al.  (1988) for untreated and placebo groups at
11     0.0 ([8.8 + 6.1] II  = 7.45), 0.3 ([12.8 + 9.9] 12 = 11.95),  and 0.6 ppm ([17.5 +  17.1] /2
12     = 17.3) as a percentage of the average baseline (5.94) and then subtracting the 0.0 ppm
13     from the 0.3 and 0.6 ppm responses (125, 191, and 291%, respectively).  Metaproterenol
14     given prior to exposure blocked the responses  to SO2.  Symptoms were  markedly reduced
15     but not eliminated.  Following the 0.6-ppm SO2 exposure with either the no-treatment or
16     placebo treatment condition,  9 out of 20 subjects needed medication to treat symptoms caused
17     by at  least one of the exposures.
18          Koenig et al. (1987) studied a group of allergic adolescents with exercise-induced
19     bronchospasm but who were not classified as asthmatic (never wheezed  except with exercise,
20     never used beta-agonist).  These subjects exhibited a 14% decrease, from post-placebo
21     baseline, in FEVl after 10 min of moderate exercise (34 L/min) at 0.75 ppm SO2. Albuterol
22     markedly attenuated the drop in FEVj caused by SO2, although it caused a modest (7%) but
23     significant improvement in baseline FEVj.  These observations in a group of subjects not
24     previously identified as asthmatic suggest that the population at risk may be slightly larger
25     than suggested earlier.  However, by the objective criteria presented in this paper, many
26     would classify these subjects as asthmatic.
27          Cromolyn Sodium.  Koenig et al. (1988a) examined the effects of four different dose
28     levels of cromolyn sodium (a nonspecific mast cell degranulation inhibitor) on subjects
29     exposed to 1.0 ppm SO2 for 10 min with exercise (VE « 35 L/min). Subjects received
30     either 0, 20, 40, or  60 mg cromolyn 20 min prior to exposure to SO2.  The 20-mg dose was
31     not significantly different than placebo.  However, the 40-mg  dose caused a partial blockade,

       March 1994                               35        DRAFT-DO NOT QUOTE OR CITE

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 1     and 60 mg almost completely obliterated the response to SO2. These observations support
 2     the previous observations of Myers et al. (1986a) that cromolyn sodium reduced responses to
 3     SO2 in asthmatic individuals in a dose-dependant manner.  However, the Koenig et al. (1988)
 4     data are more relevant to clinically acceptable doses of cromolyn.
 5          Chlorpheniramine Maleate.  Koenig et al. (1988b) evaluated the effect of an oral
 6     antihistamine, chloipheniramine maleate, on SO2 responses in a  group of allergic adolescents
 7     with exercise-induced bronchoconstriction (but who had never been treated for or diagnosed
 8     with asthma).  Subjects were exposed to 1.0 ppm SO2 via mouthpiece while exercising with
 9     a ventilation of about 34 L/min.  Medication was taken 12 h prior to exposure and included
10     placebo or 4 or 12 mg Chlorpheniramine.  The FEVj responses were similar under the three
11     conditions, with decrements of -11,  -12.6, and -12.3%, respectively. The authors
12     concluded that this oral antihistamine did not provide any protective effect from SO2-induced
13     bronchoconstriction in these allergic adolescent subjects. However, changes in nasal function
14     induced by SO2 were blocked by antihistamine.
15          In the Second Addendum (U.S.  EPA, 1986), medication usage after SOj exposure was
16     cited as an adverse outcome that could be quantified, as summarized in Table 7 based on
17     information reported in pertinent published studies.  In the more recent studies, medication
18     use following exposure has been carefully noted. After 2- to 5-min exposures to 1.0 ppm
19     SO2, 7 of 8 subjects in one study (Balmes et al., 1987) and 4 of 12 in another (Horstman
20     et al., 1988) required bronchodilator medication after exposure.  Two of the subjects  in
21     Balmes et al. (1987) were unable to complete the 5-min exposure in addition to requiring
22     medication. Linn et al.  (1988) found that 7 of 20 mild asthmatic subjects exposed to
23     0.6 ppm SO2 needed medication to treat their symptoms following exposure, whereas only
24     2 of 20 did so after 0.3 ppm SO2 exposure or  after exposure to  clean air at comparable
25     exercise rates.
26          Many asthmatic subjects take medication to relieve the symptoms and functional
27     responses associated with exacerbations of the disease.  The most commonly used of these
28     medications (beta agonists) also inhibit responses to SO2.  Thus, there have been suggestions
29     that  asthmatic persons may be protected from responses to SO2 because of medication that
30     they would have used in any case.  However,  several lines of evidence suggest that this is
31     not likely the case.

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              TABLE 7. MEDICATION USE AFTER SULFUR DIOXIDE EXPOSURE3
Reference
Bethel et al. (1984)
Koenig
Linn et
Linn et
Linn et

Linn et



Balmes
et
al
al
al

al



et
Horstman
al. (1985)
. (1984a)
. (1984b)
. (1988)

. (1990)



al. (1987)
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 SC>2
Exposure (in ppm)
2/7
2/10
1/24
3/24
2/20
7/20
6/21
5/21
12/21
10/21
7/8
4/12
©0
©0
©0
©0
©0
©0
©0
.5
.5
.6
.6
.3
.6
.3
©0.3
©0
©0
@ 1
© 1
.6
.6
.0
.0
ppm
ppm
ppm
ppm
ppm
ppm
ppm
ppm
ppm
ppm
ppm
ppm
+ cold





