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Review of the health risks associated with nitrogen dioxide and sulfur dioxide in indoor air Brauer, Michael; Henderson, Sarah; Kirkham, Tracy; Lee, Kit Shan; Rich, Kira; Teschke, Kay 2002-12-01

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Table 4.5 Controlled Human Exposure Studies of the Health Effects of SO2  Reference  Speizer and Frank, 1966  Snell and Luchsinger, 1969  Location  Boston, MA, USA  Washington, DC, USA  Route of Number of Exposure Subjects  Mouthpiece and Chamber  8 (8 male, 0 female)  Mouthpiece  11 Phase 1: n=9 (5 male, 4 female); Phase 2: n=5 (3 from Phase 1 plus 2 additional subjects), gender not provided.  Characteristics of Study  Duration of Exposure  SO2 Concentration  Subjects were exposed in groups of 6 to one of two concentrations of SO2 by nose or by mouth (24 experiments in total). Exposures were randomized, and administered at least 1 month apart.  10 minutes  15 or 28 ppm  Phase 1: adults with no history of significant pulmonary or allergic diseases, aged 20 to 40 years; Phase 2: subject description not indicated.  Phase 1: Subjects were exposed to distilled water and saline aerosol, SO2, SO2 with saline aerosol, and SO2 with distilled water aerosol. Phase 2: Subjects breathed 1 of 3 types of gas mixtures either through a mouthpiece (orally) or a mask (nasally) : 5 ppm SO2 in air, 0.5 or 5 ppm in distilled water aerosol. All exposures were on separate, randomized days.  15 minutes  Phase 1: 0.5, 1, and 5 ppm; Phase 2: 0.5, 5 ppm  3 hours  5 ppm  Subject Description  Healthy volunteers  Wolff, Dolovich et al., 1975  Hamilton, ON, Canada  Chamber  9 (7 male, 2 female)  Healthy, non-smoking adults aged 21-27  Subjects were exposed to hospital air twice and SO2 once in 3 separate experiments conducted at 1-week intervals. Subjects inhaled a radioactively tagged aerosol prior to each experiment via a bolus technique that achieves deposition in large airways.  Kreisman, Mitchell et al., 1976  New Haven, CT, USA  Mouthpiece  18  Healthy subjects including 3 smokers and 3 ex-smokers, aged 22 to 34 years.  Subjects breathed 0.5-5 ppm SO2 for 1-5 minutes at rest and during light exercise.  1-5 minutes  0.5-5 ppm  Healthy, exercising, non-smoking adults.  Subjects inhaled a radiolabelled saline aerosol (using a bolus technique to achieve deposition primarily in the large airways) before being exposed (oral breathing only) to either SO2 or to distilled water mist during intermittent exercise.  2.5 hours  5 ppm  Newhouse, Dolovich and Obminski, 1978  Jaeger, Tribble and Wittig, 1979  von Nieding, Wagner et al., 1979  Albuquerque, NM, USA  FL, USA  Germany  Chamber  10 (9 male, 1 female)  Mouthpiece  80 (45 male, 35 female)  40 healthy nonsmokers aged 25 ± 5.7 years and 40 asthmatic subjects aged 27.1 ± 9.2 years.  Subjects breathed either air or SO2 orally in an environmental chamber at the same time of day on separate, randomized occasions.  3 hours  0.5 ppm  11 (11 male, 0 female)  Healthy subjects aged 23-38 years (including 2 smokers and 2 atopics with an allergy to pollen).  Subjects were exposed in groups of 2 to purified air, 5 ppm NO2, 0.1 ppm O3 and SO2 alone, 5 ppm NO2 and SO2, 5 ppm NO2 and 0.1 ppm O3, and 5 ppm NO2, SO2 and 0.1 ppm O3.  2 hours  5 ppm  Chamber  #  Main Comparison  Positive Results  Null or Negative Results  Changes in pulmonary flow resistance, lung volume and symptoms before and after exposure were compared for the two SO2 concentrations and for nasal and oral inspiration.  Pulmonary flow resistance increased significantly in 9/12 experiments when SO2 was administered by mouth. The magnitude of this change was on average greater at 28 ppm than at 15 ppm. When exposed by mouth, most of the subjects coughed several times during the first few minutes and had slight burning sensations of the throat and substernal area for at least 5 minutes.  During exposure to the same SO2 concentrations by nose, pulmonary flow resistance increased significantly in only 3/12 experiments and decreased in 1 experiment. When exposed by nose, there was little coughing and no chest symptoms, although some subjects experienced irritation of the posterior pharynx lasting a few minutes. No changes in lung volume observed.  Maximum expiratory flow from one half vital capacity (MEF50%VC) (measured within 15 seconds of completion of each exposure in Phase 2 only) and total respiratory resistance (measured at 4 minute intervals during each exposure) were compared for each gas mixture. The results of Phases 1 and 2 were compared to evaluate the difference in effect when SO2 inhalation was through the nose rather than the mouth.  Decrements in MEF50%VC were evident at all concentrations and significant at 1 and 5 ppm SO2 in air, and a dose response relationship was evident. When SO2 was mixed with saline aerosol, the decrease in MEF50%VC was significant at 5 ppm SO2. When SO2 was mixed with distilled water aerosol, the decrease was significant at all 3 SO2 concentrations. The average MEF50%VC following challenge was lower when SO2 inhalation was through the mouth rather than the nose This difference was most marked for the dry gas.  When SO2 was mixed with distilled water, there was no appreciable difference in MEF50%VC from the highest to the lowest SO2 concentration. When SO2 was combined with distilled water in Phase 2, only a slight difference was found between MEF50%VC following nasal versus oral breathing. Nasal breathing of SO2 in combination with water resulted in a decrease in resistance at the higher concentrations of SO2. Pulmonary resistance measurements during nasal and oral inhalation of SO2 in air were similar.  The effect of SO2 versus hospital air on clearance as measured by lung retention of radiolabelled aerosol was compared. Results of spirometry performed after 2 hours exposure were compared for control and exposure conditions.  There was a 10% reduction in maximal midexpiratory flow (MMEF) that was highly significant. A small significant but transient increase in clearance was seen 1 hour after exposure to 5 ppm SO2.  Clearance was not markedly affected by exposure to 5 ppm SO2. No differences were found in vital capacity, FEV1, or closing volume for control and exposure conditions.  Pulmonary function measurements (FVC, FEV1, MEF40) and symptoms at different exposures were compared to baseline  Light exercise potentiated the effect of 3 ppm SO2. Symptoms were consistently observed on exposures > 3 ppm. At rest, a significant decrease in expiratory flow rate was seen after inhalation of 1 or 5 ppm SO2.  A 3 minute inhalation of 1 ppm several months later did not result in a significant change in 7 subjects, 5 of whom had been part of the initial group that reacted to this concentration.  Lung retention of radioactivity as well as results of pulmonary function tests carried out at the 2 hour point in all experiments were compared for SO2 versus control conditions.  Clearance was significantly faster on exposure to SO2 as compared to control values. Maximum mid-expiratory flow rates were reduced by a small but significant amount on exposure to SO2.  Differences between FEV1 and vital capacity measured during SO2 versus control conditions were small and non-significant.  Results of spirometry conducted at 4 intervals during exposure, before and immediately after exposure, were compared for control and SO2 exposure conditions.  SO2 exposure in asthmatics resulted in an almost immediate decrease of mid-maximal expiratory flow rate (MMFR) which lasted throughout the exposure.  Observed patterns of progressive bronchodilation due to circadian rhythms were not altered by exposure to SO2 in normal subjects.  Changes in lung function parameters and airway resistance for different gas mixtures were compared to baseline.  Respiratory gas exchange of O2 decreased following exposure to SO2 alone, but the change was not statistically significant.  Exposure to a combination of NO2 and SO2 or NO2, O3, and SO2 did not cause a significantly greater decrease of respiratory gas exchange than inhalation of NO2 alone.  Comments  There was no difference between the reaction of smokers who had not smoked for 20 hours before the exposure to pollutants, and that of non-smokers.  Reference  Location  Sheppard, Wong et San Francisco, al., 1980 CA, USA  Sheppard, Saisho San Francisco, et al., 1981 CA, USA  Stacy, House et al., 1981  Chapel Hill, NC, USA  Kirkpatrick, Sheppard et al., 1982  San Francisco, CA, USA  Linn, Bailie et al., 1982  Downey, CA, USA  Bethel, Erle et al., San Francisco, 1983a CA, USA  Route of Number of Exposure Subjects  Subject Description  Characteristics of Study  Duration of Exposure  SO2 Concentration  10 minutes  1, 3, or 5 ppm  7 asthmatic, 7 atopic, and 7 normal subjects, 23-37 years of age (5m, 2f in each group).  Subjects breathed 1 of 3 different concentrations of SO2 on 3 separate days at least 48 hours apart.  13 (10 male, 3 female)  Adults aged 20-30 years with history of mild asthma  Subjects were exposed to exercise alone, inhalation of SO2 alone, or the combination of exercise and SO2 (n=7). Subjects inhaled SO2 during exercise or performed eucapnic hyperventilation with SO2 (n=6). Exposures to air and SO2 were randomized.  10 minutes  0.5 and 0.25 ppm (and 0.1 ppm for subjects with the greatest bronchoconstriction at higher concentrations)  Chamber  31 (31 male, 0 female)  Healthy, non-smoking males aged 18-40 years.  15 subjects were exposed to air and 16 to SO2 in an environmental chamber at 21 °C and 60% relative humidity. Subjects performed 15 minutes of exercise at the end of the first hour of exposure.  2 hours  0.75 ppm  Mouthpiece  6 (4 male, 2 female)  Non-smoking, asthmatic subjects aged 21 to 28 years.  Subjects were exposed to humidified air through a mouthpiece, humidified air plus 0.5 ppm SO2 a) orally, b) oronasally, and c) nasally, during exercise.  5 minutes  0.5 ppm  Chamber  24 (13 male, 11 female)  Young adult asthmatics aged 23 ± 4 years.  Subjects were exposed to 0, 0.25, and 0.5 ppm SO2 at 90% relative humidity during intermittent exercise on randomized days separated by 1 week.  1 hour  0.25 and 0.5 ppm  Mouthpiece  9 (3 male, 6 female)  Non-smoking asthmatic subjects aged 20 to 37 years.  Subjects were exposed to filtered, humidified air with or without SO2 during low, moderate, and high work rates on separate randomized days.  7 minutes  0.5 ppm  Mouthpiece  Mouthpiece  21 (15 male, 6 female)  Main Comparison  Positive Results  Null or Negative Results  Change in SRaw was compared for different concentrations and different health status.  In asthmatic subjects, SRaw increased significantly at all concentrations of SO2, and the increases were greatest at 5 ppm. SRaw increases were sometimes associated with marked dyspnea requiring bronchodilator therapy in the asthmatic group. Overall, asthmatic subjects had a lower threshold and a greater magnitude of response than did normal and atopic subjects.  In normal and atopic subjects, SRaw increased only at 5 ppm.  SRaw measured before, during and every 5 minutes following exposure until it returned to baseline, was compared for all exposures.  Inhalation of 0.5 and 0.25 ppm of SO2 during the performance of moderate exercise significantly increased SRaw. In the 2 most responsive subjects, inhalation of 0.1 ppm of SO2 during exercise also significantly increased SRaw.  Neither inhalation of 0.5 ppm of SO2 at rest nor inhalation of humidified, filtered air during exercise nor hyperventilation alone had any effect on SRaw.  The results of 15 pulmonary function parameters (evaluated through body plethysmography, spirometry, and multigas rebreathing) before, during and after, and of symptom questionnaires administered before and after, exposures to SO2 and air were compared.  Increases in airway resistance with SO2 exposure were significant. 8 of the SO2-exposed subjects, who had at least one positive allergen skin test, appeared to be significantly more reactive to SO2 than skin-test negative subjects.  All subjects remained asymptomatic. Other than airway resistance, no measured lung function parameters were significantly altered by SO2 exposure.  SRaw was compared for the 4 exposure scenarios.  Breathing humidified air plus 0.5 ppm SO2 orally or oronasally during exercise significantly increased SRaw in all subjects, and breathing humidified air plus 0.5 ppm SO2 nasally significantly increased SRaw in 5 of 6 subjects. The increase in SRaw caused by oral breathing was significantly greater than the increase in SRaw caused by nasal breathing. The authors conclude that although nasal breathing is partially protective against SO2-induced bronchoconstriction, both oral and oronasal breathing of low SO2 concentrations during exercise can cause significant bronchoconstriction in asthmatics.  The increase in SRaw caused by oral breathing was not significantly greater than the increase in SRaw caused by oronasal breathing.  Airway resistance, pulmonary function and symptoms before during and after exposure were compared for each exposure condition.  There were significant decrements in FVC and FEV1 when SO2 concentrations increased from 0.25 to 0.5 ppm.  No other measures of response recorded showed statistically significant variation attributable to SO2.  SRaw was compared for exposures with and without SO2 and for oral or nasal breathing.  Inhaled by mouthpiece (oral breathing) , 0.5 ppm SO2 caused bronchoconstriction at moderate and high but not low work rates. There was a dose response relationship between exercise work rate and mean bronchoconstriction. Inhaled oronasally, 0.5 ppm SO2 caused bronchoconstriction at the high work rate only. These findings demonstrate that oronasal breathing is only partially effective in preventing the bronchoconstriction observed with oral breathing.  Comments  The increases in SRaw produced by inhalation of SO2 were prevented by treatment with atropine in asthmatic and non-asthmatic subjects, suggesting that SO2induced bronchoconstriction is mediated by parasympathetic pathways.  These findings demonstrate that SO2-induced bronchoconstriction is dependent on the work rate of exercise during exposure, that oronasal breathing is only partially effective in preventing the bronchoconstriction observed with oral breathing, and that oronasal breathing is less effective in preventing bronchoconstriction with high than with moderate exercise at this concentration of SO2.  Reference  Location  Bethel, Epstein et San Francisco, al., 1983b CA, USA  Kagawa, 1983  Japan  Route of Number of Exposure Subjects  Chamber  Chamber  10 (8 male, 2 female)  7 (7 male, 0 female)  Subject Description  Characteristics of Study  Duration of Exposure  SO2 Concentration  Non-smoking asthmatic subjects aged 22-36 years (with a history of recurrent wheezing or chest tightness since childhood, reversible bronchoconstriction, multiple allergies, recurrent allergic rhinitis, and hyperreactivity to histamine).  Subjects were exposed to either filtered air or SO2 on 2 separate randomized days for 5 minutes of rest and 5 minutes of exercise.  10 minutes  0.5 ppm  Healthy subjects aged 19-23 years, one 4-year smoker, the rest nonsmokers.  Subjects were exposed to filtered air, O3, SO2, and NO2 separately, as well as all combinations of the latter three, during intermittent light exercise. Exposures were in the same order for each subject but subjects were blinded. Exposures to O3 and O3 plus SO2 and/or NO2 were separated by at least 2 weeks.  2 hours  0.15 ppm  10 minutes  0.5 and 1 ppm  10 minutes plus the time necessary for body plethysmography, symptom questionnaires, and pulmonary function testing before and after exercise  0.75 ppm  Subjects were exposed via a mouthpiece with nose clips (orally) to 1 mg/m3 NaCl, 0.5 ppm SO2 and 1 mg/m3 NaCl, or Koenig, Pierson et al., 1983  Seattle, WA, USA  Mouthpiece  9 (6 male, 3 female)  Adolescents with extrinsic asthma aged 12 to 16 years.  1 ppm SO2 and 1 mg/m3 NaCl for 30 minutes of rest and 10 minutes of exercise on separate afternoons. Seven of the 9 underwent an additional exposure to 0.5 ppm SO2 and 1 mg/m3 NaCl through a face mask (oronasally).  Linn, Shamoo et al., 1983a  Linn, Venet et al., 1983b  Downey, CA, USA  Downey, CA, USA  Sheppard, Epstein San Francisco, et al., 1983 CA, USA  Mouthpiece  23 (15 male, 8 female)  Chamber  23 (13 male, 10 female)  Mouthpiece  8 (4 male, 4 female)  Young adult asthmatics aged 23 ± 4 years.  Subjects were exposed to SO2 or clean air during heavy exercise, once with breathing unencumbered and once with mouthpieces and nose clips (orally) on 4 separate, randomized days.  Asthmatic subjects aged 19-31 years.  Subjects were exposed to filtered air and 3 concentrations of SO2 on separate, randomized occasions 1 week apart. Exposures included 5 minutes of heavy exercise. Subjects were studied in pairs, the second member performing each step of the protocol approximately 10 min after the first.  5 minutes plus time for postexercise physiologic testing.  0.2, 0.4, and 0.6 ppm  Non-smoking asthmatics aged 22-36 years (mean 26.6).  Subjects performed 3 minutes of voluntary eucapnic hyperpnea with 0.5 ppm SO2 3 times at 30 min intervals  3 times for 3 minutes  0.5 ppm  Main Comparison  Positive Results  Null or Negative Results  Comments  The smoking subject appeared to experience smaller decreases in Gaw/Vtg with exposure, perhaps because his baseline value was the lowest of all subjects.  SRaw determined prior to and every 30 seconds post exposure for 8 minutes was compared for exposure to S02 and to filtered air.  SO2 and exercise increased mean SRaw significantly more than did exercise alone. SO2 caused considerable bronchoconstriction in exercising asthmatics.  Pulmonary function tests performed before exposure, at the 1 and 2 hour marks during exposure, and 1 hour after exposure, as well as symptom questionnaires before, during, and after exposure were compared for each combination of gases.  Significantly decreased Gaw/Vtg (specific airway conductance) was observed in 4 subjects during SO2 exposure. A significantly enhanced effect was seen (over O3 alone) on Gaw/Vtg in 4 subjects during exposure to SO2 and O3 in combination.  The severity of questionnaire-reported respiratory symptoms in combined exposures of O3, SO2, and NO2 was essentially the same as that produced by exposure to O3 alone. There were no symptoms associated with exposure to SO2 alone.  Respiratory resistance and lung function measurements during and after exposure were compared to one another and to baseline for each gas mixture. Symptoms reported after exposure were also compared for each condition.  There were statistically significant decrements in FEV1, Vmax50, and Vmax75 following exposure to 0.5 ppm and 1 ppm SO2 during exercise regardless of route of inhalation. A doseresponse relationship was evident.  There were no statistically significant changes following exposure to NaCl alone with exercise. There were no statistically significant changes in pulmonary function following 30 minutes of exposure at rest to any of the gas mixtures. During exercise, nasal breathing appeared to mitigate the SO2induced changes in lung function in some subjects.  Results of lung function, airway resistance and symptom questionnaires were compared for each exposure condition.  During clean air exposures, SRaw and symptoms increased significantly. Exposures to SO2 produced greater increases in SRaw than clean-air exposures regardless of the mode of breathing. The excess increase was significantly greater with the mouthpiece than during unencumbered breathing. Symptom changes and FVC, FEV1, and PEFR parameters also decreased more with SO2 than with clean air, although these changes were not statistically significant.  No meaningful differences were seen between mouthpiece and unencumbered breathing for clean air exposures.  Body plethysmography (pre-exposure and end-exposure) , spirometry postexposure only) and symptom questionnaire (covering the exposure period and the following week) results were compared for control and exposure to different SO2 concentrations.  Body plethysmography, spirometry, and symptom questionnaires all showed highly significant trends toward increased response with increasing SO2 concentration. Pairwise statistical comparisons showed substantial, highly significant changes at 0.6 ppm, relative to control. Fewer and smaller significant changes were seen at 0.4 ppm. Increases in symptoms during exposure were observed at all SO2 concentrations.  At 0.2 ppm, no significant physiologic changes were found. Symptoms 1 day and 1 week post exposure showed no significant variation related to SO2 level.  Specific airway resistance (SRaw) measured before and after each period of hyperpnea were compared.  SRaw increased significantly and more after the first exposure to SO2 than after the second or third exposure, indicating that repeated exposures to SO2 over a short period can induce tolerance to the bronchomotor effects of SO2 in subjects with asthma. When 7 subjects repeated hyperpnea with SO2 24 hours and 7 days later, SRaw increased as much as it had after the first exposure.  Reference  Location  Bedi, Folinsbee Santa Barbara, and Horvath, 1984 CA, USA  Bethel, Sheppard San Francisco, CA, USA et al., 1984  Hackney, Linn et al., 1984  Downey, CA, USA  Kulle, Sauder et al., Baltimore, MD, 1984 USA  Linn, Avol et al., 1984a  Downey, CA, USA  Downey, CA, USA  Route of Number of Exposure Subjects  Chamber  9 (9 male, 0 female)  Subject Description  Characteristics of Study  Duration of Exposure  SO2 Concentration  Healthy non-smoking male adults aged 19-29 years (mean = 21.8).  Subjects were exposed to air or SO2. Three 30-minute exercise periods were performed during exposure, with 10-minute rest periods.  2 hours  1 and 2 ppm  3 minutes  0.5 ppm  Mouthpiece  7 (5 male, 2 female)  Non-smoking asthmatic volunteers aged 24-36 years.  Subjects were exposed to humidified room-temperature air, humidified roomtemperature air containing SO2, cold dry air, and cold dry air containing SO2 on 4 separate randomized days at least 24 hours apart.  Chamber  17 (13 male, 4 female)  Asthmatic adults aged 25 ± 4 years.  Subjects were exposed to test air in an environmental chamber, performing vigorous exercise for the first 10 minutes (resting for rest of exposure).  3 hours  0.75 ppm  20 (10 male, 10 female)  Healthy volunteers aged 21-34 years.  Subjects were exposed to SO2, (NH4)2S04, or SO2 and (NH4)2SO4 in combination during 3 consecutive weeks. Intermittent exercise was performed during exposure. Exposures were separated by at least 1 week, and subjects were exposed to filtered air on the day preceding and the day following each exposure.  4 hours  1 ppm  14 (12 male, 2 female)  Asthmatic subjects with documented sensitivity to SO2, aged 18 to 33 years.  Subjects were exposed to the same concentration of SO2 on 2 successive days and to purified air 1 week later or earlier for 6hour periods of rest with 5 minutes of heavy exercise near the beginning and 5 minutes of heavy exercise near the end.  6 hours  0.6 ppm  Young asthmatics aged 19-29 years.  Subjects were exposed to SO2free air or one of 3 concentrations of SO2 with high (85%) or low (50%) relative humidity for 5 minutes of heavy exercise (8 exposures). Exposures were in order of increasing SO2 concentration, each with high RH and then low RH. Exposures were separated by 3-4 days.  5 minutes  0.2, 0.4, and 0.6 ppm  Young asthmatics aged 18-31 years.  Subjects were exposed to warm (22 °C) clean air, cold (5 °C) clean air, warm air with 0.6 ppm SO2, and cold air with 0.6 ppm SO2 for 5 minutes of heavy exercise on randomized occasions separated by 7 days. All exposures were under conditions of high humidity (> 80%).  5 minutes  0.6 ppm  Chamber  Chamber  Chamber  8 (4 male, 4 female)  Linn, Shamoo et al., 1984b  Downey, CA, USA  Chamber  24 (19 male, 6 female)  Main Comparison  Positive Results  Null or Negative Results  SO2 exposure and pulmonary function.  Significant association was observed between exposure to 1 or 2 ppm SO2 and an increase in SRaw (p<0.05).  No significant association was observed for exposure to 1 or 2 ppm SO2 and TGV or FVC.  SRaw determined before and after exposure were compared for the 4 different gas mixtures.  When given together, SO2 and cold dry air caused significant bronchoconstriction (as indicated by an increase in SRaw). This combination also exacerbated the symptoms of shortness of breath and wheezing in 6 of the 7 subjects.  When given independently, SO2 or cold dry air caused insignificant bronchoconstriction. No subject complained of more than an occasional minor change in symptoms or asked for a bronchodilator after any of the gas mixtures other than combined SO2 and cold dry air.  SO2 exposure with exercise and bronchoconstriction (measured by SRaw, FEV1 and symptom questionnaire)  Symptom score, FEV1 decreased and SRaw increased significantly after exercise compared to baseline however, this effect disappeared after one hour of rest.  Spirometric and body plethysmographic measurements performed before and after each control and exposure period, airway reactivity assessed at the end of each control and exposure period, and subjective symptoms reported at the end of exposure periods and postexposure days, were compared for all three gas combinations.  Symptoms were most pronounced during exposure to the combination of SO2 and (NH4)2S04.  No changes in pulmonary function (spirometry, body plethysmography, methacholine inhalation challenge) were observed with individual exposures, combined exposures, or 2 hours post exposure.  Bronchoconstriction and questionnairereported lower respiratory symptoms were compared for SO2 and clean air exposures pre-exposure, after each exercise period, and hourly during rest.  Bronchoconstriction and lower respiratory symptoms were observed during or immediately following exercise to a more marked extent with SO2 than with clean air. Bronchoconstriction and symptoms were modestly less severe on day 2 than on day 1 of SO2 exposure.  There was no meaningful difference in response between early and late exercise periods on day 1 or day 2 of SO2 exposure.  Results of spirometry, body plethysmography and symptom questionnaires performed before and after exposure were compared for each exposure condition.  FVC and FEV1 decreased and SRaw and symptoms increased with increasing SO2 concentration. Symptoms increased marginally at low humidity.  Physiologic response did not vary significantly with humidity.  Results of body plethysmography and questionnaire-reported symptoms taken before and after exposure were compared for each exposure condition.  Physiologic responses to SO2 (in excess of responses to clean air) were highly significant regardless of temperature.  Mean excess responses at low temperature compared with high temperature were not statistically significant in clean air or SO2 (moderate cold stress exacerbated response to SO2 slightly but inconsistently).  Comments  IC = inspiratory capacity ERV = expiratory reserve volume  6 of 24 subjects are the same subjects cited in Linn WS et al (1984) n=8 entry.  Reference  Location  Linn, Shamoo et al., 1984c  Downey, CA, USA  Schachter, 1984  New Haven, CT, USA  Route of Number of Exposure Subjects  Subject Description  Characteristics of Study  Duration of Exposure  SO2 Concentration  Chamber  24 (13 male, 11 female)  Asthmatic adults aged 19-33 years (mean = 24).  Subjects were exposed to three exposure concentrations at three different temperatures (21, 7, -6 °C) , while performing exercise.  5 minutes (7 minutes if warmup and cool down included).  0.3, 0.6 ppm  Chamber  20 (10 asthmatics (5 male, 5 female) and 10 healthy (4 male, 6 female))  Ten non-smoking asthmatic and 10 healthy (1 smoking, 9 non-smoking) individuals aged 27.3 ± 5.1 years and 26.1 ± 6.3, respectively.  Subjects were exposed to 0, 0.25, 0.5, 0.75, and 1 ppm SO2 for 40 minutes with 10 minutes of exercise, followed by 0 and 1 ppm SO2 in the absence of exercise on separate randomized days.  40 minutes  0.25, 0.5, 0.75 and 1 ppm  Dry air or dry air and SO2 were inhaled during successive 3 min intervals.  0.1 and 0.25 ppm  San Francisco, CA, USA  Mouthpiece  8 (5 male, 3 female)  Non-smoking asthmatic adults aged 20 to 37 years (mean = 30).  Subjects were exposed to dry air alone or dry air and SO2 via a mouthpiece, performing voluntary eucapnic hyperpnea, with increasing ventilation rates (20 L/min ±10 L/min) on 3 separate days  San Francisco, CA, USA  Mouthpiece  8 (5 male, 3 female)  Non-smoking asthmatic adults aged 20 to 37 years (mean = 30).  Subjects were exposed to doubling SO2 concentrations via a mouthpiece, performing voluntary eucapnic hyperpnea.  Doubling concentrations were inhaled for 3 minutes, 6 times.  started at 0.125 ppm  5 minutes  0.25 ppm  Sheppard, Eschenbacher et al., 1984  Bethel, Sheppard San Francisco, CA, USA et al., 1985  Folinsbee, Bedi & Santa Barbara, CA, USA Horvath, 1985  Koenig, Morgan et al., 1985  Seattle, WA, USA  Chamber  19 (16 male, 3 female)  Asthmatic adults aged 22-46 years.  Subjects were exposed to filtered air or filtered air plus SO2 on separate randomized days during 750 kilogrammeters/min exercise. The experiment was repeated at an exercise rate of 1000 kilogrammeters/min.  Chamber  22 (22 male, 0 female)  Healthy non-smoking subjects aged 19-28 years.  Subjects were exposed to filtered air, SO2, 0.3 ppm O3 or SO2 and 0.3 ppm O3 during intermittent exercise on 4 randomized days at least 1 week apart.  2 hours  1 ppm  Adolescent subjects with extrinsic asthma aged 14-18 years.  Subjects were exposed for 30 minutes of rest followed by 20 minutes of exercise to orally inspired filtered air, orally inspired SO2, or nasally inspired SO2 at the same time of day on 3 separate, randomized days.  50 minutes  0.5 ppm  Mouthpiece  10 (5 male, 5 female)  Main Comparison  Positive Results  Null or Negative Results  SO2 exposure and airway resistance (SRaw and SGaw) and symptom reporting (nasal congestion/discharge, sore throat, headache, fatigue, eye irritation, asthma). Also the effects of air temperature in combination with SO2 were evaluated.  Airway resistance and reported respiratory symptoms was significantly associated with increasing SO2 concentration.  Respiratory resistance and pulmonary function measurements before, during and after exposure were compared for each exposure condition.  In asthmatics, 1 ppm SO2 during exercise caused significant changes from baseline in airway resistance and pulmonary function (FEV1, MEF40, and Vmax50%) Consistent effects were seen at 0.75 ppm, and slight decreases were seen in Vmax50% at 0.25 and 0.5 ppm. A doseresponse relationship was evident for exercising asthmatics.  SO2 exposure and effect on SRaw with airway cooling.  The ventilation rate that caused an 80% increase in SRaw was significantly higher for dry air without SO2 than for hyperpnea with 0.1 and 0.25 ppm SO2. SO2 caused bronchoconstriction at lower concentrations when inhaled in dry air as compared to humidified warm air.  Effects of cold dry air, warm dry air or humid warm air with SO2 exposure and SRaw.  The SO2 concentration that caused a 100% increase in SRaw was significantly higher in humidified warm air (0.87 ± 0.41 ppm) than in dry cold air (0.51 ± 0.2 ppm) and dry warm air (0.6 ± 0.41 ppm).  SRaw was compared for exposures with and without SO2.  During 750 kgm/min exercise, SRaw was only slightly greater on days that subjects breathed SO2 than on days that they breathed filtered air, but the difference was significant. The authors conclude that the increase in SRaw due to 0.25 ppm SO2 is small and is largely overshadowed by the bronchoconstrictor effect of exercise alone.  Increases in SRaw for filtered air or SO2 during 1000 kgm/min as compared to 750 kgm/min exercise were not significant.  Forced expiratory maneuvers performed before exposure and 5 mins after each of the exercise periods, and voluntary ventilation, He dilution functional residual capacity, thoracic gas volume, and airway resistance measured before and after exposures were compared for all exposures.  Combined SO2 and O3 exposures produced decreases in FVC, FEV1, and FEF25-75% that were similar but smaller than those produced by O3 alone. FVC, FEV1, and FEF25-75% did not decrease over time for filtered air or SO2 exposure.  There were no significant changes in ERV, Raw, or specific airway conductance for any gas mixture. The authors conclude that there is no additive or synergistic effect of SO2 and O3 in combination on pulmonary function.  The effect of SO2 on nasal function and pulmonary function were evaluated. Changes in pulmonary function were compared for oral and nasal inspiration.  Statistically significant changes in pulmonary function parameters and respiratory resistance were seen after all exposures to SO2. The magnitude of change in FEV1 and maximum flow calculated at 50% vital capacity was higher after oral compared to oronasal inhalation of SO2. The nasal work of breathing increased 32% after oral exposure to SO2 and 30% after oronasal exposure to SO2 (p < 0.05).  The oronasal route of exposure reduces but does not eliminate the lower airway reactions to SO2 observed on oral exposure.  Comments  The authors concluded that they think that the effects of SO2 and temperature are not synergistic but additive, or less than additive. Dose response curves are illustrated in the article.  No other lung function parameters showed significant decreases for exercising asthmatics at SO2 concentrations below 1 ppm. Ten minutes after exercise there were no significant changes from baseline even though SO2 was still present. There were no changes observed for healthy individuals or for asthmatics at rest.  SRaw was measured between each three minute exposure. Authors note that an SO2 concentration of 0.1 ppm may cause potentiation of bronchoconstriction produced by hyperpnea with dry air.  Reference  Location  Linn, Fischer et al., Downey, CA, 1985a USA  Route of Number of Exposure Subjects  Chamber  24 (15 male, 9 female)  Subject Description  Characteristics of Study  Duration of Exposure  SO2 Concentration  Adults with COPD aged 49-68 years (mean = 60).  Subjects were exposed to air or 1 of 2 SO2 concentrations within an environmental chamber, with two 15-min periods of exercise.  1 hour  0.4 and 0.8 ppm  5 minutes plus brief warm-up and cool-down periods  0.6 ppm  Downey, CA, USA  Chamber  22 (13 male, 9 female)  Young adult asthmatics aged 18-33 years.  Subjects were exposed to all combinations of 2 atmospheric conditions (purified air, SO2) , 2 temperatures (21, 38 °C) and 2 levels of relative humidity (20%, 80%) for 5 minutes of heavy exercise plus brief warm-up and cool-down periods. Subjects underwent 2 exposures per week, 48 hours apart, for 4 successive weeks. Exposure conditions (except temperature) were randomized.  Research Roger, Kehrl et al., Triangle Park, 1985 NC, USA  Chamber  28 (28 male, 0 female)  Non-smoking, mild asthmatic males with hypersensitivity to methacholine, aged 1934 years.  Subjects were exposed to ambient air or SO2 within an environmental chamber while performing intermittent exercise.  Subjects were exposed for 75 minutes, with three 10-min exercise periods.  0.25, 0.5, and 1 ppm  Non-smoking, asthmatic subjects (6 with atopic histories) aged 27.3 ± 6.4 years.  Subjects were exposed to air and 4 concentrations of SO2 on 5 separate randomized days. In each case, they were exposed to air for 30 minutes, followed by 10 minutes of exposure to a given concentration of SO2 during exercise, and a further 30 minutes of exposure to the same SO2 concentration in the absence of exercise.  40 minutes  0.25, 0.5, 0.75, or 1 ppm  10 healthy and 10 asthmatic subjects of mean age 26 ± 6.3 and 27 ± 5.1 years, respectively.  Subjects were exposed to air and various concentrations of SO2 in an environmental chamber on 7 separate randomized days. Five exposures to 0, 0.25, 0.5, 0.75, and 1 ppm SO2 occurred in combination with exercise, and 2 exposures to 0 and 1 ppm SO2 occurred in the absence of exercise.  40 minutes  0.25, 0.5, 0.75, and 1 ppm  Linn, Shamoo et al., 1985b  Witek and Schachter, 1985a  Witek, Schachter et al., 1985b  New Haven, CT, USA  New Haven, CT, USA  Chamber  Chamber  8 (4 male, 4 female)  20  Main Comparison  Positive Results  Null or Negative Results  SO2 concentration and pulmonary function (FVC, FEV1, MMFR, Vtg, SRaw, SaO2, FR, VE) and reported respiratory symptoms (recorded for one week post exposure) in COPD patients.  No significant association was observed for exposure to SO2 and either pulmonary function or respiratory symptoms.  Pre- to post-exposure change in airway size (as measured by body plethysmography) and change in intensity of questionnaire-reported symptoms were compared for all possible conditions.  The addition of SO2 to the chamber showed the most marked and significant overall effect on physiologic responses. Temperature and humidity effects were also significant. In general, symptom responses paralleled physiologic responses.  High temperature and high humidity tended to mitigate the bronchoconstriction induced by SO2 exposure (group mean SRaw approximately tripled at 21 °C and low humidity, but increased by less than 40% at 38 °C and high humidity). Temperature and humidity affected symptoms less consistently than physiologic responses. The difference between symptom scores over the 24-hour period after exposure to SO2 compared to clean air was not significant.  Effects of SO2 exposure with exercise on bronchoconstriction (SRaw).  A significant association between SO2 exposure and SRaw was observed for 0.5 and 1 ppm.  No significant increase in SRaw was observed for 0.25 ppm SO2.  Changes in lung function parameters were compared for different concentrations of SO2 and for different methacholine sensitivities.  In general, statistically significant changes in MEF40 were confined to SO2 levels of 0.75 ppm and greater with exercise. SO2-induced bronchospasm was related to methacholine sensitivity.  There were no changes in lung function during exposure to 0 ppm with exercise, indicating that exercise-induced asthma was not confounding the SO2 effect under the conditions of the study.  Subject-recorded ratings of the upper airway symptoms of taste, odour and nasal discharge and the lower airway symptoms of cough, sputum, wheeze, dyspnea, sore chest, and sore throat were completed after 30 minutes in the chamber and at 8 and 24 hours after the exposure. Physiologic changes in lung function were measured during exposure. Asthmatics and nonasthmatics were compared.  The number and severity of complaints associated with SO2 increased with concentration in both healthy and asthmatic adults, generally starting at 0.25 ppm for asthmatics and at 0.5 ppm for non-asthmatics. Exercise increased the frequency of lower airway symptoms in asthmatics only.  Exercise did not increase any symptoms in healthy subjects.  Comments  HR = heart rate SaO2 = saturation of arterial haemoglobin VE = minute volume The authors do note that the older COPD patients seem less reactive to SO2 exposure than younger more athletic COPD patients, it is thought this is due to decreased ventilation rates.  (NOAEL 250 ppb)  Asthmatics indicated progressive lower respiratory complaints, such as wheezing, chest tightness, dyspnea and cough with increasing levels of SO2 while healthy subjects complained more frequently of upper airway complaints such as taste and odour with increasing levels of SO2.  Reference  Location  Research Horstman, Roger et Triangle Park, al., 1986 NC, USA  Balmes, Fine & Sheppard, 1987  San Francisco, CA, USA  Research Kehrl, Roger et al., Triangle Park, 1987 NC, USA  Linn, Avol et al., 1987  Downey, CA, USA  Route of Number of Exposure Subjects  Chamber  Mouthpiece  Chamber  Chamber  27 (29 male, 0 female)  8 (6 male, 2 female)  Subject Description  Characteristics of Study  Duration of Exposure  SO2 Concentration  Non-smoking male asthmatics aged 18-35 years.  Subjects were exposed to 4 concentrations of SO2 (0, 0.25, 0.5, and 1) for 10 minutes of moderate exercise on separate, randomized occasions separated by >1 week. Subjects whose specific airway resistance (SRaw) was not doubled by exposure to 1 ppm SO2 were also exposed to 2 ppm.  10 minutes  0.25, 0.5, 1, and 2 ppm  Non-smoking asthmatic adults aged 23-39 years (mean = 30.2).  Subjects were exposed to test air via a mouthpiece during eucapnic hyperpnea. There were 8 testing procedures including: baseline, control (filtered, humidified air) and 6 different exposure time/concentration combinations.  1, 3 or 5 minutes SO2; 5 minutes control  0.5 or 1 ppm  1 ppm  10 (10 male, 0 female)  Non-smoking, white mild asthmatic men aged 20.2 - 33.6 years (mean = 26.8).  Subjects were exposed to ambient air or SO2 within an environmental chamber while performing intermittent or continuous exercise.  Two separate exposure protocols were followed: a. One hour of exposure with 3 10-min exercise periods. b. 30-min exposure with continuous exercise.  85 (a. 15 male, 9 female; b. 12 male, 9 female; c. 10 male, 6 female; d. 10 male, 14 female)  There were four classes of subjects: a. Normal healthy individuals, aged 18-37 years old. b. Atopic subjects, aged 18-32 years old. 3. Mild asthmatics, aged 20-33 years old. d. Moderate or severe asthmatics that were dependent on medication, aged 18-35 years old (one 46).  Subjects were exposed to ambient air or one of 3 SO2 concentrations within an environmental chamber, while performing intermittent exercise.  1 hour with 3 10min exercise periods  0.2, 0.4, and 0.6 ppm  30 minutes  0.5 and 1 ppm  0 - 5 minutes  1 ppm  Subjects were exposed to 1 mg/m3 NaCl droplet aerosol alone, 1 mg/m3 NaCl droplet aerosol with 0.5 ppm SO2 (7 Rondinelli, Koenig & Marshall, 1987  Seattle, WA, USA  Research Horstman, Seal et Triangle Park, al., 1988 NC, USA  Mouthpiece  Chamber  10 (10 male, 0 female)  Healthy non-smokers aged 55-73 years.  12 (12 male, 0 female)  Non-smoking males aged 22-37 years with a history of physiciandiagnosed asthma.  subjects only) , and 1 mg/m3 NaCl with 1 ppm SO2 on 3 days separated by at least one week. Exposures were for 10 minutes of moderate exercise and 20 minutes at rest. The NaCl exposure was always first, and the 2 SO2 exposures were randomized.  Just prior to exposure, subjects performed 5 minutes of exercise. Subjects were then exposed to clean air or SO2 for 0.5, 1.0, 2 and 5 minutes during exercise on 10 separate occasions  Main Comparison  Positive Results  Null or Negative Results  SRaw measurements before and 3 minutes after exposure were used to create bronchial sensitivity to SO2 (PC (SO2), defined as the concentration at which SRaw doubled) for each individual.  Six subjects had a PC (SO2) of < 0.5 ppm, 9 subjects had a PC (SO2) between 0.5-1 ppm, 8 subjects were between 1.0-2 ppm, and 4 subjects were > 2 ppm. The median PC (SO2) was 0.75 ppm.  Duration and concentration of SO2 and bronchoconstriction (measured by SRaw).  Exposure to 0.5 and 1 ppm significantly increased SRaw above baseline levels. Effects after three and five minutes involved seven of the eight subjects, after one minute, only 2 subjects.  Effects of exercise and SO2 exposure on SRaw in mild asthmatics.  A significant association between SO2 exposure and SRaw was observed. In addition a significant increase in SRaw was observed during continuous exercise compared to intermittent exercise, when exposed to 1 ppm SO2.  Effects of SO2 exposure with intermittent exercise and pulmonary function (SRaw, FEV1) and reported symptoms (up to one week post exposure).  SRaw and FEV1 were associated with SO2 level. Normal and atopic subjects experienced only small changes, whereas both asthmatic groups had larger losses in respiratory function with increasing SO2 exposure.  No significant effect on respiratory symptoms from SO2 exposure was observed. However slight increases in response were observed for increasing SO2 exposure, in the mildly and severely asthmatic subject groups.  Total respiratory resistance (Rt) , thoracic gas volume at functional residual capacity (FRC) , and FEV1 during exposure were compared for the 3 gas mixtures.  The reduction in FEV1 seen 2-3 minutes after exercise with NaCl and 1 ppm SO2 was significantly greater than that seen 2-3 minutes after exercise with NaCl alone.  The difference between NaCl with 1 ppm SO2 and NaCl alone seen post exposure with exercise was not seen following exposure at rest. Rt and FRC demonstrated no significant changes from baseline measurements.  Respiratory resistance and respiratory symptoms recorded before and after exposure were compared for each exposure condition.  Significantly greater SO2-induced bronchoconstriction was seen for the 2 and 5 min exposures as indicated by substantially greater increases in SRaw and substantially higher ratings of respiratory symptoms.  Comments  The authors note that the effects of one minute exposure were mainly due to reaction of two subjects.  Reference  Location  Subject Description  Characteristics of Study  Duration of Exposure  SO2 Concentration  Healthy adults aged 2046 years (mean = 31.8).  Subjects were exposed to four test air conditions (on separate days) within a chamber while doing continuous exercise (free breathing, forced oral or forced nasal breathing).  30 minutes for test air, followed by 30 minutes of ambient air.  2 ppm  Chamber  14 (7 male, 7 female)  Umea, Sweden  Chamber  12  Healthy non-smoking subjects aged 22-30 years.  subjects were exposed to 4 ppm (10 subjects) and or 8 ppm (4 subjects) during exercise.  20 minutes  4 or 8 ppm  Umea, Sweden  Chamber  22 (22 male, 0 female)  Healthy, non-smoking adults aged 22-37 years.  10 subjects were exposed to 4 ppm SO2, and 8 subjects were exposed to each of 5, 8 and 11 ppm SO2 in an exposure chamber  20 minutes  4, 5, 8 and 11 ppm  Umea, Sweden  Chamber  22 (22 male, 0 female)  Healthy non-smokers aged 22-37 years.  Subjects were exposed in an environmental chamber during exercise (work load 75W)  20 minutes  8 ppm  Chamber  14 (10 male, 4 female)  Mild asthmatics aged 34 ± 14 years.  Tidal breathing of either filtered air, NO2, or SO2 followed by isocapnic hyperventilation of 0.75 ppm SO2 on 3 separate days.  30 minutes  0.5 ppm  13 (8 male, 5 female)  Allergic asthmatics with exercise-induced bronchospasm, aged 12-18 years (mean = 14.3).  Subjects were randomly exposed to three separate test sequences. Exposure to ambient air or 120 ppb O3 was followed by exposure to SO2 or O3. Subjects also performed exercise three times for 15 minutes, every 15 minutes.  15 minutes  0.1 ppm  Chamber  21 (6 male, 15 female)  Medication-dependent asthmatics aged 18-50 years.  Air or SO2 was administered in combination with low, normal or high medication during heavy exercise (9 different experimental conditions). Exposures on same weekday.  10 minutes  0.3 and 0.6 ppm  Chamber  46 asthmatics (21 male, 25 female) and 12 healthy subjects  Asthmatics aged 16-62 years (mean = 28); Healthy subjects of mean age 24 years  Subjects were exposed to air or SO2 on 2 randomized days at resting ventilation and then while performing isocapnic hyperventilation  10 minutes  0.5 ppm  Bedi and Horvath, Santa Barbara, CA, USA 1989  Sandstrom, Stjernberg et al., 1989a  Route of Number of Exposure Subjects  Sandstrom, Stjernberg et al., 1989b  Jorres and Magnussen, 1990  Koenig, Covert et al., 1990  Linn, Shamoo et al., 1990  Magnussen, Jorres et al., 1990  Germany  Seattle, WA, USA  Downey, CA, USA  Germany  Chamber  Main Comparison  Positive Results  Null or Negative Results  No association was observed between breathing 2 ppm SO2 and pulmonary function.  SO2 exposure and pulmonary function (FVC, FEV1, FEF25-75, and Raw)  Results of bronchoalveolar lavage (BAL) performed before exposure (n=12) were compared to BAL results 24 hours after exposure (n=10 for 4 ppm SO2, n=4 for 8 ppm SO2) , and 72 hours after exposure to 8 ppm SO2.  BAL fluid 24 hours after exposure to 4 ppm SO2 showed increased alveolar macrophage activity. 24 hours after 8 ppm SO2 showed a further increase, as well as an increase in total numbers of macrophages and lymphocytes.  72 hours after exposure to 8 ppm SO2, cell numbers had virtually returned to preexposure levels.  Cell response in bronchoalveolar lavage (BAL) fluid prior to and following exposure were compared for different concentrations of SO2.  Mast cells, lymphocytes, lysozyme positive macrophages, and the total number of macrophages were significantly increased after SO2 exposure and a dose-dependent increase in the cell response in BAL fluid was observed after exposure to 4 to 8 ppm SO2.  No further increase was seen after exposure to 11 ppm SO2.  Results of BAL performed 2 weeks before exposure (n=22) were compared to results of BAL performed 4 (n=8) , 8 (n=8) , 24 (n=8) , and 72 (n=8) hours following exposure. Lung function measurements taken before and immediately after exposure were also compared.  4 hours after exposure significant increases were found in the numbers of lysozyme-positive macrophages, lymphocytes, and mast cells. Lymphocytes, lysozyme-positive macrophages, total count of alveolar macrophages, and total cell number increased to peak values 24 hours after exposure. 72 hours after exposure the cell numbers and distribution had returned to normal. Lung function recordings showed small and nonsignificant decreases in FEV1.  8 hours after exposure no significant increase in mast cells was seen compared with before exposure.  The provocative ventilation necessary to increase SRaw by 100% (PV100SRaw) was compared following exposure to filtered air, NO2, or SO2.  Comments  The authors do note that forced oral breathing 2 ppm SO2 causes the subjects to start breathing orally at a lower workload than the other exposure conditions.  This article reports concentrations of "10 mg SO2/m3 (4 ppm)" and "20 mg SO2/m3 (8 ppm)."  PV100SRaw was significantly lower after NO2 (37.7 ± 3.5) as compared to filtered air (46.5 ± 5.1) or SO2 (45.4 ± 4.2).  The effect of SO2 exposure following O3 exposure or ambient air on pulmonary function (FEV1, RT, Vmax50).  SO2 exposure following O3 exposure resulted in a significant decrease in FEV1 (8%) and Vmax50 (15%) and a significant increase in total respiratory resistance (RT, by 19%).  SO2 exposure following ambient air did not cause a decrease in pulmonary function.  Lung function (immediately, 30 minutes after, 60 minutes after) and heart rate (before and during) of all 9 experimental conditions were compared.  With normal medication, symptomatic bronchoconstriction occurred with exercise and was exacerbated by 0.6 ppm SO2. Postexposure lung function (FEV1, SRaw) was noticeably worse in the low-medication state.  High medication prevented most bronchoconstrictive effects of SO2 and exercise. Heart rate did not vary significantly with SO2 or medication conditions.  Pulmonary function 2, 5 and 10 minutes after the end of hyperventilation was compared for air and SO2. Results of a histamine challenge performed within a period of one week of exposure were also compared.  Mean maximum post-hyperventilation SRaw after air and after SO2 differed significantly.  Baseline SRaw values for air and SO2 exposure did not differ significantly for the group.  NOTE: response curves for all patients are illustrated in the article. RT = total respiratory resistance Vmax50 = maximal flow  Reference  Location  Huang, Wang and Taipei, Taiwan Hsieh, 1991  Islam, Neuhann et al., 1992  Devalia, Rusznak et al., 1994  Heath, Koenig et al., 1994  Germany  London, U.K.  Seattle, WA, USA  Gong, Lachenbruch Downey, CA, et al., 1995 USA  Subject Description  Characteristics of Study  Duration of Exposure  SO2 Concentration  Mite-sensitive asthmatic children of 10 to 14 years (mean = 12).  Taipei road tunnel or ambient air, included 0.45-0.5 ppm NOX (NO2 and NO)  5 minutes  0.07 to 0.12 ppm  26 (17 male, 9 female)  Healthy subjects aged 15-26 years  Exposures to air and SO2 with eucapnic hyperventilation were separated by 30 minutes. Thirteen subjects breathed air first and the other thirteen breathed SO2 first.  5 minutes  1.6 to 2 mg/m3  8 (4 male, 4 female)  Non-smoking, mildly asthmatic adults aged 18-45 years (mean = 27.6), with a minimum of 70% predicted FEV1 for age and height.  Subjects were exposed to one or more of the gases in a random order, one week apart.  6 hours  0.2 ppm  10 African American (18-43 years old) , 12 Caucasian (20-37 years old) methacholine positive asthmatic males aged 18-43 years.  Subjects breathed pure air or SO2 inside a polycarbonate head dome for 10 minutes of rest and 10 minutes of exercise  20 minutes  1 ppm  Subjects exposed to SO2 at three exercise levels (ventilation rate, light = 20-29 L/min, moderate = 30-39 L/min and heavy = 40-49 L/min).  10 minutes  0, 0.5, 1 ppm  Route of Number of Exposure Subjects  Mouthpiece  Chamber  Chamber  6 (5 male, 1 female)  Breathing inside 22 (22 male, 0 head dome female)  Chamber  14  Adults aged 18-50 years diagnosed with clinically stable chronic asthma, absence of nasal disorders, FEV1 > 50% predicted, no medications, tolerance for 10 min of heavy exercise and SO2 sensitive (> 75% increase in SRaw with exposure to 1 ppm during heavy exercise).  Children aged 9-12 years, 15 healthy, 26 with allergy or asthma.  Subjects were exposed to mixed O3, SO2 and sulphuric acid during intermittent exercise  4 hours  0.1 ppm  Adults aged 20 to 44 years.  SO2 inhalation challenges were performed during isocapnic hyperventilation at a constant rate  3 minutes  max 2 ppm  Asthmatic adults aged 18-39 years.  Subjects exposed during moderate exercise  10 minutes  0.5 ppm  Linn, Gong et al., 1997  Downey, CA, USA  Chamber  41 (19 male, 22 female)  Nowak et al., 1997  Hamburg, northern Germany  Mouthpiece  790  Mouthpiece  47 (14 male, 33 female)  Trenga, Koenig and Seattle, WA, Williams, 1999 USA  Main Comparison  Positive Results  Methacholine and allergen sensitivities and pulmonary function after breathing polluted or ambient air were compared.  Very slight, non-significant decrements in FVC, FEV1, and expiratory flow rate were noted.  Pulmonary function measured before, immediately, 10 and 20 min after each eucapnic hyperventilation was compared for SO2 and air.  A greater increase in SRaw was observed after SO2 (164%) than after air (36%). In the responder group (individuals who showed an increase of SRaw > 100% after hyperventilation of SO2) , increases in SRaw were 275, 116 and 53% immediately, 10 and 20 minutes after SO2, whereas increases in the non-responder group were 53, 17 and 4%, respectively.  Exposure to SO2 and airway response (FEV1, FVC, CBU, PD20FEV1).  Decrease in FEV1 and FVC with exposure to SO2 alone (not significant), increased with coexposure to NO2 (significant).  Results of nasal lavage and pulmonary function tests were compared to baseline and between Caucasians and African Americans.  Significant increases in total respiratory resistance and decreases in FEV1 and V50 observed in some subjects in both groups following SO2 exposure. Three Caucasian and five African-American subjects showed greater than 20% increases in total respiratory resistance.  Effect of SO2 on effect on lung function (FEV1, SRaw), symptom scores (lower respiratory tract - cough, sputum production, wheeze, shortness of breath, substernal irritation, chest tightness; upper respiratory tract throat irritation, nasal congestion or discharge; and non-respiratory symptoms - headache, fatigue and eye irritation) and stamina ratings.  FEV1 and SRaw showed a highly significant SO2 exposure-response relationship. Exercise alone also had adverse effect on FEV1 and SRaw. Significant exposure-response relationship for total and lower respiratory score and stamina ratings. Combined SO2 and exercise had a more than additive effect (synergistic) on symptoms of shortness of breath, wheeze, and chest tightness.  Spirometry, symptoms and overall discomfort were compared for SO2 and clean air.  Subjects with allergy/asthma showed a positive association (p = 0.01) between symptoms and acid dose; in healthy subjects, that association was negative (p = 0.08).  Proportion of subjects with S02 hyperresponsiveness (20% decrease in FEV1) was assessed.  3.4% of subjects showed airway hyperresponsiveness to SO2. Among those hyperresponsive to methacholine, 22.4% were also hyperresponsive to SO2.  FEV1 tested before and after exposure  25 subjects (53%) had > 8% drop in FEV1 (range: -8% to -44%, mean -17.2%).  Null or Negative Results  Methacholine and allergen sensitivities of airways were not increased after polluted air was inhaled.  No ethnic differences in respiratory resistance, pulmonary or nasal measurements were observed. No significant changes in epithelial or white blood cell count were observed.  The entire group responded non-significantly to pollution exposure (relative to clean air) as determined by spirometry (FEV1, PEFR), symptoms and overall discomfort level during exercise.  Comments  Reference  Winterton, Kaufman et al., 2000  Tunnicliffe, Hilton et al., 2001  Location  Seattle, WA, USA  Birmingham U.K.  Subject Description  Characteristics of Study  Duration of Exposure  SO2 Concentration  63 (22 male, 41 female)  Asthmatic subjects aged 19-51 years (mean = 29). 53 subjects completed the SO2 challenge and 10 contributed buccal cells.  Subjects were exposed to SO2 to determine if they were SO2 responders. Subjects were also tested for specified genetic polymorphisms.  10 minutes  0.5 ppm  24 (12 male, 12 female)  12 normal (5 male, 7 female) adults aged 2249 years; 12 asthmatic (7 male, 5 female) adults aged 20-54 years.  Randomized exposure to either bottled medical air or SO2 at rest  1 hour  0.2 ppm  Route of Number of Exposure Subjects  Mouthpiece  Chamber  Main Comparison  Positive Results  Null or Negative Results  Comments  Genetic polymorphisms were compared for SO2 responders (FEV1 decreased by > 12% after SO2 exposure) and nonresponders to determine which biomarkers indicated sensitivity to inhaled SO2.  13 of the 62 subjects were responders. Response to SO2 was associated with the wildtype allele of the TNF-α promoter polymorphism (12 of 12 responders vs. 28 of 46 nonresponders, p < 0.05).  Response to SO2 was associated with none of the other polymorphisms.  Markers tested were B2-adrenergic receptor, IL-4 receptor a subunit, Clara cell secretory protein (CC16) , TNF-a gene promoter, and first intron of the lymphotoxin a (LTa) gene.  Heart rate variability before and during exposure and lung function before and after exposure were compared for normal and asthmatic subjects  SO2 exposure was associated with an increase in electrocardiogram frequency domains in the normal subjects, and a reduction in asthmatics.  No change in FVC, FEV1, respiratory symptoms, or heart rate was observed in either group.   Table 4.4 Epidemiological Studies of Other Health Outcomes of SO2 Exposure Reference  Sorsa et al., 1982  Year & Season of Study  Location  Exposure Source  (not reported)  (not reported) investigators from Sweden  Industrial (aluminum smelter)  16 (8 plant Cross-sectional workers and 8 clerks)  Exposed: males with an average of 20 years at the foundry, including three smokers. Controls: male clerks, including 5 smokers.  Industrial (pulp mills)  162 (81 sulfur exposed and 81 age and Cross-sectional smoking-habit matched unexposed controls)  Pulp mill workers with and without occupational exposure to organic and inorganic sulfides in 2 adjoining mills.  (Year not Kangas, reported) Winter, Jappinen & Spring and Savolainen, 1984 Summer  Englander, Sjoberg, et al., 1988  Meng & Zhang, 1990  Yadav & Kaushik, 1996  1961 - 1985  Finland  Sweden  (not reported)  Taiyuan City, Northern China  (not reported)  (not reported) investigators from Kurukshetra, India  Study Design  Number of Subjects  Subject Description  Special Characteristics of Study  Duration of Exposure  All exposed employees complained of some symptoms, including cough, nose or eye irritation, and previous respiratory inflammation.  5 to 39 years of employment  (not reported)  Male workers employed for at least 6 months during the period 19611981.  Measurements performed in the respiratory zone of workers "over the years" provide estimates of SO 2 levels in the factory. Other exposures include dust and arsenic.  82 (40 plant workers and 42 Cross-sectional controls from Shanxi University)  Exposed: sulphuric acid plant workers Controls: university employees and students, matched on age, sex, and smoking habits  No differences between exposed workers and controls with respect to recent viral infections, vaccinations, previous occupational exposures, drug intake and alcohol consumption  (not reported)  84 (42 SO2 Industrial Cross-sectional exposed and 42 (fertilizer factory) unexposed controls)  Exposed: fertilizer factory workers exposed to SO2 Controls: matched for age, sex, smoking and alcohol consumption.  More workers than controls were smokers (34 vs. 27); fewer workers consumed alcohol (17 vs. 23).  0 to 20 years  Industrial (sulfuric acid factory)  Industrial (sulfuric acid factory)  Retrospective cohort  400 (all males)  ≥ 6 months  SO2 Concentrations  Main Comparison  Positive Results  Null or Negative Results  No differences in chromosome aberrations (4.8 vs. 4.3), and sister chromatid exchanges (8.9/cell vs. 9.2/cell) were observed in the exposed group compared to controls.  0.2 to 3 ppm (daily averages), mean = 1.0 ± 0.85 ppm  Occurrence of genotoxic effects (sister chromatid exchanges and chromosome aberrations).  SO2 concentrations measured in 4 sulfite mills and 6 Kraft pulp mills ranged from 0.08 to 1.8 ppm in summer and 0.07 to 7.4 ppm in winter. (not specific to workers in health study)  Comparison of sulfur exposed and unexposed. 75-item questionnaire about respiratory, cardiovascular, neurological and psychic symptoms. Absenteeism over previous 12 months.  More exposed workers reported chronic headaches (p<0.025), neurological symptoms and a decrease in concentration capacity (neither statistically significant) than matched controls. The number of sick leaves in the previous 12 months was greater in the exposed workers than among the controls (p<0.1).  No differences in cardiovascular symptoms found.  3.60 mg/m 3 (median exposure of workers at factory not specific to study subjects)  ICD codes from death certificates and information on tumours from the National Swedish and Southern Swedish Regional Tumour Registers were obtained. Causespecific standardized mortality/morbidity ratios (SMRs) were calculated.  The overall mortality ratio for the period 1961-1985 was significantly elevated (53 deaths observed vs. 37 expected). Deaths from mental disease (n=2), nonmalignant gastro-intestinal disease (n=6), violence and intoxication (n=10), and bladder cancer (n=5) were significantly increased. Cardiovascular disease mortality elevated but not significantly.  There was no increased risk of total or gastrointestinal tumours in the factory population. There were no observable trends in disease mortality with duration of employment.  0.34 to 11.97 mg/m 3 (measured at time of study, not clear if exposures subject specific)  Occurrence of genotoxic effects (sister chromatid exchanges and chromosome aberrations).  Significant increases in chromosome aberrations (264 vs. 54), and sister chromatid exchanges (6.72/cell vs. 2.71/cell) were observed in the exposed group compared to controls.  No pattern with duration of employment  Occurrence of genotoxic effects (mitotic index, sister chromatid exchanges, satellite associations, and chromosome aberrations).  Significant increases in mitotic index (7.09 vs. 4.34), chromosome aberrations (3.262 vs. 0.833 per 100 metaphases), satellite associations (17.1 vs. 8.1 per cell) and sister chromatid exchanges (7.27 vs. <4) were observed in the exposed group compared to controls. Chromosome aberrations and sister chromatid exchanges increased with duration of exposure.  Mitotic index decreased with duration of exposure.  Workers were exposed to an average SO2 level of 41.7 mg/m 3. (not known whether exposure levels subject specific)  Reference  Year & Season of Study  Location  Exposure Source  Study Design  Number of Subjects  Subject Description  Shinkura, Fujiyama & Akiba, 1999  1978 - 1988  Yamashita district of Kagoshima City, Japan  Ambient (in vicinity of active volcano)  Cohort study (time series analysis)  29,789 (estimate of live births)  Live births and neonatal deaths occurring within the first 28 days of life.  Special Characteristics of Study  Subjects lived near Mt. Sakurajima, one of the most active volcanoes in the world  Duration of Exposure  SO2 Concentrations  up to 28 days  ambient seasonal averages from 0.010 to 0.013 ppm (ecological data)  Main Comparison  Neonatal mortality was compared to SO 2 monthly average and maximum hourly average concentrations, as well as to ash and suspended particulate concentrations.  Positive Results  The monthly average SO 2 concentration was positively associated with neonatal mortality.  Null or Negative Results  The maximum hourly average SO 2 concentration, ash and particulate concentration were not associated with neonatal mortality.   Table 4.3 Epidemiological Studies of Respiratory Effects of SO2 Exposure Reference  Kehoe et al, 1932  Skalpe, 1964  Ferris, Burgess & Worcester, 1967  Smith, Peters et al., 1977  Archer & Gillam, 1978  Lebowitz et al., 1979  Year & Season of Study  (not reported)  (not reported)  Number of Subjects  Subject Description  Special Characteristics of Study  Industrial (refrigerator manufacturing plant)  200 (100 who worked with SO2 as a Cross-sectional refrigerant, and 100 working in other jobs in the plant)  Exposed workers, mean age = 37 years; Controls, mean age = 35.7 years  Physical examinations conducted of each subject  Industrial (pulp mills)  110 (54 exposed pulp mill Cross-sectional workers and 56 unexposed paper mill workers)  Exposed workers from 4 mills, controls from paper mill portions of these plants or from other paper mills in region.  271 (147 exposed pulp mill workers and Cross-sectional 124 unexposed paper mill workers)  Pulp mill workers were exposed to chlorine and sulfur dioxide. Controls were paper workers in same complex; many were found to have moved from pulp mill jobs to avoid the gas exposures.  Examined joint effects of smoking and gas exposures. Chlorine, chlorine dioxide and hydrogen sulfide exposures also measured.  Caucasian smelter workers aged 1964 years (mean age = 36).  Smelter workers were chronically exposed to SO2 from the processing of copper sulfide concentrates.  Smelter workers: mean age = 41.3 years, 8.9% non-white, 9.9 cigarettes/day controls = 37.0 years, 13.5% nonwhite, 8.0 cigarettes/day  Personal air samples taken of SO2 and arsenic, copper, manganese, iron, and other metals (all metal concentrations 5 to 250 times lower than then current occupational exposure limits).  Workers ranged in age from < 45 to 65+  Smelter workers classified into 4 exposure groups: no exposure, < 2.5 ppm, 2-5 to 5 ppm and = 5 ppm; based on sampling for each job and the job history of the employee. Dust exposure also classified.  Location  Exposure Source  Dayton, OH, USA  Norway  Study Design  1962, October  Berlin, NH, USA  Industrial (pulp mills)  1973 - 1974  Salt Lake City, UT, USA  Industrial (copper smelter)  Cross-sectional (with longitudinal follow-up over one year)  Industrial (copper smelter)  1,215 (953 smelter employees, and 262 mine truck Cross-sectional maintenance shop employees, all males)  Industrial (copper smelter)  Cross-sectional (with follow-up spirometry available for a subset of 244 subjects)  430 (all males)  Cross-sectional  162 (81 sulfur exposed and 81 age and smoking-habit matched unexposed controls)  (not reported)  1976  (Year not Kangas, Jappinen reported) Winter, & Savolainen, Spring and 1984 Summer  Garfield, UT, USA  Salt Lake City, UT, USA  Finland  Industrial (pulp mills)  113 (all males)  Pulp mill workers with and without occupational exposure to organic and inorganic sulfides in 2 adjoining mills.  Duration of Exposure  SO2 Concentrations  Exposed workers mean = 4 years; Controls mean = 4.5 years  10 to 100 ppm, based on area sampling.  Positive Results  Null or Negative Results  Respiratory symptoms, based on questionnaire and physical findings.  Exposed men had more pharyngitis, tonsillitis, abnormal reflexes, altered sense of taste and smell, increased sensitivity to other irritants, dyspnea on exertion and fatigue.  No differences in weight gained or lost, overall health, constipation, headaches, or chest x-ray findings.  1 month to 44 years  2-36 ppm based on grab samples within working day, with some excursions as high as 100 ppm when blowing digesters (area samples).  Respiratory symptoms as reported in interview and pulmonary function (vital capacity and maximal expiratory flow rate).  Higher frequency of cough, expectoration and dyspnea on exertion among exposed group, especially among workers under 50 years of age. Decreased expiratory flow rate in those under 50.  No differences in vital capacity, or in expiratory flow rates for those over 50.  Average = 16.3 years (pulp mill) and 6.0 years (paper mill)  < 0.1-33 ppm (mean = 8 17, over three sampling campaigns) (area samples)  Prevalence of chronic bronchitis, obstructive lung disease and asthma.  Pulp mill workers had higher prevalence of obstructive lung disease. Smoking pulp mill workers had high rates of respiratory disease than smoking paper mill employees.  No overall difference in chronic bronchitis.  Changes in pulmonary function measured before and after 8-hour work shifts. Personal exposure measurements taken over a one-year period used to categorize subjects by SO2 exposure (<1.0 ppm, >1.0 ppm) for analysis. Respirable particulate, copper, and sulphates also measured.  Significant decline in FEV1 associated with exposure to >1 ppm SO2. Similar but weaker results were observed for FEV1/FVC. Workers with FEV1 below normal on initial measurements (based on age and height) showed evidence of even greater losses of pulmonary function related to SO2 exposure. Effects on FEV1 remained after controlling for respirable dust (which was also associated with FEV1 declines).  No associations were found between changes in FVC and exposure to air contaminants.  1 to 6 ug/m3  Respiratory symptoms by questionnaire and pulmonary function. Analyses stratified by smoking status.  Significant decline in FEV1, FVC associated with exposure to SO2. Increases in cough, phlegm, dyspnea on exertion, chest tightness, chronic bronchitis among smelter workers. More smelter workers than maintenance workers took early retirement (17.6 vs. 8%).  from < 2.5 to > 5 ppm  Pulmonary function compared by exposure group, and dust group. Multiple regression analysis controlling for age, height, smoking, and dust exposure.  Declines in FEV1 associated with SO2 exposure in those employed for less than 20 years only. Higher rate of chronic obstructive pulmonary disease in those who were highly exposed and who smoked.  SO2 concentrations measured in 4 sulfite mills and 6 Kraft pulp mills ranged from 0.08 to 1.8 ppm in summer and 0.07 to 7.4 ppm in winter. (not specific to workers in health study)  Comparison of sulfur exposed and unexposed. 75-item questionnaire about respiratory and other symptoms.  (not reported)  (not reported)  Some less than and others more than 20 years.  (not reported)  1.6 to 45 ppm (personal exposure measurements of study subjects)  Main Comparison  No associations were found between FVC, FEV1, ratio and exposure to air contaminants in cross-sectional comparisons.  No differences in respiratory symptoms found.  Year & Season of Study  Location  1978-1982  Morenci, Kingman and San Manuel, AZ, USA  Rom, Wood, et al., Salt Lake City, 1980, 1980 - 1983 UT, USA 1986  Reference  Dodge, Solomon et al., 1985  Englander, Sjoberg et al., 1988  Broder, Smith et al., 1989  Osterman, Greaves, et al., 1989  1961 - 1985  June-November 1985  1980 to 1983  Sweden  Subject Description  Special Characteristics of Study  Cross-sectional 678 (with Ambient longitudinal (3rd to 5th grade (in smelter town) follow-up for 3 children) years)  343 children in Morenci, a smelter town, 134 children from San Manuel, another smelter town, and 201 children from Kingman a nonindustrial town. Mean age of children 9.8 years.  