(low med)
(norm med)
(low med)°
(norm med)c


        Medication 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.
       cMedication use data obtained from Hackney et al. (1988b) may not agree with independently provided
        individual data.
 1          Mild asthmatic persons who constitute the majority of asthmatic individuals, use beta
 2     agonists on an as needed basis.  Even once a week use exceeds the norm for such
 3     individuals, as discussed in Section 2.2.  Only about 20%  of moderate asthmatic persons
 4     regularly use inhaled bronchodilators, the most effective medication in minimizing SO2
 5     responses.  Even among moderate asthmatic persons on regular bronchodilator therapy (oral
 6     and inhaled), compliance with medication use ranges from 50% to 70%.  Thus one third to
 7     one half of regularly medicated asthmatics do not take all prescribed medication.  National
 8     Heart Lung and Blood Institute guidelines indicate that daily bronchodilator use suggests the
 9     need for additional therapy.   Indeed there is some suggestion that excessive use of beta-
10     agonists leads to a worsening of asthma status (Sears et al., 1990b; van Schuyk et al., 1991).
11      The frequency of use of medication prior to  outdoor exercise is unknown.  Furthermore
12     there are a substantial number of individuals with Effi who are not aware of the need for or
13     benefits of treatment (Voy, 1984).
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 1     4.5   MODIFICATION OF SULFUR DIOXIDE RESPONSIVENESS BY
 2           OTHER AIR POLLUTANTS
 3          The effect of prior ozone exposure on response to SO2 was examined by Koenig et al.
 4     (1990) in 13 allergic adolescent asthmatic individuals.  A 45-min exposure to 0.12 ppm
 5     ozone caused a modest exacerbation (from a 3 % decrease to an 8 % decrease) of FEVl
 6     response to 0.1 ppm SO2. Ozone does produce an increase in nonspecific bronchial
 7     responsiveness (NSBR); these observations may reflect a change in NSBR due to ozone or an
 8     additive effect of ozone, SC>2, and exercise.  The importance of these observations, from a
 9     risk assessment point of view, depends upon the prevalence in the ambient environment of
10     the sequential occurrence of elevated levels of ozone followed by SO2 peaks. However, the
1 1     possibility that stimuli such as ozone that may cause changes in NSBR and may also alter
12     responses to SO2 is important because other non-specific stimuli (e.g., cold air, exercise,
13     etc.) may occur in temporal and spatial proximity  to increased levels of SO2.
14          The effects of prior NO2 exposure on SO2-induced bronchoconstriction has been
15     examined in two other studies (Jorres and Magnussen,  1990; Rubinstein et al., 1990). Jorres
16     and Magnussen  (1990) exposed 14 mild to moderate asthmatic subjects to 0.25 ppm NO2 for
17     30 min while breathing through a mouthpiece at rest.  There were no changes in SRaw as a
18     result of the exposure.  After the exposure, airways responsiveness to SO2 was assessed by
19     isocapnic hyperventilation of 0.75 ppm SO2 using stepwise increases in ventilation; the  initial
20     level was 15 L/min with subsequent increases to 30, 45 L/min, and so forth. After each
21     3-min period of hyperventilation, SRaw was determined.  The ventilation of SO2 required to
22     produce a 100% increase in SRaw (PV100SRaw[SO2]) was estimated using interpolation of
23     ventilation versus SR^ (dose-response) curves.  The PV100SRaw(SO2) was significantly
24     reduced after NO2 exposure compared to after filtered air exposure, suggesting that the
25     airways were more responsive to SO2 as a result of the prior NO2 exposure. However, this
26     response is not specific to SO2 as other studies have suggested increased nonspecific
27     bronchial responsiveness in subjects exposed to NO2 (Folinsbee, 1992).
28          Rubinstein et al. (1990) exposed nine asthmatic subjects to 0.30 ppm NO2 for 30 min
29     (including 20 min light exercise).  There were no  significant effects of NO2 exposure on lung
30     function (single breath nitrogen washout, SRaw, FVC, FEVj) or respiratory symptoms,
31     although a slight increase in SR^ was observed as a result of exercise.
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 1     An SO2-bronchoprovocation test was administered after exercise, but using a different
 2     technique than Torres and Magnussen (1990).  Increasing amounts of SO2 were administered
 3     by successive doubling of the SO2 concentration (0.25, 0.5, 1.0, 2.0,  4.0 ppm) at a constant,
 4     isocapnic ventilation of 20 L/min, maintained for 4 min.  Specific airway resistance was
 5     measured after each step increase in SO2 concentration.  The concentration of SO2 required
 6     to increase SRaw by 8 units (PDgySO^ was interpolated  from a  dose-response curve of SO2
 7     concentration versus SRaW.  The PD8uSO2 was 1.25  ± 0.70 ppm after air exposure and
 8     1.31 ± 0.75 after NO2 exposure, indicating no mean change in responsiveness to SO2. Only
 9     one subject showed a tendency toward increased responsiveness  to SO2 after NO2 exposure.
10          The contrasting findings in these two studies are somewhat puzzling because the
11     subjects of Rubinstein et al.  (1990) were exposed to a higher NO2 concentration and
12     exercised during exposure.  However, Torres  and Magnussen's  subjects appeared to have
13     had slightly more severe asthma and were  somewhat older. The modest increase in SRaw
14     induced by exercise in the Rubinstein et al. study may have interfered with the response to
15     SO2 (i.e., the subjects may have been in a refractory state). Finally, the different method of
16     administering the SO2 bronchoprovocation test (i.e., increased VE  at constant SO2 versus
17     increasing SO2 at constant VE) may produce a different response, because hyperventilation
18     alone could contribute to the increase in SR,^ (Deal et al., 1979; Eschenbacher and
19     Sheppard, 1985). Thus, although similar,  the two SO2 challenges are not necessarily
20     comparable.
21
22     5.0   SUMMARY AND CONCLUSIONS
23          In general, the conclusions reached hi the 1986 Second Addendum have been supported
24     by subsequent research.  Those conclusions were restated at the beginning of the present
25     supplement, and there is little poi "* in repeating them here. However, the newer studies
26     reviewed in this supplement provide further information useful in drawing conclusions of
27     relevance to developing criteria for a possible  short-term (< 1 h) SO2 NAAQS.
28
29
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 1     5.1   EXPOSURE DURATION/HISTORY AS SULFUR DIOXIDE
 2           RESPONSE DETERMINANTS
 3         Two new studies (Balmes et al., 1987; Horstman et al., 1988) have shown that airways
 4     resistance changes resulting from SO2 exposure can occur with as little as 2 min exposure at
 5     SO2 levels ranging from 0.5 to 1.0 ppm.  Significant changes were seen with 2 min exposure
 6     at 1.0 ppm and with 3 min exposure at 0.5 ppm.  These observations clearly indicate that
 7     brief exposures to high concentrations, which may be masked by ambient SO2 monitoring
 8     procedures using averaging times of 1 h or greater, can have detectable health consequences.
 9         Other studies (e.g., Linn et al., 1987; Roger et al., 1985) evaluated the effects of prior
10     exposure to SO2 on the magnitude of bronchoconstriction responses to subsequent SO2
11     exposures. Prior exposure history to SO2 over the course of several weeks (as opposed to
12     several hours) was found to be largely irrelevant in determining responsiveness to later SO2
13     exposures. However, the response to a second exercise period was diminished in comparison
14     to initial bronchoconstriction observed in response to a first exercise period within a 1-h SO2
15     exposure, thus further confirming a  likely refractory period to SO2 exposures accompanied
16     by exercise or hyperpnea repeated within a span of a few hours.
17
18     5.2   SULFUR DIOXIDE RESPONSES AND ASTHMA SEVERITY
19         Several new studies have  evaluated responses to SO2 among asthmatic individuals with
20     moderate or severe disease.  One new study (McManus et al., 1989) of older (>55 years)
21     "intrinsic" asthmatic individuals suggests that they may experience bronchoconstriction with
22     mouthpiece SO2 exposure while resting.  Another study (Linn et al., 1987), while indicating
23     similar relative responses to SO2 among mild and moderate asthmatic subjects, demonstrates
24     larger absolute increases in airway resistance among the moderate to severe asthmatic
25     subjects.  However, the question of the relationship of ar'"una severity and response to SO2,
26     while suggestive of greater responsiveness among those with more severe disease, remains to
27     be unequivocally resolved.
28
29     5.3   RANGE  OF SEVERITY OF SULFUR DIOXIDE RESPONSES
30         Efforts have been made to help characterize the range of severity of respiratory effects
31     exhibited  by asthmatic subjects in response to SO2 exposure, and some of these were

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 1     discussed in earlier sections of this Supplement.  Many of the newly available studies provide
 2     substantial additional information that is helpful in delineating the range of severity of SO2-
 3     induced respiratory responses.  For example, two additional studies support the concept
 4     advanced by Horstman et al. (1986) of the estimation of a median response to SO2 among
 5     asthmatic individuals. Results  from the studies by Linn et al. (1987) and Jorres and
 6     Magnussen (1990), using relatively large groups of subjects,  are consistent with the
 7     estimation of Horstman et al. (1986). These data suggest that the  average asthmatic
 8     individual will experience increased airway resistance (i.e., at least a doubling of baseline
 9     resistance) with exposure to 0.75 ppm SO2 for 10 min while performing moderate exercise.
10     Numerous factors can modify these responses, as noted previously in the Second Addendum
11     (U.S. EPA, 1986), and there is a broad range of response among asthmatic individuals.
12          In the earlier Second Addendum (U.S. EPA, 1986), a table was presented which
13     defines a continuum of responses of increasing severity and concern  in asthmatic subjects.
14     A modification of this table is presented below as Table 7. In Section 4.2 of this
15     supplement, the range of responses among asthmatic subjects exposed to SC^ was discussed.
16     Although most asthmatic subjects tested in studies reviewed here had only relatively mild
17     responses at low SO2 concentrations (0.2 to 0.5 ppm), some  of the more responsive
18     asthmatic subjects had responses to SO2 exposures at 0.6 ppm or higher that included SR^
19     increases exceeding 50 units, FEVj decreases (corrected for exercise response)  exceeding
20     20%, the presence of marked wheezing and breathing discomfort,  and the need for
21     medication to resolve these symptoms.  Such responses, in the most  sensitive subjects, which
22     would be considered to be severe or incapacitating according to definitions of increasing
23     severity in Table 8, likely constitute adverse health effects.  Also, tables contained in
24     Appendix B materials provide further detailed, quantitative analyses  of combinations of
25     respiratory function effects, severity of symptoms and pc +-SO2 exposure medication use, by
26     which to estimate percentages of mild or moderate asthmatic  subjects that experience SO2-
27     induced responses that meet Table 8 criteria for moderate, severe or incapacitating
28     respiratory effects.  Based on the Appendix  B analyses, it is clear  that (a) substantial
29     percentages of mild and moderate asthmatic subjects experience combinations of lung
30     function changes and respiratory symptoms at 0.6 or 1.0 ppm SO2 that  meet the criteria in
31     Table 8 for severe or incapacitating effects and (b) the magnitude of the observed SO2