Exposure to SO2 from local smelters. The concentration fluctuates between areas of the town due to winds and location of smelter stacks.  66 in 1980, Cross-sectional 48 of these (longitudinal participated in Industrial follow-up of 1983, as well as (copper smelter) previous study, 15 additional and additional 3workers year follow-up) (all males)  Caucasian smelter workers involved in Smith, Peters, et al., 1977 study (mean age = 44.2 in 1980 and 47.7 in 1983)  Smelter workers were chronically exposed to SO2 from the processing of copper sulfide concentrates.  Male workers employed for at least 6 months during the period 1961-1981.  Measurements performed in the respiratory zone of workers "over the years" provide estimates of SO2 levels in the factory. Other exposures include dust and arsenic.  Exposure Source  Industrial (sulfuric acid factory)  Sudbury, ON, Canada  Industrial (nickel smelter)  Quebec, Canada  Industrial (silicon carbide plant)  Study Design  Number of Subjects  Retrospective cohort  400 (all males)  Cross-sectional  260 (143 smelter workers and 117 civic labourers)  Nickel smelter workers worked with a high sulfide ore and civic labourers from same community  Smelter workers were exposed to SO2, iron, nickel, copper, and particulates. 19% of civic workers had worked in smelter in the past. More smelter workers smoked (50% vs. 38%).  177  Plant workers with at least two years experience between 1977 and 1982. Other potential exposures include respirable silica, polycyclic aromatic hydrocarbons, carbon monoxide, graphite.  Internal comparisons done according to average and cumulative exposure levels. Respirable dust measurements also made.  Cross-sectional  Duration of Exposure  SO2 Concentrations  Main Comparison  Positive Results  Null or Negative Results  (not reported)  Stargo section of Morenci: 103 +/- 282 ug/m3; Central Morenci: 14 +/- 77 ug/m3; San Manuel: 48 +/- 172 ug/m3; Kingman: <4 ug/m3  Parent's reports of their children's respiratory symptoms (asthma, shortness of breath with wheeze, cough, sputum production) and measured FEV1, FVC, VMAX50, VMAX75. Comparisons according to SO2, sulfate, ammonia, and particulate levels.  Cough prevalence was significantly associated with SO2 exposure level (chisquare = 5.6, p=0.02).  No relationship between other symptoms or lung function measures and SO2 exposure.  > 7-10 years  0.1 to 6.5 ppm, mean around 2 ppm. Data from company personal exposure surveys in 1976 and 1982 (data not specific to study subjects)  FEV1 and FVC of subjects in 1973, 1974, 1980, and 1983 were compared. Study does not seem to consider subject-specific exposures after 1974.  = 6 months  3.60 mg/m3 (median exposure of workers at factory - not specific to study subjects)  ICD codes from death certificates and information on tumours from the National Swedish and Southern Swedish Regional Tumour Registers were obtained. Causespecific standardized mortality/morbidity ratios (SMRs) were calculated.  mean duration of smelter employment = 17 years, mean duration of employment civic workers = 10 years  Smelter workers' mean = 0.67 ppm SO2 (40-fold greater than the controls), personal measurements of study subjects.  At least 2 years working at station, average = 13.9 years  mean = 0.63 mg/m3 mean cumulative exposure = 9.5 mg/m3 * years (exposures measured for each job, subjects assigned exposure according to their job history)  Results of spirometry did not agree with those of the previous longitudinal study. Both workers exposed to < and > 1ppm SO2 in 1973-1974 did not have continued lung function declines. Workers whose initial FEV1 was < 90% predicted displayed improvements in 1980. When SO2 concentrations were similar to 1974, no accelerated decline in lung function was observed from 1980 to 1983.  Deaths from respiratory tumours elevated (5 observed vs. 2.5 expected), but not statistically significant.  No increase in non-malignant respiratory disease.  Respiratory symptoms based on questionnaire administered on day 1 of a work week, and FEV1, FVC, FEF50 and FEF75 based on pulmonary function tests administered on days 1 and 4 of the same work week, were compared between smelter workers and the control group.  Smelter workers showed an increased frequency of a history of pneumonia, and decreased FEV1, FEF50 and FEF75. Some limited evidence that less healthy workers had left smelter employment.  Civic workers showed more shortness of breath relative than the smelter workers. Lung function decrements among smelter workers not significant after adjustment for age, height, smoking status, duration of employment, mask wearing. Increasing SO2 exposure associated with increased FEV1, FVC, and FEF50 among smelter workers.  Respiratory symptoms (cough, phlegm, wheezing, dyspnea), as reported by questionnaire  Positive dose dependent relationships between SO2 exposure and phlegm, wheeze and dyspnea. Smoking and sulfur dioxide exposure interacted to create a greater than additive response.  Cough not associated with exposure.  Reference  Froom, Sackstein et al., 1998  Donoghue & Thomas, 1999  Wang, Peng et al., 1999  Year & Season of Study  (not reported)  1993-1996  1995  Smith-Sivertsen, May 1994 to April Bykov et al., 2001 1995  Location  Exposure Source  Tel Aviv, Israel  Industrial (electric power generating station)  Mount Isa, Australia  Ambient (in a city of 25,000 with a copper smelter and a lead smelter)  Study Design  Subject Description  Special Characteristics of Study  Power station operators who were exposed worked near burning chambers, unexposed controls worked near burning chambers under negative pressure.  SO2 from burning chambers  Number of presentations to hospital with complaints of asthma, wheeze or shortness of breath over the three year study period (n ~1,600). Number of admissions to hospital for these conditions (~400).  Outdoor exposure to ambient SO2 in town with two point sources (copper smelter and lead smelter) were measured at 10 monitoring stations. Other pollutants (particulate, metals, ozone, nitrogen oxides) were not studied. City has about 25,000 people.  1096 (420 men, 676 women)  Subjects men aged 35 to 60, never smokers, non-users of coal for cooking or heating. Subjects were administrative staff and officials to decrease the possibility of confounding due to occupational exposures.  Chongqing is largest city in China, with 30,000,000 people; it is surrounded by mountains. Subjects residing within 1 km of one of three ambient air monitoring stations, in urban industrial, urban residential and suburban areas. Particulate measurements also made; little difference between urban and suburban levels.  5051 (2147 men; 2904 women)  Subjects were adults aged 18 to 69 (mean ~42) from a nickel-smelter town in Russia (10.6% of male subjects and 2.7% of female subjects worked at the smelter) and a nearby town across the border in Norway.  These towns are in an isolated northern area with little automobile traffic and low levels of ambient particulate (monthly means from 4.2 to 19.4 ug/m3, and monthly 48-hour maxima of 8.3 to 44.7 ug/m3).  Number of Subjects  72 (38 exposed power station Cross-sectional technicians and 34 unexposed technicians)  Time series  Chongqing, China  Ambient (city with several steel, iron and power plants, Cross-sectional industry and residences mainly use coal for energy)  Sor-Varanger, Norway and Nikel, Russia  Ambient (in small cities, one with a nickel Cross-sectional smelter and the other nearby)  (not reported)  Duration of Exposure  SO2 Concentrations  Main Comparison  Positive Results  Null or Negative Results  Cough and sputum production were significantly elevated in the exposed group, and dyspnea was elevated. Exposed workers who complained of dyspnea had significant decrements in lung function. Prevalence of cough affected by synergy between exposure and smoking: non-exposed/non-smokers 16%, non-exposed/smokers 22%, exposed/non-smokers 50%, and exposed/smokers 67%, p=0.0077.  There were no differences in pulmonary function between exposed and control subjects. For exposed workers who complained of cough, there were no decreases in lung function.  At least 2 years working at station  Exposed group were exposed to 0 to 15 ppm, mean = 0.7 ppm  Respiratory symptoms as reported on questionnaire and FEV1, FVC, FEF based on pulmonary function tests were compared between the two groups of workers.  (not reported)  Concentrations ranged from "zero" to 8700 ug/m3. The maximum (5minute interval) concentrations recorded each day were used in the analysis.  Numbers of presentation and admissions for asthma symptoms (asthma, wheeze or shortness of breath) compared in time series analysis, with the maximum (5-minute interval) SO2 concentrations recorded each day. No lagging of exposure done, because effects expected to be immediate and of short duration.  (not reported)  Urban levels ranged from ~ 150 to 275 (mean = 213) ug/m3; suburban levels ranged from ~50 to 175 (mean = 103) ug/m3, as measured by 24-hour measurements at stationary monitors.  (not reported)  Monthly ambient levels were less than 20 ug/m3 in the Norwegian area, and ranged from 20 to 150 ug/m3 in the Russian town. Each subject assigned to daily average on the day of and the day before screening, based on ambient monitoring data with some dispersion modelling.  FVC and FEV1 based on pulmonary function measurements were compared for areas of different SO2 concentration.  FVC and FEV1 based on pulmonary function measurements, and respiratory symptoms based on questionnaire responses were compared for subjects categorized into 4 different SO2 exposure groups: < 10, 10-50, 50-90, and > 90 ug/m3. Occupational exposures do not appear to have been adjusted for.  No association found between peak SO2 exposure and hospital presentations or admissions for asthma, wheeze or shortness of breath.  FVC, FEV1, and FEV1/FVC ratio significantly reduced men and women living in the urban areas with higher SO2 concentrations. Differences remained after removing subjects with any occupational exposures to dusts, gases, or fumes.  Men and women from the Russian town had better lung function than those from the Norwegian town. More from the Russian town reported persistent cough and phlegm and these symptoms increased with increasing SO2 exposure on the screening day (though proportions of smokers were also associated with SO2 concentrations).  No associations observed between SO2 concentration and lung function. In the adjusted analysis, respiratory symptoms were included as co-variates, and therefore adjusted for chronic respiratory disease.   Table 4.2 Studies of Indoor and Outdoor Exposures to SO2  Reference  Biersteker, de Graaf & Nass, 1965  Year & Season of Study  Location  Type of Exposure  1964, January to March  Rotterdam, the Netherlands  Indoor and Outdoor (residential)  Spengler, Ferris & Dockery, 1979  (year not reported) one-year period  6 cities in USA: Kingston/ Harriman TN; Portage WI; Steubenville OH; St. Louis MO; Topeka KS; Watertown MS  Indoor and Outdoor (residential or public facilities)  Stock, Kotchmar et al., 1985  May to October, 1981  Sunnyside and Clear Lake neighbourhoods of Houston, TX  Indoor and Outdoor (residential)  Méranger and Brulé, 1987  (year not reported) March and April  Antigonish, Nova Scotia  Indoor and Outdoor (residential)  Number of Sites  Site Description  60  Homes representative of bungalows, multistoried houses, flats, and high rise apartments. indoor samples taken in living room, outdoor samples taken outside same house  Duration  Sampler Used  ~14 to 22/site; half indoors and half outdoors  24 hours  Drechsel bottle with hydrogen peroxide solution, analyzed by titration of total acidity  ~ 60  Indoor samples taken in main activity room of home (living room, TV room, den) or in public building, outdoor sites are ambient sampling stations.  ~ 30-50/site; one taken every 6th day for at least one year  24 hours  Bubblers, analyzed using West-Gaeke method.  12  Houses representative of those of participants in an epidemiological study.  2/site; one indoors and one outdoors, providing ~200 hours of data for each site  8-9 days  Pulsed fluorescence continuous gas analyzer  2  60 year old house at town centre, site outside town  (not reported, 8 weekly averages per location, in dining room and outside house, outdoors only outside town)  not reported  Flame photometric continuous gas analyzer  2 hours  Pararosanaline  1987, June to August 4 cities in Eastern China: Yuhui, Xiaoming Chengde et al., 1991 Shenyang 1987 - 1988, Shanghai December to Wuhan February  Lee, 1997  Kukadia & Palmer, 1998  1996, January to March  Hong Kong  1996, Winter Birmingham, UK  Indoor (residential)  120  30 homes/city: 15 coal-burning; 15 gas-burning  Indoor and Outdoor (residential)  30  15 units in each of 2 staff quarters: Tsim Sha in a heavy traffic area; and Shatin in a low traffic, but industrial area  Indoor and Outdoor (office)  2  1 ground floor office in naturally ventilated building, and 1 third floor office in mechanically ventilated building.  Number of Measurements  16 per site: 4 samples per day, 2 days in summer and 2 in winter, in the kitchen and bedroom at breathing level. 1) 6-8 am 2) 9-11 am 3) 1-3 pm 4) 6-8 pm  8 per site: one in the living room and one on the balcony, one on a weekday morning and one in the evening, one on Sunday morning and one in the evening  ~ 2000 records/site (recorded every 5 minutes over sampling period)  20 minutes  Tedlar bag and pump (1 L/min), analysis by pulsed fluorescence SO2 analyzer  1 week  Data logging continuous gas analyzer  Measured Concentration of SO2 Units  ug/m3  ug/m3  Minimum  Mean  I/O Ratio  Indoor 0  ~0.20  Kingston, TN Portage, WI Steubenville,OH St. Louis, MO Topeka, KS Watertown, MS  indoor 1 6 22 10 1 8  indoor 5.1  outdoor 2.8  outdoor 12 8 52 40 2 25  indoor 0 5 16 10 0 0  Outdoor 73  outdoor 4 7 35 28 1 11  Maximum  Indoor 246  indoor 1 10 26 26 2 10  Standard Deviation  Multiple regression analysis showed increasing % indoor SO2 with older construction. Smoking in the home, outdoor SO2, and gas, coal and oil heating (order highest to lowest; versus central) also associated with increased levels. Natural gas in Rotterdam at the time contained 100-250 mg S/m3  Outdoor 384  outdoor 12 10 59 60 5 31  Indoor concentrations consistently and significantly lower than outdoor. Differences between cities significant.  Indoor 5.3  ppb  Outdoor 5.0  2 - 10 3 - 16 0 - 30  indoors in town outdoors in town outdoors control  SUMMER Kitchen/coal Bedroom/coal Kitchen/gas Bedroom/gas  Chengde 71 60 47 39  Shenyang 75 51 74 53  Shanghai 694 334 53 33  Wuhan 174 67 76 87  WINTER Kitchen/coal Bedroom/coal Kitchen/gas Bedroom/gas  Chengde 482 274 163 140  Shenyang  Shanghai 860 502 65 37  Wuhan 173 87 70 41  Tsim Sha Shatin  indoor 4.3 3.9  outdoor 6.0 4.3  I/O Ratio 0.72 0.91  Mean I/O Ratio  Nat Vent 4.4 0.4  Mech Vent 3.9 0.4  Outdoor 11  Winter exposure higher than summer; kitchen higher than bedroom, and coal higher than gas. In the 4 cities studied, concentrations of SO2 in kitchens and bedrooms in homes using coal stoves in winter almost all exceeded national standard (150 ug/m3 - daily average). In summer, all levels met requirement except for Shanghai.  I/O 0.54 0.86  I/O 0.85 0.97  indoor 1.4 1.0  nL/L (ppb)  ppb  Despite higher indoor than outdoor SO2 levels, authors caution that this result may be confounded by differences between homes and diurnal patterns.  Usually lower levels indoors than outdoors at town site. Outdoor concentrations depended on direction of prevailing winds, compared to pollutant sources (oil-burning power plants at the hospital and university).  ug/m3  ug/m3  Results  Nat. 10.6 0.3  Mech. 13.4 0.3  outdoor 2.5 1.3  Outdoor levels higher than indoor levels, but indoor and outdoor levels were significantly correlated. Outdoor levels at Tsim Sha highest for all times of day, likely due to traffic. No differences observed between morning and afternoon, except that lower levels seen on Sunday evenings.  Outdoor levels greater than indoor. No distinction between natural and mechanical ventilation with regards to indoor air quality,  Reference  Year & Season of Study  Bailie, Pilotto et al., 1999  (not reported: possibly South Winter (year Africa, based on not reported) acknowledgement)  Camuffo, Brimble1996, combe et al., February and 1999 August  Location  Venice, Italy  Type of Exposure  Number of Sites  Site Description  Indoor (residential)  72  Houses, none with chimneys, some with no paraffin use, some with use of paraffin for heating, lighting, and/or cooking  Indoor and Outdoor (museum)  Exotox 75 continuous gas analyzer  6 per site: 3 days per site (fall, spring and winter), twice per day (once in the morning and once in the afternoon)  36 test runs under various conditions inside and outside clamshell. Sampling probes positioned close to breathing zone of a sleeping person.  5 hours  Draeger Multigas Multiwarn II continuous gas analyzer  8 per site: 4 outdoors by fresh air intake of airconditioning unit, 4 in middle of living area  48 hours  Ogawa PS-100 passive samplers  7 days  Diffusion monitor with glass fibre filter coated with sodium bicarbonate, analysis by ion chromatography  Zhou & Cheng, (not reported) 2000  Indoor (tent)  1  Hong Kong  Indoor and Outdoor (residential)  10  Apartments of non-smokers in different areas of city, 20 -140 m2, 2 - 5 occupants and from 2nd to 35th floors  25  12 single-family homes in Boyle (rural, population 860) and 13 in Sherwood Park (population 42,000 and near Edmonton, population 800,000, refineries and power generating facilities nearby)  Indoor and Outdoor (residential)  6 hours  115  50 very low income households, 40 low income households, and 25 middle income households; in cooking and living areas of each home  Vinyl-backed canvas army tent inside clamshell structure, with unvented kerosene/jet fuel heaters inside (2 convection type, and 1 radiant type) modelled to simulate Gulf War conditions of 1990-1991  Boyle and Sherwood Park, Alberta  20 minutes  Teflon bag and pump (1 L/min), analysis by pulsed fluorescence SO2 analyzer  14  (not reported: possibly New Mexico, US, based on authors' location)  1998, Late Fall  2 to 4 weeks  Diffusion tubes, with stainless steel mesh coated with potassium hydroxide, analysis by ion chromatography  2 per site: indoors (in most densely occupied area) and outdoors (near fresh air intake during peak hours) at each  South Africa  Kindzierski & Sembaluk, 2001  Exotox 75 continuous gas analyzer  3 restaurants, 2 libraries, 3 recreation sites, 3 shopping malls, 2 sports centres, and 1 car park, in rural areas and in commercial and residential urban areas  Sanyal & Maduna, 2000  1997, May to June  (not reported)  1  1995 - 1996, February to December  Indoor (residential)  Sampler Used  15 total for the site: 1 in winter only at three of the locations and 2 (one winter and one summer) at 6 of the locations  1996 - 1997, October to March  Chao, 2001  Indoor and Outdoor (public places)  (not reported)  Duration  Correr museum: 3 outdoor sites around the museum and 6 rooms indoors  Lee, Chan & Chui, 1999  Hong Kong  Number of Measurements  4 per site: 2 indoors in main living area near kitchen and 2 outdoors under rain shelter  Measured Concentration of SO2 Units  Minimum  Mean  0.54  0  Maximum  Standard Deviation  6.8  After electricity, paraffin was the most commonly used fuel (69% of households and 64%, respectively). Fuel use not associated with SO2 levels.  ppm  OUTDOORS Piazza San Marco Enclosed Courtyard 1 Enclosed Courtyard 2 INDOORS Bellini Room 1 Bellini Room 2 Lotto Room 1 Lotto Room 2 Lotto Room 3 Lotto Room 4  ppb  Feb. 40 34.2 19.9  Aug. 25.8  5.8 5.9 4.8 4.4 5.0 5.6  <6  Indoor 0.006 0.006 0.003 0.006 0.003 0.005 0.003 0.012 0.003 0.003 0.008 0.006 0.003 0.003  Outdoor 0.006 0.007 0.003 0.007 0.003 0.005 0.003 0.009 0.009 0.003 0.008 0.006 0.003 0.005 June - Sept  Site Comments  Oct - Dec  March - May  cooking  60  35  27.5  living  33  28  35.5  Low income  cooking  42.5  16.5  16.5  living  20  20  24  Middle income  cooking  21.5  11.5  11.5  living  12.5  9.5  12  restaurant 1 restaurant 2 restaurant 3 library 1 library 2 uL/L recreation site 1 recreation site 2 (ppm) recreation site 3 shopping mall 1 shopping mall 2 shopping mall 3 sports centre 1 sports centre 2 car park Very low income  mg/m  3  ppm  16.8  Outdoor concentrations higher than indoor. Higher levels than those recorded at the V&A Museum in London and at the Residenz in Wurzburg.  <6 <6 <6  Rural SO2 concentrations about half of those in urban areas. Differences between indoor and outdoor levels were small (I/O Ratio = 0.92), and there was reasonable correlation between indoor and outdoor values (R2 = 0.56). Outdoor and indoor concentrations were well below the ASHRAE recommended 24-hour average of 0.14 uL/L and the NAAQS annual average of 0.03 uL/L.  rural rural  diesel machine outside site  rural  SO2 values significantly higher in kitchen than in living room from JuneSeptember (winter in South Africa).  SO2 concentrations rose throughout time heaters were on and decreased rapidly after they were turned off. Convection heaters produced higher concentrations than the radiant heater.  0 - 1.5 depending on heater, fuel, and air exchange rate  Indoor Outdoor I/O Ratio  6.3 8.1 1.01  (MEDIANS) Indoor Outdoor I/O  Boyle 0.5 4.3 0.13  2.6 2.6 0.25  10.4 15.7 3  2.2 3.8 0.78  ug/m3  ug/m  3  Sherwood 1.4 9.9 0.13  Results  Boyle 0.2 3.7 0.05  Sherwood 0.9 8.2 0.08  Boyle 2.3 5.6 0.52  Sherwood 5.2 13 0.4  SO2 levels low inside and outside residential apartments; authors indicate that levels now are lower than previously due to the implementation of restrictions on sulfur content in fossil fuels  Indoor levels much lower than outdoor. Higher indoor and outdoor (2x) levels in Sherwood Park than Boyle due to increased traffic and industrial emissions.   Table 3.6 Controlled Human Exposures to NO2 Reference  Location  Orehek, Massari et al., 1976  Goings, Kulle et al., 1989  Jorres & Magnussen, 1990  Rasmussen, Kjaergaard & Petersen, 1990  Single-blind  Baltimore, USA  Germany  Denmark  Roger, Horstman et al., North 1990 Carolina, USA  Rubinstein, Bigby, et al., 1990  Study Design  Placebocontrolled, randomized double-blind  Crossover  Randomized double-blind  Number of Subjects  Subject Description  Characteristics of Study  Duration of Exposure  NO2 Concentration  1 hour  0, 0.1 ppm, 0.2 ppm (4 subjects only)  20  Outpatients with slight to mild asthma (symptom free during study and did not take medication 24 hours prior to study).  Controlled exposure to NO2 in a chamber.  152  Healthy, non-smoking adults who were seronegative to influenza A/Dorea/82 (H3N3) virus. Aged 18-35 years.  Subjects were exposed to NO2 or ambient air in a environmental chamber.  Mild asthmatics aged 34 (+/-14) years.  Tidal breathing via mouthpiece of filtered air, NO2, or SO2 followed by isocapnic hyperventilation of 0.75 ppm SO2 (on 3 separate days).  30 minutes  0.25 ppm  20 with slight to moderate asthma and 20 healthy. Median age of 33.5 years (20 to 73).  Participants divided into 20 matched asthmatic/healthy teams. Each team exposed via chamber 4 times to randomized concentrations. 10 minutes of exercise between 2nd and 3rd hour.  3 hours (no NO2 in first hour).  0 ppm; 0.1 ppm; 0.2 ppm; 0.8 ppm  Non-smoking asthmatic Caucasian males (aged 1935 years). 13 in preliminary experiment and 21 in concentrationresponse experiment.  Both: Exposure via chamber. 20 minutes rest followed by three 10 minute cycles of treadmill exercise followed by 20 minutes of testing and rest. Concentrationresponse experiment: Airway responsiveness measured by methacholine challenge 2 hours after exposure.  75 minutes  0.30 ppm for the preliminary experiment; 0.15 ppm, 0.30 ppm or 0.60 ppm for concentration-response experiment.  Non-smoking asthmatics, 23-34 years.  Subjects breathed test air through a mouthpiece at 20 L/min  4 minutes  Doubling doses 0.25-4.0 ppm  14 (10 male, 4 female)  40 (24 male, 16 female)  Crossover  34 (all male) in two separate studies  Chamber  9 (4m, 5f)  Year one: ambient air or 2 Exposure in the ppm NO2; Year two: chamber was for 2 ambient air or 3 ppm NO2; hours on three Year three: ambient air, 1 or consecutive days. 2 ppm NO2  Main Comparison  Positive Results  Null or Negative Results  NO2 induced a slight significant increase in specific airway resistance (initial at 6.0, after NO2 = 6.9) and enhanced bronchoconstrictor effect of carbachol in 13 subjects (mean dose producing a two-fold increase in initial specific airway resistance decreased from 0.66 mg to 0.36 mg with NO2).  NO2 did not modify initially SRaw nor bronchoconstrictor effect of carbachol in 7 subjects, 4 had variable results.  NO2 exposure and human susceptibility to respiratory virus infection and lung function (FEV1, FVC, and FEF25-75).  A significant association was found between FEV1 decrement and day of observation between exposed and the control group (-2%).  No significant association between NO2 level and susceptibility to respiratory virus infection was observed. However, people exposed to 1 or 2 ppm in the third year had a higher incidence of infection than controls. No significant difference in lung function was observed between the 2 and 3 ppm exposed groups.  The provocative ventilation necessary to increase SRaw by 100% (PV100SRaw) was compared following exposure to filtered air, NO2, or SO2.  Mean + SEM PV100SRaw was 'significantly' (p<0.01) lower after NO2 (37.7+3.5) as compared to filtered air (46.5+5.1) or SO2 (45.4+4.2).  NO2 and direct bronchomotor effects (specific airway resistance, with carbachol and without) in asthmatics.  NO2 exposure and enhanced airway responsiveness from increasing SO2 exposure.  Double blind trial. The authors do state that there was a statistically significantly linear trend of decreasing reactivity over the day of observation (p<0.01) for all subjects from day 0 to day 3.  No significant effects among asthmatics at 0.1 ppm, as reported by Orehek. With respect to symptom scores it appears that short-term exposure to NO2 in concentrations up to 0.8 ppm is unlikely to elicit subjective symptoms of mucous membrane irritation.  Difference between SRaw and FEV1 in first hour (no exposure) and 3rd hour (after two hours of exposure). Asthmatic versus controls.  FEV1 following exercise in NO2 versus clean air.  Comments  Preliminary experiment: Decreases in FEV1 and FVC and increases in SRaw were significantly greater in 0.30 ppm than in clean air. 11% decrease in FEV1 in 0.30 ppm NO2 versus 7% in air after first set of exercises.  Concentration-response experiment: No overall group-averaged indication of a concentration-related effect of NO2 on pulmonary function. Symptoms were not significantly different than those reported in clean air, which included decreased lung function and increased airway resistance after exercise.  Results from the first experiment (preliminary) were not duplicated in the second experiment (concentrationresponse).  Exposure to NO2 was not associated with any change in the reported symptoms or in measured pulmonary tests.  Subjects exercised for 20 min during NO2/placebo exposure. Exposure to NO2 and ambient air was done in a double-blind randomized fashion.  Reference  Frampton, Morrow et al., 1991  Location  Rochester, New York  Huang, Wang & Hsieh, Taipei, Taiwan 1991  Jorres & Magnussen, 1991  Kim, Koenig et al., 1991  Sandstrom, Stjernberg et al., 1991  Hamburg, Germany  Seattle, Washington, USA  Sweden  Study Design  Number of Subjects  Group 1 9 (7 male, 2 female); Group 2 15 Experimental (11 male, 4 female); Group 3 15 (12 male, 3 female)  Duration of Exposure  NO2 Concentration  Healthy, non-smoking adults aged 19-37 years with no pulmonary disease history.  Subjects were exposed to ambient air and/or NO2 in an environmental chamber while exercising (10 minutes out of every 30 minutes).  3 hour exposures, with one week between NO2 exposure and ambient air.  Group 1: 0.6 ppm; Group 2: 1.5 ppm; Group 3: 0.05 ppm with three intermittent peak exposures of 2 ppm.  Taipei road tunnel air or ambient air administered via mouthpiece.  5 minutes  70-120 ppb SO2 and 450500 ppb NOX (NO2 and NO) combined.  Crossover  6 (5 male, 1 female)  Crossover  11  Asymptomatic asthmatics aged 17-55 (mean 29).  Subjects breathed test gas through a mouthpiece in a sitting position.  20 minutes of rest followed by 10 minutes of exercise.  0.25 ppm  9  Healthy men from 19-23 years of age who were actively involved in intercollegiate crosscountry track or a comparable level.  Test atmospheres were inhaled via a rubber mouthpiece with a nose clip in place for 30 minutes including 16 minutes of heavy exercise.  30 minutes  0.18 or 0.30 ppm  Healthy, non-smoking males aged 22-32 years.  NO2 with continuous bicycle activity (ergometer) with a work load of 75 W for the last 15 minutes of exposure in an environmental chamber.  20 minutes  4 mg/m3  Asthmatics aged 8-16 years.  Exposures were to clean air, 0.30 ppm NO2, or polluted Los Angeles air on summer mornings when relatively high NO2 was expected. Alternating 10 minute periods of exposure and rest. Exposures were done in an chamber and separated by one week (not completely randomized).  3 hours  0.30 ppm (controlled); 0.09 ppm mean with range 0.010.26 ppm (ambient)  Residents with physician diagnosed COPD, aged 45-70 years. Subjects all had heavy smoking history and low FEV1.  Subjects were exposed to NO2 or ambient air in a chamber with four exercise periods.  40 (COPD = 13 Double-blind male, 7 female; Crossover Normal = 10 male, 10 female)  Elderly normal and COPD patients with mean age of 61 and 60 years, respectively.  Exposed to air or NO2 in chamber; Randomized at least 5 days apart; Intermittent exercise.  4 hours  0.3 ppm  Double-blind Crossover  Healthy, non-smoking adults with mean age of 34.4 years (22-66).  Subjects exposed via chamber in two groups (2 females, 5 males) to air and to NO2. Exposures were 1 week apart.  5 hours  2.3 ppm  Crossover  Experimental (not crossover)  18  Downey, California, USA  Crossover  34  Hackney, Linn et al., 1992  Los Angeles, CA, USA  Chamber  26 (15 male, 11 female)  Morrow, Utell et al., 1992  Rochester, NY, USA  Denmark  Characteristics of Study  Mite-sensitive asthmatic children with mean age 12 years. Moderate severity, given no asthmatic medications for at least 7 days.  Avol, Linn et al., 1992  Rasmussen, Kjaergaard, et al., 1992  Subject Description  14 (10 male, 4 female)  4 hour exposures. Exercise periods Ambient air or 0.3 ppm NO2. lasted 7 minutes.  Main Comparison  NO2 exposure and pulmonary function (SGaw, PEFR, MEFR, FVC and FEV1) and airway reactivity.  Positive Results  A greater decrease in FVC and FEV1 was observed in response to carbachol in the 1.5 ppm exposed group compared to ambient air (FVC = 1.5% air, 3.9% NO2, p<0.01). This was not observed for the other two groups.  Null or Negative Results  Comments  No direct association was found between NO2 level and pulmonary response for any of the exposure groups.  Methacholine and allergen sensitivities and pulmonary function after breathing polluted or ambient air were compared.  No difference in pulmonary function was noted, and methacholine and allergen sensitivities of airways were not increased after polluted air was inhaled.  LUNG FUNCTION: Specific airway resistance during exposure to NO2 versus exposure to filtered air.  Mean and SD values for specific airway resistance (SRaw) were comparable for NO2 and filtered air during both rest and exercise.  Pulmonary function parameters (FEV1, PEFR (peak expiratory flow rate), Rt (total respiratory resistance), and FVC (forced vital capacity) were compared before and after exposures.  No statistically significant changes were observed in FEV1, Rt, PEFR, or Vmax50% after exposure to 0.18 or 0.30 ppm NO2 (small decreases did occur).  Results of FEV1, FVC and BAL after exposure were compared to those prior to exposure.  An inflammatory cell response was found after exposure to all concentrations (mast cells, lymphocytes, lysozome positive alveolar macrophages).  There was no significant change in lung function after exposure. The inflammatory mediators fibronectin, hyaluronan, angiotensin converting enzyme (ACE) and beta-microglobulin were unchanged by exposure.  There were a total of 18 subjects (prior), but only 8 participated in each exposure group.  Questionnaire-reported symptoms and lung function measured just prior to and after 1, 2, and 3 hours of exposure, as well as bronchial reactivity to cold dry air measured 1 hour after exposure were compared for the three different exposures.  Lung function declined slightly during the first hour at 0.3ppm, but improved over the remaining 2 hours. Compared to other conditions, symptoms were increased during 1-week periods following 0.3ppm NO2 exposure.  Ambient exposures did not significantly affect lung function, symptoms, or bronchial reactivity to cold air, relative to the control condition. Compared to other conditions, symptoms were not increased during 0.3 ppm exposures.  Effects of 0.3 ppm exposure may be confounded by decreases in lung function immediately before and severe asthma symptoms during 1 week periods before 0.3 ppm exposures.  Lung function (FEV1, FVC, PEF and FEF25-75) was compared between exposure to ambient air and to 0.3 ppm NO2.  No significant correlation between NO2 exposure and decreased lung function was observed.  Pulmonary function following exposure to air and NO2 for COPD patients was compared to that of normal elderly subjects.  COPD subjects demonstrated progressive decrements in FVC and FEV1 compared with baseline with 0.3 ppm NO2 but not with air. NO2-induced FEV1 reduction was greater among smokers than neversmokers in normal subjects.  Analyses suggested that responsiveness to NO2 decreased with COPD severity.  Lung function (FVC, FEV1, FEV1/FVC, MEF25,50&75), glutathione/glutathione perioxidase, and alveolar permeability during and after exposure.  Significant decrease (at the 5% level) of alveolar permeability 6 hours after NO2 exposure. Significant decrease (5% level) of glutatione peroxidase in serum 18 hours after exposure.  No indication of mucous membrane irritation or decreased lung function during or after exposure.  Background concentration of NO2 (in air) did not exceed 0.03 ppm.  Reference  Location  Devalia, Rusznak, et al., 1994  Hazucha, Folinsbee et al., 1994  Experimental  Chapel Hill, NC, USA  Tunnicliffe, Burge & Ayers, 1994  Wang, Duddle et al., 1995  Kelly, Blomberg et al., 1996  Double-blind Crossover  Number of Subjects  Subject Description  Characteristics of Study  Duration of Exposure  NO2 Concentration  8 (4 male, 4 female)  Non-smoking, mild asthmatic adults aged 1845 years (mean age 27.6 years), with a minimum of 70% predicted FEV1 for age and height.  Subjects were exposed to one or more of the gases in a random order, in an environmental chamber.  6 hour exposures, one week apart  Ambient air, 400 ppb NO2 or 400 ppb NO2 with 200 ppb SO2.  Aged 18-35 (many were college students).  Exposure to air or NO2 via chamber for 2 hours followed three hours later by a 2 hour exposure to O3 (with intermittent exercise) on two separate days.  2 hours  0.6 ppm  Non-smoking asthmatic adults aged 16-60 years.  Subjects were exposed to NO2 or ambient air from a Douglas bag via mouthpiece, which was attached to a Rudolph valve.  1 hour (exposures were spaced at least one week apart).  Ambient air, 100 ppb and 400 ppb NO2.  2 hours  0.60 ppm NO2 or 0.60 ppm NO2 and 0.45 ppm O3  21 (all female)  Double-blind 10 (4 male, 6 female)  Crossover  8 (6 male, 2 female)  Healthy adults aged 56-85 years.  Subjects were exposed to air, NO2, or NO2 & O3 via chamber on separate days more than 1 week apart. Alternating 20 minute periods of exercise and rest.  Germany  Single-blind Crossover  20 (11 male, 9 female)  12 asthmatic (8m, 4f) aged 21-37 (mean 27) and 8 healthy subjects (3m, 5f) aged 21-33 (mean 27).  Exposures to air or NO2 via mouthpiece; Alternate exercise and rest; Randomized (>1week apart).  3 hours  1 ppm  UK  Single-blind Crossover  16 (6 male, 10 female)  Asymptomatic adults with history of seasonal allergic rhinitis aged 18 to 55 years (mean = 26.4).  