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       TABLE 8. COMPARATIVE INDICES OF SEVERITY OF RESPIRATORY EFFECTS
                       SYMPTOMS, SPIROMETRY, AND RESISTANCE
Gradation of Response Severity
Type of Response
Change in SR,^
Change in
spirometry
(FEVLO, FVC)
Duration of effect/
treatment needs
Symptoms
None
No change
No change
NA
No
respiratory
symptoms
Mild
Increase <100%
<10%
Spontaneous
recovery
OOmin
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 units
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 units
Decrease much
greater than 20%
or <50%
predicted.
Possible emergency
treatment required
if persistent
Severe breathing
distress
       Source: Modified from Figure 7 on page 4-7 of U.S. EPA (1986).
 1      responses for such individuals clearly exceed the range of daily variations in lung function or
 2      responses to other stimuli (i.e., cold air, exercise) often experienced by them.  It is also
 3      notable that up to 15 % of mild  or moderate asthmatics experienced sufficiently severe lung
 4      function changes and/or respiratory symptoms at 0.6 or 1.0 ppm SO2 so as not to be able to
 5      continue to maintain moderate exercise workload levels under the SO2 exposure conditions or
 6      to have to terminate SO2 exposure entirely—in contrast to none requiring reduced workloads
 7      hi response to comparable exercise alone.
 8
 9      5.4   MODIFICATION OF SULFUR DIOXIDE RESPONSE BY ASTHMA
10            MEDICATIONS
11          Asthma medications can reduce or eliminate the airway resistance increase in response
12      to SO2 exposure.  The most effective medications appear to be beta2 sympathomimetic
13      medications, such as albuterol or metaproterenol.  Cromolyn sodium, a nonspecific mast cell
14      degranulation inhibitor, given in therapeutic doses will partially or completely prevent
15      bronchoconstriction in response to SO2  exposure.  Other  standard asthma medications such as
16      inhaled steroids or methylxanthine medications appear to  be less effective. Withdrawal of
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 1     normal asthma medication causes degradation of baseline lung function but does not
 2     necessarily increase the response to SO2, although this has not been studied extensively.
 3     In the two investigations where patients on "normal medication" (mainly theophylline) were
 4     exposed to SO2, there did not appear to be any protective effect (Koenig et al., 1989; Linn
 5     et al., 1990).  Specifically, the  SO2 responses were similar whether the patients were using
 6     medication or not, although baseline function was depressed by the absence of regular
 7     medication.
 8           Only anecdotal information on medication use after SO2 exposures was mainly available
 9     from studies earlier reviewed in the Second Addendum (U.S. EPA, 1986). That information
10     indicated that  a few of the most sensitive asthmatic individuals exposed at  0.5 or 0.6 ppm
11     SO2 during moderate exercise required medication  after such SO2 exposure, but not after
12     comparable exercise levels in clean air (see Table 7).  Newer studies reviewed in this
13     supplement have more systematically evaluated medication use as a response endpoint of
14     clinical significance. Two of the newer  studies Linn et al. (1988,  1990) found no greater
15     proportions of subjects to require medication use after 0.3 ppm SO2 exposure than after clean
16     air exposure at comparable exercise levels.  On the other  hand, additional new information
17     presented from recent studies conducted  by three different laboratories (Balmes et al., 1987;
18     Horstman et al., 1988; Linn et  al., 1988, 1990) indicates  that many asthmatic individuals
19     (who either withheld medication prior to SO2 exposure or did not normally require
20     medication) did need medication due to severity of responses after exposure to SO2 at 0.6 or
21     1.0 ppm.  However, in some cases, a substantial number  of asthmatic subjects also needed
22     medication following clean air exercise exposure as well (Linn et al., 1990); in the study
23     reported  by Hackney et al. (1988) and Linn et al. (1990), for example, approximately half of
24     the asthmatic subjects used medication after 0.6-ppm SO2 exposure, but among those on a
25     reduced (low) medication regime, approximately the same number used medicatio^ following
26     the exercise-alone exposure.  Overall, the available published findings point toward more
27     substantial percentages of individuals likely requiring medication use after SO2 exposure
28      >0.6 ppm than  at exposure concentrations of 0.5 ppm or below (as is also indicated by the
29     more detailed  Appendix B Smith memo analyses of raw data from the 1988 and  1990 Linn
30     et al. studies).
31

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 1     5.5   MODIFICATION OF SULFUR DIOXIDE RESPONSIVENESS BY
 2           OTHER AIR POLLUTANTS
 3          One new study by Koenig et al. (1990) reported that prior exposure to ozone at the
 4     current NAAQS level (0.12 ppm, 1 h) causes a moderate exacerbation of lung function
 5     decrements due to a later exposure to 0.1 ppm SO2. However, the particular results make it
 6     difficult to separate out clearly the degree of nonspecific bronchial responsiveness due to
 7     O3 alone or to combined effects of O3, SO2, and exercise.
 8          Other pollutants may also modify the response to SO2 exposure, although currently
 9     available evidence is still inconclusive.  More specifically, NO2 may also possibly increase
10     responses to SO2 in asthmatic individuals. One study by Jones et al. (1990) appears to
11     provide indications of increased responsiveness to SO2 after prior NO2 exposure, whereas a
12     second study by Rubenstein et al. (1990) failed to find analogous NO2 exacerbation of SO2
13     effects.  This may have been due to  somewhat older and slightly more severe asthmatic
14     subjects being exposed in the first study. It appears that a pollutant that increases nonspecific
15     bronchial responsiveness may also increase airway responses to SO2.
16
17     5.6   HEALTH RISK IMPLICATIONS
18          Based both on earlier criteria evaluations (U.S. EPA, 1982a,b,c,d, 1986) and the
19     present supplemental assessment of more recent findings on SO2 respiratory effects, several
20     salient points can be made with regard to implications of the reviewed findings for assessing
21     health risks associated with ambient  SO2 exposures. First, it is now clear that, whereas
22     healthy nonasthmatic individuals are essentially unaffected by acute (< 1 h) exposures to SO2
23     at concentrations of 0 to 2 ppm, even very brief (2 to 10 min) exposures of asthmatic
24     subjects to SO2 concentrations at or below 1.0 ppm can cause detectable respiratory function
25     changes * d/or symptoms—if such exposures occur while the subjects are sufficiently active
26     to achieve breathing rates typical of at least moderate exercise  (i.e., 30 to 50 L/min).  Given
27     this fact, mild to moderate asthmatic persons are much more likely to be at risk for
28     experiencing respiratory effects in response to ambient SO2 exposures than are those with
29     chronically severe asthma.  The severe asthmatic individuals, by definition (NIH, 1991;  see
30     Table 1) have very poor exercise tolerance with marked limitation of activity and, therefore,
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 1     are extremely unlikely to engage in sufficiently intense activity (exercise) so as to achieve
 2     requisite breathing rates for notable SO2 respiratory effects to occur.
 3           Of key importance, then, for criteria development purposes is the characterization of
 4     exposure-response relationships for the induction by SO2 of respiratory function changes and
 5     symptoms in mild to moderate asthmatic subjects and to provide a framework which will
 6     assist in determining which SO2 responses may be of sufficient magnitude and severity so as
 7     to be of significant health concern.  The health significance of SO2 respiratory effects can be
 8     evaluated in terms of several criteria, such as:  (1) the point at which substantial percentages
 9     of SO2 exposed asthmatic subjects experience respiratory function changes or symptoms  that
10     exceed usual daily variations or responses to other commonly encountered stimuli (e.g.,
11     exercise, cold/dry air, etc.) that trigger bronchoconstriction and other asthma symptoms;
12     (2) whether the responses evoked by SO2 are sufficient to require reductions in exercise
13     workloads,  termination of the SO2 exposure entirely, use of asthma medication after the SO2
14     exposure, and/or seeking of medical attention; and (3)  the persistence of the observed acute
15     SO2 exposure effects and/or their relationship to any other more serious chronic  health
16     impacts.
17           Collectively, the foregoing analyses in this Supplement of exposure-response
18     relationships and severity of acute (^10 min) SO2 exposure effects in asthmatic  subjects
19     suggest that:
20            (1)  Only relatively small percentages (^ 10 to 20%) of mild or moderate asthmatic
21                 individuals are  likely to exhibit lung function decrements in response to SO2
22                 exposures of 0.2 to 0.5 ppm during moderate exercise that would be  of distinctly
23                 larger magnitude than typical daily variations in their lung function or changes in
24                 lung function experienced by them in response to other often encountered stimuli,
25                 e.g., comparable exercise levels  alone and/or cold/dry air.  Furthermore, only
26                 exceptionally sensitive responders might experience sufficiently large lung
27                 function changes and/or respiratory symptoms of such severity as to be of
28                potential health concern,  leading to  disruption of ongoing activities (e.g.,
29                 reduction or termination of physical exertion), the need for bronchodilator
30                 medication, or  seeking of medical attention. If so affected, however, it is also
31                 likely that use of bronchodilator  medication would be effective in rapidly
32                 ameliorating the affected individual's distress or that the SO2-induced effects
33                 would be short-lived (i.e., less than a few hours; usually less than 1 h).  Further,
34                 although the persons' symptoms,  however brief, may be perceived by some as an
35                 "asthma attack", it is unlikely that many would seek emergency medical treatment
36                 (i.e., physician or hospital visit),  given the rarity with which such individuals
37                normally respond in such a fashion  to other "asthma" events (as discussed in