Subjects were exposed to ambient air and/or NO2 in an environmental chamber during the pollen season.  6 hours  Ambient air or 400 ppb NO2.  44  Non smoking, asymptomatic male and female volunteers (1945yrs) randomly separated into 3 groups. Group 1: bronchoscopy after 1.5hrs; Group 2: bronchoscopy after 6hrs; Group 3: bronchoscopy after 24 hrs.  Controlled exposure via chamber. Light exercise alternated with rest in 15 minute intervals.  4 hours  0 or 2 ppm  Santa Drechsler-Parks, 1995 Barbara, CA, USA  Jorres, Nowak et al., 1995  Study Design  Single-blind  Main Comparison  Positive Results  Null or Negative Results  Comments  CBU = Cumulative breath units of allergen (D pteronyssinus ). PD20FEV1 = amount of allergen required to cause a 20% fall in FEV1. NOTE: dose response curves for two subjects are depicted in the report, others available through Lancet.  Exposure to NO2 (alone or in combination with SO2) and airway response (FEV1, FVC, CBU, PD20FEV1) to allergen inhalation.  A significant association was observed between exposure to both NO2 and SO2 and PD20FEV1 (60.5%, SE=8.1%, p=0.015).  No significant association was observed for either NO2 or the combination of NO2 and SO2 and FEV1 or FVC. No significant association was recorded between NO2 exposure and PD20FEV1 (41.2%, p=0.125).  Spirometry and plethysmography after exposure to air followed by O3 or NO2 followed by O3.  Following NO2-O3 exposure, median PD10FEV1 (dose required to reduce FEV1 by 10%) was reduced from 5.6 mg/ml to 1.7 mg/ml compared with air-O3 exposure (n=16, p<0.05).  NO2 exposure alone did not reduce FEV1. No 'significant' effects were observed in plethysmography.  NO2 exposure and airway response (FEV1 and FVC).  A significant difference in early and late asthmatic response (FEV1) was observed between ambient air exposure and 400 ppb NO2 exposure (-4.01%, 95%CI = -1.34 to 6.69%, p<0.009; and -5.28, 95%CI = -0.73 to -9.83%, p<0.02, respectively).  No significant difference in early or late asthmatic response (FEV1) was observed between ambient air and 100 ppb, and 100 ppb and 400 ppb.  An electrocardiogram was monitored throughout each exposure, and heart rate was recorded at 5 minute intervals during exercise. Cardiac output, stroke volume and systolic time intervals were measured at rest preceding exposure, and during the last 2 minutes of each period of exercise. Results were compared for air, NO2, and NO2 in combination with O3.  The exercise-induced increase in cardiac output with NO2/O3 exposure was significantly smaller (p<0.05) than with air or O3 alone.  There were no statistically significant differences in heart rate, respiratory frequency or oxygen uptake between exposures. There were no significant differences in stroke volume or systolic time intervals among the four exposures.  Six of the subjects completed all 4 exposures, one completed 2 exposures, and one completed 3 exposures.  Results of bronchoscopy with BAL 1 hour after exposure, and results of lung function 2, 10, 20, and 30 minutes after exposure were compared for healthy and asthmatic subjects.  In the asthmatic subjects, NO2 induced a small mean drop in FEV1. In subjects with asthma, NO2 was capable of inducing an activation of cells.  Differential cell counts in BAL fluid did not reveal significant effects of NO2.  Activation of cells induced by NO2 is compatible with enhancement of airway inflammation.  NO2 exposure and nasal airway resistance (NAR) and changes in inflammatory mediators (eosinophil cationic protein, mast cell tryptase, myeloperoxidase and interleukin-8).  A significant increase in eosinophil cationic protein was observed in subjects when exposed to NO2 compared to ambient air during allergen challenge.  There was no significant association observed with NAR and NO2 exposure.  Exposure to NO2 results in oxidative depletion of antioxidants from the respiratory tract lining (measured reduced glutathione, uric acid, ascorbic acid and malondialdehyde as a marker for lipid peroxidation in bronchial and bronchoalveolar lavage fluid).  Significant decrease in uric acid (after 24 hours returned to control levels) and ascorbic acid (returned to control levels at 6 hours) within 1.5 hours of exposure to NO2 (both bronchial and bronchoalveolar lavage fluid). Significant increase in GSH at 1.5 and 6 hours in bronchial lavage fluid which returned to control levels at 24 hours.  No change in GSH or malondialdehyde concentrations seen after NO2 exposure in bronchoalveolar lavage fluid.  Antioxidants in lung fluids react and modulate NO2 impact on lung.  Reference  Location  Study Design  Number of Subjects  Subject Description  Characteristics of Study  Duration of Exposure  NO2 Concentration  Salome, Brown et al., 1996  Sydney, Australia  Crossover  20  9 adults (19-65) and 11 children (7-15) with diagnosed asthma requiring daily medication.  Ambient air, NO2, or NO2 and combustion byproducts.  60 minutes  0.3 or 0.6 ppm  19 (9 male, 10 female)  Subjects with mild asthma aged 20-48 years.  Subjects breathed either clean air or NO2 during intermittent exercise in chamber. On two randomized days separated by 3 to 4 weeks.  30 minutes  0.26 ppm (488 + 13 ug/m3)  Single-blind  22  Three groups were enrolled: Group 1: 7 healthy non-smoking adults (mean age 34 +/-5 years); Group 2: 8 mild asthmatics (mean age 29+/-14 years); Group 3: 7 COPD patients (mean age 58+/-12 years).  Subjects were exposed to NO2 and/or ambient filtered air in an exposure chamber, at least one week apart.  Crossover  30 (18 male, 12 female)  Healthy adults aged 20-30 years (mean 35).  Randomized exposure to air or NO2 via chamber. Alternate 15minute periods of rest and exercise. Exposures separated by > 3 weeks.  18  Mild seasonal asthmatics aged 18-50 years.  Exposure at rest to either air or NO2 via chamber; Randomized and separated by more than 2 weeks.  Strand, Salomonsson et al., 1996  Huddinge, Sweden  Vagaggini, Paggiaro et al., 1996  Blomberg, Krishna et al., 1997  Umea, Sweden  Strand, Rak et al., 1997  Huddinge, Sweden  Azadniv, Utell, et al., 1998  Strand, Svartengren et al., 1998  Rochester, NY, USA  Crossover  Crossover  Crossover  15 (11 male, 4 female)  12 subjects aged 22-35 years participated in each phase. 15 subjects total.  Exposure to air or NO2 via chamber; Intermittent exercise; Randomized; Alternate exposure > 3 weeks after the first. (Both NO2 and air administered separately on the same subject in each PHASE).  Experimental  16 (10 male, 6 female)  Non-smoking, mild asthmatic adults aged 2152 years with allergy to pollen.  Subjects were exposed to NO2 and/or ambient filtered air in an exposure chamber, at least four weeks apart.  One hour exposure with moderate Ambient air and/or 0.3 ppm intermittent exercise NO2 (10 minutes every 15 minutes).  4 hours  2.0 ppm  30 minutes  490 ug/m3  6 hours  2.0 ppm  30 minute exposures over four subsequent days.  Ambient air and/or 500 ug/m3 NO2  Main Comparison  Positive Results  Null or Negative Results  Difference in airway hyperresponsiveness (AHR) and peak expiratory flow during and 1 hour after exposure were compared to baseline.  There was a small but statistically significant increase in AHR after exposure to 0.6 ppm NO2 in ambient air.  Exposure to NO2 either in ambient air or mixed with combustion by-products from a gas heater had no significant effect on symptoms or lung function in adults or children. There was no effect of 0.6 ppm NO2 on AHR when combustion byproducts were included in the test atmosphere nor of 0.3 ppm NO2 under either exposure condition.  Airway responsiveness to histamine, SRaw, and thoracic gas volume 30 minutes, 5 hours, 27 hours and 7 days after exposure, and peripheral blood inflammatory mediators and the expression of an adhesion molecule (Mac-1) on granulocytes 30 mins and 27 hours after exposure were compared for air and NO2.  Bronchial responsiveness to histamine was significantly increased 5 hours after NO2 exposure when compared to air (PDSRaw100 of 110 ug for NO2 vs 203 ug for air). A nonsignificant increase (153 vs 100 ug) was seen 30 minutes after NO2 exposure. TDV was significantly reduced after NO2 exposure. Expression of Mac-1 on granulocytes was increased 30 minutess after NO2 exposure when compared to pre-exposure values.  NO2 exposure did not affect SRaw. No effect was seen on tryptase, eosinophil cationic protein (ECP) or myeloperoxidase (MPO).  Short term NO2 exposure and airway inflammation.  COPD subjects showed a slight decrease in FEV1 after exposure to NO2 compared to ambient air.  No significant association between NO2 exposure and pulmonary function tests in normal subjects and mild asthmatics was observed.  Flexible fiberoptic bronchoscopy with BW and BAL performed either 1.5 or 6 hours after exposure was compared for air and NO2.  In BW, exposure to NO2 induced a 1.5-fold increase in IL-8 (p<.05) at 1.5 hours and a 2.5-fold increase in neutrophils (p<.01) at 6 hours. In BALF, small increases were observed in CD45RO+ lymphocytes, Bcells, and natural killer (NK) cells only.  Examination of bronchial biopsy specimens showed no signs of upregulation of adhesion molecules, and failed to reveal significant changes in inflammatory cells at either time point after NO2 exposure.  Allergen inhalation challenge 4 hours after exposure. Response to histamine 1 day after exposure. Lung function during and after exposure. Peripheral blood cell counts and serum levels of eosinophil cationic protein (ECP) before and after NO2/allergen.  PEF after allergen challenge was on average 6.6% lower after NO2 exposure than after air exposure. The number of subjects with a fall in FEV1 >15% was 7 after air, 10 after NO2.  NO2 did not affect lung function before allergen challenge. NO2 was neither associated with an increase in eosinophil numbers nor with ECP levels.  BAL results compared following air or NO2 exposure. (PHASE 1: BAL performed 18 hours after exposure. PHASE 2: BAL performed immediately after exposure).  PHASE 1: Exposure to NO2 'caused airway inflammation'. Polymorphonuclear leukocytes increased from 2.2+0.3 to 3.1+0.4% (p=0.05). Small decreases in percentage of blood CD8T lymphocytes (p=0.01) and in blood T lymphocytes expressing neither CD4 nor CD8 (p=0.03).  These variables were not 'significantly' different in PHASE 2.  NO2 exposure and lung function (Raw, TGV, FEV1) in combination with allergen exposure.  A significant decrease in FEV1 was observed following NO2 exposure and allergen compared to allergen alone (early phase:- 2.5 versus -0.4%, p=0.02; late phase: -4.4 versus -1.9%, p=0.01).  Comments  Single blind trial. Note: the authors did record symptoms before and after exposure. This showed a slight increase in symptom score after NO2 exposure versus ambient air exposure for all groups.  Results indicate that "short exposure to an ambient level of NO2 followed several hours later by allergen inhalation enhances allergen-induced late asthmatic reaction."  Note: the authors state that there was an increase in early phase response after a single NO2 exposure (p=0.03).  Reference  Location  Blomberg, Krishna et al., 1999  Umea, Sweden  Study Design  Crossover  Number of Subjects  12 (8m, 4f)  11 Jenkins, Devalia et al., 1999  Randomized, single-blind  10  Subject Description  Mean age of 26 years.  Mild atopic asthmatic volunteers, non-smokers, aged 18-45 years.  Characteristics of Study  Duration of Exposure  NO2 Concentration  Exposure once to filtered air and on 4 consecutive days to NO2 via chamber. Intermittent exercise.  4 hours  2.0 ppm  6 hours  0, 100 ppb O3, 200 ppb NO2, and 100 ppb O3 + 200 ppb NO2  3 hours  200 ppb O3, 400 ppb NO2, and 200 ppb O3 + 400 ppb NO2  Controlled exposure via chamber.  Mild atopic asthmatic volunteers, non smokers, aged 18-45 years.  Avissar, Reed et al., 2000  Single-blind  21 (12 male, 9 female)  Aged 18-40 years, nonsmokers with normal spirometry and no symptoms of upper respiratory infection at least 6 weeks prior to study.  Solomon, Christian et al., 2000  Single-blind  15 (11 male, 4 female)  Healthy non-smokers with no respiratory illness in the three weeks prior to testing. Mean age = 29.3 +/- 4.8 years.  Subjects were exposed to NO2 or ambient filtered air in an exposure chamber.  4 hour exposures over three consecutive days.  Ambient air and/or 2.0 ppm NO2.  Crossover  10 (3 male, 7 female)  Healthy, non-smoking subjects with mean age 35.1 years (range 23-51).  Exposure to NO2 or medical air in a perspex head dome.  20 minutes  1.5 ppm  Chambers & Ayres, 2001  Birmingham, UK  Controlled exposure via special chamber. Separated by 3 weeks.  3 hours  0, 0.6 ppm and 1.5 ppm  Main Comparison  Positive Results  Null or Negative Results  Results of bronchoscopy with endobronchial biopsies, bronchial wash (BW), and BAL 1.5 hrs after air exposure were compared to those after the last consecutive NO2 exposure. Lung function measurements were compared before and after all 5 exposures.  BW following the last NO2 exposure revealed a two-fold increase in neutrophil content (p<0.05) and a 1.5-fold increase in myeloperoxidase (p<0.01). 'Significant' decrements in FEV1 and FVC were found after the first NO2 exposure.  Antioxidant status of neither BW nor BAL fluids were changed following NO2 exposure as compared to air. Changes in pulmonary function after the first NO2 exposure were attenuated with repeated NO2 exposure.  No significant increase in airway response to inhaled allergen when compared to exposure with air.  Exposure to NO2 and O3 on response to inhaled allergen in exercising mild atopics.  Comments  Pollutant induced changes in airway response of mild atopic asthmatics to allergen may be dependent on threshold concentration rather than the total amount of pollutant inhaled over a period of time.  Significant decrease in the dose of allergen required to decrease FEV1 by 20% compared with exposure to air.  Effect of exposure to NO2 on glutathione peroxidase and extracellular glutathione peroxidase concentrations, polymorphonuclear cells and epithelial permeability markers (albumin) in the epithelial lining fluid of the lung (by bronchoalveolar lavage).  NO2 had no effect on glutathione peroxidase or extracellular peroxidase concentration, NO2 had no effect on lung function or in polymorphonuclear cells or epithelial permeability markers.  NO2 level and leukocyte level in bronchoalveolar lavage.  An increase in the percentage of neutrophils were observed in those exposed to NO2 compared to those exposed to filtered air (10.6, 4.8-17.2% versus 5.3, 2.5-8.3%; p=0.005). A decrease in the percentage of T-helper cells was observed when exposed to NO2 versus filtered air (55.9, 40.8-62.7% versus 61.6, 52.6-65.2%; p=0.022).  Change in expired NO (ppb) and FEV1 were compared before and for 3 hours after exposure.  NO2 induced a decrease in mean postexposure exhaled NO. This was not observed after exposure to medical air.  No 'statistically significant' change in FEV1 was observed post exposure to NO2 compared to placebo exposure.  Post-exposure FEV1 results were not shown.   Table 3.5 Epidemiological Studies of the Health Effects Associated with NO2 Exposure  Reference  Melia, Florey & Chinn, 1979  Speizer, Ferris et al., 1980  Year & Season of Study  1973 - 1977  England and Scotland, UK  1977 - 1978  Watertown, MA; Kingston, TN; St. Louis, MO; Steubenville, OH; Portage, WI; Topeka, KS, USA  Melia, Florey et al., January to March 1982  Hoek, Brunekreef et al., 1984  Ogston, Florey & Walker, 1985  Location  1980  Middlesbrough, England, UK  Exposure Type  Indoor (residential)  Indoor (residential)  Indoor (residential)  Study Design  Cohort  Prospective Cohort  Crosssectional  Subject Description  Characteristics of Study  School children 6 to 11 years from 28 randomly chosen areas  3017 children from homes with electric cookers compared to 1810 children from homes with gas cookers. Children were followed for four years.  8866  School children aged 6 to 10 years.  Indoor measurements were taken in several homes within the different exposure groups (gas stoves / electric).  179  Students (aged 5 to 6 years) from 4 schools within 4 km square area. All from homes with a gas stoves.  Measurements made in child's bedroom and living room. NO2 exposure groups defined as low (<20 ppb), medium (20-40 ppb) and high (>40 ppb).  Weekly indoor averages in each home were collected using Palmes diffusion tubes in the kitchen, living room and bedroom.  Number of Subjects  4827  Rotterdam, Netherlands  Indoor (residential)  Case-control  Cases: 128 Controls: 103  Cases: young children who were reported to have suffered from bronchitis, asthma, frequent cough or colds and allergy; Controls: children matched for age, sex and location.  Tayside, Scotland, UK  Indoor (gas stoves)  Prospective Cohort  1565  Children born in 1980 to women who were primigravidas in Tayside.  Indoor exposure to various sources of NO2, in particular gas stoves.  Prospective Cohort  121  Children younger than 13 yeas of age (mean = 6.7 years). 59 had kerosene heaters and 62 had electric.  Personal and indoor exposures for those exposed to kerosene/gas and those with no indoor NO2 source.  Longitudinal  (not reported)  Women living in rural (Vlagtwedde) and urban (Vlaardingen) areas.  Personal and indoor measurements were taken using passive diffusion samplers.  Berwick, Leaderer et al., 1989  1983  New Haven, CT, USA  Personal and Indoor (residential)  Fischer, Brunekreef et al., 1989  1982 - 1985, Winters  Vlaardingen and Vlagtwedde, Netherlands  Personal and Indoor (residential)  Duration of Sampling  Main Comparison  Positive Results  Null or Negative Results  Prevalence of respiratory symptoms (morning cough, day/night cough, wheeze, colds going to chest, asthma, bronchitis, any respiratory illness) between children living in homes with gas cookers compared to those living in homes with electric cookers.  Crude prevalence for day/night cough in boys and colds going to chest in girls was significantly higher in children from gas cooking homes compared to electrical cooking homes. Crude prevalence in both sexes for one or more symptoms or disease was higher in children from homes with gas cookers versus children with electricity. This was also found when age, sex, social class, number of cigarette smokers in home and latitude were taken into account, but only for urban areas.  As cohort grew older, relative risk showed considerable variation (some groups had negligible or less risk than that in electric homes). No association between use of gas and respiratory illness or disease in rural area (when taking age, sex, social class, number of cigarette smokers in home and latitude taken into account).  24-hour measurements were taken every sixth day for a 1year period.  NO2 level (from gas or electric heating) and respiratory function/disease ( FEV1, FVC, diagnosed bronchitis, previous respiratory disease before the age of two and a history of respiratory illness in the last year).  A significant increase in respiratory illness before the age of two was observed in children living in homes with gas stoves than children in homes with electric heating (OR = 1.12; 95%CI = 1.00-1.26). A significant (but small) decrease in FEV1 and FVC was observed in children living in homes with gas stoves compared to those with electric stoves (F ratios = 8.11 and 7.94, respectively).  1 week  Relationship between NO2 and respiratory illness (morning/day/night cough, colds going to chest, wheezy or whistling chest sounds, attach of asthma or bronchitis within the past 12 months).  For both sexes, the unadjusted prevalence rates for one or more respiratory conditions appear to be positively associated with levels in living room. Prevalence of having one or more respiratory condition highest for high levels of NO2 and lowest in homes with low levels.  Weekly averages.  The prevalence of respiratory symptoms (breathlessness, wheezing, bronchitis, asthma) and NO2 exposure.  No significant association was found between existing respiratory health symptoms and measured NO2 level between cases and controls.  Infants were followed for one year after their birth.  NO2 exposure (gas appliances) and respiratory illness (infection of lower or upper respiratory tract, and any code for respiratory illness in the International Classification of Diseases: 406-519. 9)  No significant association was found for exposure to gas appliances and an increase in reported respiratory illness.  NO2 was measured over two weeks.  NO2 level and lower respiratory symptoms (fever, chest pain, productive cough, wheeze, chest cold, physician-diagnosed bronchitis, physician-diagnosed pneumonia, and asthma)  Children younger than 7 exposed to 30 ug/m3 or greater had an increased risk of reporting respiratory symptoms than those not exposed (OR = 2.25, 95%C I= 1.694.79).  NO2 level and pulmonary function (IVC, FEV, PEF, MMEF).  A significant association was found between NO2 exposure and decreased pulmonary function among non-smoking women living in the rural area.  NO2 was measured during a one week period.  Comments  Note: exposures were only measured in a subset of the study population, and the authors state that some of the measurements may be from nonstudy homes.  Adjusted prevalence rates for all respiratory conditions not found to be associated with bedroom levels of NO2 (p>0.30) or living room levels.  Study also looked at temperature and relative humidity (RH). A significant positive association was found between prevalence of respiratory conditions and RH (p<0.05).  The authors do note that there is probably a small association, but a very large study population would be required to be convincing. Parental smoking was strongly associated with respiratory illness.  Exposure data were based on monitoring in 93% of the subjects' homes.  No significant association was found among smoking women in the rural area or among the smoking and non-smoking women in the urban area. (FEV1 = -4.51, p<0.01 and MMEF = 9.63, p<0.05)  Subjects are a subset of the original longitudinal study population. IVC = inspiratory vital capacity; PEF = Peak flow; MMEF = maximum mid expiratory flow.  Reference  Brunekreef, Houthuijs et al., 1990  Dijkstra, Houthuijs et al., 1990  Koo, Ho et al., 1990  Year & Season of Study  1985 - 1986, January and December  1985 - 1987  1985  Location  Exposure Type  Netherlands  Indoor (residential)  Netherlands  Indoor (residential)  Hong Kong  Indoor (residential, in an industrial area)  Study Design  Crosssectional  Longitudinal  Number of Subjects  Subject Description  Characteristics of Study  876  Children aged 6 to 12 years from 10 schools in 5 small, non-industrial communities. 597 from homes without a kitchen geyser, 135 from homes with a vented geyser, and 144 from homes with an unflued kitchen geyser.  Passive diffusion samples taken in kitchen, living room and bedroom of child.  1051  Non-smoking Dutch children aged 6 -12 years (mean = 9.1 years).  362  Primary school children, mean age 10.0 years. Ambient NO2 levels from various sources (smoking, gas cooking, etc.), measured using passive badge samplers.  Crosssectional  319  Neas, Dockery et al., 1991  1983-1988  Watertown, MA; Kingston, TN; St. Louis, MO; Steubenville, OH; Portage, WI; Topeka, KS, USA  Quackenboss, Krzyzanowski & Lebowitz, 1991  1986 - 1988, May to November  Tucson, AZ, USA  Indoor exposure to NO2. collected by Palmes' diffusion tubes in kitchen, living room and bedroom. Measurements  Indoor (residential)  Cohort  1567  Indoor (residential)  CrossSectional  30 (17 male, 13 female)  Mothers of the children in the study, mean age 37.9 years.  Caucasian children aged 7-11 years.  Household NO2 concentrations (58% smoking households, 48% with gas cooking stove or kerosene heater), monitored in summer and winter.  Asthmatic children between 6 and 15 years of age.  Sampling done in kitchens, living rooms, bedrooms and outdoors at each home.  Duration of Sampling  Weekly averages.  Main Comparison  Positive Results  Presence of NO2 sources and indoor NO2 measurements as predictors of pulmonary function in children (FVC, FEV1, PEF and MMEF). Indoor NO2 measurements separated into 3 categories (21-40 ug/m3, 4160 ug/m3, and >60 ug/m3).  1 week  Samples were taken over 24 hours.  1 week  Weekly averages.  NO2 level and respiratory health (cough, wheeze, asthma, FVC, FEV1, PEF, MMEF)  Measured NO2 level and level of reported respiratory symptoms (allergic rhinitis, asthma, bronchitis, chronic chough, chronic sputum, pneumonia, runny nose, tuberculosis and wheeze).  Null or Negative Results  Association between lung function and indoor NO2 exposure were negative.  Children of non Dutch origin or smoked were excluded from study. Negative findings may have been due to relatively low exposure level, since only 10% of homes had weekly average indoor concentrations >60 ug/m3. Possible exposure misclassification due to weekly averaged concentrations  No significant association was found between increasing NO2 exposure and respiratory health.  A weak dose-response relationship was observed for MMEF and increasing NO2 exposure.  No association was found between children's NO2 levels and increased reports of respiratory symptoms  The respiratory symptoms were self reported from a questionnaire. Children's respiratory symptoms were reported by the parent.  Increase in reported allergic rhinitis and chronic cough with increased NO2 level among never smokers (p=0.002 and 0.05 respectively). Increase in multiple respiratory symptoms with increasing NO2 level (p=0.01), showing a dose response.  Household NO2 concentrations were compared for subjects with and without lower respiratory symptoms (report of one or more of attacks of shortness of breath with wheeze, chronic wheeze, chronic cough, chronic phlegm, or bronchitis).  A 15 ppb increase in household annual NO2 mean was associated with an increased cumulative incidence of lower respiratory symptoms (OR = 1.4; 95%CI = 1.1-1.7). Girls showed a stronger association than boys.  NO2 exposure and effects on peak expiratory flow rate (PEFR - measured 3 times daily, and largest value noted), symptoms (allergic irritation - eye irritation, rhinitis, acute respiratory illness - sore throat, cough, wheezing/whistling in chest, shortness of breath with wheezing, chest tightness or asthma, and non-specific complaints dryness in mouth, dizziness, fatigue/achy feeling, nausea, and/or headache) and medication usage.  Random effects model - significant decrement in overall PEFR associated with increasing NO2 concentrations measured outside subject's home (40 L/min decrement in PEFR for every 20 ug/m3 increase in NO2). Additional decrements of morning PEFR linked with higher morning NO2 levels measured in children sleeping in bedrooms with higher NO2 levels. Morning and noon PEFR decrements linked to higher morning NO2 levels measured at central monitoring station. Increase in allergic symptoms in homes with high NO2 levels in kitchen OR = 1.6 (95%CI = 1.042.49) for asthmatics and OR = 1.17 (95%CI = 1.04-1.37) for non-asthmatics per 10 ug/m3 increase in NO2.  Comments  No effects found in nonasthmatic children.  Reference  Year & Season of Study  Adgate, Reid et al., 1992  Hackney, Linn et al., 1992  Maeda, Nitta & Nakai, 1992  Samet, Lambert et al., 1992  Location  North Carolina, USA  Fall and Winter  1987 - 1990  1988 - 1991  Los Angeles, CA, USA  Three areas in Tokyo, Japan  Albuquerque, NM, USA  Exposure Type  Personal and Indoor (residential)  Personal  Personal, Indoor and Outdoor (residential)  Indoor (residential)  Infante-Rivard, 1993  1988 - 1990  Montreal, Canada  Indoor  Samet, Lambert et al., 1993  1988 - 1990  Albuquerque, NM, USA  Indoor (residential)  Study Design  Crosssectional  ?  Number of Subjects  Subject Description  Characteristics of Study  Preschool children aged 3 months to 5.5 years who were enrolled daycare.  Personal, indoor and school NO2 measurements were taken using active chemiluminescent monitors, Bendix process instruments and passive diffusion monitors.  26 (15 male, 11 female)  Residents with physician diagnosed COPD, aged 45-70 yrs. Subjects all had heavy smoking history and low FEV1.  Self monitoring of NO2 during normal activities, both indoor and outdoor. Logging of activities were made every hour to track exposures. Midpoint throughout the week subjects were experimentally exposed to NO2 or ambient air in a chamber, as mentioned above.  1991  30 - 60 year old females who have resided within the survey area for > 3 years  20 (13 male, 7 female; 8 African American, 12 Caucasian)  Crosssectional  Personal, indoor and outdoor exposures were obtained by passive diffusion badges in each zone.  305  3 - 6 year olds who have lived within the survey area for > 1 year  411  Infants (followed from birth for first 2 years).  Personal exposures in the home.  61 cases and 79 Case-control controls  Cases: newly confirmed asthmatic children aged 3-4 Controls: age matched non-asthmatic children  Ambient indoor NO2 levels measured by passive diffusion badges  Prospective Cohort  Healthy term births from Albuquerque hospitals, with non-smoking family members in the home.  Indoor exposures were measured in bedrooms of enrolled infants, using passive diffusion tubes.  Prospective Cohort  1205  Duration of Sampling  Main Comparison  Measurements were taken over one week during the heating season.  NO2 exposure level and urinary excretion of hydroxyproline and desmosine.  24 hour passive badge samples were taken over a 2 week period.  Average weekly lung function response (FVC, FEV1 and FEF25-75) and symptom response (cough, sputum, dyspnea, wheeze, chest tightness and substernal irritation) was compared among ambient air and 0.6 ppm of NO2 exposures from chamber exposure.  Null or Negative Results  Comments  No significant association was found between NO2 level and their hydroxyproline to creatinine and desmosine to creatinine ratios.  Note: the authors stated that there were significantly higher ratios observed in the children, compared with mothers (p<0.001 and 0.003).  The authors did note that lung function and symptom response was worse in the morning compared to during the day (p<0.005), but stable throughout the study period.  No significant correlation between the NO2 exposure during the chamber study and decreased lung function/ symptom response was observed throughout the rest of the test week.  Outdoor NO2 exposures and personal NO2 exposures correlated with one another.  NO2 levels in the three zones and respiratory health (chronic cough, chronic phlegm, chronic cough and phlegm, current asthma, remission asthma, chronic wheezing, shortness of breath, FVC and FEV).  After controlling for age, years of residence, job status, smoking habits, heater types and house structure, prevalence of chronic phlegm, chronic wheezing and shortness of breath was statistically higher for those living in zone A (mean personal exposure = 44 ppb) than those in zones B and C (mean personal exposures = 36.8 and 28.7 ppb, respectively).  No significant change in pulmonary function was observed with NO2 level.  Respiratory symptoms were recorded using a translated form of the ATS-DLD-78 questionnaire. Note: FEV and FVC measurements were done for only 444 subjects.  NO2 levels in the three zones and respiratory health (chronic cough, chronic phlegm, chronic cough and phlegm, current asthma, remission asthma, chronic wheezing, shortness of breath)  A significant increase in the prevalence of chronic phlegm was observed with NO2 exposure level.  Respiratory symptoms were recorded using a translated form of the ATS-DLD-78 questionnaire.  2 week measurements.  Exposure to NO2 and increased incidence and severity of respiratory infections during first 18 months of life.  Rates of illness for upper respiratory tract were highest in winter (1.6/100 days) and lowest in summer (1.0/100 days), first born children (1.0/100 days) had lower illness rates than children with siblings (1.4/100 days).  Paper mainly reviewed methods, characteristics of subjects and NO2 concentration.  24 hour measurements.  NO2 exposure levels were compared among children with asthma and children without asthma.  A significant increase in NO2 exposure (>15 ppb) was found among asthmatic children compared to non-asthmatics, OR = 10.54 (95%CI = 3.46-31.9). A dose response relationship was found with increasing NO2 exposure and asthma.  This was a subset of the original study. Only 20% of the original study underwent monitoring.  Cohort was followed for 18 months. Average 2-week exposures were determined.  Residential exposure to NO2 and incidence and severity of respiratory illnesses (runny or stuffy nose, dry cough, trouble breathing, trouble feeding, rash and fever), during first 18 months of life.  Samples were taken over 48 hours.  Positive Results  No significant association was found between indoor NO2 level and illness incidence rates (OR = 0.999; 95%CI = 0.995-1.002), or illness duration.  Severity of illness was measured by illness duration.  Reference  Year & Season of Study  Location  Exposure Type  Study Design  Number of Subjects  Subject Description  Characteristics of Study  1991  Helsinki, Finland  Personal, Indoor and Outdoor (residential and school)  Prospective Panel  163  Children aged 3-6 years attending 8 municipal daycares.  Personal, Indoor/Outdoor (residential) and Indoor/Outdoor (school)  1993  Bristol, England  Indoor  Crosssectional  921  Infants aged 3-12 months born and enrolled in ongoing cohort.  Indoor exposure to NO2 in infant bedrooms, using Palmes monitoring tubes.  Personal exposures (children living in homes with unflued gas appliances) and exposures at school (41 classrooms) were monitored. For doseresponse, children allocated to <40 ppb, 4060 ppb, 60-80 ppb, 80100 ppb and >100 ppb groups.  Mukala, Pekkanen et al., 1996  Mukala, Pekkanen et al., 1999  Mukala, Alm et al., 2000  Farrow, Greenwood et al., 1997  Pilotto, Douglas et al., 1997  Smedje, Norback & Edling, 1997  1992, April and September  Western Sydney, Australia  Personal and Indoor (school)  Prospective Cohort  388  Children (6 to 11 years) from 8 schools (4 with electric and 4 with unflued gas heated classrooms).  1993  Uppsala, Enkoping, and other small communities in Sweden  Indoor (school)  Crosssectional  627  627 schoolchildren aged 13 to 14 years (includes 40 asthmatics).  Schoolchildren exposed to existing levels during school hours.  Adults who smoke fewer than 10 cigarettes per day. Mean age was 39 +/- 15 years for men and 37 +/-13 years for women.  Personal samples were taken using diffusion tube samplers.  Schoolchildren on Montreal Island (78% caucasian) aged 5-13 years.  Living in homes with different cooking fuels.  Bernard, Saintot et al., 1997  1994  Montpellier, France  Personal  Crosssectional  107 (40 male, 67 female)  Demissie, Ernst et al., 1998  1990 - 1992  Montreal, Canada  Indoor (gas stoves)  Case-control  989  Duration of Sampling  Main Comparison  Positive Results  Weekly average for 13 weeks in winter and spring (168+/- 24hr).  NO2 exposure and the report of respiratory symptoms (runny or stuffy nose with discharge, dry cough, phlegm, dyspnea/wheezing during rest or exercise, ear pain and discharge, itching and redness of the eyes, runny eyes, eye discharge, fever, abdominal pan, diarrhoea and emesis).  Increased risk of cough with increasing exposure (RR = 1.52; 95%CI = 1.00-2.31). In winter, risk of cough (RR = 3.63; 95%CI = 1.41-9.3) in highest personal exposure group.  No significant association was found between individual NO2 exposure and respiratory incidence rates.  Respiratory symptoms were logged in a diary by the parents over the study period.  10 days in infant's bedroom.  NO2 exposure and health symptoms (streaming eyes, red eyes, runny nose, stuffed-up nose, sneezing, cough, breathlessness, wheezing earache, ear discharge, high temp, nappy rash, other rash, colic, fretful, restless, sleep problems, feeding problems, diarrhoea and vomiting).  A significant increase in diarrhoea, with doubling of NO2 indoor exposure, was reported (OR = 1.38; 95%CI = 1.11-1.70)  No significant relationship was seen among the other 19 recorded symptoms.  Outdoor levels were approximately double indoor levels.  