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 1                Section 2.1).  Given the refractory period found to exist after SO2 exposures, it
 2                would be less likely for the individual to experience notable responses upon
 3                reexposure to SO2 within the next several hours after the initial exposure, should
 4                they choose to resume physical exertion after amelioration or cessation of any
 5                initial SO2-induced distress.
 6
 7            (2)  In contrast to the above projected likely consequences of ambient exposures to
 8                0.2 to 0.5 ppm SO2 of mild or moderate asthmatic persons, considerably larger
 9                lung function changes  and respiratory symptoms of notably greater severity would
10                be expected to occur due to exposure of such individuals to SO2 concentrations of
11                0.6 to 1.0 ppm while physically active.  That is, substantial percentages (5:20 to
12                25%) of mild or moderate asthmatic individuals exposed to 0.6 to 1.0 ppm SO2
13                during moderate exercise would be expected to have respiratory function changes
14                and severity of respiratory  symptoms that distinctly exceed those experienced as
15                typical daily variation  in lung function or in response to other stimuli, e.g.,
16                moderate exercise or cold/dry air. The severity of the effects for many of the
17                responders, furthermore, are likely to be sufficient to be of concern, i.e., to cause
18                disruption of ongoing activities, use of bronchodilator medication, and/or possible
19                seeking of medical attention. Again, however, for those so affected,
20                bronchodilator treatment would likely lead to rapid amelioration of the distress  or
21                it would be relatively transient  (not more than a few hours) and unlikely to
22                reoccur if reexposure to SO2 occurred within the next several hours after initial
23                exposure.  Also, the intensity of distress is much more likely to be perceived as
24                an "asthma attack" than would  be the case for most 0.2 to 0.5 ppm SO2 effects,
25                although it still would appear to be  relatively unlikely that the short-lived
26                symptoms would be sufficient to cause many to seek emergency medical attention
27                for reasons noted above.
28
29            (3)  The relative health significance of the above types of response is difficult to
30                judge.  However,  the degree of concern for effects of the magnitude and severity
31                expected at 0.6 to 1.0 ppm SO2 exceeds that for those responses likely to be seen
32                with 0.2 to 0.5 ppm exposures of physically active asthmatic individuals. For
33                most mild to moderate asthmatic persons, effects induced by acute, brief (2  to
34                10 min) exposures to SO2 at such concentrations (^0.5 ppm) would generally be
35                barely perceptible (if perceived at all) and not of any medical concern.  For a few
36                others among the most sensitive responders, responses may be of such magnitude
37                and severity to be viewed as more than a mild annoyance—although the resulting
38                distress would probably be short-lived even if not treated with medication and has
39                not been demonstrated to be a harbinger of any more serious, chronic health
40                sequelae.  At 0.6 to 1.0 ppm SO2, on the other hand, the effects per  se are more
41                likely to be of sufficient magnitude and severity for S:20 to 25 % of mild or
42                moderate asthmatic individuals to be both perceptible  and thought of as being of
43                some immediate health concern.  If such effects were  to be experienced often in
44                response to ambient SO2 exposures, then the degree of concern would increase.
45                Therefore, the likely frequency of occurrence of such SC^-induced effects is one
46                of the factors that should be considered in determining the public health
47                significance of ambient SO2 exposures.

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 1            (4)  The possibility exists that, bronchodilator medication use before engaging in
 2                physical exercise might prophylactically protect against the above types of effects
 3                due to SO2 exposure during physical exertion.  This may be true for some
 4                asthmatic individuals, but given relatively low medication usage compliance rates
 5                for many mild or moderate asthma patients (see Section 4.4 and Appendix B
 6                Smith memo), pre-exercise bronchodilator use would not be likely to occur  (and,
 7                therefore, offer protection) for many potentially affected sensitive individuals.
 8                In evaluating the possible frequency with which mild to moderate asthmatic
 9                persons may be sufficiently affected by SO2 exposures so as  to disrupt their
10                normal daily activities,  attention should be focussed on estimation of the
11                frequency of occurence of SO2 exposures (at 0.6 to 1.0 ppm or higher) in
12                combination with increased physical activity (moderate or greater exercise levels).
13                Greater concern would  exist for S^ effects in that fraction of adolescent or adult
14                mild or moderate asthmatic population segments who regularly exercise outdoors
15                (e.g., jogging, tennis, etc.), are involved with outdoor athletics (e.g., high school
16                sports), or are employed in occupations requiring frequent increased physical
17                exertion. Similarly,  children with mild to moderate asthma may also be of
18                concern, given the tendency for children to generally be much more physically
19                active than adults.
20

21     5.7   POPULATION GROUPS AT RISK

22           As noted above, mild or moderate asthmatic children and physically active adolescents

23     or adults represent population  segments likely to be  at special risk for potential SO2 exposure
24     effects. In addition, based on information discussed in  Section 2.1  certain minority group

25     individuals (e.g., Black, Hispanic)  may also represent population segments at increased
26     potential risk for SO2 respiratory effects, given the finding of distinctly higher asthma

27     mortality rates reported among non-white individuals in large urban centers such as Chicago
28     and New York.  It should be noted that no specific evidence  has been brought forward to
29     date that implicates SO2 as contributing to increased asthma mortality rates observed among
30     non-white population groups.  Furthermore, epidemiologic evaluations of possible SO2
31     effects on asthma rates in New York City's "asthma alley" areas (Brooklyn, Harlem) did not
32     find evidence of significant associations between either 24 h average SO2 concentrations or

33     briefer 1 h SO2 excursions above 0.1 ppm and increased visits to hospital emergency rooms

34     for asthma (Goldstein and Block, 1974; Goldstein and Arthur, 1978; Goldstein and

35     Weinstein, 1986). However, it is not clear to what  extent epidemiologic studies might

36     feasibly detect possible associations between very  brief  (< 10 min), geographically highly

37     localized peak SO2 exposures and respiratory  effects in asthmatic individuals.


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54


         March 1994                                     49         DRAFT-DO NOT QUOTE OR CITE

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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
                         A-l

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            TABLE A-l.  SUMMARY OF KEY CONTROLLED HUMAN EXPOSURE STUDIES  (PRIOR TO 1987)
      OF PULMONARY FUNCTION EFFECTS DUE TO  EXPOSURE OF ASTHMATICS TO SO2 (AS EVALUATED
                                                               IN U.S. EPA, 1986)
                       Number of
Concentration  Duration   Subjects*    Exposure Mode  Exposure Status
                                                                Observations
                                                                                                      Comments
                                                                                                                                   References
0.1 ppm 3 min 8
Oral-
mouthpiece
22 °C
0%RH
, AH < 1
Hyperventilation
to VE =
51 1/min
Ventilation rate needed to increase SR,,W by
80% over resting baseline shifted by 3.8 1/min
(7 %) less than that needed for comparable
HIB in dry air.
Symptom data not reported. Suggests
marginal increase in hyperventilation needed
to produce HIB in dry air. Health
significance unclear.
Sheppard et al. (1984)
0.2 ppm
5 min
23
0.2 ppm      5 min      8
0.25 ppm
10 to      10
40 min
0.25 ppm      5 min      (1) 19
                       (2)9
0.25 ppm      10 min    28
             to
             75 min
           Chamber-
           23 °C
           85% RH
           AH = 17.5

           Chamber-
           5 °C
           (1) 50% RH
           AH = 3.4
           (2) 85% RH
           AH = 5.8
           Chamber-
           23 °C
           70% RH
           AH = 14.4
           Chamber
           23 "C
           D.P.  = 7.6 °
           (36% RH)
           AH = 7.4
                     Chamber
                     26 °C
                     70% RH
                     AH = 17.1
                                   Exercising
                                   VE = 48 1/min
                                   Exercising
                                   VE = 50 1/min
Exercising
VE = 35 1/min
Exercising
(1) VE =
60 1/min
estimated
(750 kpm-min)
<2)VE =
80-90 1/min
estimated
(1,000 kpm-min)
Intermittent
exercise
(3  10 min
periods)
VE = 42 1/min
                No significant change in SR,,,, FEVj, FVC,
                PEFR, Vmax25_75 over exercise control.
                Possibly statistically significant increase in
                overall symptom score but not for any one
                symptom.
                No significant changes in SRaw, FEVj, FVC,
                SOaw over exercise control for either RH
                level. Suggestion of small increase in
                symptoms but no statistics given.
No significant changes in Raw, FEVj,
MEF4Q, with small (4%) change in Vmax50.
No clear increase in symptoms, suggestion of
increased response in 2 of 10 subjects.
With 750 kpm/min exercise, increase in SRaw
in S02 (mean = 134%) signif. greater than
clean air (mean = 77%).  At 1,000 kpm/min,
no sig. diff. between S02 and clean air.
                                         No significant changes in SRaw, TGV,
                                         resistance impedence for any of measurement
                                         periods. No significant changes in symptoms.
                                      No measurable physiologic changes with      Linn et al. (1983b)
                                      possible increase in symptom scores of
                                      uncertain significance.
                                      No measurable enhancement of SC>2 response   Linn et al. (1984a)
                                      for 5 °C, 50% RH. Symptom score results
                                      of uncertain significance.
Schachteretal. (1984)
                                                                                                                              Bethel et al. (1985)
Indicates no effect.  Changes even in
sensitive subjects of uncertain health
significance.

Effects at this level small or non-existent in
comparison to heavy exercise alone. No
symptoms reported. Response highly
variable. Suggests 0.25 close to threshold for
bronchoconstriction.
                                      No measurable physiological or symptoms     Roger et al.
                                      changes seen with .25 ppm SO2 at this       (1985)
                                      exercise level.

-------
      TABLE A-l (cont'd).  SUMMARY OF KEY CONTROLLED HUMAN EXPOSURE STUDIES (PRIOR TO  1987)
     OF PULMONARY FUNCTION EFFECTS DUE TO EXPOSURE OF ASTHMATICS TO SO2 (AS EVALUATED
                                                             IN U.S. EPA, 1986)
Concentration  Duration
Number of
Subjects*    Exposure Mode
Exposure Status
                             Observations
                                                                                                                  Comments
                                                                                             References
0.25 ppm 3 min 8



0.3 ppm 5 min 24








0.4 ppm 5 min 23



Oral-mouthpiece
22 °C
0% RH
AH = <1
Chamber
80% RH
(l)-6 °C
(2)7 °C
(3) 21 °C

(1) AH = 2.5
(2) AH = 6.2
(3) AH = 14.7
Chamber
23 °C
85% RH
AH = 17.5
Hyperventilation to
VE = 51 1/min


Exercising
VE = 50 1/min







Exercising
VE = 48 1/min


Ventilation needed to increase SRaw by 80%
over resting base-line shifted to 5.6 1/min
(10%) less than that needed for comparable
HIB in dry air.
At -6 "C, SRaw increased 94% in air and
105% inS02.

At 7 °C SRaw increased 59% in air and 87%
in SO2.

At 21 °C SRaw increased 28% in air and 59%
in SO2. Increase in symptom scores at all
temperatures slightly greater in SO2 than in air.
Increased SRaw in S02 (69%) sig. diff. than
increase in clean air (35%). Significant
decrements in Vmax (25-75) (mean = 10%),
but no significant changes in FEVj . Significant
Symptom data not reported. Suggests small
decrease in exercise needed to produce HIB
in dry air. Health significance unclear.

Significant main effects at 0.3 ppm not
reported. Symptom score changes generally
mild and of uncertain significance to health.
Under test conditions, results indicate that
SO2 and moist cold air effects are additive
or less than additive.



Indicates moderate broncocontriction.
Overall symptom changes mild, but
responses suggestive of clinical significance
in at least one subject.
Sheppard et al.
(1984)


Linnetal. (1984b)








Linnetal. (1983b)



0.4 ppm      5 min     8
0.5 ppm       10 to      10
             40 min
0.5 ppm      5 min      10
           Chamber
           5 °C
           (1) 50% RH
           (2)81%RH
           (1) AH = 3.4
           (2) AH = 5.8
           Chamber
           23 °C
           70% RH
           AH = 14.4
           Chamber
           23 °C
           41%RH
           AH 8.4
Exercising
V  = 50 1/min
Exercising
VE = 35 1/min
Exercising
VE = 60 1/min
estimated
(750 kpm-min)
                increase in overall symptom score, but only one
                of 12 symptom categories signif. increased.
                One subject required medication to relieve
                distress.
                Apparent increase in SRaw (based on graphical
                depiction) and symptom score over exercise
                alone.  Symptom score increase clearly larger
                for 50% RH than for 81 % RH.
                No signif. changes in Raw, FEVj,
                small (mean = 6%) decrement in Vmax5Q-  N°
                clear increase in symptoms. Some suggestions
                of increased FEVj response in 2 or 3 subjects.
                Increase in SRaw in SO2 (mean = 238%) sig.
                diff. than increase in clean air (mean = 39%).
                Substantial variability in subjects; one showed
                eight-fold increase
No statistics reported for SRaw changes.
Significance of SOaw and FEVj at 0.4 ppm
not reported; indicates subjective response
enhanced for dryer cool air even when
measure of functional changes comparable
to moist air.
Indicates minimal constriction for group at
this exercise rate.
Indicates substantial SOj-induced
bronchoconstriction at high exercise rate
and mod. RH.  No symptom data reported
but extent of SRaw changes suggestive of
clinical significance.
Linn et al. (1984a)
Schachteret al.
(1984)
Bethel et al. (1983a)

-------
      TABLE A-l (cont'd).  SUMMARY OF KEY CONTROLLED HUMAN EXPOSURE STUDIES (PRIOR TO 1987)
      OF PULMONARY FUNCTION EFFECTS DUE TO EXPOSURE OF ASTHMATICS TO SO2 (AS EVALUATED
                                                               IN U.S. EPA, 1986)
                      Number of
Concentration  Duration  Subjects*   Exposure Mode  Exposure Status
                                                                Observations
                                                                                                       Comments
                                                                                                                                  References
0.5 ppm
5 min
80% RH,
23 °C
(1) Face mask
(2) Mouthpiece
AH = 16.5
                                   Exercising
                                   (1) VE = 27 1/min
                                   (2) VE = 41 1/min
                                   (3) VE = 61 1/min
0.5 ppm
30 min
 rest
10 min
exercise
22 °C
75 + %RH
AH =  14.6+
0.5 ppm
              Mouthpiece
              5-6 x rest VE

30 min
rest
20 min
exercise
7
10
(14-18 yr)


22 °C
75% RH
AH = 14.6

Facemask
5-6 x rest VE
Mouthpiece
43 1/min exercise

                                   Facemask
Facemask exposure: No slat. sig. mean
change in SR,,W with air or SC>2 at low or
mod. exercise rate.  For high exercise,
increase in SRaw in SC>2 (219%) sig. larger
than increase in clean air (25%) compared to
mean baseline SRaw. Percent ventilation
breathed orally for the three exercise rates
were: (1) 50%, (2) 52%,  (3) 61 %.

Mouthpiece exposure:  No sig. mean change
in SRaw for low exercise rate with moderate
exercise, increased SRaw in SC>2 (231 %) sig.
larger than clean air (5%).  With high
exercise, increased SRaw in SO2 (306%) sig.
larger than clean air (25%).
Mouthpiece exposure:  FEVj0 decreased,
-15% (-4% in air); RT increased 47%;
Vmax50> Vmax75 decreased -30, -35%.
                                                   Facemask: No significant
                                                   changes.
                                                   Increase in nasal resistance of 32%, but not
                                                   significant.  FEVj decrease -24%, V^^Q
                                                   -46%; Vrog^s -56%. RT increased 60 %.
                                                                Significant increase in nasal resistance of
                                                                30%. FEV,  decreased -16% VmaxS,
                                                                Vmax75 -26%
                                                                     Indicates SOj induced constriction enhanced
                                                                     by increased work rate, with protection
                                                                     afforded by oronasal (vs. oral) breathing
                                                                     greater at mod. than at high exercise rates.
                                                                     Asthmatics with rhinitis or other nasal
                                                                     blockages breathe more through mouth and
                                                                     appear at greater risk to SC>2 effects.
                                     Bethel et al. (I983b)
Indicates that mouthpiece
breathing exacerbates the
effect of SC>2 in asthmatics.
                                      Indicates SO2 may cause increased nasal
                                      resistance in asthmatics, which may result in
                                      more oral breathing and consequently more
                                      bronchoconstriction.
Koeniget al. (1983)
                                                                                                         Koenig et al. (1985)

-------
TABLE A-l (cont'd). SUMMARY OF KEY CONTROLLED HUMAN EXPOSURE STUDIES (PRIOR TO 1987)
OF PULMONARY FUNCTION EFFECTS DUE TO EXPOSURE OF ASTHMATICS TO SO2 (AS EVALUATED
                                 IN U.S. EPA, 1986)
Concentration
0.5 ppm








0.5 ppm









0.5 ppm






Number of
Duration Subjects*
10 min 28
to 75 min







3 min, 8
repeated 3
times in
succession
at 30 min
intervals,
again after
24 h and
1 week
later
3 min 7






Exposure Mode
Chamber
26 °C
70% RH
AH = 17.1





Oral-mouthpiece
23 °C
82% RH
AH = 16.9






Oral-mouthpiece
(1) 23 °C
77% RH
(2) -11 °C,
"Dry"
(1) AH = 15.8
P) AH < 1
Exposure Status
Intermittent
exercise
(three 10 min
periods)
VE = 42 1/min




Hyperventilation
(varied for each
subject)







Hyperventilation
to "Threshold"
Vg for each
subject
(30-50 1/min)


Observations
Increased SRaw in S02 (93%) sig. larger than in
clean air (47%). SRaw increase after second and
third exercise periods sig. less than after first
exercise period. No significant changes in FVC,
FEVj, FEF. Group mean symptoms for 20
subjects not sig. increased. Substantial variability
in subjects, with one showing 11 -fold increase in
SRaw and requiring medication to relieve
pronounced symptoms.
Sig. increase in SRaw (x~= 104%) after first
3 min exposure. After 30 min rest, second
response sig. but smaller (x~= 35%); response
after third exposure still smaller (x~ = 30%).
SRaw increase at 24 h (x~= 83 %) and 1 week
(x~ = 129%) not sig. difT. from increase after first
3 min exposure.