Mean 6 hour averages (school) and daily over four evenings (personal).  Study of respiratory symptoms (hoarse voice, sore throat, cough with phlegm, dry cough, sneezing, stopped up nose, runny nose and wheezing) through the winter period from daily exposure to gas use at home and at school.  Sore throat, colds and absences associated with exposure to NO2 >80 ppb when compared to background exposure (20 ppb) following adjustment for confounders, statistically significant positive dose response trends found for mean rates for cough with phlegm, absences from school, and sore throat, and also for proportions of children with colds, absent from school and sore throats when adjusted for confounding (asthma, early severe chest illness, allergies/hay fever, geographical area, age (<9 versus >9) and gender). Absence from school OR = 1.92 (95%CI = 1.13-3.35) between high and low exposure groups.  Mean symptom rates for hoarse voice, cough with phlegm, dry cough, sneeze, stopped up nose, runny nose, and wheeze not found to be different between high and low exposure groups. Runny nose was significantly lower in high exposure versus low exposure, OR = 0.45 (95%CI = 0.25-0.82). For all other symptoms (hoarse voice, sore throat, cough with phlegm, dry cough, sneeze, stopped up nose, wheeze, and cold) OR not significant (all 95% confidence intervals included 0).  Greater mean symptom rate for cough with phlegm between high and low exposure group very close to significance (P=0.06) following adjustment.  Measurement via passive sampling badge for 6-7 days.  Asthma status reported on questionnaires (filled out by 627 children) was compared to NO2 concentration in 28 classrooms  Tubes in place for 14 days.  Personal NO2 level and plasma antioxidant level (B-carotene, vitamin A and E, Glutathione, GSH-peroxydase, uric acid and MDA).  Not given.  FEV1 and FVC versus type of cooking and heating fuels used in the home.  Null or Negative Results  Comments  No significant relationship was seen between current asthma and NO2.  An inverse correlation was found between uric acid and GSH levels with NO2 level in men only.  No correlation was found between NO2 exposure and MDA or B-carotene.  Note: (GSH = glutathione, MDA=malondialdehyde)  No effect on lung function of use of different cooking fuels could be demonstrated.  No direct measurements of NO2. Electric baseboard units were independently and "significantly" associated with a lower FEV1/FVC. >90% of subjects used electricity for cooking.  Reference  Garrett, Hooper et al., 1998  Giroux & Ferrieres, 1998  Year & Season of Study  1994 - 1995  (not reported)  Magnus, Nafstad et al., 1998  Schindler, 1990 - 1993, AckermannVarious seasons Liebrich et al., 1998  Location  Victoria, Australia  Exposure Type  Indoor (residential)  Toulouse, France Indoor (industrial)  Oslo, Norway  8 cities in Switzerland (Aarau, Basel, Davos, Geneva, Lugano, Montana, Payerne and Wald)  Indoor (residential)  Personal  Study Design  Longitudinal  Crosssectional  Nested casecontrol  Crosssectional  Number of Subjects  Subject Description  Characteristics of Study  148 (74 male, 74 female)  Asthmatic and nonasthmatic children aged 7-14 years, mean age = 10.4 yrs. (53 asthmatics)  Indoor exposure to NO2 from various sources such as gas stoves, heaters and smoking, measured by passive badge samplers.  332 cases, 51 controls  Male nitrogen fertilizer factory workers (age range 24-57 years) and controls recruited from outside the factory but living within 2 km of it.  The population of factory workers was divided into 6 groups as a function of the atmospheres in the different workshops (groups were exposed to various levels of NO, NO2, NO3, and NH3).  Cases: 153 Controls: 153  New born infants born in Oslo in 1992 and 1993. Cases: children who developed two or more episodes of bronchial obstruction or one episode lasting >4 weeks. Controls: children matched for date of birth.  Type of heating in home between birth and age 6.  7656  Randomly selected adults between the ages of 18 and 60 years who have resided in one of the listed communities for at least 3 years.  560 personal samples were taken to estimate the different communities' exposures.  Duration of Sampling  Badges in place for 4 days.  Main Comparison  Correlation between indoor NO2 exposure level and reported respiratory symptoms/asthma (peak expiratory flow rate, allergies, cough, shortness of breath, waking due to shortness of breath, wheeze, asthma attacks, chest tightness, cough in the morning, and chest tightness in the morning).  Positive Results  Increased risk of having asthma if you lived in a home with a gas stove (OR = 2.23; 95%CI = 1.06-4.72). Also increased risk of having cough (OR = 2.25; 95%CI = 1.134.49) and/or chest tightness (OR = 3.11; 95%CI = 1.07-9.05) with presence of gas stove. An increase in respiratory symptoms was also observed for a 10ug/m3 increase in NO2 during the summer (OR = 2.71; 95%CI = 1.11-6.59) and gas stove exposure (OR = 2.32; 95%CI = 1.04-5.18). The author also reported a dose response for NO2 exposure level and respiratory  Null or Negative Results  Comments  No significant increase in respiratory symptoms was recorded for a 10ug/m3 increase in NO2 level.  Authors suggest that there is an additional risk apart from average NO2 exposure associated with gas stove use for developing respiratory symptoms. Allergies were tested by a skin prick test. The aeroallergens tested included: cat, dog, grass mix no.7, Bermuda grass, house dust, house dust mite and fungi.  Further analysis of the results showed that inhaled nitrogen oxides and ammonia were only partly responsible for the circulating nitrates. The excess nitrates were thought to have an endogenous origin due to inflammatory reactions induced by the pollutants, especially ammonia.  Excess creatinine was thought to have derived from the interaction of the exogenous NO with arginine metabolites.  No association was found between NO2 level and cases (bronchial obstruction) and controls.  Parallel measurements were made on cases and matched controls for NO2 monitoring.  symptoms (>20 ug/m3 versus <10 ug/m3; OR = 3.62; 95%CI = 1.08-12.08; p=0.09).  Factory measurements were made over 10 days. Duration of exposure is not reported.  Serum levels of three nitrogen-containing derivatives involved in arginine metabolism (nitrates, creatinine and urea) for factory workers in location-dependent groups were compared to those for the control group.  2 weeks  The measured NO2 levels were compared between children who experienced bronchial obstruction and those who didn't.  NO2 exposure level (communities and zones of residences) and lung function (FEV and FVC).  Workers most exposed to the hydrogenated and oxygenated compounds of nitrogen were found to have the highest serum nitrates. Workers from the 2 groups exposed to both NO and NH3 had significantly elevated levels of serum creatinine (p<0.001).  A 10ug/m3 increase in outdoor and personal NO2 level, between zones of residence of the same community was associated with a change in FVC by -0.59% (95%CI = 0.01 to 1.19) and -0.74% (95%CI = -0.07 to -1.41) respectively. This was also seen between communities by -1.67% (95%CI = -1.01 to 2.33) and -2.93% (95%CI = -2.11 to -3.75) respectively.  Note: The following variables were controlled for when estimating personal exposures: atopy; severe respiratory infection before age 5; parental asthma; siblings' asthma; parental atopy; siblings' atopy; maternal/paternal smoking during childhood; low education; foreign citizenship; current exposure to dust, gas, vapour fumes and/or aerosols; exposure to dust, gas, vapour and/or fumes, ever; regular ETS exposure; ETS exposure at work; cooking with gas.  Reference  Gomzi, 1999  Rosenlund & Bluhm, 1999  Year & Season of Study  1990 - 1991, December to June  Sanyal & Maduna, 2000  Shima & Adachi, 2000  Smith, Nitschke et al., 2000  Croatia  Exposure Type  Indoor (school)  Study Design  Crosssectional  Number of Subjects  Subject Description  Characteristics of Study  223  Children aged 8 to 10 years. 164 from a school in an industrial area, 59 from a school in a rural area. 54% boys, 46% girls.  3 sampling sites at each school, samples taken during cold period (Dec 90 - Mar 91) and warm period (Apr - Jun 91).  Investigation of an incident that resulted in an acute outbreak of respiratory illness among adolescent hockey players who had all played at the same ice arena.  Stockholm, Sweden  Indoor (ice rink)  Crosssectional  155  99 exposed hockey players aged 8 to 28 years (median =13) and 56 non-exposed hockey players aged 12-19 years (median = 14 ).  Southampton, England  Personal  Longitudinal  63 boys and 51 girls  Asthmatic children (7 to 12 years) from nonsmoking homes.  Weekly personal exposures.  1993  Uppsala, Sweden  Indoor (school)  Crosssectional  234  School Personnel  Passive Sampling in schools.  1995 - 1996  Ku-Ntselamanzi Township, South Africa  Children under the age of 14 from three different socioeconomic status levels (very low, low and middle income).  Exposures to indoor contaminants were measured in the cooking and living areas of the homes in a subset of the population.  1991 - 1993  7 different communities in Japan (Chiba, Funabashi, Ichikawa, Kashiwa, Eirakudia, Ichihara and Tateyama)  Fourth grade pupils aged 9-10.  Indoor exposures in subjects homes. Samples taken using passive diffusion badges.  Random asthmatic subjects, aged 2-84 years. 49 younger than 14 years, 28 betweeen 15 and 34 years, 27 between 35 and 50 years, 25 older than 50 years. 55% male & 45% female.  Household exposure  1994, December 4th  Linaker, Coggon et al., 2000  Norback, Walinder et al., 2000  Location  South Australia  Indoor  Longitudinal  1820  Indoor  Prospective Cohort  842 (434 boys, 408 girls)  Personal  CrossSectional  125  Duration of Sampling  24 hour measurements, colorimetric method (Levaggi modification of Jacob-Hocheiser method).  Main Comparison  Positive Results  Effects of low level NO2 exposure on frequency of acute respiratory illness (data analysis on frequency of respiratory diseases that kept child home for 3 days or more).  Null or Negative Results  Measured air pollutants only had a slight effect on respiratory health of children.  Comments  No specific results for NO2 exposure mentioned.  Examine possible relationships between NO2 exposure (shown in simulations to be greater than 2500 ug/m3 after ice resurfacing) and pulmonary symptoms.  Increased RR of pulmonary symptoms. Any pulmonary symptom RR = 7.8 (95%CI = 3-20.3); Cough RR = 24.9 (95%CI = 3175.8); Shortness of breath RR = 7.2 (95%CI = 2.3-22.2); Headache RR = 5.1 (95%CI = 1.6-16); Dyspnea RR = 3.4 (95%CI = 0.8-14.6). Increased RR for pulmonary symptoms with increased time spent on ice: for time <37.5 minutes RR = 5.0 (95%CI = 1.2-20.1) and for time >37.5 minutes RR = 10.2 (95%CI = 2.7-39.1)  Pulmonary symptom = cough, chest pain, shortness of breath.  At least 16 weeks.  NO2 and aggravation of asthma by increasing chance of asthmatic episodes.  Increased risk of a decreased PEF episode with increased exposure. <8 ug/m3, RR = 1; 8-13 ug/m3, RR = 1.1 (95%CI = 0.6-1.8); 13-28 ug/m3, RR=1.2 (95%CI = 0.7-2.1); >28 ug/m3, RR=1.9 (95%CI = 1.1-3.4).  Adjustment for season and use of anti inflammatory medication reduced statistical significance of relationship.  6-7 days  To examine relationship between nasal patency, nasal lavage biomarkers (eosinophil cationic protein (ECP), myeloperoxidase, lysozyme and albumin) and nasal symptoms with concentrations of indoor air contaminants (NO2).  Nasal patency (anterior min. cross-sectional area of nasal cavity only!) decreased with higher concentrations of NO2, Lysozyme and ECP were increased at higher concentrations of NO2.  40 hours of monitoring during simulations designed to recreate the conditions that triggered the incident.  Six hour area samples were taken three times over a 23 month period (JuneSeptember, OctoberDecember, and March-May).  Indoor air pollution (NO2) exposure and recurring ailments (Bronchitis, cough, asthma, fever, sore eyes, runny nose, earache, hay fever, chest ailments and pneumonia).  An increase prevalence of respiratory ailments was observed in group 1 and 2, and a significant increase was observed during the night time and winter months. In addition, acute respiratory infections were increased among those who used firewood and coal as their primary energy source.  Approximately 2226 hours for each measurement.  Outdoor and indoor NO2 levels and the prevalence and incidence of respiratory symptoms (allergic disease, bronchitis, wheeze, and asthma).  A significant increase in the prevalence of bronchitis, wheeze and asthma was associated with increases in indoor NO2 levels, in girls (not seen in boys). A significant increase in the incidence of wheeze and asthma was found with increased outdoor NO2 levels.  Daily (4.5hr/day) for 6 weeks.  Examine relationship between asthma symptoms (wheeze, breathlessness, chest tightness, cough, breathlessness on exertion, daytime asthma attacks and night asthma attacks) and short term personal NO2 exposures during household gas appliance use.  No relationship of nasal symptoms with NO2 concentrations.  ECP level is a measure of the activity of eospinophil granulodcytes, is cytoxic and can destroy the epithelium of airways.  Group one: lived in mud huts or shacks. Their main source of energy is organic fuels such as wood and coal. Group two: lived in shared or semi-detached huts with iron roofing. Their main energy sources are coal, wood and paraffin. Group three: lived in electrified, brick structures. Their main energy sources are electricity, gas and paraffin.  No significant association was found between increasing indoor NO2 level and the incidence of wheeze and asthma.  Respiratory symptoms were evaluated every year by mail out questionnaires. Note: the incidence of asthma increased with increasing outdoor NO2 levels.  For all subjects, indoor NO2 levels not significantly associated with outcome symptoms on same day or with 1 day lag.  Association strongest and significant when assessed exposure with personal measurements in winter.  Reference  Year & Season of Study  Location  Exposure Type  Study Design  Number of Subjects  Subject Description  Characteristics of Study  Ciuk, Volkmer & Edwards, 2001  1996 - 1997  Adelaide, South Australia  Indoor  Crosssectional  202  Four-year-old asthmatic children from south Australia.  Indoor exposures were measured with passivediffusion badges in the bedrooms.  Kilpelainen, Koskenvuo et al., 2001  1995 - 1996, Winter  Finland  Indoor  Case-control  10667  University students aged 18-25 years.  Type of heating in home between birth and age 6.  Singapore  Indoor (kitchen)  Crosssectional  16  38-62 year-old female persistent asthmatics (6 mild asthma, 3 moderate asthma, 7 severe asthma).  Exposure to gas hobs (cooking).  Canberra, Australia  Personal and Indoor (school)  CrossSectional  344  Children 8-9 years old, 33% with asthma.  Personal passive samples (separated by home characteristics) and school samples.  Ng, Seet et al., 2001  Ponsonby, Glasgow et al., 2001  1999  Duration of Sampling  Two samples were taken for each child for 2 to 12 hours.  Main Comparison  Relationship between NO2 exposure and chest tightness, breathlessness on exertion, and daytime asthma attacks.  Positive Results  Higher levels of NO2 were found in homes with children with asthma than in homes without children with asthma.  Subjects with wood stove heating at age 0-6 years were analyzed against a reference group (with central heating, electrical heating, and some less frequently used systems) for asthma and allergies up to young adulthood.  Null or Negative Results  Comments  No significant association was found between increasing NO2 exposure and urinary nitrates.  Authors note that urinary nitrates are not a good indicator of nitrogen exposure.  Significant negative association between childhood wood stove heating and allergic rhinitis or conjunctivitis (OR = 0.61; 95%CI = 0.61-0.91). This disappeared after adjusting for family, indoor and outdoor factors.  The association between wood stove heating and allergic rhinoconjunctivitis was mainly confounded by childhood residential environment, especially the farm environment.  Longer cooking duration lowered exposures.  Short term exposure was measured for a duration of 5-34 minutes (mean = 15 minutes); Two week average exposure.  Effects of short term exposure to NO2 during single episodes of actual gas cooking on changes on peak expiratory flow rate (PEFR) and effects of mean continued personal exposure to NO2 from repeated intermittent episodes of gas cooking on PEFR variability, severity of asthma symptoms and medication usage.  For short term exposure a PEFR mean fall of -3.4% (95%CI = -5.9 to -0.8). Greater PEFR falls with higher levels of short term exposure. Mean two week exposure was associated with increased use of bronchodilator.  Longer cooking duration resulted in smaller changes in PEFR. For mean two week exposures PEFR variability and total symptom severity not correlated with increased levels.  15:15-09:00 for 2 days, sampler placed in classrooms for 2 days, Total NO2 = personal+school exposure  NO2 exposure and lung function (FEV1, FVC and FEV1/FVC - baseline and after four minutes of cold air challenge) and respiratory history (rhinitis, hay fever, eczema, asthma and recent wheeze). Skin prick test (to house dust mite (Der p 1 and Der f 1), cat, dog, alternaria, ryegrass, birch, plantain, paspalum and wattle).  Higher personal NO2 exposure reduced FEV1/FVC after cold air challenge, [adjusted -0.12% (-0.23% to -0.01%) per 1 ppb increase]. Gas heater use reduced FEV1/FVC -2.0% (-3.7% to -0.2%), Greater reductions in FEV1/FVC for non-mite sensitized children.  No relationship between total or personal NO2, gas heater use or gas cooking and baseline FEV1, FVC and FEV1/FVC). Personal exposure, gas heater use and gas cooking was not associated with asthma or wheeze. Gas heater use and cooking not associated with altered risk for mite sensitization.   Table 3.3 Studies Measuring Personal, Indoor and Outdoor concentrations of NO2  Reference  Year & Season of Study  Location  Exposure Measured  # of Sites  Site Description  # of People  Speizer, Ferris et al., 1980  1977 - 1978, May to April  Watertown, MA; Kingston, TN; St. Louis, MO; Steubenville, OH; Portage, WI; Topeka, KS, USA  Indoor (residential)  (not reported)  Homes representative of the overall population being studied.  N/A  N/A  1 sample (taken in the living room) every 6 days for 1 year.  Remijn, Fischer et al., 1985  1982, November and December  Vlagtwedde and Vlaardingen, Netherlands  Indoor (residential)  152  Homes of non-smoking, adult women  N/A  N/A  1 set of measurements (kitchen, bedroom and living room) per site.  Berwick, Leaderer New Haven, CT, 1983, Winter USA et al., 1989  Indoor (residential)  N/A  At least 1 set of measurements (kitchen, living room and bedroom) per home.  62  Residential homes  N/A  Subject Description  Number of Measurements  Duration  Sampler Used  Units  24 hours  Bubbler  ug/m3  1 week  Palmes  ug/m3  Palmes  3  2 weeks  ug/m  Kerosene heat+gas Kerosene heater only Gas stove only No NO2 Source  Unvented geyser  Vented geyser Fischer, Brunekreef et al., 1989  1984  Netherlands  Personal, Indoor and Outdoor (residential)  612  313 in homes in rural areas and 299 homes in urban areas.  612  Women  1 set or measurements (personal, kitchen, living room, bedroom and outdoor) per participant.  1 week  Palmes  ug/m3 No geyser  Brunekreef, Houthuijs et al., 1990  Dijkstra, Houthuijs et al., 1990  No Geyser Vented Geyser 1985 & 1987, January  Netherlands  Indoor (residential)  Personal, Indoor 1987 - 1988, Chan, Yanagisawa Taipei and and Outdoor December to & Spengler, 1990 Central Taiwan (residential) January  Houthuijs, Dijkstra et al., 1990  Melia, Chinn & Rona, 1990  1985 & 1987, January  1988, February  1984, April, Noy, Brunekreef et October and al., 1990 December  Netherlands  Personal  London  Indoor and Outdoor (residential)  Veenendaal, Netherlands  Personal (weekly and peak), Indoor (residential, weekly and peak), Indoor (classroom) and Outdoor (school)  876  Homes of children participating in the study.  23  11 homes in Taipei City (urban) and 12 homes in Central Taiwan (rural).  N/A  29  110  N/A  4 homes with electric cookers, 20 with gas cookers, and 5 with gas cookers and kerosene heaters  107 homes and 3 schools  N/A  23  56  N/A  193  N/A  Housewives  Children 6-12 years of age. 25 from homes without gas-fired geysers, 15 from homes with vented geysers, and 16 from homes with unvented geysers.  1 set of measurements (kitchen, living room and bedroom) per site.  2 simultaneous sets of measurements (personal, kitchen, living room, bedroom and outdoor) taken for each participant. 1 set with Palmes tubes, and 1 set with badges.  1 measurement per child.  N/A  1 set of measurements (kitchen, living room, child's bedroom and outdoor) per site.  107 mothers and 86 children  3 sets of measurements for each household. Personal and peak personal (during use of gas-fired appliances) for mothers and children. Indoor (kitchen, living room and bedroom) and peak indoor (in kitchen and living room during use of gas-fired appliances) for each home. Indoor (classroom) and outdoor for each school.  1 week  Palmes  1 week for Palmes tubes and 2 days for badges.  Palmes tubes and badges.  1 week  1 week  Palmes  Palmes  ug/m3  Unvented Geyser  Kitchen Living Room Bedroom Outdoor Personal  ppb  ug/m3  All No Geyser Vented Geyser Unvented Geyser  Kitchen Living Room Bedroom Outdoor  ppb  Classroom Outdoor (school)  1 week  Palmes  ug/m  3  Measured Concentrations of NO2 Mean  Standard Deviation  Median/Geometric Mean Median Portage Topeka Kingston St. Louis Steubenville Watertown  Electric 3.6 19.4 10.9 17.1 21.9 41.4  Gas 14.7 31.6  Electric 2.13 1.26 1.43 2.01 2.59 1.14  40.8 27.4 54.3  Kitchen 79 Living Room 39 Bedroom 23  Maximum 95%ile Electric 17.6 41.6 29.8 63.3 74.5 95.2  Gas 1.02  1.42 2.24 1.21  2.2 2 1.5  Minimum  Gas 39.3 73.6  NO2 levels 4 to 7 times higher in homes with gas stoves than in homes with electric. 24-hour measurements were generally lower than the US federal 24hour standard. Peak levels in excess of 1100 ug/m3 occurred regularly.  79.3 103.9 116.3  391 241 66  9 9 8  n 6 49 13 4  Kitchen 89.5 41 41 6.4  Living 76 43 25 6.2  Kitchen Living Bedroom Personal Kitchen Living Bedroom Personal Kitchen Living Bedroom Personal  Urban 120 55 39 58 71 43 35 43 49 32 23 36  Rural 143 51 23 55 60 34 15 41 32 23 11 23  n 597 135  indoor 23.6 40.3  75%ile 24 50  25%ile 14 24  144  61.7  73  46  Taipei City Palmes Badges 34.4 25.6 32.1 22.6 29.7 20.5 40.1 25.7 30.8 22.3  Bedrm 105 38 29 5.2  Results  Geometric Standard Deviation  Central Taiwan Palmes Badges 24.5 24.7 20.4 18.8 17.5 15.4 23.5 20.3 19.9 17.3  1995 29.9 22.6 27.9 43.3  1997 27.6 21.2 25.3 39.6  overall 34.7 23.3 23.5 21.4  kerosene 37.8 65.9  gas 36.9 24.4 24.1  Apr. 12 34  Oct. 14 40  Dec. 12 51  Values collected used to estimate personal exposures ranging from 11 to 139 ug/m3, with a geometric mean of 39 ug/m3.  Average 90 71 31 5.9  Urban 55 24 17 21 53 26 27 43 30 23 8 19  Rural 60 30 11 17 38 21 6 26 24 19 4 17  Taipei City Palmes Badges 9.1 9.3 9.6 8.4 9 6.5 9.6 10.5 5.7 6.1  1995 11.3 6.1 7.8 8.3  Unvented water heaters a major source of NO2 in Dutch homes. Inconclusive differences between urban and rural results.  If short term exposure is more instrumental in causing pulmonary function changes it would be best to monitor short term rather than long term concentrations.  Central Taiwan Palmes Badges 6.6 10.9 5.9 7 5 6.5 6.3 5.9 6.4 6.6  Measurements by Palmes tubes 1.5 times higher in the city than the rural area, measurements by badges 1.2 times higher, with the exception of kitchens. Indoor trend from high to low was kitchen, living room, bedroom in both areas.  1996 13 8.6 8.8 14.1  1995  1997  1995  1997  42.2 40 54.8  46 40 66  14.7 14 24.6  11 10 17  19.2 13.7 12.9  Good test/retest correlation between 1985 and 1987 indoor results (results not shown), showing excellent reproducibility.  Indoor NO2 levels highest in kitchens. Gas cooker associated with significant increase in NO2 level in kitchen and living room and kerosene heater in living room associated with increase in NO2 level in living room.  Per. Per. (child) Kitchen Living Room Bedroom Peak Peak (child) Peak Peak (living)  Apr. 25 22 28 22 16 144 139  Oct. 24 22 30 24 17  Dec. 24 22 30 24 16  209 129  Apr. 1.6 1.5 2.2 2 1.5  Oct. 1.6 1.4 2 1.9 1.4  Dec. 1.6 1.5 2.1 2 1.5 614 767 2509 1182  10 7 35 19  Weak association between measured weekly average exposures and peak exposures, both personal and indoor. Presence of an unvented gas geyser was significantly associated with mean peak concentrations. Presence of gas cooker was weakly associated with peak levels and it is hypothesized that usage patterns rather than presence/absence would be a better predictor of peak levels.  Reference  Yoshino, Matsumoto et al., 1990  Year & Season of Study  1985, Winter  Liao, Baconshone & 1990, July to Kim, 1991 September  Madany & Danish, 1991  (not reported)  Location  Exposure Measured  Japan  Indoor (residential)  Hong Kong  Indoor and Outdoor (shops and offices)  Bahrain, Persian Gulf  Indoor (residential)  # of Sites  Site Description  13  Homes built between 1980 and 1984 with wood frame construction.  70  35 shops (opening directly on to street) and 35 offices (serving 20+ employees).  32  Homes evenly distributed throughout the country.  # of People  N/A  N/A  N/A  Subject Description  Number of Measurements  N/A  1 set of measurements (kitchen and living room) per site.  N/A  1 set of measurements (indoor and outdoor) per site.  N/A  1 set of measurements in each home (kitchen, living room and main hallway).  Duration  3 days  4 to 12 hours  2 weeks  Sampler Used  Badges  Badges  Palmes  Units  uL/L  ug/m3  ug/m3  1 2 3 4 5 6 7 8 9 10 11 12 13 Inside shops Outside shops Inside offices Outside offices  Bedroom Hall Kitchen Outdoor I/O ratio  Watertown Kingston  Neas, Dockery et al., 1991  Watertown, MA; Kingston, TN; St. Louis, MO; 1983, Winter Steubenville, and Summer OH; Portage, WI; Topeka, KS, USA  Indoor (residential)  1657  Residences of subjects participating in the study.  N/A  N/A  2 sets of measurements per home (kitchen, living room and bedroom) per site. 1 in summer and 1 in winter.  St. Louis 7 days  Palmes  ppb  Steubenville Portage Topeka All  Quackenboss, Krzyzanowski & Lebowitz, 1991  1986 - 1988, May to November  Tucson, AZ, USA  Indoor and Outdoor (residential)  657  446 homes with gas cookers and 211 homes with electric cookers.  N/A  N/A  2 sets of measurements (kitchen, living room, bedrooms and outdoor) per site.  ug/m3  1 week  Palmes  4 indoor measurements per site: 2 taken with a continuous monitor and 2 taken with a passive sampler. 2 personal measurements for each mother and child.  1 week  Continuous monitoring done with a chemiluminesce nt analyzer. Passive and personal samples done with Palmes tubes.  ppb  SUMMER  Adgate, Reid et al., 1992  Hackney, Linn et al., 1992  Lambert, Samet et al., 1992 Samet, Lambert et al., 1992 Samet, Lambert et al., 1993 Schwab, McDermott et al., 1994  Winter and Summer  Chapel Hill, NC, USA  Personal and Indoor (residential)  20  1989  Los Angeles, CA, USA  Personal  N/A  1988-1991: October to March  Albuquerque, NM, USA  Indoor (residential)  653  5 homes with gas stoves; 5 homes with kerosene space heaters; 5 homes with 1 or more smokers; 5 controls (with none of the above)  40  N/A  26  15 men and 11 women aged 47-69 with history of heavy smoking.  14 per subject (consecutive 24hour measurements for 2 weeks).  24 hours  Badge  ug/m3  N/A  N/A  At least 1 set of measurements (kitchen, living room and bedroom) for each summer and winter season between 1988 and 1991.  2 weeks  Palmes  ppb  Residential homes.  20 mothers and 20 children, aged 0 to 5 years.  Gas Stove Smoker Controls WINTER Kerosene heater Gas stove Smoker Controls Overall  Summer 1998 Winter 1988-1989 Summer 1989 Winter 1989-1990 Summer 1990 Winter 1990-1991  Measured Concentrations of NO2 Mean 22 470 10 63 7 13 11 31 10 20 11 9 4 mean 65 79 20 108  Standard Deviation  Results  Geometric Standard Deviation  Maximum  Minimum  29 420 18 49 12 21 11 60 11 29 9 11 25 median 59 69 16 84  15.2 22.1 52.3 26 1.2  NO2 source? No Yes No Yes No Yes No Yes No Yes No Yes No Yes  Median/Geometric Mean  6.1 10.4 28.4 8.6 0.6  n 63 162 173 91 69 208 148 93 194 110 169 87 816 751  annual 12.5 27.9 6.1 11 16 31.3 11.4 24.2 5.7 17.2 7.4 16.7 8.6 23.5  winter 10.2 31.5 7.3 23.1 15.4 35.5 11.7 31 5.9 20.1 8.4 21.4 8.9 28.7  142 161 94 1000  29 39 5 14  26.5 54.3 141.2 47 3  4.5 10 14.5 16.7 0.4  Shops generally have no door separating them from the street, so the indoor levels are not surprising. Indicates that outdoor air has a major impact on indoor values in naturally ventilated areas.  NO2 highest in kitchens. Home with an electric cooker had the lowest levels of NO2. Significant correlation between NO2 and the number of meals cooked per week. Smoking not seen to be a factor.  summer 15.9 25.5 5.9 5.9 17.7 29 12.3 12.3 6.1 15.5 7.5 14.2 9.2 20.9  Annual average 14.9 ppb higher for children in households with a major NO2 source. This disparity is seen in both winter and summer. Highest values seen in the kitchen and lowest values in children's bedrooms.  Kitchen Living Room Bedrooms Outdoors  n 6 7 7  Contin. 13 6.5 3.8  Palmes 19 7.3 5  Child 10.5 10 6  Mother 14.4 7.6 6.2  n 5 5 5 5 101  Contin. 70 22.4 12 6.4  Palmes 71.4 26.5 14.7 4.6  Child 50.6 19.3 16.3 9.5  Mother 44.1 23.8 16.9 6.8  SUMMER Contin. Palmes 5.6 10.7 2.6 4 2.8 5.1 WINTER Contin. Palmes 81.2 73.2 15 14.2 12.2 14.6 3.6 3.2 13  Electric 13.6 13.2 11.5 19.4  Gas 36.8 31.3 26.4 25.8  Elec. 19.4 18.5 17.7 28.5  Gas 58.5 47.2 34.3 34.1  Elec. 9.2 9.1 7.5 13  Gas 26 24 19 18.9  Principal source of NO2 in homes with asthmatic children was outdoor air. Only 5 came from homes with gas ranges.  Contin. Child 5.6 5.3 3.8  Mother 4.4 2.5 2.3  Child 41.6 17.8 13.2 3.5  Mother 41.1 17 14.4 1  175 37 30 11 235  Tubes were compared to continuous monitoring with an R2 value of 0.97. Correlation was generally good, though tubes gave readings 2.8 ppb (on average) higher than the continuous monitors. Indoor tubes were affixed 5 inches from the intake of the indoor tubes.  59 Good and statistically significant correspondence between personal and ambient measurements. Generally personal 24-hour levels were 20% less than ambient levels. Smoking appears not to significantly affect personal NO2 exposure.  Gas stove with pilot 20.32 28.58 15.25 27.72 14.8 20.87 (1001)  No Pilot  Electric  11.7 19.76 9.03 16.92 9.24 15.01 (994)  7.97 (217) 7.85 (415) 7.35 (662) 7.3 (578) 6.95 (591) 6.29 (321)  Gas with pilot 11.6 26.33 8.31 24.81 9.57 13.02  No pilot  Electric  6.16 23.3 4.92 16.61 4.54 12.84  5.11 11.77 5.69 5.01 3.87 4.32  Gas stove with pilot 18.1 22.89 13.66 22.01 13.29 17.33  No pilot Electric 10.84 15.33 8.07 13.88 8.44 12.42  6.39 5.75 6.15 6.27 5.97 5.59  Indoor NO2 can differ significantly from year to year, and studies relying on data from a single year should extrapolate with caution. Exposure misclassification is likely when relying on one-time measurements.  Reference  Year & Season of Study  Location  Exposure Measured  # of Sites  Site Description  # of People  Subject Description  Number of Measurements  Duration  Sampler Used  Units  Loizidou, Lagoudi & Petrakis, 1992  Argiriou, Asimakopoulos et al., 1994  1990, March Athens, Greece to December  Indoor and Outdoor (hospital)  1  Near surgery rooms in the basement of the building  62  Residential homes. 25 in Zone A (within 20m of a busy road). 22 in Zone B (20 to 150m from the same road). 15 in Zone C (no heavy traffic).  N/A  N/A  2 sets (indoor and outdoor) of 1hour averages; 4 sets (indoor and outdoor) of 24-hour averages.  1 month for each set.  Continuous chemiluminescent analyzer.  ug/m3  Maeda, Nitta & Nakai, 1992  Nakai, Nitta & Maeda, 1995  1987-1990, Fall to Winter  Tokyo, Japan  Personal, Indoor and Outdoor (residential)  62  Housewives  10 sets of indoor (living room) and outdoor measurements for each site; 10 personal measurements for each participant; 1 measurement per season for 10 seasons.  1-hour (both sets) 24-hour March 24-hour June 24-hour September 24-hour December  Personal Indoor Outdoor 2 days  Badges  ppb  Gas appliances No gas appliances Sega, Fugas & Kalinic, 1992  (not reported)  Zagreb, Croatia  Indoor (residential)  90  Residential homes  N/A  Infante-Rivard, 1993  1988 - 1990, January to December  Montreal, Canada  Personal  N/A  N/A  140  Kawamoto, Matsuno et al., 1993  Paulozzi, Spengler et al., 1993  1992, January  1991, February  Japan  Vermont, USA  Personal and Indoor (residential)  Indoor (recreational)  85  9  Residential apartment units. 20 with oil heaters; 17 with kerosene heaters; 1 with a gas fan heater; 47 with electric or "clean" heaters.  Enclosed Skating Rinks  85 (76 male, 9 female)  N/A  N/A  Children. 61 cases with asthma and 79 healthy controls. 20% subset of a larger study population.  University students aged 21-34 years. 21 smokers and 64 nonsmokers.  N/A  2 sets of measurements (kitchen and living room) per site. 1 taken in winter and 1 taken in summer.  1 week  Palmes  ug/m  1 per child  24 hours  Badge  ppb  3  Gas Stove No Gas Stove  1 personal and indoor measurement per subject/site.  8 at each site during one hockey game.  1 week  (not reported)  Badge  Gastec monitor  ug/m3  Personal (overall) Atmospheric NO2 Smokers Non-smokers "Clean heaters" Smokers (N=11) Non-smokers (N=31) Kerosene heater Oil Fan heater During Cooking  A B C D E F G H I MEAN  ppm  Urban  1990-1991, February to February  Sundsvall, Sweden  Personal, Indoor and Outdoor (residential), Indoor and Outdoor (school) and Outdoor (fixed ambient stations)  1991, January  Sundsvall, Sweden  Personal and Indoor (ice rink)  2  1 old ice rink and 1 new ice rink.  41  Winter  New England, USA  Indoor and Outdoor (ice rink)  70  Ice skating rinks  N/A  24 hours  Badges for personal, residential and school samples. Continuous chemiluminiscent analyzers at fixed stations.  ug/m  Reported here with the mean concentrations. Measurements taken under different ventilation conditions.  12 hours for rinkside measurements and 1 hour for personal measurements.  Badge  ug/m3  Reported here with mean concentrations. Ideally, 1 set of measurements (bench, rink side, resurfacer and outdoor) per site.  7 days  Palmes  ppb  56  24 urban and 30 rural homes; 1 urban and 1 rural school  54  School children followed from 5th (1990) to 6th (1991) grade.  4 sets of 7 consecutive 24-hour measurements: 28 personal measurements per child; 28 indoor (child's bedroom) and outdoor measurements for each home; and 24 indoor (classroom) and outdoor measurements for each school.  32 Children playing hockey and 9 rink personnel.  3  Rural  Bergland, Braback et al., 1994  Brauer & Spengler, 1994  N/A  0% fresh air (4.5 days) 100% fresh air (1 day) 50% fresh air (1 day) 0% fresh air (1 day)  Measured Concentrations of NO2 Mean  Standard Deviation  indoor 34.8 51.8 51.1 46.6 49.3  outdoor 100 123.3 139.6 127.3 104.4  0.42 0.37 0.37 0.47  I/O ratio  indoor 13.26 8.1 8.1 6.9 7.1  outdoor 53.02 35 33.4 32 20.1  Zone A 44 45.8 43.3  Zone B 36.8 39.6 35.9  Zone C 28.7 35.3 19.7  Zone A 17.5 19.1 8.3  Zone B 13.4 17.8 4.9  Winter Summer Winter Summer  Living 39 35 22 24  Kitchen 97 65 26 28  n 6 134  mean 17.6 9.2  Median/Geometric Mean  Results  Geometric Standard Deviation  Maximum indoor 127 65 67 62 62  outdoor 404 180 198 184 131  Minimum indoor 5 39 38 34 32  outdoor 22 53 80 55 64  Zone C 9.3 18.9 1.9  Seems like data can be classified into two groups: spring/summer and fall/winter. In the spring and summer measurements the mean outdoor NO2 is higher than the mean indoor and personal. Opposite in fall/winter. This can be attributed to the use of unvented kerosene space heaters (see figure 2). Winter 204  Summer Winter 89 6  Summer 8 Good correlation between winter and summer NO2 values in homes with gas. Low but significant correlation between NO2 and carpet age, kitchen size (winter) and living rooms size (summer). Also correlation between NO2 and number of occupants. More people, more space, more cooking?  