By design, increases in SRaw or symptoms not sig.
for SO2 in warm, humidified air or cold dry air
alone. Sig. increase in SRaw (x~ = 222%) for
combination of SO2 and cold dry air. Six of seven
subjects report wheezing and/or shortness of
breath; two asked for medication. Symptoms not
good indicator of of measured SRj,w.
Comments
Extent of effects are decreased after short-term
repeated exercise. Broad degree of sensitivity
to SC>2 with about 25 % of subjects showing a
100% increase in SRaw. Symptoms in at least
one subject of clear clinical significance.




Indicates repeated esposures to SO^ can induce
tolerance to bronchoconstrictive effects of SO2
over short periods (>30 min) but not for
longer periods.






Indicates that airway cooling or drying can
increase SO2 associated bronchoconstriction in
hyperventilating asthmatics. Suggests possible
synergism for these combinations.



References
Roger et al. (1985)








Sheppardetal. (1983)









Bethel et al. (1984)







-------
       TABLE A-l (cont'd). SUMMARY OF KEY CONTROLLED HUMAN EXPOSURE STUDIES (PRIOR TO 1987)
       OF PULMONARY FUNCTION EFFECTS DUE TO EXPOSURE OF ASTHMATICS TO SO2 (AS EVALUATED
                                       IN U.S. EPA, 1986)
ON
Concentration Duration
0.6 ppm 5 min







0.6 ppm 5 min







0.6 ppm Total 6 h
on 2
successive
days (2 X
5 min exerc.
each day,
separated by
5h)
0.6 ppm 5 min





Number of
Subjects* Exposure Mode Exposure Status
24 Chamber Exercising
80% RH VE = 50 1/min
(1) -6 °C
(2)7°C
(3) 21 °C
(1) AH = 2.5
(2) AH = 6.2
(3) AH = 14.7
22 Chamber Exercise
21 °C, 38 °C VE = 50 1/min
20% RH,
80% RH
AH = 3.7,
14.7 at 21 °C
AH = 9.3,
37.0 at 38 °C
14 Chamber Exercise
(18-33) 22 °C VE = 50 !/min
85% RH
AH = 16.5




24 Chamber- Exercising
85% RH VE = 50 1/min
(1) 5 °C
(2) 22 °C
(1) AH = 3.4
(2) AH = 16.5
Observations
Increased SRaw in SOj sig. greater than in
clean air for all three temperatures. At
-6 "C, SRaw increased 94% in air and
187% in SO2. At 7 °C, SRaw increased
58% in air and 207% in SO2. At 21 °C,
SRaw increased 28% in air and 150% in
SO2. Symptom scores sig. greater in SO2
than in air at all three temperatures.
SRaw changes in clean air ranged from -4%
to +12%. With S02, at 21 °C SRaw
increased 206% with dry and 157% with
humid air, while at 38 °C SRaw increased
89% in dry air and 39% in humid air.



After correction for clean air EIB, SRaw
increased 136, 120, 147, 100% on the
early-day 1 , late-day 1 , early-day 2, late-
day 2. No difference between times or
days.



At 5 °C, increased SRaw with S02 (182%)
sig. greater than clean air (38%). At
22 °C, increased SRaw with S02 (132%)
sig. greater than clean air (27%). Lower
respiratory and total symptom scores much
greater in S02 than in clean air.
Comments
Suggests that the bronchconstrictive effects
of cold air and SC>2 combine in an additive
or less-than-additive fashion. Also some
suggestion of cold air-SO2 interaction in
total asthma score. SRaw changes are
suggestive of clinical significance at all
temperatures.

Indicates the importance of airway drying as
an exacerbating factor in the induction of
SO2-bronchoconstriction .





Indicates that refractory period for SO2-
induced bronchoconstriction is less than 5 h.






Suggests bronchoconstrictive effects of cold,
moist air may increase SO2 effects, but
under these conditions, enhancement is
inconsistent and not significant). Both
symptoms, SRaw changes suggestive of
clinical significance at both temperatures.
References
Linn et al. (1984b)







Linn et al. (1985)







Linn et al. (1984c)







Linn et al. (1984a)






-------
             TABLE A-l (cont'd).  SUMMARY OF KEY CONTROLLED HUMAN EXPOSURE STUDIES (PRIOR TO  1987)
            OF PULMONARY FUNCTION EFFECTS DUE TO EXPOSURE OF ASTHMATICS TO SO2 (AS EVALUATED
                                                                        IN U.S. EPA, 1986)
      Concentration  Duration
          Number of
          Subjects*
                                         Exposure Mode   Exposure Status
                                            Observations
                                                                                    Comments
                                                                                                                 References
      0.6 ppm
5 min
          8
      0.6 ppm
5 min
          23
>
-Li
      0.75 ppm
      0.75 ppm
3h
10 min
exercise
at
beginning
                    10 min
                              17
                             23
Chamber-
5 °C
(1) 50% RH
(2) 81%RH
(1) AH = 3.4
(2) AH = 5.8
Chamber-
23 °C
85% RH
AH = 17.5
Chamber
22 °C,
85% RH
AH = 16.5
                     Chamber
                     23 °C,
                     90% RH
                     (1) oralnasal
                     (2) mouthpiece
                    , AH =18.5
Exercising       Significant increase in SRaw and symptom
VE = 50 1/min   scores over exercise alone for both humidities
               (graphical depiction). No sig. diff. between
Pilot study       humidities at this temperature.
Exercising       Increased SRjW in SC>2 (120%) sig. greater
VE = 48 1/min   than in air (36%).  Significant decline in FVC
               (mean = 3%), FEVj (mean = -13%), PEFR
               (mean = -26%) Vmax25_75 fx"=  -26%).
               Sig. increase in:  total symptom score; number
               of subjects with increased  symptom score (21
               of 23), and positive reading on discomfort
               meter (12 of 23), and in 4 individual symptom
               categories (cough, substantial irritation,
               wheezing and chest tightness). Three subjects
               required medication to relieve symptoms. No
               apparent effects next day or week.

Exercising       No clean air control.  With SO2, SRaw
45 1/min        increased 263 %, FEV1 decreased 20 % after
               exercise (SRaw increased 322% in second series
               with no spirometry).  Symptom scores
               increased after exercise. SRaw and symptom
               scores were not significantly elevated after 1 h
               of recovery in SC>2.

Exercising       In clean air, SRaw increased 54 % by either
VE = 40 1/min   oronasal or mouthpiece breathing.  In  SC>2,
               SRaw increased 186% by oronasal breathing
               and 321 % by mouthpiece.  Decline in FVC,
               FEVj, PEFR, and Vmax25_5Q for both exposure
               routes. Sig. increase in symptom score, both
               routes. SRaw increase sig. greater for oral
               exposures; symptoms/other functional  measure
               changes greater for oral, but not sig. so.
                                                                                            Suggests that under these conditions, SOj
                                                                                            response apparently not enhanced by lower
                                                                                            humidity or cool air which has a low water
                                                                                            content already.
                                                                                            Bronchoconstriction function changes, high
                                                                                            symptom scores, and medication requests
                                                                                            indicate SOj effects of likely medical
                                                                                            significance.  However, effects short-lived,
                                                                                            do not persist into next day.
Indicates that recovery is complete for most
subjects within 1 h of SC>2 + exercise-
induced bronchoconstriction.
                                                                      Indicates oronasal breathing ameliorates
                                                                      bronchoconstrictive effects of SC>2, but less
                                                                      effective against symptoms. Functional
                                                                      changes and symptoms indicate clinical
                                                                      significance.
                                      Linn et at. (1984a)
                                      Linnet al. (1983b)
Hackney et al. (1984)
                                     Linnet al. (1983a)

-------
         TABLE A-l (cont'd). SUMMARY OF KEY CONTROLLED HUMAN EXPOSURE STUDIES (PRIOR TO 1987)
         OF PULMONARY FUNCTION EFFECTS DUE TO EXPOSURE OF ASTHMATICS TO SO2 (AS EVALUATED
                                                  IN U.S. EPA, 1986)
>
oo
Concentration
0.75 ppm






0.75 ppm



1 .0 ppm



1 .0 ppm



Duration
10 to 40
min





10 min



30 min
rest
10 min
exercise
10 to
40 min


Number of
Subjects* Exposure Mode
10 Jhamber-
23 °C
70* RH
AH = 14.4



10 22 °C
75% RH
AH = 14.6

9 22 °C
75% RH
AH = 14.6

10 Chamber-
23 °C
70% RH
AH = 14.4
Exposure Status
Exercising
VE = 35 1/min





Mouthpiece
Exercising
VE = 34 1/min

Mouthpiece
5-6 x rest VE
(30-50 1/min)

Exercising
VE = 35 1/min


Observations
Significant changes in FEV j (mean = -8 %),
MEF40 (mean = -22%), Vmax50 (mean =
1 1 %), and RAW (mean = 40%). No sig.
discomfort persisted 10 min after exposure.
Apparent large increase in lower airway
symptom complaints. Wide variable responses
among subjects.
Premedication with albuterol blocked the 15%
decrease in FEVj which occurred with SC^.
Albuterol also caused a 6-8% increase in
baseline FEVj 0.
FEV10 (-23%), Vmax50 (-51%), Vmax7S
(-61 %), RT (+71 %). Recovery was slower
than after 0.5 ppm exposures.

Significant changes in FEVj (mean = —14%),
MEF40 (mean = 27%), V^^Q (mean =
-22%), and RAW (mean = -54%). No sig.
decrements persist 10 min after exposure.
Comments
Indicates bronchoconstriction Symptoms,
functional changes and additive effects of
clinical significance began between
0.5 and 0.75 ppm for this study group and
conditions on average.


No symptoms. Albuterol prevented
SO2-induced bronchoconstriction.


Suggests that more severe SO^-induced
bronchoconstriction requires longer
recovery than less pronounced changes at
lower concentration.
Indicates bronchoconstriction. Symptoms
and functional changes suggestive of
clinical significance.

References
Schachteretal. (1984)






Koeniget al. (1987)



Koenigetal. (1983b)



Schachteretal. (1984)



                                                 Apparent large concentration-related increase in
                                                 lower airway symptom complaints. Three
                                                 subjects apparently nonresponsive (based on
                                                 FEVj) even at this concentration, with at least
                                                 one very sensitive subject showing > 50%
                                                 FEV, decline.

-------
TABLE A-l (cont'd). SUMMARY OF KEY CONTROLLED HUMAN EXPOSURE STUDIES (PRIOR TO 1987)
OF PULMONARY FUNCTION EFFECTS DUE TO EXPOSURE OF ASTHMATICS TO SO2 (AS EVALUATED
                                          IN U.S. EPA, 1986)
Concentration Duration
1.0 ppm 10 to 75 min












1.0 ppm (1) 10 mins..
reported
3 times in
succession
with 15 min
intervals

(2) 30 min
continuous
exercise
0.25 to 10 min,
2 ppm different days


Number of
Subjects* Exposure Mode Exposure Status
27 Chamber-
26°C
70% RH
AH = 17.1









10 Chamber Intermittent
26°C Exercise
70% RH VE = 41 1/min
AH - 17 1






27 Chamber Exercise
26 "C VE = 42 1/min
70% RH
AH = 17.1
Observations
Sig. decrease in SRaw after all 3 exercise
periods but response decreases with time.
First Exercise: Increased SR,,W in SO2
(190%) sig. greater than air (47%).
Second Exercise: Increased SR,,W in SO2
(147%) sig. greater than air (34%). Third
Exercise: Increased SRgw in S&2 (116%)
sig. greater than in air (30%). Group mean
symptom analysis for 20 subjects showed
sig. increase in shortness of breath and
chest discomfort. Substant. variability in
subject response; one unable to go beyond
35 min point.
First Exercise: Significant increase in total
SRaw (mean = 172%). Second Exercise:
Significant increase in total SRaw
(mean = 137%). Third Exercise: Sig.
increase in total SRaw (mean = 106%).
Attenuation with time occurred in 4 of
10 subjects. Continuous Exercise: Sig.
increase in total SRaw (mean = 233 %)
after 30 min.

Concentration response relationships for
four exposures interpolated for each subject
to determine PC^O^, the SO2
concentration producing a 100% increase in
Comments
Respiratory impedence suggests SOj
induced bronchoconstriction mostly in
peripheral airways. Decreased response
with time suggests short-term tolerance,
but effects of clincal significance occur
even after third exercise period.







Indicates mechanism responsible for
apparent tolerance to repeated short-term
exposures to SO2 does not reduce
responses to continuous exercise for
comparable time periods.





Reflects additional analyses of data from
first exposure period in experiment
reported in Roger et al. (1985).
Quantifies the variability in response
References
Roger et at. (1985)












Kehrl et al. (1987)









Horstmanet al. (1986)



                                            Cumulative plot shows 25 % of subjects
                                            with PC(SC>2) <0.5 ppm, median PC(SO2)
                                            was 0.75 ppm, and about 20% of subjects
                                            have a PC(SO2) > 1.95 ppm.
among asthmatics for functional changes
of potential clinical significance. Suggests
effects of concern in some subjects may
extend down to near 0.25 ppm.

-------
     TABLE A-l (cont'd).  SUMMARY OF KEY CONTROLLED HUMAN EXPOSURE STUDIES (PRIOR TO 1987)
    OF PULMONARY FUNCTION EFFECTS DUE TO EXPOSURE OF ASTHMATICS TO SO2 (AS EVALUATED
                                         IN U.S. EPA, 1986)
Concentration
0.125 to
2 ppm











0.25 to
8 ppm




0.25 to
8 ppm





Duration
3 min,
doubling
successive
exposures
with no
breaks







3 min at each
concentration




3 min at each
concentration





Number of
Subjects* Exposure Mode
8 Oral-
mouthpiece
(1) -20°C
0%RH
(2) 22 °C
0%RH
(3) 22°C
70% RH
(1) AH < 1
(2) AH < 1
(3) AH = 13.6


10 23 °C
(Dewpoint
15°C)
AH = 12.5
RH = 61 %

10 23 °C
(Dewpoint
15°C)
AH = 12.5
RH = 61 %


Exposure Status
Hyperventilation
(to VE = 30 to
40 1/min)










Mouthpiece
Isocapnic
Hyperpnea
VE = 40 1/min


Mouthpiece
Isocapnic
Hyperpnea
VE = 40 1/min



Observations
By design, SRaw increase for clean air
alone not sig. Concentration response
relationships for 4 to 5 exposures
interpolated for each subject to determine
PC100 (SO2 level producing a 100%
increase over resting baseline). Mean
PCjQQ for differing conditions were: Dry
Cold Air - 0.51 ppm; Dry Warm Air -
0.60 ppm; Humid Warm Air =
0.87 ppm; PCjgo f°r humid warm air sig.
greater than for dry cold or dry warm air
(which were not sig. different from each
other).
Premedication with placebo, 20 mg, or
200 mg cromolyn. SO2 dose-response to
3 min exposures starting at 0.25.
SOj dose which increased SRaw by 8
units was 0.35, 0.94, and 1.98 ppm
respectively.
Premedication (200 mg cromolyn plus
2 mg atropine) more effective than either
drug alone in inhibiting SO2-induced
bronchoconstriction. SO^ dose which
increased SRaw by 8 units was 1.16 ppm
(atropine), 1.20 ppm (cromolyn), or 3.66
ppm (both).
Comments
Nature of doubling concentrations may
have affected PC^ estimates. Results
quantify wide variability among subjects.
Indicates very dry air potentiates SO2
bronchoconstriction regardless of
temperature.







Cromolyn decreased airway reactivity to
SO2. High dose of cromolyn caused
increased response to methacholine.



Similar effect on dry air hyperpnea-
induced bronchoconstriction. The
reproducibility of SO2 dose response was
poor.



References
Sheppardet al. (1984)












Myers et al. (1986a)





Myers et al. (1986b)






AH = absolute humidity = g H20 vapour/m of air.
g/m = mglt.
HIB = Hyperventilation Induced Bronchoconstriction

-------
               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

-------
   TABLE B-l.  AVERAGE MAGNITUDES OF LUNG FUNCTION CHANGES AT TESTED SO2 EXPOSURE LEVELS
   AND PERCENTAGES OF SUBJECTS EXHD3ITING CHANGES OF INCREASING SEVERITY AT MODERATE TO
       HIGH EXERCISE LEVELS (VENTH.ATION RATE 40 TO 50 L/MIN), BASED ON U.S. EPA EVALUATION
                        OF DATA FROM SELECTED RECENT CONTROLLED HUMAN STUDDZS
SO2
Cone.
(ppm)
0.4
0.4
0.4
0.4
0.5
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
1.0
Status4
Mild Rl
ModRl
Mild Rl
ModRl
Mild
Mild Rl
ModRl
Mild
Mod
Mild Rl
ModRl
Mild
Mod
Mild
No. of
Subj
16
24
16
24
28
16
24
20
21
16
24
20
21
286