8.26 7.57  No noticeable difference between cases and controls with regard to prevalence of other emission sources.  295 13.7  11.3 13.5 No significant differences in exposure levels between smokers and nonsmokers (also seen in clean heater group). 50% of oil fan heaters users and 11.8% of kerosene heater users has personal exposures above the Japanese Air Quality Standard (112.8 ug/m3). Use of clean heaters did not increase personal exposure to NO2. For kerosene heaters and oil heaters, personal exposure increased with time used.  55.7+/51.7+/21.8+/-8.1 20.5+/219 474 290 (estimate)  1 0 0.3 0.3 <0.1 0.38 0 1 0 0.25  24-hour concentrations are a poor indicator of peak concentrations throughout the day, and should be used cautiously to assess the environments of sensitive populations (i.e.. Hospitals). Little variation of indoor levels due to season (see figure 4). Outdoor fluctuations reflected, but by orders of magnitude less.  PERIOD 2 0.05 0.25 0.35 <0.1 0.5  Bed. Out. (h) Class. Out. (s) Pers. Fixed Bedrm Out. (h) Class. Out. (s) Pers.  0 1.38 0 0.32 Week 1 8 13 15 14 20 40 5 5 8 5 24  Rink Side 256 84 (4) 127 (4) 167 (4)  Personnel 199 (9) 64 (2) 61 (2) 112 (2)  3 1 0.65 0  Game Average 0.02 0.4 0.22  Minnesota has established a ceiling of 0.5 ppm NO2 measured 20 minutes after resurfacing. Two arenas had levels higher than this, but none exceeded the level of 3 to 5 ppm seen in one outbreak. Most arenas did not have mechanical ventilation or did not use their fans because of excessive cooling.  0.05 <0.5 0 1.28  0.31  0.32 Week 2  0.36 Week 3  Week 4  13 11 24 29  18 20 14 41  22 23 30 44  3 4 8  6 9 6  8 6 8  Player 315 (10) <100 (2) <100 (1) 123 (1)  Rink Side 4557 (16) 2501 (2) 350 (4) 1189 (4)  Old Arena  0 1.22  New Arena  Week 1 Week 2 3.3 5.3  Week 3 Week 4  55 11 2.7 1.8  46 12  4.7 8.9  69 17  11  13  13  82  7.2  5.6  5.5  8  6  6  Old Arena  Player Rink 4368 (10) 95 18 749 (4) 52 2027 (2) 58  Player 164  Week 1  Week 2 Week 3 Week 4 18 28  4 8  14  551 82 10 11  25 13 1 3  6  561  2  24 hour personal exposures of urban children were low compared to levels measured at the ambient monitoring station. Poor correlation between personal and ambient levels suggest that ambient results are not a good surrogate for personal exposure. Students were asked to keep a diary of activities (over 30 minute intervals) while monitoring was in process, which showed high levels in ice skating children.  New Arena Rink 2170  Player 2553  152 441  505  Old Rink Old Old Player New Rink New Player  Outdoor Resurfacer Bench Rinkside Propane-Fuelled Gasoline-Fuelled Cat. Converter on No Cat. Converter Enclosed Open Rink No Ventilation Ventilation System  n 54 57 57 53 27 30 25 31 58 9 7 51  mean 17.6 128 169 168 221.1 134 214 140 169.5 16.2 329.7 154.7  2.4 3.6 4 4 3.2 4.6 3.3 4.3 4 1.57 3.7 4  193 1428 2141 2470  461 339 526 7000 7946  Old Rink Old Old New New Player  0.44 3.11 3.11 1.76  73 81 <100 207 283  Levels up to 60 times higher than the 24hour Swedish standard for ambient air, and almost 2 times the 8-hour occupational exposure limit for NO2 from motor exhaust. Cost of heating associated with 50% or 100% fresh air ventilation encourages ice rinks not use it.  Assuming these levels are typical of 2000+ ice rinks in North America, 500,000 or more individuals may be exposed to NO2 levels well above normal indoor averages on a daily basis. It can be expected that 1-hour concentrations could reach 2 to 5 times the levels of the 1-week averages shown.  Reference  Year & Season of Study  Location  Exposure Measured  # of Sites  Site Description  # of People  Subject Description  Number of Measurements  Duration  Sampler Used  Units  Rink # 1 (enclosed) 2 (enclosed)  Lee, Yanagisawa et al., 1994a  Winter  (not reported)  Indoor and Outdoor (ice rink)  8  7 enclosed ice rinks and 1 outdoor ice rink.  N/A  N/A  At least one set of measurements taken per site with at least 3 samplers. Sampling was conducted during recreational and high school hockey games.  Length of hockey game (approximately 1.5 hours).  Badges  3 (enclosed) 4 (enclosed)  ppb  5 (enclosed) 6 (enclosed) 7 (enclosed) 8 (outdoor)  Lee, Yanagisawa & Spengler, 1994b  Winter  Spengler, Schwab 1987 - 1988, et al., 1994 May to May  Massachusetts, USA  Los Angeles, CA, USA  Indoor and Outdoor (ice rink)  Personal, Indoor and Outdoor (residential)  1  482  20 samplers were placed around a single ice rink. 4 at rink side, 6 in the stands, 2 in the locker room, 2 in the building corners, 1 in a players booth, 1 at the score table, 1 along the far wall, 1 in an observation stall, 1 in the office, and one on the seat of the resurfacer.  Residential homes  N/A  752+  N/A  Measurements taken on 5 days under different conditions. Day 1 = 14 resurfacings (RE), no edger use (ED), no extended exhaust (EE) pipe on resurfacer, and no mechanical ventilation (MV); Day 2 = 14 RE, no ED, full EE use, and partial MV; Day 3 = 14 RE, some ED use, no EE, and full MV. Day 4 = 9 RE, no ED, no EE and no MV; Day 5 = 9 RE, no ED, no EE and full MV.  Adults. 682 participated in the main study, and 70+ participated in a more focussed micro study.  Reported here with the mean concentrations. 1 set (personal, indoor and outdoor) for each participant of the main study, and 8 sets for each participant of the micro study.  14 hours  48 hours for the main study and 24 hours for the micro study.  Badges  Badge  nL/L  Average Indoor Rink Side Stands Corner 1 Corner 2 Wall Score Keeper Player Booth Observation Locker Room Office Resurfacer Outdoor  Day 1 Personal (micro) Day 2 Personal (micro) 48-hour personal (main) 48-hour bedroom 48-hour outdoor (main)  ppb  (during work hours) Building 1  Ekberg, 1995  1993, September  1984 - 1986, Lee, Yanagisawa et November to al., 1995 October  Sega, 1995  Arashidani, Yoshikawa et al., 1996  Goteborg, Sweden  Indoor and Outdoor (office)  5  Boston, MA, USA  Indoor and Outdoor (residential)  517  Summer and Zagreb, Croatia Winter  (not reported)  Japan  Indoor (residential)  Emission from space heaters  90  1  4 office buildings in high traffic areas, and 1 reference site in a low traffic area.  N/A  N/A  1 set of indoor (taken at the building exhaust) and outdoor (taken at the building intake) measurements per site.  Residential homes  N/A  N/A  8 sets of measurements (kitchen, living room, master bedroom and outdoor) per home. 1 for each season of the study.  N/A  1 measurement (living room) per site.  1 week  N/A  3 conditions for each of the 6 heaters tested. #1 - fan off and the room door closed; #2 - fan on and the room door closed; #3 fan off and the room door half open.  3 hours for each measurement (plus 3 hours preburning and 3 hours postburning)  N/A  Maximum of 3 sets of measurements (indoor and outdoor) per site. One in each of winter, summer and fall.  Residential homes  Room measuring 20m2 and 3 45m .  N/A  N/A  4 days  Continuous chemiluminescent analyzer.  2 weeks  Palmes  Palmes  Continuous chemiluminescent analyzer.  Building 2 Building 3 Building 4 Reference  ppb  ug/m  ppm  3  No Gas Used Natural Gas Propane-Butane  Convection Kerosene Reflection Kerosene Kerosene Fan Town Gas Propane Gas Electric  Winter 1984 - 1996, Lee, Yanagisawa et Winter, al., 1996 Summer and Fall  Boston, MA, USA  Indoor and Outdoor (residential)  550  192 single dwelling units (SDUs); 207 small multidwelling units (SMDUs); 131 large multi-dwelling units (LMDUs)  N/A  2 weeks  Palmes  ppb  Fall  Spring  Measured Concentrations of NO2 Mean  Standard Deviation Rink 1  Median/Geometric Mean  Results  Geometric Standard Deviation  Maximum  Rink 538 342 934 688 752 2729 2676 1531 547 752 807 37  Outdoor 49  day 1 684 671 673 699 718 665 678 679 689 415 318 645 24  day 2 564 640 637 657 137 618 645 614  n 661 669 682 648 660  mean 38.14 37.19 37.57 27.23 38.26  intake 26  exhaust 22  intake 33  exhaust 24  20 18 20 10  14 12 40  37 46 34  24 30 64  2 42 33 12 28  3 4  38  5 6 7 8  N/A  289 198 610 36  day 3 306 346 300 292 234 288 365 332 291 177 153 291 12  day 4 406 412 400 421 437 394 387 416 383 226 186 271 26  Minimum  Outdoor 68 59 46 13 35 325 368 38 97 83 93 13  Skaters and hockey players probably exposed to levels high enough to change airway resistance in enclosed arenas. Recommended that a 1-hour maximum allowable limit of 250 ppb be set for enclosed arenas.  day 5 52 45 41 48 55 31 103 47 50 31 31 39 25  The addition of an exhaust-pipe extension did serve to reduce NO2 levels slightly, but had little impact on CO levels. The reduction of resurfacing operations from 14 to 9 (compare day 1 and day 4) also had some impact on NO2 levels, though they still remained high. Full and partial use of the indoor recirculation system (days 3 and 2, respectively) also had some impact on the NO2 levels. Use of the full mechanical ventilation system (day 5) had the most significant impact. On all other days it is averages were well above the 200 nL/L guideline. median 36.4 33.6 35.2 24.6 35.8  17.95 19.36 17.45 16.14 20.91  max 162.4 197.4 137.4 153.9 137.5  25%ile 25.2 23.8 25.4 16.7 23  Personal exposure for those from homes with gas stoves with pilot lights was 10 ppb higher (on average) than for those from homes with electric. 4 ppb higher for gas stoves without pilot lights.  Good correlation between concentrations of different traffic pollutants at air intakes of buildings in urban environment. Outdoor and indoor peaks can be expected during periods of high traffic.  Houses with a gas stove with a pilot light had kitchen NO2 levels higher than measured outdoor NO2 levels.  Summer 26 36.4 38.6  Winter 22.2 39.5 39.3  #1  #2  Summ. 12.1 19.6 16.6  winter 7.9 35.5 37.3  summer 62 83 71  winter 33 204 141  sum. 8 5 9  winter 8 4 11  Outdoor levels contribute more to indoor levels in the summer than the winter, due to better ventilation (open windows). Fuel type influences exposure.  #3  0.36 0.27 0.53 0.12 0.28  0.1 0.04 0.12 0.02 0.06  0.07 0.03 0.16 0.03 0.05  Indoor Outdoor I/O Indoor Outdoor I/O Indoor Outdoor I/O  SDU 17 17 1.08 17.8 18.4 0.97 17.3 15.9 1.16  SMDU 28.9 23 1.29 30.2 25.1 1.28 28.7 23.7 1.18  Concentrations of NO2 during use of electric heater were negligible and therefore not reported. Both systems of mitigation significantly reduced NO2 concentrations in the room while heaters were in use. NO2 concentrations in the room prior to heater being turned on were low (less than 0.01 ppm). NO2 was almost entirely dissipated 3 hours after the heater was turned off. LMDU 26.8 23.6 1.54 25.4 25.4 0.97 29.1 24.5 1.03  Single 10.8 6.2  Small M 14.9 6.8  Large M 20 9.6  11.9 4  19.3 6.9  22.1 5.4  7.9 6.3  7.9 6.9  17 9.7  Reference  Year & Season of Study  1994, Linaker, Chauhan et January to al., 1996 March  Location  Exposure Measured  Southampton, England  Mukala, Pekkanen 1991, Winter Helsinki, Finland et al., 1996 and Summer  Ross, 1996  1993 - 1994, May to May  Southern England  # of Sites  Site Description  Personal, Indoor (residential), Indoor and Outdoor (school)  48  Homes of 46 participants and 2 schools. Both schools in neighbourhoods of Southampton previously shown to have very different NO2 levels. Both heated with gas-fired system.  Personal  N/A  Indoor and Outdoor (residential)  12  N/A  Residential homes  # of People  Subject Description  Number of Measurements  46  Children 9-11 years of age.  3 sets of personal, residential (kitchen and living room) and school (classroom and playground) measurements. 2 were taken while school was in session and 1 was taken over the Christmas holidays.  172  Preschool children aged 3-6 years.  15 measurements per child (7 weeks in winter and 8 in summer).  N/A  N/A  1 set of measurements (kitchen, living room, bedroom and outdoor) per site. Palmes tubes and continuous monitors were used simultaneously.  Duration  Sampler Used  Units  1 week  Palmes  ug/m3  1 week  Palmes  ug/m3  1 week  Palmes and continuous.  ppb  Home A B C D E F G H I J K L  Propane Gasoline Electric/Outdoor Yoon, Lee et al., 1996  1994 - 1995, November to February  Boston, MA, USA  Indoor and Outdoor (ice rink)  19  18 enclosed ice rinks and 1 outdoor ice rink.  N/A  N/A  4 sets of 2 measurements at each rink.  1 week  Palmes  nL/L  Residential Office Restaurant  1994 - 1995, Baek, Kim & Perry, Summer and 1997 Winter  Brauer, Lee et al., 1994, Winter 1997  Cotterill & Kingham, 1997  1994, Fall  Seoul and Taegu, Korea  International  Huddersfield, England  Indoor/Outdoor (residential, office and restaurant)  Indoor and Outdoor (ice rink)  Indoor and Outdoor (residential)  36  Simultaneous indoor and outdoor tests were done at 6 residences, 6 offices and 6 restaurants in both cities.  332  Indoor ice rinks: 135 in Canada; 69 in Finland; 24 in Norway; 21 in Slovakia; 12 in Japan; 4 in China; 22 in USA; 16 in Czech Republic; 10 in Denmark  40  Residential homes. 20 near heavy traffic and 20 ~ 50 to 85 m from traffic; 20 (1/2 each previous) with gas cookers and 20 with electric; 20 (1/2 each previous) with single glazed windows and 20 with double.  N/A  N/A  N/A  N/A  1 indoor and outdoor measurement at each site.  N/A  1 set per rink. Includes 2 indoor measurements and 1 outdoor.  N/A  3 consecutive sets of measurements (kitchen, living room, bedroom and outdoor) for each site.  24 hours  1 week  2 weeks  Advantech badge  Palmes  Palmes  ppb  ppb  ug/m3  Canada Finland Norway Slovakia Japan China USA Czech Denmark  Outside Kitchen Living Room Bedroom Kitchen Living Room Bedroom  Measured Concentrations of NO2 Mean  Standard Deviation  Median/Geometric Mean n Personal 97 Kitchen 95 Living Room 95  mean 36 52 40  Playground Week 1 Playground Week 2 Classroom Week 1 Classroom Week 2  school 1 57 63 27 16  all urban suburban  Fuel Gas Gas Gas Gas Some Electric Electric Gas Gas Gas Gas Some Electric  Kitchen 38 / 215 22 / 259 21 / 282 18 / 125 13 / 53 12 / 44 3 / 13 32 / 293 22 / 320 17 / 100 25 / 169 33 / 211  Living 16 / 70 14 / 120 15 / 102 15 / 100 9 / 37  n 5 12 2-Jan  Nov. 443 55 37  Dec. 93 64 36  Indoor 33 22 58  Outdoor 32 31 42  Bench 333 173 97 53 123 12 342 35 250  Rink End 325 173 88 43 129 14 262 29 287  Outdoor 14 9 12 12 24 11 25 9 24  I/O ratio 19.5 41.4 7.8 4.4 5.9 0.985 11.2 3 4.5  period 1 37 41 23 17 gas 68 33 22  period 2 44 44 25 18 electrical 19 17 14  period 3 39 46 27 18  overall 40 44 25 18  0/5 25 / 295 13 / 191 10 / 56 11 / 49  Results  Geometric Standard Deviation  Maximum  Minimum  257 447 315  11 14 14  45.8  11  Factors associated with increased NO2 included use of gas stove in the home, presence of one or more smokers, and traveling to and from school by some means other than a car. Higher personal exposures seen while school was in session (see figure 2 in paper) despite little change in NO2 concentrations in the home.  school 2 54 77 23 24  21 27.4 18.2  Significant difference between urban and suburban exposures attributable to automobile traffic.  Bedrm Gas cooking principal cause of peak levels in the homes monitored. NO2 levels exceeded WHO 1-hour guideline in 6 of the 10 homes, all of which used gas for cooking. Ratio of Palmes to Continuous measurements = 1.04. Good correlation was shown. Also good correlation between Palmes measurements and peak 1-hour measurements taken by continuous monitors. Investigation into the use of fume hoods on stoves suggest they may be effective in removing NO2 from the surrounding air.  18 / 180 16 / 115 11 / 41 4 / 34 8 / 28 3 / 19 15 / 305 10 / 250 2 / 16 21 / 115  Jan. 212 46 22  Feb. 190 55 20  Nov. 221 26  Dec. 21 39  Indoor 22 10 22  Outdoor 14 13 14  period 1 4 32 13 9  period 2 5 34 14 8  Jan. 280 22  period 3 6 37 20 8  Feb. 146 42  overall 6 34 16 8  Nov. 447 46  Dec. 74 44  Indoor 24 19 56  Outdoo 29 29 40  Bench 125 81 51 41 85 14 137 13 70  Rink 117 75 46 33 90 17 108 15 66  Jan. 72 33  Outdoor 12 7 9 12 22 9 22 6 20  Feb. 100 34  I/O ratio 9.2 13.4 4.5 3.5 3.8 0.8 5.8 2.4 2.2  724 146 37  Bench 3.9 3.7 3.2 2.1 2.4 1.9 3.5 2.6 5.7  Rink 3.9 3.9 3 2 2.4 1.6 3 2 6.4  56 17 21  4 of the 5 rinks with propane resurfacers had NO2 levels higher than 200 nL/L in November, while none of those with gasoline resurfacers exceeded this concentration. Fuel type and resurfacer age were significantly associated with NO2 concentrations.  Indoor 96 58 105  Outdoor 67 73 77  Indoor 9 9 21  Outdoor 12 10 19  Bench 2680 1023 659 140 462 23 1768 323 1131  Rink End 3175 998 566 137 405 26 1046 194 1504  Bench 5 1 6 12 25 1 21 1 7  Rink End 5 1 8 11 29 1 22 5 8  overall 55 175 118 52  overall 25 7 4 5  NO2 concentrations were not shown to be significantly higher in the winter than in the summer (outdoor), which is in direct contradiction of observations made at fixed monitoring stations in both Seoul and Teagu showing values to be 1.5 to 2 times higher in the winter. This calls the sampling method into question, especially at higher NO2 concentrations. High NO2 levels in restaurants, due to smoking and fuel type.  Good correlation between the bench sample and the rink-end sample indicating good mixing within arenas. Significant differences between countries, but comparisons hard to make because of number distributions (n) between countries. Depending on the estimate used, up to 40% of the rinks could have levels about the WHO guideline. Propane-powered resurfacers the biggest contributing factor to high levels. Also the number of resurfacings per day.  Most significant factor in determining indoor NO2 is the type of cooker used. For kitchens with gas cookers significantly higher levels of NO2 found in homes with double-glazed windows. No significant difference found between window type for homes with electric cookers. Traffic levels had little effect on indoor concentrations.  Reference  Year & Season of Study  Location  Farrow, Greenwood 1993, March Bristol, England et al., 1997  Exposure Measured  # of Sites  Indoor and Outdoor (residential)  921  Homes of infants participating in the study.  30  15 units in each of 2 staff quarters buildings. TSTE = Tsim Sha Tsui East and ST = Shatin  20  Site Description  # of People  921  Subject Description  Number of Measurements  Duration  Sampler Used  Units  Infants aged 3 to 12 months.  1 set of measurements (personal, infant's bedroom and outdoor) per participant.  2 weeks  Palmes  ppb  TSTE ST Lee, 1997  Lolova, Uzunova et al., 1997  1996, January to February  (not reported)  Pennanen, Salonen 1993-1994, et al., 1997 Winter  Pilotto, Douglas et al., 1997  Raaschou-Nielsen, Skov et al., 1997  1992, April to September  Hong Kong  Indoor/Outdoor (staff quarters)  Bulgaria  Personal, Indoor and Outdoor (home)  20  Homes of participating children: 5 in Lulin; 5 in Al. Stamboliiski; 5 in Vrasta; 5 in Assenovgrad  Finland  Indoor and Outdoor (ice rink)  5  Indoor arenas of different sizes, with different heating, ventilation and resurfacing technology.  Sydney, Australia  Personal and Indoor (classroom)  October in Copenhagen Personal, Indoor 1994; April, and surrounding and Outdoor May and rural areas, (residential) June in 1995 Denmark.  N/A  N/A  4 sets of measurements (indoor and outdoor) at each site.  20 minutes  Teflon bag and pump (1 L/min)  nL/L  Children aged 10-12 years.  1 set of measurements (personal, kitchen, living room and outdoor) per child/site.  12 days  Palmes  ug/m3  N/A  N/A  2 days of measurements at each site.  Day 1= 5 hours during regular rink usage; Day 2 = 3 hours during a hockey game  Continuous chemiluminescent analyzer.  ug/m3  3 per day in each classroom for 9 weeks. 4 evening measurements for each of the 121 children.  6 hours for the classroom measurements, and up to 4 hours for the evening personal measurements.  Badges  ppb  1 set of measurements (personal, child's bedroom and outdoor) for each child/home.  1 week  Badges  ppb  1 measurement per classroom.  1 week  Badges  ug/m3  Reported here with the median concentrations. Measurements made of 6 consecutive weeks in winter and 7 consecutive weeks in spring.  1 week  Palmes  ug/m3  41  Classrooms in 8 different schools. 4 with unflued gas heating and 4 with electric heating.  121  Children attending the 8 schools. Only those exposed to gas appliances (and no tobacco smoke) at home were chosen for personal monitoring.  196  Homes of participating children. 97 located within 10 km of Copenhagen city centre; 99 located 30 to 50 km away from Copenhagen city limits.  196  Children between 4 and 12 years of age.  28  Classrooms in two high schools.  N/A  N/A  8  4 urban (U) and 4 suburban (S) daycare centres.  219  Preschool children  Personal Kitchen Living Room Outdoor (home)  1 2 3 4 5 (winter average) School 1 School 2 School 3 School 4  5 Smedje, Norback & 1993, Spring Edling, 1997  Uppsala and Enkoping, Sweden  Indoor (classroom)  Alm, Mukala et al., 1998 Mukala, Pekkanen et al., 1999 Personal, Indoor 1990 - 1991, Winter and Helsinki, Finland and Outdoor (day care) Spring Mukala, Alm et al., 2000  Gas Stoves Bernard, Saintot et 1994, March to October al., 1998  Colbeck, 1998  1994, November to March  Montpellier, France  Colchester, England  Personal and Indoor (residential)  Indoor (shops) and Car Parks  (not reported)  Homes of study participants.  4  2 shops on the street with traffic flow of approx 9000 vehicles per day; 2 car parks serving 9800 to 12900 vehicles per week.  107  N/A  40 adult men and 67 adult women.  N/A  Reported here with the mean concentrations. 1 set (personal and kitchen) per participant.  For each shop: 2 at entrance and 2 on lamp post outside; For each car park: 2 at exit, 2 at entrance, and 1 at booth.  2 weeks  1 week  Palmes  Palmes  ug/m3  ug/m3  Electric Stoves  Shop A Shop B St John's - area St.John's Payment St.John's overall St Mary's - area St.Mary's - Payment St.Mary's - Overall  Measured Concentrations of NO2 Mean  Standard Deviation  Median/Geometric Mean  Results  Geometric Standard Deviation  Maximum  Minimum  median gmean Indoor Outdoor  6.8 12.6  6.9 12.2  86 46  0.6 1.7  indoor 44.8  outdoor 57.6  I/O 0.78  indoor 15.1  outdoor 13  I/O 0.87  I/O 0.7  29.3  29.8  0.97  16.1  13  1.03  0.89  Lulin 14.5 55.8 7.1 9.5  Al. Stam. 59.2 154 66.1 109.5  Vrasta 4.1 5.1 5 10.5  Assen. 7.7 35.3 6.8 16.6  116 405 125 208  1.91 2.29 3.33 4.51  DAY 1  DAY 2  Mean 350 130 10 6090 6230  Mean 590 210 9 7310 2100  1-hour 610 320 10 7440 2320  15-min 640 320 10 7530 2500  Gas 50.4 74.4 24.8 103.6  Electric 22 13.8 11.2 7.8  resurf. propane gasoline electric propane propane  24.5 25.6  Kitchen 30.3 37.6 34.1 18.7 16.4 17.5  Pers. 31.6 37 34.4 31.2 23.3 27.1  Kitchen 17 15 16.2 14 5.8 10.5  Pers. 9.8 19.4 15 12.6 5 10  ~ 19 ~5 ~ 6.5 ~ 2.5 ~8 ~4  n 658 829 46 41 45 36  winter 25 17 36 29 40 27  spring 28 17 46 25 49 25  winter 1.4 1.5 1.2 1.2 1.3 1.5  ~ 31 ~ 10.5 ~ 13 ~ 8.5 ~ 21.5 ~ 7.5  ~ 6.5 ~ 2.5 ~2 ~1 ~ 4.5 ~1  9  2  spring 1.4 1.4 1.5 1.4 1.6 1.5  Urban exposures higher than rural exposures. All responding households with smokers and/or gas appliances were excluded from the study. Older children and female children had higher exposures on average, though no explanation other than the possible conscientiousness of these children is given.  Children from homes with gas stoves had higher exposure than those from homes with electric. Children with smoking parents had higher exposure than those without. Children with both had highest exposure. Good correlation between personal exposure and both indoor and outdoor measurements (Pearson's CC ~ 0.75 and 0.80 respectively). Poor correlation of data with city's fixed stations. 81.4  11.5 Though kitchen values varied considerably between those with gas cookers and those without, personal exposures were not significantly different.  34 38 90 60  13 17 58 43  78 56  54 42  51.3  49.4  Smoking only shown to impact indoor NO2 when no other indoor sources present and when outdoor concentrations were low. Gas heating and/or cooking had significant impact.  Of the 121 children monitored, 101 recorded mean concentrations of greater than 40 ppb (the 1-hour limit of detection). Of these 32 homes experienced means up to 80 ppb, 32 between 80 and 120 ppb, 26 between 120 and 200 ppb and 11 greater than 200 ppb.  Personal (U) Personal (S) Indoor (U) Indoor (S) Outdoor (U) Outdoor (S)  n 14 15 29 13 14 27  Paper compares levels at different times of the day (weekday mornings, evenings, Sunday mornings, evening) and shows Sunday evening as having high NO2 values at ST. TSTE surrounded by heavy traffic, and outdoor values always higher than NAAQS annual average of 50 nL/L.  No correlation between CO and NO2 levels. High levels in rinks with propane resurfacers. No correlation between indoor and outdoor NO2.  Urban FD Rural FD Urban BR Rural BR Urban P Rural P  Men Women Both Men Women Both  Significant and positive association found between indoor NO2 and gas cooking, kerosene heaters, cigarette smoke and surrounding traffic density. Significant negative association with the use of a fume hood.  For shops, indoor/outdoor ratios - 0.340.54, avg. 0.44.  Car parks had similar NO2 concentrations as those measured at curbside. Concentrations in payment booths higher than those in shops.  Reference  Year & Season of Study  Location  Exposure Measured  # of Sites  Site Description  # of People  Subject Description  Number of Measurements  Duration  Sampler Used  Units  Garrett, Abramson et al., 1998  Garrett, Hooper & Hooper, 1999  1994 - 1995, Latrobe Valley, March to Australia February  Kulkarni & Patil, 1998  1996, February and April  Leung, Lam et al., 1998  Levy, Lee et al., 1998  Levy, 1998  Magnus, 1998  Indoor and Outdoor (residential)  80  Residential homes  37  Residences of study participants.  Mumbai, India  Personal, Indoor and Outdoor (residential)  (not reported)  Hong Kong  Indoor (residential)  40  High-rise apartment units.  1994 - 1997, Winters  Boston, MA, USA  Personal and Indoor (ice rink)  19  Enclosed Skating Rinks  1996: Winter  1992 - 1995  International. 18 cities in 15 countries.  Personal, Workplace, Indoor and Outdoor (residential)  Oslo, Norway  Personal, Indoor (daycare), Indoor and Outdoor (residential).  > 570  306  Homes and workplaces of all participants.  Home of children participating in the study  N/A  N/A  6 sets of measurements (kitchen, living room, bedroom and outdoor) for each household.  37  21 participated in winter study and 22 participated in summer study. Six subjects participated in both winter and summer.  1 set of measurements (personal, indoor and outdoor) was made for each participant. 2 made for the 6 subjects that participated in both summer and winter studies.  N/A  N/A  1 set of measurements (kitchen, living room and bedroom) per site.  (not reported)  Resurfacer drivers  4 per site in winter 1993-1994. 3 per site in winter 1995-1996. 5 per site in winter 1996-1997.  568  306  Children less than 2 years of age.  560  Adults. 64 from Geneva (Urban); 112 from Basle (Urban); 64 from Lugano (Urban); 80 from Aarau (Urban); 64 from Payerne (Rural); 64 from Wald (Rural); 64 from Davos (Alpine); 48 from Montana (Alpine)  Monn, Brandli et al., 1998  Schindler, Ackermann-Liebrich et al., 1998  1993 - 1994, Urban, rural and Personal, Indoor Winter and alpine regions of and Outdoor Summer Switzerland (residential)  Pennanen, Salonen 1994 - 1996, Winter et al., 1998  Finland  Indoor (ice rink)  560  Homes of participants.  16  5 rinks where resurfacers that had emission control technology (ECT) in place at the beginning of the study, and 11 rinks that introduced ECT after the first measurement.  Adults  Reported here with the mean concentrations. 1 set of measurements (personal, home and office) for each participant.  Reported here with mean concentrations. 1 set of measurements (personal, kitchen, bedroom, living room, outdoor and daycare) for each participating child.  3 personal, 3 indoor and 12 outdoor measurements for each participant.  4 days  Modified Badge  ug/m3  No NO2 Source Gas Stove Gas Heater Smoking Multiple  Personal Indoor Outdoor 2 days  Badge  ppb  1 week  Palmes  ppb  1 week in 19941995; 7 to 17 hours in 19951997  Palmes in 19931994; Badges in 1995-1997.  ppb  2 days  2 weeks  1 week  Badge  Palmes  Palmes  ppb  ug/m3  ug/m3  Bedroom Living Room Kitchen  Ottawa, Canada Beijing, China Zagreb, Croatia Kuopio, Finland Berlin, Germany Erfurt, Germany Bombay, India Sapporo, Japan Tokushima, Japan Seoul, Korea Taejon, Korea Mexico City, Mexico Kjeller, Norway Sosnowiec, Poland Manila, Philippines Geneva, Switzerland London, UK Boston, USA Personal Indoor (kitchen) Indoor (living room) Indoor (bedroom) Outdoor (home) Indoor (daycare)  Geneva Basle Lugano Aarau Payerne Wald Davos Montana  retrofitted original  N/A  N/A  2 for resurfacers retrofitted with ECT, and 3 for resurfacers with original ECT.  1 week  Palmes  ug/m3  Measured Concentrations of NO2 Mean n 15 15 14 7 29  Bedroom 5.8 12.1 9.6 10.8 21.3  Winter 43.7 40.8 38.7  Summer 23.6 26.2 21.5  Standard Deviation Living 7.2 12.8 13.1 11.5 27.7  Median/Geometric Mean  Kitchen 7.3 15.3 14 12.6 20.5  Results  Geometric Standard Deviation  Maximum  17.7 46.1 50.1 52.9 246  Winter 16.0 17.1 13.7  Summer 2.9 12.2 3.2  Winter 87.5 80.9 77.2  30.9 31.7 48.7  <0.7 <0.7 <0.7 1.8 1.8  Summer 42.9 51.2 48.4  69.1 73.7 157.9  prop. Year 1 (1994- 132 Year 2 117 Year 3 (1996- 164  n 29 44 15 31 31 33 21 59 30 33 40 30 30 15 15 33 61 20 n 306 80 296 79 302 141  Indoor 10.7 25.4 16.8 5.5 12.3 9 40.8 23.1 41.9 43.2 38.7 62.7 7.8 34.4 23.4 8.3 21.5 19.2 mean 15.5 14.9 14.7 13.2 25.3 16.9  Outdoor 21.3 35 30.5 14 37.2 15 38.7 22 16.4 52.2 41.7 37.7 13.8 48.5 25 11.9 35.1 33.7  personal 39.6 30.3 35.3 26.4 21.6 21.4 20.7 20.1  indoor 35 25 33 17 16 13 12 12  outdoor 46.9 39.7 46.8 30.8 24.4 19.9 20.2 15.8  1994 650 125  1995 69  1996 147 161  Work 14.3 24.8 26.1 24.1 26 20.2 46.3 26.9 26.4 35 51.9 106.1 19.9 56.2 30 10.6 34.2 26.2  Personal 15.7 27.5 24.1 15.1 20.5 17.5 43.7 28.3 41.2 47.9 50 41.6 12.9 51.5 25.8 11 25 28  Indoor 6.4 14.2 5.8 3.2 7 5.6 17.1 14.1 42 14.8 18.2 24.4 4.4 12.9 11.3 6.3 12.5 15.8  Outdoor 6.7 10.2 5.2 5.3 8.2 6.7 13.7 13.8 7 20 16.2 15 8.2 10 11.5 5.5 10.3 20.1  Work 1.5 5.6 6.3 4.7 8.4 11.1 45.3 10.4 10.6 16.1 40.3 13.1 2.9 18.6 8.8 3 10.9 9.1  indoor 15 12 14 7 6 5 5 5  outdoor 21 19 21 14 12 9 9 7  10 samples exceeded the Australian 24hour ambient guideline of 115 ug/m 3. 6 were from households with unvented gas heaters. Presence of a gas stove and outdoor NO2 values shown to have significant influence on indoor values.  All exposures much higher in winter than in summer. Some workplace monitoring also conducted, showing concentrations of 14.4 ppb in the Centre for Environmental Science and Engineering, 46.4 ppb in a street-side shop, and 110.4 ppb at the traffic police station. 10.1 6.5 20.5  elec. 33 29 34  NO2 exposure higher than reported by Koo et al. Indoor levels generally lower than outdoor levels, with the exception of the kitchen.  Median personal exposure of resurfacer drivers working 8 to 10-hour shifts = 69 ppb. Proper ventilation use and maintenance are key for lowering NO2 levels.  Pers. 5.6 9.4 5.8 2.8 4.1 12.8 16 14.2 23.9 15.5 28.5 9.5 2.8 16.4 6.5 5 7.3 10.7  Indoor:Outdoor ratios ranged from 0.3 +/0.2 in Berlin to 2.8 +/- 2.8 in Tokushima. The trans-national mean was 1.0. Clear geographic distinction between high and low I/O values (Mexico and Asian countries (excluding China) versus western countries). Personal exposures more strongly correlated with indoor measurements than with outdoor or workplace values. Participants reported spending much of their time in their homes. Gas ranges, smoking and kerosene space heaters all shown to significantly increase personal exposure.  7 6.6 6.5 5.4 10.9 9.5  pers. 15 13 13 10 8 8 8 7  gas. 42 85 107  Minimum  personal 37 31 35 24 21 20 20 18  59 38 43 33 60 60  <2 5 2 5 5 <2  pers. 78 98 84 89 48 62 37 49  pers. 19 4 8 3 8 7 4 5  1994/1995 1996 1750 400 275/150 300  1994/19 1996 95 100 20 25/25 75  Mean for cases = 15.65 (SE 0.60) and mean for controls = 15.37 (SE 0.54).  NO2 outdoor levels 25-40% higher in winter than in summer. No significant differences between personal exposure in summer and winter. NO2 was 5 to 8 ug/m3 higher in homes with gas cookers, and personal exposures were 5 to 6 ug/m3 higher for people from these homes. Smoking had significant effect 3 on personal exposure (2 to 6 ug/m ).  Testing done at 69 arenas, but results only reported with respect to ECT.  Reference  Year & Season of Study  Location  Exposure Measured  # of Sites  Site Description  # of People  1993, Winter and Summer  Chiba, Japan  Indoor (residential)  950  Residential homes. 83 up to 49 m from a major road; 499 > 50 m from a major road; 125 suburban; 243 rural.  N/A  Winter  (Not reported. Possibly Australia given location of the authors.)  Subject Description  Number of Measurements  Duration  Sampler Used  Units  2 measurements per site, taken in the living room. 1 during the heating season and 1 during the non-heating season.  24 hours  Badges  ppb  Shima & Adachi, 1998  Shima & Adachi, 2000  Bailie, Pilotto et al., 1999  N/A  hourly 15 Indoor (residential)  72  Residential homes  N/A  N/A  1 measurement per home, taken in the living room.  Camuffo, Brimblecombe et al., 1999  1996, Correr museum, February Venice, Italy and August  Indoor and Outdoor (museum)  1  3 outdoor sites 6 indoor sites around the museum.  N/A  N/A  1 at three of the sites, 2 at 6 of the sites  Gomzi, 1999  1990 - 1991, December to Zagreb, Croatia June  Indoor (school)  3  2 schools in industrial areas and 1 in a rural area.  N/A  N/A  114 measurements in winter and 82 measurements in spring.  Lee, Chan & Chui, 1999  1996 - 1997, October to March  1994 - 1995, October to December  24 hours  Continuous  ppb  Piazza San Marco Enclosed Courtyard 1 Enclosed Courtyard 2 Bellini Room 1 Bellini Room 2 Lotto Room 1 Lotto Room 2 Lotto Room 3 Lotto Room 4  2 to 4 weeks  Passive  ppb  24 hours  Continuous analyzer  ug/m3  Indoor  Hong Kong  Indoor and Outdoor (public places)  14  Southampton, England  Personal and Outdoor (ambient)  N/A  Montreal, Quebec, Canada  Indoor (public buildings)  2  Stockholm, Sweden  Indoor (ice rink)  1  3 restaurants, 2 libraries, 3 recreation sites, 3 shopping malls, 2 sports centres, and 1 car park, in rural areas and in commercial and residential urban areas  1 indoor and 1 outdoor measurement at each site.  N/A  N/A  114  Asthmatic children between 7 and 12 years of age.  N/A  N/A  3 sets in building A and 1 set in building B.  N/A  N/A  1 continuous measurement under changing rink conditions.  20 minutes  Teflon bag and pump (1 L/min)  nL/L  1 week  Palmes  ug/m3  5 days (only during working hours)  Pump and Tube  ug/m  46 hours  Continuous  ug/m3  Linaker, Chauhan et al., 1999  Linaker, Coggon et al., 2000  Nayebzadeh, Cragg- 1996, Winter Elkouh et al., 1999 and Summer  Rosenlund & Bluhm, 1999  1994, December  N/A  Building A - Urban. Train station and shopping complex attached on ground floor; Building B - Urban. No train station or shopping complex.  Ice rink  At least 16 week-long measurements per child.  3  Outdoor  restaurant 1 restaurant 2 restaurant 3 library 1 library 2 recreation site 1 recreation site 2 recreation site 3 shopping mall 1 shopping mall 2 shopping mall 3 sports centre 1 sports centre 2 car park  Measured Concentrations of NO2 Mean  Standard Deviation  Median/Geometric Mean  0-49m to major > 50mroad to  Geometric Standard Deviation  Results Maximum  unvent. vented  unheat.  73  20  18  unvented  172  5  66  21  16  vented  112  6  unheat.  47  2  major road Suburban  73  19  15  Rural  64  19  11  hourly 24  Feb. 25.9 25.9 21 11.1 8.2 9.6 8.7 10.6 11.8  Aug. 16.2  Winter Spring Winter Spring  Industrial 12 8 16 16  Rural 8 14 13 17  indoor 40 63 11 33 12 54 37 37 25 38 47 26 8 42  outdoor 52 82 20 43 20 62 73 44 44 63 22 39 19 63  Site Comments  Minimum  Cigarette smoking significantly increases NO2 concentration during non-heating period, and in houses with non-vented heating. No difference relative to house structure for heating period. For nonheating period NO2 higher in non-wooden structures. NO2 higher in houses with aluminum window frames (rather than wood) during both periods for houses with non-vented heaters.  hourly 0  After electricity, paraffin was the most commonly used fuel (69% of households and 64%, respectively). Hourly average exceeded WHO NO2 standard at 6 of the 72 houses.  Lower levels than those recorded at the V&A Museum in London, and about the same as those recorded at the Residenz in Wurzburg. No evidence of indoor levels being significantly higher in winter than in summer despite the marked difference in outdoor levels. The average indoor concentration was 43% of the outdoor concentration in the window, and 75% of the outdoor concentration in the summer. This could be due to open windows allowing more traffic pollution into the building.  12.1 10.7 10.7 10.3 10.5  Indust. 7 7 10 4  Rural 6 7 7 9  Indust. 55 4 46 23  Rural 30 30 48 38  Indust. 0 3 2 1  Rural 1 5 3 5  Only slight differences seen between pollution levels in rural and industrial districts.  Outdoor concentrations at RE1, RE2, CP1, RP1, RP2 and SM2 were greater than 50 nL/L, the NAAQS and ASHRAE suggested annual average. Indoor concentrations at RE2 and RP1 also higher than 50 nL/L. Indoor concentration higher than outdoor concentration at SM3, probably due to the doors of the shopping mall being left open during business hours. Good correlation between indoor and outdoor NO and NOX concentrations (R2 = 0.921  rural rural  diesel machine outside site  and 0.919 respectively). R2 for NO2 = 0.59.  rural  Personal Ambient  mean 17 12.3  A Grnd 11 19 Unoccupied 10 28 Roof Occupied  Building A  Building B  median 11 12.8  Feb. 161 97 65 68 88 61 June Ent. 91.5 Recep. 60.2 Hall 81 Ent. 71 Recep. 78.7  496 29.8  Februar May 1.46 1.34 1.51 1.44 1.42 1.29 1.65 1.19 1.13 1.2 1.24 1.31 June 1.57 1.35 1.23 1.23 1.23 2hrs after use of resurfacing machine Peak NO2 after 0.5hr use of machine Catalytic converter, vent off Increased exhaust pipe, 2h after use Increased exhaust pipe, 2h after use, vent on  0.7 4.3  May 90 64 82 56 68 40  No evidence of seasonal variation in outdoor NO2 concentrations. No significant correlation found between outdoor and personal concentrations. Higher personal exposures seen during first three months of study with no corresponding outdoor trend. More variance within individuals(74%) than between children (26%). Blank value subtracted from all concentrations on a week-by-week basis.  Air quality generally acceptable in both buildings. Some concern about occupants of ground floor being exposed to NO2 levels in exceedance of ASHRAE guideline. Some seasonal differences observed. IAQ on ground floor of building A influenced by the train station and heavy traffic in the vicinity.  2358 2294 1018 242 172  450 Should replace propane fuelled iceresurfacing machines with electric ones  Reference  Year & Season of Study  Location  Exposure Measured  # of Sites  Site Description  # of People  Duration  Sampler Used  Subject Description  Number of Measurements  Units  Non-smoking adults aged 22 to 45.  1 personal measurement for each of the 60 participants; 1 set of measurements (kitchen, living room, bedroom and outdoor) for the 12 subset homes.  1 week  Palmes  ug/m3  2 sets of measurements (living room, bedroom and outdoor) at each home. 1 in winter and 1 in summer.  1 week  Palmes  ug/m3  All participants (n = 60) Subset (n = 12)  Chao & Law, 2000  1997, Summer  Hong Kong  Personal, Indoor and Outdoor (home)  12  Residences of a 20% subset of the total study population.  60  Cyrys, Heinrich et al., 2000  1995 - 1996, June to November  Hamberg, West Germany and Erfurt, East Germany  Indoor and Outdoor (residential)  305  Residential homes. 201 in Hamberg and 204 in Erfurt.  N/A  Lee, Yang & Bofinger, 2000  1999, June  Brisbane, Australia  Personal, Indoor (office), Indoor and Outdoor (residential)  N/A  Home Indoor Home Outdoor Workplace Personal I/O Ratio  63  Homes of the 57 participants and the 6 office buildings they were working in at the time of the study.  N/A  57  Adult office workers.  1 set of measurements (personal, office, living room and outdoor) for each participant.  2 days  Passive filter badges  ppb  Day 1 (Jan 12)  1996, Levesque, Allaire et January 12 al., 2000 14  Quebec City, Canada  Indoor (arena during monster truck rally)  1  One sampler located in midsection of the rink (west side) and one sampler in upper section of the rink (west side).  Day 2 (Jan 13) N/A  2 samplers operation during 3 monster truck shows.  36 minuets to 197 minutes  Toxilog  ppm  1 per classroom and 1 per subject.  1 week  Badge  ug/m3  3 days of sampling at each site (fall, spring and winter), 2 samples per day.  6 hours  Continuous  ug/m3  Day 3 (Jan 14)  Overall Norback, Walinder et al., 2000  1993, All year  Uppsala, Sweden  Occupational (classroom)  24  2 randomly chosen classrooms in each of 12 schools.  234  Sanyal & Maduna, 2000  1995 - 1996, February to December  South Africa  Indoor (residential)  115  Households of study participants.  N/A  School personnel  Group 1 N/A  Group 2 Group 3  Smith, Nitschke et al., 2000  (not reported)  Port Adelaide, Australia  Personal and Outdoor (ambient)  3  Ciuk, Volkmer & Edwards, 2001  1993  Adelaide, Australia  Indoor (residential)  193  Dennekamp, Howarth et al., 2001  Gauvin, 2001  1999, March and December  Aberdeen, UK  Emission from a gas range.  1998, April to October  Grenoble, Toulouse & Paris  Personal and Outdoor (ambient)  N/A  3  Fixed ambient monitoring stations in geographically distinct areas of Port Adelaide.  125  Homes of 4-year-old children participating in study.  N/A  N/A  Fixed ambient monitoring stations in French cities.  Self-reported, regularly medicated asthmatics.  N/A  N/A  Non-vented gas stove with 4 rings and 1 oven.  79  Children 4 to 14 years: 24 in Grenoble; 32 in Toulouse; 23 in Paris.  1 personal measurement daily per participant for six 1-week periods  1 measurement taken in each child's bedroom.  38 total: 4 with 1 ring on; 2 with 2 rings; 3 with 3 rings; 6 with 4 rings; 4 boiling water; 5 making a stir-fry; 6 frying bacon; 2 baking cakes; 3 roasting meat; and 3 baking potatoes.  1 personal sample for each child.  From arrival home after completion of day's activities to bedtime (mean = 4.5 hours)  Badges  ppb  2 to 12 hours  Badges  ppb  5 to 75 minutes  Continuous chemiluminescent analyzer.  Passive badges for personal 2 days for the sample, and personal samples; continuous 18 to 24 days for chemiluminesce the ambient data. nt analyzers at ambient sites.  ppb  ug/m3  Gas cooking and heating Gas heating Gas cooking All electric Unflued gas stove Unflued gas heater  1 ring 2 rings 3 rings 4 rings boiling water stir fry frying bacon baking cake roast meat bake potatoes Grenoble - personal Paris - personal Toulouse - personal  Measured Concentrations of NO2 Mean Pers. 46 47.3  Standard Deviation  Living Rm Kitchen  Bedrm  Outdoor  53.8  50.9  71.8  61  Pers. 10.9 10  Median/Geometric Mean  Living  Kitchen Bedrm  Out.  21  22.4  15  12.2  (median) living room bedroom outdoor  10.5 14.5 18.2 15 0.78  1 2 1 2 1 2  Erfurt 15 15 29  Hamb. 17 18 31  5.6 5.8 5 5.2 0.55  Time (min) 197 110 180 36 183 183  Results  Geometric Standard Deviation  Maximum Pers. 73.1 67.3  Kitchen  Pers. 26.6 30.8  Kitchen  96.1  95%ile E 33 36 49  95%ile H 37 34 52  5%ile E 8 8 15  5%ile H 8 8 15  31.1 35 23.3 31.3 3.62  TWA <0.5  0.8  <0.5  0.7  <0.5  0.6  5.1  Minimum  24.4  1.2 2 10.1 5.7 3.52  Cooking and kitchen activities have significant impact on personal and overall indoor exposure. Ventilation hood with direct connection to an exhaust fan was the most effective mitigation method. Outdoor NO 2 levels quite high, also contributing to personal exposures.  Most important predictors of indoor NO2 were gas cooking (41% increase), smoking (18% increase), ventilation and outdoor NO2. Indoor values in Hamberg more strongly influenced by outdoor values, possibly due to urbanization. Indoor values high relative to outdoor values in summer, due to increased ventilation (windows open).  Demonstrated that the presence of gas ranges (n = 18) was the predominant factor affecting indoor concentration of NO2 and personal exposure. Estimated personal exposure (from equation using indoor, outdoor and workplace value) correlated well with personal exposure, though values calculated were significantly lower than actual values.  Sensitivity of NO2 measurement device (personal detector, Toxilog Biosystems) did not allow verification of compliance with Canadian air quality standards. Maximum values fluctuated between 0.6 and 0.8 ppm, which occurred mainly when monster trucks were present in the arena.  11  2 Highest NO2 levels measured in schools situated near roads with heavy traffic  kitchen living kitchen living kitchen living  Gas cooking and heating  June 18 57.5 17.5 9 10 8.5 28.7 20 32 12 67 23  October 16.5 37.5 13 9 8 8  March 21.5 46 13 17.5 8 11.5  Concentrations of NO2 higher in living areas than in cooking areas for group 1 only. Also higher concentrations during winter for this group.  Highest NO2 levels measured in homes with unvented gas appliances.  Overall Gas apps. No gas apps. Winter Summer 473 310 584 996 184 92 104 230 296 373 30.7 32.3 25  219 52 13 139 52 5 19 13 52 70 Grenoble - personal Paris - personal Toulouse - personal  10.3 17.1 8.3 13.6 7.8  2.7 2 2.5 2.4 3.1  155.6 (7h)  0.1 (6h) Higher NO2 levels found in homes with lower socio-economic status (~ 4ppb difference).  No NO2 associated with electrical cooking as evidenced by no change from the baseline readings. Gas stove produces no NO2 when off.  7.7 9.9 11  Grenoble - ambient Paris - ambient Toulouse - ambient  19.3 48.9 43.8  Gren. - amb. Paris - ambient Toul. - amb.  1.8 1.2 1.5  personal 46 59 50  ambient 40.8 75.9 44.2  pers. 17 17 8  ambient 5.8 31.8 8.7  Crude correlations between ambient air conc and personal exposures were poor for all 3 cities (R2 = 0.009 Grenoble, R2 = 2 0.04 in Toulouse and R = 0.02 for Paris), but was improved when taking into account other sources for NO2 (0.43, 0.4,and 0.37) Traffic index and proximity and use of a gas cooker at home explained personal exposures most (multiple linear regression). Ambient air monitoring sites a poor predictor of personal exposures.  Reference  Year & Season of Study  Location  Basel, Switzerland; Kousa, Monn et al., 1996 - 1997 Helsinki, 2001 Finland; Prague, Czech Republic  Ng, Seet et al., 2001  (not reported)  Ponsonby, Glasgow 1999, July to et al., 2001 September  Rijinders, Janssen et al., 2001  1997 - 1998  Singapore  Canberra, Australia  Utrecht, Netherlands  Exposure Measured  # of Sites  Personal, Workplace, Indoor and Outdoor (residential)  (not reported)  Personal  N/A  Personal and Indoor (classroom)  Personal, Outdoor (residential), Indoor and Outdoor (school)  4  6  Site Description  Homes and workplaces of all participants.  N/A  Schools. 3 government-run and 1 private.  Schools: 1 very urban (VU); 1 fairly urban (FU); 1 nonurban (NU); 1 near to a busy highway (VB); 1 near to a fairly busy highway (FB); and 1 on a non-busy road (NB)  # of People  Subject Description  Number of Measurements  Duration  Sampler Used  286  Adult participants in the EXPOLIS study: 201 from Helsinki; 35 from Prague; 50 from Basel  258 indoor; 237 outdoor; 188 workplace; 261 personal  16  Adult female asthmatics  1 set per participant, including 2 consecutive 1-week measurements and 1 peak measurement while cooking.  Palmes for 11 week; Between week; Pump for 30 and 60 peak. minutes for peak.  1 measurement for each child and each classroom.  2 days. Personal measurements done only in nonschool hours (18 hours/day).  344  242  Children with mean age of 9.1 years  School children between 6 and 12 years of age.  4 set of measurements (winter, spring, summer, fall) done in duplicate for each child and each child's home. Total of 791 personal and 708 outdoor. 4 sets of measurements done in duplicate for inside and outside of each school.  48 hours  1 week  Palmes  Units  ug/m3  Indoor Outdoor Workplace Personal  ug/m3  Classroom Personal Non-School Time-weighted Total Badge  Palmes  ppb  ug/m3  VU class FU class NU class VB class FB class NB class VU sch. out FU sch. out NU sch. out VB sch. out FB sch. out NB sch. out VU per FU per NU per VB per FB per NB per VU home out FU home out NU home out VB home out FB home out NB home out Home Location Home Type Age of Home Floor Area Heating  1996 - 1997, Rotko, Kousa et al., Metropolitan October to Helsinki, Finland 2001 December  Personal  N/A  N/A  176  Adults between 25 and 55 years  Reported here with the mean concentrations.  Traffic Volume Nearby 48 hours  Palmes  ug/m3 Work Location Season Gas Stove Windows Open Exposed to ETS Commuting Time  Lee, Xue et al., 2002  1996, April and May  Southern California, USA  Indoor and Outdoor (residential)  111  Residential homes: 56 in Upland (valley site) and 55 in San Bernardino (mountain)  Indoor Outdoor I/O ratio N/A  N/A  1 set of measurements (living room and outdoor) per site.  6 days  Badges  ppb  Measured Concentrations of NO2 Mean Helsinki 24 18 27 25  Prague 61 43 30 43  Standard Deviation Basel 36 27 3 30  Median/Geometric Mean Helsinki 21.2 14.7 22.8 22.6  Prague 57 37.7 25.9 40.7  Basel 32.3 22.8 32.3 28.4  Geometric Standard Deviation Hels. 1.8 2.1 2.2 1.7  Prag. 1.5 1.9 1.8 1.5  Results Maximum  Basel 1.6 2.2 1.6 1.4  Ambient fixed site monitoring alone a poor predictor for personal NO2 exposure variation. Outdoor air NO2 concentrations, use of gas appliances and workplace location turned out to be strongest and most consistent NO2 exposure determinants  2 week Peak Ambient  10.1 10.4 10.1  autumn 20.9 8 9.3 19.1 11.9 8.5 31.6 27.6 26.7  35.1 25.9 18.7 14.2 26.1 19.2 19.1 29.8 27 24.7 38 31.9 34  n 92 88 87  4.9 11.1 8.6  winter 29.4 16 12.4 33.5 16 19.3 59 41.6 33.2 82.3 57 46.7 42.1 23.4 19.1 36 29.7 25.1 49 41.5 36.1 58.3 56.1 44.9  spring 22.9 13.4 12.5 25.3 17.1 16.9 32.4 29.2 26.8 36.8 37.1 32.3 33.3 19.6 15.8 29.2 25 18.2 38.1 29.8 22.6 39.3 34.9 26.9 n Downtown 41 Suburban 135 High Rise 107 House 65 <1970 62 >1970 114 <60m2 63 >60m2 110 No Extra 152 Oil/Wood 24 Low/Mod 138 Heavy 38 Downtown 40 Suburban 126 Summer 107 Winter 69 No 167 Yes 9 <20/48 h 117 >20/48 h 57 Yes 54 No 122 <1 h 96 >1 h 65 mean 28 20.1 2.08  8.3  summer 19 12.4 9.6 19.2 12.5 13 24.8 20.5 15.7 21.8 17.3 19.5 19.7 17.8 14.8 15.6 15.1 17.9 25.6 21.3 16 15.7  AM 30.2 23.4 26.8 21.7 29.6 22.5 26.9 24 24.7 26.5 23.5 30.1 30.1 23.7 26.3 22.8 24.5 32.9 23 28.8 27.5 23.8 25.4 24.6  11.4 10.2 10.5 10.5 11.6 9.6 10.5 11.1 10.6 12.5 10.6 10.4 10.3 10.6 12 8.6 10.5 15.5 9.9 12 11.1 16.6 11.1 10.2 12.6 14 1.69  median 28 21.9 24.7 21.2 27.2 21.6 23.8 21.8 22.9 24.1 21.7 27 30.6 22.4 23.8 21.4 22.4 33.5 21.9 25.9 26.2 21.9 23.4 22.2 median 28.9 17.4 1.33  Minimum  130 490 135  75%ile 11.1  163.1 58.9 30.8 82.6 46.8 59.9 71.4 49.5 43.5 67.2 82.1 66.9 95%ile 46.6 44.7 46.1 41.3 47.3 41.3 45.3 45.9 45.3 47.3 44.7 46.6 47 44.3 46.1 38.6 45.9 60.5 41.3 50.6 45.9 45.9 46.6 44.3 max 52 47.8 10.62  36 0 36  25%ile 6.8  9.2 4.7 7.2 6 6.4 6.4 12.9 8.3 6.1 9.6 24 13.5  GM for unflued gas heater = 14.53 ppb. GM for flued gas heater = 11.19 ppb. GM for children from households with only electrical heating and cooking = 7.92 ppb, used as baseline to compare other combinations of potential sources.  Personal and outdoor NO2 concentrations are significantly influenced by the degree of urbanization and by traffic density. Personal exposures were significantly higher for children from homes with gas-fired appliances. Parental smoking did not significantly influence personal exposures. An increase of ~3ug/m3 for children living in smoking homes with gas-fired appliances, but not increases for children living in smoking homes with electrical appliances.  Average personal exposure was 25 ug/m3, which is similar to that measured SAPALDIA (Swiss Study on Air Pollution And Lung Disease In Adults) where the overall personal exposure was 27 ug/m3 (Monn et al, 1998). Downtown participants had higher personal exposure (23%) than those in suburban areas. Those living in older building had a 24% increase in exposure, and those living close to high traffic areas has a 22% increase. Often these three groups are the same -- old building located in high traffic, urban areas. Use of a gas stove was associated with significantly increased exposure, though few participants had gas stoves. NO2 concentrations not associated with age or occupational status, though unemployed men have lower exposure than employed men.  95%ile 49.3 42.1 5.41  min 4.3 3.2 0.22  The community (mountain vs. valley) was significantly associated with indoor NO2 concentrations (higher in valley). Homes with air conditioning and a gas range had higher concentrations as well. Presence of a humidifier had no significant effect. HONO about 17% of NO2 concentration.   REVIEW OF THE HEALTH RISKS ASSOCIATED WITH  Nitrogen Dioxide and Sulfur Dioxide in Indoor Air  Report to Health Canada December 1, 2002  Michael Brauer1, Sarah Henderson1, Tracy Kirkham1, Kit Shan Lee1, Kira Rich1, Kay Teschke1,2  ß  School of Occupational and Environmental Hygiene Faculty of Graduate Studies  ß  Department of Health Care and Epidemiology Faculty of Medicine University of British Columbia Vancouver, BC V6T 1Z3  TABLE OF CONTENTS 1  INTRODUCTION  1  2  METHODS  2  3  2.1  LITERATURE SEARCH ..........................................................................2  2.2  INCLUSION AND EXCLUSION CRITERIA ..................................................3  2.3  CATEGORIES OF STUDIES....................................................................5  NITROGEN DIOXIDE (NO2) 3.1  PROPERTIES AND SOURCES ................................................................6 3.1.1 3.1.2 3.1.3  3.2  Studies of Respiratory Symptoms and Disease ........................................ 17 Studies of Lung Function ............................................................................ 21 Studies of Other Health Outcomes............................................................. 22  STUDIES OF CONTROLLED HUMAN EXPOSURES TO NO2 ......................23 3.5.1 3.5.2 3.5.3 3.5.4  3.6  Indoor Sources of NO2 ................................................................................ 11 Outdoor Sources of NO2 ............................................................................. 13 NO2 Exposure in Ice Rinks ......................................................................... 15 Summary ..................................................................................................... 15  EPIDEMIOLOGICAL STUDIES OF POPULATIONS EXPOSED TO NO2 .........16 3.4.1 3.4.2 3.4.3  3.5  Biochemistry .................................................................................................. 8 Pulmonary Effects ......................................................................................... 9 Immune Response ........................................................................................ 9 Other Effects................................................................................................ 10  PERSONAL AND INDOOR EXPOSURE TO NO2 .......................................10 3.3.1 3.3.2 3.3.3 3.3.4  3.4  Anthropogenic Sources of NO2 .................................................................... 7 Indoor Sources of NO2 .................................................................................. 7 Indoor Nitrogen Oxides Chemistry ............................................................... 8  TOXICOLOGIC CHARACTERISTICS .........................................................8 3.2.1 3.2.2 3.2.3 3.2.4  3.3  6  Overview of Studies .................................................................................... 23 Studies of Lung Function and Airway Responsiveness ............................ 24 Studies of Lavage Fluids............................................................................. 26 Insight from Published Reviews of Controlled NO2 Exposures................. 26  LOAELS FOR CHRONIC AND ACUTE EXPOSURE TO NO2 .....................28 3.6.1 3.6.2  Chronic Exposure........................................................................................ 28 Acute Exposure ........................................................................................... 29  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  4  SULFUR DIOXIDE (SO2) 4.1  PROPERTIES AND SOURCES ..............................................................31 4.1.1  4.2  Absorption and Biochemistry...................................................................... 33 Pulmonary Effects ....................................................................................... 33 Immune Response ...................................................................................... 34 Other Effects................................................................................................ 34  INDOOR EXPOSURE TO SO2 ..............................................................34 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5  4.4  Sources of SO2 ............................................................................................ 32  TOXICOLOGIC CHARACTERISTICS .......................................................32 4.2.1 4.2.2 4.2.3 4.2.4  4.3  31  Overview of Studies .................................................................................... 34 SO2 Concentrations Indoors ....................................................................... 35 Factors Associated with SO2 Indoors......................................................... 36 Factors Associated with SO2 Outdoors...................................................... 36 Limitations.................................................................................................... 37  EPIDEMIOLOGICAL STUDIES OF POPULATIONS EXPOSED TO SO2 ..........37 4.4.1 Overview of Studies .................................................................................... 37 4.4.2 Studies of Respiratory Symptoms, Lung Function and Other Respiratory Outcomes .................................................................................................................. 38 4.4.3 Studies of Other Health Outcomes............................................................. 41 4.4.4 Limitations.................................................................................................... 43  4.5  STUDIES OF CONTROLLED HUMAN EXPOSURES TO SO2 ......................44 4.5.1 4.5.2 4.5.3 4.5.4 4.5.5 4.5.6 4.5.7  4.6  LOAELS FOR CHRONIC AND ACUTE EXPOSURES TO SO2 ....................52 4.6.1 4.6.2  5  Overview of Studies .................................................................................... 44 Adults: Studies of Pulmonary Function ...................................................... 45 Adults: Studies of Airway Resistance......................................................... 46 Adults: Studies of Respiratory Symptoms.................................................. 48 Adults: Studies of Other Measures of Response....................................... 49 Studies of Children...................................................................................... 50 Limitations.................................................................................................... 51 Chronic Exposure........................................................................................ 52 Acute Exposure ........................................................................................... 53  REFERENCES  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  55  LIST OF TABLES Table 2.1  Categories of papers reviewed .................................................................................. 5  Table 3.1  Summary of the physical and chemical properties of nitrogen dioxide .................... 6  Table 3.2  Numbers of studies of personal and indoor NO2 exposure, by continent and country....................................................................................................................... 11  Table 3.3  Studies measuring personal, indoor and outdoor concentrations of NO2 .............. 60  Table 3.4  Numbers of epidemiological studies of NO2, by study design and characteristics ........................................................................................................... 13  Table 3.5  Epidemiological studies of the health effects associated with NO2 exposure........ 81  Table 3.6  Controlled human exposure studies of the health effects of NO2........................... 96  Table 4.1  Summary of the chemical and physical properties of sulfur dioxide ...................... 26  Table 4.2  Studies of indoor and outdoor exposures to SO2 .................................................. 107  Table 4.3  Epidemiological studies of respiratory effects of SO2 exposure ........................... 112  Table 4.4  Epidemiological studies of other health outcomes of SO2 exposure.................... 119  Table 4.5  Controlled human exposure studies of the health effects of SO2 ......................... 122  Table 4.6  Ambient Air Standards for SO2 (in ppm).................................................................. 46  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  1 INTRODUCTION The purpose of this report is to provide a review of the scientific literature on the health effects of nitrogen dioxide (NO2) and sulfur dioxide (SO2) which will be used as a background document by Health Canada in its process of revising the Exposure Guidelines for Residential Indoor Air Quality. Specifically, the report reviews ß  the chemical and physical properties of the two gases;  ß  the toxicological characteristics identified in animal studies, at exposure concentrations near the range of ambient human exposures;  ß  the expected levels of non-industrial indoor exposure of Canadians, with comparisons to other regions with and without comparable climates;  ß  the sources of indoor exposure, including the contribution of outdoor pollution to indoor levels;  ß  results of epidemiological studies of non-industrial indoor exposures (e.g., in homes, offices, and schools);  ß  where few or no studies of non-industrial indoor exposures are available, results of epidemiological studies of exposed workforces or of populations exposed to ambient pollution that was distinguishable from other air pollutants; and  ß  results of controlled human exposures in clinical settings.  Based on the evidence provided in the literature, we suggest lowest observable adverse effect levels (LOAEL) for both the acute and chronic effects of the two gases. Where possible, populations at higher risk of adverse health effects are identified. Throughout the review, sources of uncertainty in the research findings and weaknesses in the study designs are discussed. Areas where there is a dearth of information are identified as avenues for future research.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  1  2 METHODS 2.1 Literature Search Health Canada initially identified a list of 85 references related to this review. These were supplemented by an extensive search of bibliographic databases of the medical and scientific literature, listed below. All available years of all the databases were searched, between December 15th and December 31st 2001. -  BIOSIS Previews is a life sciences database that combines the journal reference content from Biological Abstracts with the content from Biological Abstracts/RRM, which covers reports, reviews and meetings. Covers 1970 forward.  -  The Cochrane Controlled Trials Register (CCTR) is a bibliography of controlled trials individually identified by contributors to the Cochrane Collaboration.  -  The Cochrane Database of Systematic Reviews (COCH) includes regularly updated systematic reviews of the effects of healthcare, as prepared by the Cochrane Collaboration.  -  The Cambridge Scientific Abstracts (CSA) cover 15 science and engineering databases, including the Aluminium Industry Abstracts, the Aquatic Sciences and Fisheries Abstracts, the Ceramic Abstracts/World Ceramics Abstracts, the Conference Papers Index, the Copper Data Center Database, the Corrosion Abstracts, the Engineered Materials Abstracts, the Environmental Sciences and Pollution Management Database, the Materials Business File, the Mechanical Engineering Abstracts, METADEX, the Oceanic Abstracts, TOXLINE, WELDASEARCH, and the Zoological Record. Covers 1966 forward.  -  The Database of Abstracts of Reviews of Effectiveness (DARE) contains critical assessments of systematic reviews from a variety of medical journals. The DARE records cover topics such as diagnosis, prevention, rehabilitation, screening and treatment.  -  EMBASE indexes over 3,500 international journals focused on biomedical, pharmaceutical and other life sciences. Covers 1988 forward.  -  Medline indexes over 3,600 international journals focussed on clinical medicine, experimental medicine and health care. Some book chapters are also included. Covers 1965 forward, and includes some references between 1957 and 1965.  -  PubMed is the US National Library of Medicine's search service that provides access to over 11 million citations in Medline, PreMedline, and other related databases. Same years as Medline covered.  -  The National Technical Information Service (NTIS) is the US government database of scientific, technical, and engineering information. Covers 1990 forward.  -  Toxnet covers toxicology data from the Hazardous Substances Data Bank (HSDB), the Integrated Risk Management System (IRIS), the Chemical and Carcinogenesis Research Information System (CCRIS), and GENE-TOX. It also covers toxicology literature from TOXLINE, the Environmental Mutagen Information Center (EMIC), and the Developmental and Reproductive Toxicology and Environmental Teratology Information Center (DART/ETIC).  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  2  -  The Web of Science covers the Science Citation Index (expanded), the Social Sciences Citation Index, and the Arts and Humanities Citation Index. Covers 1989 forward.  Each database was searched using the following four groups of keywords in the five combinations shown below. Boolean operators (in capitals) separate terms. Group 1  “kerosine” OR “kerosene” OR “gas cooking” OR “gas heating” OR “gas stove” OR “gas stoves” OR “combustion products” OR “wood cooking” OR “wood burning” OR “wood stove” OR “wood stoves” OR “zamboni” OR “vehicle exhaust”  Group 2  “sulfur oxides” OR “ sulphur oxides” OR “ oxides of sulfur” OR “oxides of sulphur” OR “SO2” OR “sulfur dioxide” OR “sulphur dioxide” OR “NO2” OR “nitrogen oxides” OR “nitrogen dioxide” OR “oxides of nitrogen”  Group 3  “hospital” OR “ice rink” OR “indoor” OR “residential” OR “domestic” OR “indoor environment” OR “indoor pollution” OR “personal exposure” OR “classroom”  Group 4  “health effects” OR “asthma” OR “pulmonary function” OR “lung” OR “bronchial constriction” OR “respiratory” OR “diarrhea” OR “neurological” OR “cohort” OR “cancer” OR “toxicology” OR “controlled exposure studies” OR “cross-sectional” OR “epidemiology” OR “case-control”  Combination #1 Combination #2 Combination #3 Combination #4 Combination #5  Group 1 AND Group 4 Group 2 AND Group 4 Group 1 AND Group 3 AND Group 4 Group 2 AND Group 3 AND Group 4 Group 3 AND Group 4  The results of all searches were imported into Endnote (ISI ResearchSoft, Berkeley, CA) and duplicate references were removed. References for papers published before 1990 were moved to a separate file, and the 6000+ that remained were reviewed for relevance. Literature published prior to 1990 was not considered in the review, except where there was insufficient literature from that date forward and except for “classic” studies vital to the evidence. These exceptions are detailed below. 2.2 Inclusion and Exclusion Criteria Articles specifically related to the following topics were sought for further review: 1. The measurement of indoor concentrations of nitrogen and/or sulfur dioxide. Pre1990 papers were sought for SO2 due to limited more recent material. 2. The measurement of personal exposure to nitrogen and/or sulfur dioxide. 3. Studies exploring the relationship between indoor and outdoor concentrations of nitrogen and/or sulfur dioxide. Pre-1990 papers were sought for SO2 due to limited more recent material. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  3  4. Epidemiological and clinical studies characterizing the relationships between indoor nitrogen and/or sulfur dioxide and human health. 5. Epidemiological studies focused on characterizing the relationship between outdoor sulfur dioxide ambient point sources and human health. Pre-1990 papers were sought due to limited post-1990 material. 6. Epidemiological studies focused on characterizing the relationship between occupational exposures to sulfur dioxide and human health. Pre-1990 papers were sought due to limited post-1990 material. 7. Any review articles covering one or more of the above topics. Epidemiological and clinical studies which did not include quantitative exposure measurements were usually not considered relevant to the review, since they could not be used to suggest exposure guidelines. Case reports and case series without comparisons to control populations were not considered in the review. In some cases, “classic” studies (described below) that did not meet these criteria were also included in the literature summary. To identify relevant articles, the references were sorted in Endnote by title and abstract (where available). The 3000+ references that contained at least one of the following keywords (or partial keywords) were moved to a new file for further review. nitrogen dioxide sulphur dioxide sulfur dioxide  NO2 SO2 NOx  SOx NO(sub)2 SO(sub)2  NO(sub)x SO(sub)x burn  cook gas  heat combustion  Any of these references that contained one or more of the following keywords (or partial keywords) were considered potentially relevant, and were moved to a new file to be systematically considered on an individual basis. air allergy arena  asthma domestic effect  exposure health home  hospital indoor lung  occupation office pollut  pulmonary respiratory school  Of the resulting 1300+ references, those concerning experimental studies on animals or in-vitro cell cultures were removed to separate files, and those that were obviously irrelevant were deleted. All remaining articles (approximately 400) were collected from University of British Columbia (UBC) libraries, the Canada Institute for Science and Technical Information (CISTI), or elsewhere through UBC’s interlibrary loan service.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  4  2.3 Categories of Studies Once collected, the abstracts of all articles were reviewed and the papers were sorted into the seven categories described in Table 2.1, overleaf. In addition, the reference lists for several review articles were searched for consistently-cited papers published prior to 1990. These “classics” (approximately 25) were collected and sorted with the others. Any additional relevant articles cited in the papers already collected were identified and retrieved. Table 2.1 Categories of Papers Reviewed Category  Approximate Number  Description  Review  45  Includes all review articles.  Exposure Only  80  Includes all articles for which personal and/or indoor concentrations were measured without reporting health effects.  Indoor/Outdoor  10  Includes studies aimed at characterizing the relationship between indoor and outdoor pollutant levels.  Epi/Exposure  50  Includes all epidemiological studies for which personal and/or indoor concentrations were measured.  Epi/No Exposure  40  Includes epidemiological studies focussed on the presence of pollutant sources rather than measurements of actual concentration.  Clinical  100  Ambient  75  Includes studies focussed on the links between human health and ambient air pollution.  Discard  60  Includes articles that were identified as irrelevant after reading their abstracts.  Includes all clinical and experimental studies on human subjects.