Lung Fxn
Measure
SRaw
SR«w
FEV
FEV
SRaw
SRaw
SRaw
SRaw
SRaw
FEV
FEV
FEV
FEV
SRaw
LUNG
% Total
Change
84
107
-13.4
-16.3
108
206
221
247
208
-18.5
-25.3
-19.4
-28.3
196
FUNCTION DATA1'"'
% Change
from
Exercise
36
83
-1.6
-8.3
48
36
83
58
39
-1.6
-8.3
-3.1
-13.8
48
% Change
from SO2
48
24
-11.5
-7.9
60
170
138
190
168
-17.0
-17.0
-16.3
-14.5
148
CUMULATIVE NO.
>100%
S-15%
25%(4)
21%(5)
38% (6)
25% (6)
18%(5)5
38% (6)
33%(8)
60%(12)
48% (10)
63% (10)
42% (10)
55%(11)
45%(9)
50%(14)7
>200%
<-20%
6%(1)
8% (2)
25% (4)
21%(5)
4%(1)
25% (4)
29% (7)
35% (7)
33% (7)
50% (8)
42% (10)
55%(11)
35% (7)
25% (7)
OF RESPONDERSJ
>300%
«£-30%
0
4%(1)
6%(1)
17%(4)
4%(1)
13% (2)
21%(5)
10% (2)
14%(3)
0
38%(8)
5%(1)
19%(4)
14%(4)
5:500%
<-40%
0
4%(1)
0
8%(2)
4%(1)
6%(1)
13%(3)
5%(1)
5%(1)
0
17%(4)
0
19%(4)
4%(1)
References
Linn et al. (1987)
Linn et al. (1987)
Linn et al. (1987)
Linn et al. (1987)
Roger et al. (1985)
Linn et al. (1987)
Linn et al. (1987)
Linn et al. (1988)
Linn et al. (1990)
Linn et al. (1987)
Linn et al. (1987)
Linn et al. (1988)
Linn et al. (1990)
Roger et al. (1985)
 Lung function (LF) changes given as: the percent total change observed after SO2 exposure, relative to baseline; the percent attributable to exercise, as determined
 from a control exposure with no SO2; and the percent change attributable to SO2, which is the difference between the total change and the change due to exercise.
 The calculations performed were:  % Total Change: ((SO2 Post-Exposure LF—Baseline LF Prior to SO2 Exposure)/Baseline LF Prior to SO2 Exposure) • 100;
 % Change due to Exercise:  ((Exe, Jse [Clean Air] Post-Exposure LF—Baseline LF prior to exercise exposure)/Baseline LF prior to exercise exposure) • 100.
 Thus, in abbreviated form: % Change due to SO2 : ((SO2 Post LF—SO2 Base LF)/SO2 Base LF)—((Exc Post LF—Exc Base LF)/Exc Base LF)) • 100; Change
 due to SO2 and % Change due to Exercise may not total exactly to % Total Change due to rounding.
 Changes in LF calculated by averaging each subject's own individual percent change in LF, rather than from group mean LF measurements.
 Numbers in these columns indicate both percentage and number of subjects (in parenthesis) having a LF change, after correction for exercise, greater than or
 equal to designated LF cutpoints.  The numbers are cumulative; thus the > 100% SRaw category includes individuals with SRaw changes of 200%, 300% etc.
 For instance, 5 moderate asthmatic subjects from Linn et al. (1987) study experienced at least a 100% change in SRaw at 0.4 ppm;  of these 5, 2 had at least a
 200% change and, of these 2, 1 had at least a 500% change.  For FEVj as the LF measure, the lower numbers in the column heading apply. Also, FEVj
 cutpoints refer to number of subjects with a 15% or greater decrease in FEVj, (i.e., FEVj changes 15% or more in a negative direction, indicated as <  —15%
 decrease).
 Status of asthmatics  as mild ("Mild") or moderate ("Mod").  "Rl" indicates data from first round of Linn et al. (1987) study was used here.
 Another subject had  a LF change of 99+ %; if considered essentially a 100% SRaw change, then 21 %(6) had doubling of SRaw.
'Only 27 subjects exposed to 1.0 ppm in Roger et al. (1985) study. The other subject was unable to complete the protocol at 0.5 ppm after experiencing greater
 than 500% increase in SRaw, and he was not exposed to 1.0 ppm.  However, all numbers in this row include this subjects' lung function changes at 0.5 ppm,
 under the assumption that, on average, he would experience at least as great changes in lung function at 1.0 ppm.
 Another subject had  a SRaw change  of 99+%; if considered to be a 100% change in SRaw, then 54%(15) of the subjects doubled SRaw.

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                                    March 4, 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
                                 A—
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
Paniculate 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,
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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 SO^) 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 subj  o*s
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
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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
(FEVi Chg, SYM,
MEDUSE)
MOD for all 3 categories
SEV FEVt + MOD SYM
SEV for all 3 cat.
1990 Mod Asth -50 L/min
Normal Meds
SO2
86%
52%
43%
10%
EXC
33%
10%
5%
0
1988 Mild Asth -50 L/min
Untreated
S02
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 FEVt + MOD SYM
SEV for both cat.
1987 Mod Asth
44 L/min Round 1
S02
58%
33%
33%
8%
EXC
13%
0
0
0
1987 Mild Asth
44 L/min Round 1
S02
50%
13%
6%
0
EXC
0
0
0
0
1.0 ppm SO2
First Exercise Period
Exposure
SEV for SRaw Chg or
SYM
MOD for SRaw + SYM
SEV SR™, MOD SYM
SEV for SRaw and SYM
1985 Mild Asth
42 L/min
SO2
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
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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 SO^.  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).
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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 ¥EV1  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 FEV^ 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 ORCADIAN 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)
n=28
Daily
Change
-8%

-13%

7

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 SC>2 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 FEVj, 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 FEV,," or "Total SR^"
are used when the total change in lung function, representing both the change due  to exercise and the change due
to SO2, is given.
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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 FEVl 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
re* ""led 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 FEVj 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 ¥EVl (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 FEVj (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 g;- sn
lung function change can vary markedly from subject to subject, thus it is possible to have
symptoms without a large change in lung function.  However, by comparing the  figures from
    ^o 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
MAXSYMP =
MOD or worse
28%
38%
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  FEV^
     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 w ~AS 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 8% of the weeks for the 1990 moderate asthmatic
subjects and only 4% 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 (38%) 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,  ough 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 vary considerably
from subject to subject.  Whether these asthmatics would rate their response to SO2 as an
asthma attack is also unclear, although at least some 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
S02
71%
40%
EXC
29%
10%
     Medication use has traditionally been seen as a fairly severe response to an exposure to
an environmental pollutant.  The 1988 and 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 took inhaled bronchodilators at all during the  8 weeks of the
study,  and none of them took 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 in 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 seems 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 asthmatic subjects used inhaled
bronchodilators at least five times a week, on average.  About one-quarter of the moderate
asthmatic subjects may take 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 made on the basis of medication use (Hackney  et al., 1987),
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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 is of interest for several reasons.  First, 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.  Second, information on bronchodilator use allows the
probability of medication use prior to exercise to be roughly estimated.  The  available data
on medication use clearly suggests that very few, if any, of the mild asthmatic individuals in
these studies would be expected to use a bronchodilator routinely before exercise.  The 1987
asthmatic subjects reported very rarely using bronchodilators,  and the 1988 mild asthmatic
subjects that used medications reported using them to relieve symptoms or i  -mticipation of
respiratory stress (allergens or irritants), with very few citing exercise specifically as a
respiratory stress (Hackney et al., 1988a).  Thus, it seems highly unlikely that a significant
portion of these mild asthmatic individuals would use bronchodilators ordinarily 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 tunes 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 hi clinical trials have felt compelled to diminish their workload or terminate
exposure to a pollutant.  Such changes in activity are 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 VH-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
S02
9.5%
15%
12.5%
0%
7%
term. exp. by 1.0 ppm
EXC
0
0
0
0
0
 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 SO % 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 FEVl 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  should 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
           S02.

        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

EPA (U.S. Environmental Protection Agency) (1982) Air Quality Criteria for Particulate Matter and Sulfur
       Oxides.  Environmental Criteria and Assessment Office.  Research Triangle Park, N.C.  EPA-600/8-82-
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EPA (U.S. Environmental Protection Agency) (1986a) Addendum to Air Quality Criteria for Particulate Matter
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EPA (U.S. Environmental Protection Agency) (1986b) Review of the National Ambient Air Quality Standards for
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EPA (U.S. Environmental Protection Agency) (1989) Review of National Ambient Air Quality Standards  for
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EPA (U.S. Environmental Protection Agency) (1994) Supplement to the second addendum (1986) to air quality
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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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Hackney, J.D.; Linn, W.S.; Avol, E.L. (1988b) Responses to sulfur dioxide and exercise by  medication-
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Horstman,  D.H.; Seal,  E., Jr.; Folinsbee, L.J.; Ives, P.; Roger, L.J.  (1988) The relationship  between exposure
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Linn, W.S.; Avol, E.L.; Peng, R.C.; Shamoo, D.A.; Hackney, J.D.  (1987) Replicated dose-response study of
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Linn, W.S.; Avol, E.L.; Shamoo, D.A.; Peng, R.C.; Spier,  C.E.; Smith, M.N.; Hackney, J.D. (1988) Effect of
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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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Roger, L.J.; Kehrl, H.R.; Hazucha, M.; Horstman, D.H. (1985) Bronchoconstriction in asthmatics exposed to
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Smith, E. (1994)  Additional information on the analysis described in Smith (1994) "Assessment of data.  . ." ,
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