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  5  3 NITROGEN DIOXIDE (NO2) 3.1 Properties and Sources Information in this section has been drawn from the following sources: ChemInfo. “Nitrogen Dioxide” ChemInfo Record #748, http://ccinfoweb.ccohs.ca/cheminfo. [2002] US Environmental Protection Agency. Indoor Air Quality (IAQ): Nitrogen Dioxide, http://www.epa.gov/iaq/no2.html. [2002] US Environmental Protection Agency. Air Quality Criteria for the Oxides of Nitrogen. [1991]  Nitrogen dioxide is a corrosive and oxidizing reddish-orange-brown gas with a characteristic pungent odour. It belongs to the highly reactive NOx (nitrogen oxides) family. The major nitrogen oxides present in indoor air are NO (nitric oxide) and NO2 (nitrogen dioxide), although other species, such as HNO3 (nitric acid) and HONO (nitrous acid) are also present in measurable quantities. Table 3.1 summarizes some of the physical and chemical properties of NO2. Table 3.1 Summary of the Physical and Chemical Properties of Nitrogen Dioxide PROPERTY CAS #  10102-44-0  Synonyms  dinitrogen tetroxide, nitrogen peroxide, nitrogen oxide, nitrito, nitro  Molecular Formula  NO2  Structural Formula  O=N–O  Molecular Weight Air Concentration Units Conversion  46.01 g/mol  Colour  Yellowish to dark brown in liquid form; reddish-brown in gaseous form  Odour  Pungent, suffocating odour. Odour thresholds of 0.11-0.14 ppm have been reported.  Melting Point  -11.2°C at 101.3 kPa  Boiling Point  21.2°C at 101.3 kPa  Critical Temperature  158.2°C  Vapour Pressure  101.33 kPa at 21.1°C  Vapour Density  1.58 (air = 1)  Specific Gravity  1.45 at 20°C (water = 1)  Solubility in Water  Reacts to form nitric acid (HNO3) and nitrous acid (HONO)  Solubility in Other Liquids  Soluble in alkalies, chloroform, carbon disulfide, concentrated nitric acids and concentrated sulfuric acids  Stability  Normally stable. Thermally decomposes to nitric oxide (NO) and oxygen at temperatures greater than 160°C.  Flammability  Does not burn.  3  1 mg/m = 0.53 ppm at 101.3 kPa  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  6  The reactivity of NO2 plays a significant role in photochemical smog production, as described in the reactions listed below. NO2 produces red-brown discoloration and reduces visibility in the polluted lower troposphere. NO2 + hn ‡ O + NO (1) O + O2 ‡ O3 (2)  Atmospheric Production of NO2 NO2 is produced from NO in the atmosphere by the following reactions: 2NO + O2 ‡ 2NO2 (slow in ambient air, only important when NO > 1 ppm) (3) NO + O3 ‡ NO2 + O2• (4) HO2• + NO ‡ NO2 + OH• (5) RO2• + NO ‡ RO• + NO2 (6)  Natural sources of NOx include the burning of biomass (forest fires), organic decay, and lightning. Reactions 4, 5 and 6 are fast, but formation of NO2 in ambient air is predominantly from reactions 4 and 5. 3.1.1  Anthropogenic Sources of NO2  The global nitrogen cycle involves a total flux of approximately 350 x 106 tons per year, 60 x 106 tons of which are estimated to be from atmospheric release of NOx from anthropogenic sources. The combustion of fossil fuels and biomass are the most important sources of atmospheric nitrogen, and it is estimated that 5-10% by volume of total NOx emissions from these sources is in the form of NO2. 3.1.2  Indoor Sources of NO2  NO2 exposure indoors can be from outdoor or indoor sources. Indoor NO2 sources include gas-fired appliances (stoves, ovens, etc.), unvented gas space heaters, unvented kerosene heaters, wood stoves, and environmental tobacco smoke. As in ambient air, the primary nitrogen oxide emitted by indoor sources is NO, which is converted in open flames and in air to NO2. Indoor sources can contribute significantly to personal exposures. The average level in homes without identified indoor NO2 sources is generally about half of the outdoor level. In homes with gas stoves, kerosene heaters, or unvented gas space heaters, indoor levels can often exceed outdoor levels.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  7  3.1.3  Indoor Nitrogen Oxides Chemistry  Several studies have evaluated the fate of indoor NO2 in relation to indoor surface reactions and the subsequent formation of reaction products such as HONO [Brauer et al., 1991]. Lee and colleagues [2002] reported that indoor HONO was highly correlated with indoor NO2 concentrations and corresponded to approximately 17% of the measured NO2 concentrations. The relevance of the conversion of NO2 to HONO to health impacts is that different indoor environments and sources may result in different HONO levels at a given NO2 concentration. Given that there have been some demonstrations of human health impacts resulting from HONO exposure [Rasmussen et al., 1995], it has been hypothesized that differences in the HONO:NO2 ratio may account for some of the observed differences in the results of studies of the health effects of NO2. 3.2 Toxicologic Characteristics Section 3.5 reviews the large number of clinical experiments which have exposed human volunteers to nitrogen dioxide. Because the human exposure trials are considered most relevant to human health outcomes, the animal toxicology literature is only briefly summarized here, using the following reviews as a basis. ChemInfo. “Nitrogen Dioxide” ChemInfo Record #748, http://ccinfoweb.ccohs.ca/cheminfo. Accessed September 2002. Moldeus, P (1993). Toxicity induced by nitrogen dioxide in experimental animals and isolated cell systems. Scandinavian Journal of Work, Environment and Health 19(2): 28-36. Schlensinger, RB (2000). Nitrogen Oxides. In: Lippmann M (ed). Environmental Toxicants nd (2 edition). New York, NY: Wiley-Interscience, 595-638.  Following the example set by other reviews of nitrogen oxides [Schlensinger, 2000; US EPA, 1997], this section will place emphasis on the results of experimental animal studies conducted with NO2 concentrations of 5 ppm (9400 ug/m3) or less, as these are considered to be most relevant to human populations. 3.2.1  Biochemistry  NO2-induced lipid peroxidation has been detected at exposure levels between 0.04-5 ppm (75-9,400 ug/m3) in live animals and in in vitro systems. Lipid peroxidation results in the alteration of phospholipids, leading to changes in the physical state of membrane tissue, disruption of enzyme activity, and subsequent impairment of membrane function. It is believed to be an important biochemical mechanism in NO2 toxicity, contributing to many of the other effects associated with exposure. Nitrogen dioxide exposures between 1-10 ppm (1880-18800 ug/m3) have also been shown to disrupt the function of non-membranous enzymes in the lung, potentially leading to damage of important structural proteins. Because NO2 is an oxidant, much of Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  8  the research concerned with mitigation of these toxic effects has been centred on antioxidants such as glutathione, vitamin E and vitamin C, the protective effects of which have been demonstrated in both in vivo and in vitro systems. 3.2.2  Pulmonary Effects  Research indicates that ciliated bronchial epithelial cells are sensitive to the effects of NO2 exposure at levels ranging from 0.5-5 ppm (940-9,400 ug/m3). Damage sustained to the cilia results in reduced mucociliary clearance. It has also been demonstrated that similar levels of nitrogen dioxide (0.3-4 ppm) affect the structure and function of the alveolar macrophages that are responsible for absorbing waste material and pathogenic microorganisms. The severity of these effects is dependant on the magnitude and duration of the exposure studied. Chronic exposure (52 weeks or more) to NO2 concentrations between 0.5-6 ppm (94011,280 ug/m3) has resulted in the reduction of end-expiratory volume, vital capacity, and forced expiratory flow rate, and in increased airway responsiveness to histamine. It is interesting to note that more significant changes were generally observed in studies that superimposed peak concentrations on the baseline exposure. It is also important to note that in many cases the results of different studies with similar designs simply do not agree, and that many lung function studies conducted at the aforementioned concentrations reported no significant findings. This is analogous to the disparities observed in human clinical studies, discussed in section 3.5. 3.2.3  Immune Response  The effect of inhaled nitrogen dioxide on immune response is an important manifestation of NO2 toxicity. Acute, sub-chronic and chronic exposures to concentrations ranging from 0.2-5 ppm (370-9400 ug/m3) have resulted in compromised immune response at different functional levels. To begin, the previously discussed damage to ciliated cells and alveolar macrophages reduces the effectiveness of early response mechanisms, and allows infectious agents to move more easily between the environment and potential hosts. If these agents cannot be removed from the respiratory tract, the next stage of immune response is provided by lymphocytes which circulate in body fluids (B-cells) or cluster in lymph organs (T-cells) and identify antigens and replicate the appropriate antibodies. Short- and long-term exposure to nitrogen dioxide has been shown to reduce lymphocyte counts, and to suppress the speed at which they are capable of synthesizing antibodies. The significance of these results has been seen in comparative mortality trials, in which control and NO2-exposed animals are subsequently exposed to bacteria or viruses, and the number of deaths in each group are compared. Studies using different species and different exposure levels have consistently demonstrated NO2-induced suppression of immune response, but results have varied markedly between specific infectious agents. Unfortunately, little of this research has been done with agents that specifically target the Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  9  respiratory tract, and the effect of NO2 on host response to respiratory diseases is largely unknown. 3.2.4  Other Effects  There has been some concern about the possible carcinogenic effects of nitrogen dioxide, mostly due to the fact that exposure can result in nitrate in the blood, which, after further reactions in the body, may produce nitrogen-based carcinogens. There is little hard evidence to support any link between nitrogen dioxide exposure and cancer, and the few studies that have shown any significant tumour development (after chronic exposure to 10 ppm) have been severely criticized by the scientific community for methodologic faults. Nitrogen dioxide has not been classified by the International Agency for Research on Cancer (IARC). Research concerning the genotoxicity of NO2 is limited, and the interpretation of the results remains unclear. Most studies are conducted in vitro at concentrations much greater than 5 ppm with varied and unpredictable findings. Hamster cells exposed to 1-8 ppm (1880-15,000 ug/m3) have yielded equally inconclusive results about the nature of the relationship between NO2 exposure and changes to DNA at lower concentrations. Finally, there is some limited evidence supporting the potential for NO2 to affect extrapulmonary endpoints, such as birth weight, blood chemistry, and liver function. The data do not provide consistent evidence in either direction. This work is a reminder, however, that biochemical changes induced by NO2 have the potential to affect the whole body, and not just the respiratory system. 3.3 Personal and Indoor Exposure to NO2 A total of 83 separate studies were reviewed to compile the following information regarding indoor NO2 sources and concentrations and major determinants of exposure. The studies that were reviewed were conducted mainly in North America or Western Europe. Three were conducted in Canada. Table 3.2 (overleaf) indicates the number of studies from different locations. The articles, including their quantitative information about exposure levels, are summarized in Table 3.3, which can be found at the back of this report.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  10  Table 3.2 Numbers of Studies of Personal and Indoor NO2 Exposure, by Continent and Country LOCATION North America United States Canada Europe United Kingdom The Netherlands Finland Croatia France Sweden Germany Greece Italy Bulgaria Switzerland Norway Denmark Switzerland, Finland, Czechoslovakia Asia Taiwan Japan Hong Kong Korea India Singapore Australia Middle East (Bahrain) Africa (South Africa) International Studies Unspecified  3.3.1  NUMBER OF STUDIES 19 16 3 38 8 7 5 3 2 5 1 1 1 1 1 1 1 1 14 1 5 5 1 1 1 6 1 1 2 2  Indoor Sources of NO2  Gas-Fired Appliances Numerous studies have shown that residences with gas stoves or gas heaters have higher NO2 levels than those with electric appliances [Speizer et al., 1980; Berwick et al., 1989; Melia et al., 1990; Quakenboss et al., 1991; Adgate et al., 1992; Lambert et al., 1992; Saga et al., 1992; Infante-Rivard, 1993; Spengler et al., 1994; Lee et al., 1995; Sega et al., 1995; Arashidani et al., 1996; Linaker et al., 1996; Ross 1996; Cotterill et al., 1997; Farrow et al., 1997; Lolova et al., 1997; Pilotto et al., 1997; Alm et al., 1998; Bernard et Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  11  al., 1998; Garrett et al., 1998; Levy 1998; Monn et al., 1998; Cyrys et al., 2000; Lee et al., 2000; Smith et al., 2000; Dennekamp et al., 2001; Kousa et al., 2001; Ponsonby et al., 2001; Rjinders et al., 2001; Rotko et al., 2001; Lee et al., 2002]. These studies were conducted in locations with different climates and population densities and in a variety of countries, indicating that the impact of gas stoves and heaters on indoor NO2 concentrations is universal and consistent, although there is variability in the quantitative impact of these appliances. A study by Neas et al. [1991] indicated that gas sources were associated with an increase in long-term average NO2 concentrations of approximately 28 ug/m3 (15 ppb) which, depending upon outdoor concentrations, could correspond to a doubling of outdoor levels. A more recent study [Levy, 1998] suggests that gas appliances are associated with more modest increases, approximately 70% greater than outdoor concentrations. An international study conducted in 19 cities in 15 different countries indicated that gas ranges, as well as kerosene heaters and environmental tobacco smoke were significant predictors of increased personal exposures to NO2 [Levy, 1998]. Some of these studies included only a few homes with gas stoves [Rotko et al., 2001; Infante-Rivard, 1993], but even in these cases, an increase in levels was observed. Pilot Lights Three studies specifically evaluated the impact of gas stove pilot lights on indoor NO2 levels [Lambert et al., 1992; Spengler et al., 1994; Lee et al., 1995]. In all cases, gas stoves with pilot lights were associated with higher NO2 levels in the home compared to gas stoves without pilot lights. Spengler et al. [1994] found a 5.3 ug/m3 (10 ppb) increase in personal exposures for gas stoves with pilot lights compared to a 2.1 ug/m3 (4 ppb) increase for gas stoves without pilot lights. Lambert et al. [1992] reported similar results. Ventilation Three studies assessed the impact of gas stove and/or heater ventilation on NO2 levels indoors [Ponsonby et al., 2001; Smith et al., 2000; Dennekamp et al., 2001]. Ponsonby et al. [2001] and Smith et al. [2000] both reported that unvented gas stoves and heaters were associated with higher NO2 levels inside the home than vented gas stoves or electric stoves. Posonby et al. [2001] reported a geometric mean concentration of 7.9 ppb (14.8 ug/m3) for homes with electrical heating and cooking appliances, a 3.3 ppb (6.2 ug/m3) increase in the geometric mean for homes with ventilated gas heaters and a 6.6 ppb (12.4 ug/m3) increase in the geometric mean for homes with unvented gas heaters. A controlled experiment on electrical versus gas stoves conducted by Dennekamp et al., [2001] indicated that no NO2 is released when cooking on an electric stove. NO2 concentrations of up to 1880 ug/m3 (996 ppb) were reported for cooking on an unvented gas range with all four rings lit. The peak concentration was dependent upon the specific cooking activity being conducted. No NO2 was measured when the gas stove was turned off.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  12  Hot Water Heaters (Geysers) In the Netherlands, unvented gas-fired hot water heaters (“geysers”) were a historical source of elevated indoor concentrations. Five studies indicated that homes with these heaters had higher levels of NO2 than those without [Fischer et al, 1989; Brunekreef et al., 1990; Dijkstra et al., 1990; Houthujis et al., 1990; Noy et al., 1990]. As with gas stoves, venting of the heaters was shown to have an effect on NO2 levels. These studies reported that homes with unvented geysers had indoor concentrations that were 20-40 ug/m3 (10–21 ppb) higher than the concentrations in homes with vented geysers. Homes with vented geysers had NO2 concentrations that were 20-44 ug/m3 (7.5-38 ppb) higher than homes without geysers. Kerosene Heaters Six studies found kerosene heaters to be associated with higher NO2 levels [Berwick et al., 1989, Maeda, Nitta and Nakai 1992, Kawamoto et al., 1993, Arashidani et al., 1996, Farrow et al., 1997, Kulkarni et al., 1998, Levy 1998]. Although the quantitative impact of kerosene heaters varies from study to study, increases as high as 130 ug/m3 (70 ppb) compared to homes with no gas appliances have been reported, producing a 10-fold increase in personal exposures [Adgate et al., 1992, Kawamoto et al., 1993]. Arashidani et al. [1996] conducted an experimental study that evaluated emissions from different heaters with different types of ventilation under controlled conditions; they found that ventilation could reduce NO2 levels indoors. Environmental Tobacco Smoke In contrast to the sources described above, there is weaker evidence associating environmental tobacco smoke with increased indoor NO2 levels. Three studies showed no association between NO2 levels and smoking [Madany and Danish 1991; Hackney et al., 1992; Kawamoto et al., 1993]. Positive associations between smoking and indoor concentrations were reported in six studies [Linaker et al., 1996; Farrow et al., 1997; Alm et al., 1998; Levy 1998; Monn et al., 1998; Cyrys et al., 2000]. Cyrys et al. [2000] reported an 18% increase in NO2 levels indoors due to the presence of a smoker, while Monn et al. [1998] reported that the personal exposure of individuals who smoked was between 2-6 ug/m3 (1 – 3 ppb) higher than for non-smokers. 3.3.2  Outdoor Sources of NO2  In addition to indoor sources of NO2, infiltration of NO2 from outdoor air also contributes to indoor concentrations. The absolute increase in indoor NO2 concentrations due to contaminated outdoor air and the proportion of indoor NO2 that can be attributed to outdoor versus indoor sources will clearly vary from location to location, depending upon outdoor NO2 concentrations and infiltration rates.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  13  Traffic Eight studies reported an association between indoor NO2 levels and levels of or proximity to traffic [Ekberg 1995; Mukala et al., 1996; Farrow et al., 1997; Nayebzadeh et al., 1999; Norback et al., 2000; Gauvin et al., 2001; Rijinders et al., 2001; Rotko et al., 2001]. Three studies showed an association between indoor levels of NO2 and outdoor concentrations [Liao et al., 1991; Garrett et al., 1998; Chao and Law 2000]. Cyrys et al [2000] and Sega [1995] found that outdoor levels were associated with indoor levels during the summer when windows were opened. Four studies showed that indoor levels of NO2 are higher in urban compared to rural areas, possibly due to differences in traffic [Chan et al., 1990; Mukala et al., 1996; Raaschou et al., 1997; Cyrys et al., 2000], though one study by Fischer et al [1989] did not measure any urban:rural difference. Season Relatively few studies explicitly evaluated the impact of season on indoor NO2 concentrations. As part of the Harvard Six Cities Study, Neas et al. [1991] demonstrated that indoor levels were higher in winter than in summer in all cities, in homes with a major indoor NO2 source. On average indoor concentrations were 7.8 ppb (14.7 ug/m3) higher in winter than in summer in these homes. This seasonal effect was not observed for homes without an indoor source [Neas et al., 1991]. Adgate et al.[1992] reported similar findings for a smaller number of homes in North Carolina. An extended study in Albuquerque reported that indoor NO2 concentrations can vary significantly from year to year [Schwab et al., 1993]. Winter concentrations were 6-12 ppb (11 – 23 ug/m3) higher than summer concentrations for homes with a gas stove with a pilot light, and 6-8 ppb (11-15 ug/m3) higher for homes with a gas stove without a pilot light. Sega et al. [1995] reported on measurements conducted in Zagreb, Croatia and concluded that outdoor concentrations contributed more to indoor concentrations in summer than in winter. In homes without gas stoves, indoor concentrations were higher in summer than in winter while the opposite was true for homes with NO2 sources. Neas et al. [1991] reported a similar relationship in summer for the cities with the highest outdoor NO2 concentrations. Similar summer relationships were also reported for residential measurements in Hamburg and Erfurt, Germany [Cyrys et al., 2000]. Camuffo et al. [1999] reported that indoor concentrations in a museum in Venice did not differ by season even though outdoor NO2 concentrations were significantly higher in the winter. The authors suggested that in summer, air exchange, and consequently the penetration of NO2, was greater. Together these studies indicate that indoor concentrations are determined by a complex interaction between the outdoor concentration, the ventilation rate and the presence of indoor sources. For environments with indoor sources, winter concentrations tend to be higher due decreased air exchange and, in some cases, increased use of the source appliance. In indoor environments without sources, summer concentrations tend to be Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  14  higher than winter concentrations due to increased air exchange in summer, although this relationship in also dependent upon the level and seasonal differences in outdoor NO2 concentrations. 3.3.3  NO2 Exposure in Ice Rinks  Major non-residential, indoor sources of exposure are ice rinks. [Paulozzi et al., 1993; Bergland et al., 1994; Brauer and Spengler 1994; Lee et al., 1994; Lee et al., 1994; Yoon et al., 1996; Brauer et al., 1997; Pennanen et al., 1997; Rosenlund et al., 1999]. High indoor NO2 levels in these facilities have been associated with the use of propane fuelled ice resurfacers and lack of mechanical ventilation. Indoor concentrations in ice rinks are typically 10 times higher than outdoor concentrations and may be extremely high (> 2000 ppb). Bergland et al., [1994] reported that children who ice skate have higher personal NO2 exposures than children who do not skate. 3.3.4  Summary  Gas stoves, kerosene heaters and gas-fired hot water heaters (geysers) all increase NO2 levels in the home. This has also been the case for non-industrial occupational settings (schools and offices). The magnitude of the increase is dependent on ventilation (homes with less ventilation generally report higher concentrations). For homes with gas stoves or heaters, the presence of a pilot light and the frequency of use (in the winter, heaters tend to be used more than in the summer) also affect the magnitude of the indoor source. Outdoor sources, such as traffic can also contribute to indoor levels, especially in urbanized areas. This association is stronger in the summer when outdoor air is readily introduced indoors through windows. Smoking may also contribute to elevated indoor NO2 levels. The indoor air volume may also be associated with indoor NO2 levels [Sega et al., 1992; Kulkarni et al., 1998], as smaller homes are expected to have higher indoor concentrations for a given source emission rate. Many studies have shown that short-term peak exposures to NO2 from exposure to unvented gas stoves have reached levels that exceed national standards. While gas fireplaces were not evaluated as specific sources in the literature that was reviewed, there is little reason to believe that they would in fact be major sources as they are vented. It is expected that the impact of unvented gas fireplaces would be similar to unvented gas heaters that are discussed in detail in this report. In an Australian study, lower socio-economic class was found to result in higher NO2 levels in the home, by about 2 ug/m3 (4ppb) [Ciuk et al., 2001]. No such relationship was found by Rotko et al. [2001] who measured lower NO2 personal exposures among unemployed men in Finland; this result may have been confounded by a lower use of appliances among the unemployed. More study is required before drawing any conclusions on the effect of economic status on NO2 exposure. Ice rinks, especially those with propane fuelled ice resurfacers, have been consistently found to have high NO2 concentrations. There have been incidents when the levels of NO2 were high enough to cause acute adverse human health outcomes. Given the  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  15  popularity of ice-skating and associated activities in Canada, exposures in ice rinks may be an important source of population exposure to NO2. Many investigators have commented on the problems with using outdoor ambient monitoring data as a surrogate estimate of indoor concentrations or personal exposure to NO2 [Bergland et al., 1994; Alm et al., 1998; Gauvin et al., 2001; Kousa et al., 2001]. Outdoor levels tend to be lower than and only moderately correlated with the levels measured indoors, suggesting that reliance on ambient monitoring to predict indoor exposure is not appropriate. In an international survey, the correlation between outdoor concentrations and personal exposures across all locations was 0.57, lower than the correlation between indoor concentrations and exposures (r = 0.75) [Levy 1998]. Similar results have been reported in other studies, with lower correlations between outdoor concentrations and personal exposures (r = 0.5 – 0.6) generally observed when indoor sources are present or operating [Alm et al., 1998]. 3.4 Epidemiological Studies of Populations Exposed to NO2 A total of forty-one epidemiological papers were reviewed, three of which report on a single study. Thirty-four of these papers were published in 1990 or later, and seven “classic” studies published prior to 1990 were included. The general characteristics of these papers are summarized in Table 3.4, and the specific details of each are summarized in Table 3.5 at the back of this report. With a few exceptions, we limited the review to those studies in which NO2 measurements (either measurements of indoor concentrations or personal exposures) were made. Numerous studies comparing individuals living in homes with or without suspected NO2 sources were not considered. In the studies that were evaluated, NO2 exposures or indoor concentrations varied between “zero” ppb and 292 ppb (549 ug/m3). In addition, two studies evaluated somewhat higher exposures associated with industrial and ice arena exposure: 11 ppb to 1254 ppb (21-2542 ug/m3). Although many of the studies considered more than one health outcome, the majority focused on general respiratory symptoms and diseases. These studies typically relied on subject self-reporting through questionnaires and/or diaries.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  16  Table 3.4 Numbers of Epidemiological Studies of NO2, by Study Design and Characteristics  Study Design  Cohort Case-Control Cross-sectional Longitudinal Panel Other  NUMBER OF STUDIES 9 5 18 5 3 1  Location  Asia Australia North America Western Europe Other  4 5 10 20 2  Study Population*  Adults Children  12 31  Health Status of Study Population  COPD Identified Asthmatics Not Specified  1 10 30  Measured Outcome*  Lung Function Respiratory Symptoms, Illnesses and Diseases Other  13 33  VARIABLE  8  *total is greater than 41 (the number of studies) because several studies evaluated several different groups.  3.4.1  Studies of Respiratory Symptoms and Disease  Adults Five studies reported on respiratory symptoms and diseases in adults exposed to indoor NO2; two of these found a positive association between NO2 exposure and respiratory health. In a cross-sectional study conducted by Koo et al. [1990], 24-hour indoor NO2 samples were collected for 319 women, and a dose-response relationship was reported for multiple respiratory symptoms with increasing NO2 concentration. In another crosssectional study, conducted by Maeda et al., [1992], 48-hour personal, indoor and outdoor exposures were measured for 1,991 women living in three zones (defined by their proximity to heavy traffic). Women in zone A (within 20 m of a major road) had a mean personal exposure of 83 ug/m3 (44 ppb), and had significantly higher prevalence of chronic phlegm, chronic wheezing and shortness of breath than women in zone B (20-150 m from a major road, mean personal exposure of 37 ppb) and zone C (residential neighbourhood, mean personal exposure of 29 ppb).  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  17  The other three studies [Hackney et al., 1992; Smith et al., 2000; and Kilpelainen et al., 2001] found no significant relationship between indoor and/or personal NO2 exposure and increased incidence of respiratory symptoms. The 28 subjects studied by Hackney et al. [1992] were older (aged 45-70), physician-diagnosed COPD patients with a history of heavy smoking and low FEV1, and the 76 adult subjects studied by Smith et al. [2000] were physician-diagnosed asthmatics. In Hackney et al. [1992], subjects self-monitored for personal exposure (passive badges), lung-function (spirometry) and clinical status (diaries) on a 24-hour basis for two weeks. Halfway through each week some subjects were exposed for 4-hours to 560 ug/m3 (300 ppb) NO2 in an environmental chamber, and some were exposed to ambient air, and the results for both groups were compared. Although no significant associations between NO2 and lung function were found, the clinical aspect of this study may reduce its relevance to populations exposed to ambient conditions. Infants Six studies reported on the association between NO2 exposure and respiratory symptoms and illnesses in children less than two years of age. Of these, only Samet et al. [1992] reported results that indicated some relationship between NO2 and respiratory health effects. 411 infants were followed for 2 years after birth. The incidence of respiratory illness was found to be highest in winter (1.6/100 days, upper tract; 1.0/100 days, lower tract) when indoor NO2 levels were highest in gas-heated homes (approximately 75% of the homes in the study). In 1993, Samet et al. published another study involving the same cohort. All subjects (823) who had participated in at least 30 days of follow-up were grouped into three exposure categories (0-20 ppb, 20-40 ppb and greater than 40 ppb) and no significant association between NO2 and incidence of respiratory illness was found. In studies of similar cohorts, Ogston et al. [1985] and Farrow et al. [1997] found no significant association between NO2 exposure and the respiratory health of infants. In a nested case-control study conducted by Magnus et al. [1998], the NO2 exposure of 153 infants who developed two or more episodes of persistent (longer than 4 weeks) bronchial obstruction was compared to that of controls matched on date of birth. Parallel monitoring was carried in the homes of cases (mean concentration = 15.7 ug/m3 or 8.3 ppb) and controls (mean concentration = 15.4 ug/m3 or 8.2 ppb). In their study of a cohort of children aged 6 to 10, Speizer et al. [1980] reported that children living in homes with gas stoves had a significant increase in respiratory illness before the age of 2 (OR = 1.1, 95% CI: 1.0-1.3). The retrospective exposure information came from a questionnaire distributed to the parents and guardians of the 8,866 subjects; NO2 exposures were not measured Children Twenty-two studies (one of which resulted in three papers) reported on the relationship between NO2 exposure and respiratory symptoms and diseases in children older than two years of age. The study populations for eight of these included identified asthmatics, and Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  18  five of them focussed on the development of asthma as the health outcome of interest. Infante-Rivard [1993] and Garrett et al. [1998] drew the similar conclusion that children from homes with elevated levels of NO2 are at an increased risk of developing asthma. Infante-Rivard [1993] reported NO2 concentration differences of greater than 28 ug/m3 (15 ppb) between the Montreal homes of 3- and 4-year-old asthmatic children and their age-matched non-asthmatic controls (OR = 10.5, 95% CI: 3.5-40). Garrett et al. [1998] report an increased risk of asthma in 7- to 14-year-olds living in homes with gas stoves (OR = 2.2, 95% CI: 1.1-4.5). In contrast, Smedje et al. [1997], Ciuk et al. [2001] and Ponsonby et al. [2001] found no significant relationship between NO2 exposure and asthma prevalence. Four of these studies included fewer than 350 subjects (Smedje et al. [1997] had 627 subjects), and three were conducted in Australia, which may limit their applicability to Canadian circumstances. In a cross-sectional study comparing the environments of asthmatic children (n = 30) and non-asthmatic children (n = 202), Quackenboss et al. [1991] found that children living in homes with high levels of NO2 were at increased risk of suffering from allergic symptoms. The estimated odds ratio per 10 ug/m3 (5 ppb) increase in exposure was 1.6 (95% CI: 1.0-2.5) for asthmatics, and 1.2 (95% CI: 1.0-1.4) for non-asthmatics. No association was found between NO2 concentration and other respiratory symptoms. In a case-control study comparing children with chronic respiratory illnesses (n = 128) to ageand location-matched controls (n = 103), Hoek et al. [1984] found no significant association between residential NO2 concentrations (ranging from 110 to 789 ug/m3 in the kitchen; 58 to 420 ppb) and respiratory symptoms. In a study involving only asthmatic subjects, Smith et al. [2000] report that personal NO2 exposure (ranging from 22 to 126 ug/m3; 12 to 67 ppb) was not significantly associated with exacerbations of asthmatic symptoms. Once again, these three studies were relatively small in size, which limits the detection of general patterns, something that must be considered when interpreting the reported results. Of the remaining fourteen studies, nine found some significant association between NO2 exposure and respiratory symptoms [Melia et al., 1979; Berwick et al., 1989; Neas et al., 1991; Maeda et al., 1992; Mukala et al., 1996, 1999 and 2000; Pilotto et al., 1997; Roselund and Bluhm, 1999; Sanyal and Maduna, 2000; and Shima and Adachi, 2000], while the other five did not [Speizer et al., 1980; Melia et al., 1982; Dijkstra et al., 1990; Koo et al., 1990; and Gomzi et al., 1999]. In 1973, a cohort of 4,827 children aged 6 to 11 was established with the goal of determining whether or not the presence of a gas stove in the home had any impact on their respiratory health. Melia et al. [1979] followed the cohort for four years, and it was found that the crude and adjusted (age, sex, social class, smokers and latitude) prevalence of one or more respiratory symptom or disease was higher in children from homes with gas stoves than in those from homes with electric stoves. It was also reported that the crude prevalence of cough in boys and chest colds in girls was higher for those from homes with gas stoves. These trends applied only to children living in urban areas; no association between gas stoves and respiratory health was found for children living in rural areas.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  19  Four other studies considered the effect of the presence of an NO2 source inside or near to the home. Berwick et al. [1989], Maeda et al. [1992] and Sanyal and Maduna [2000] report associations between respiratory symptoms and NO2 sources. Berwick et al. [1989] studied 121 children younger than 13 (mean age 6.7) and reported that children younger than 7 who lived in homes with kerosene heaters had a higher incidence of respiratory symptoms and illness than those with electric heating. Indoor exposures of 30 ug/m3 (16 ppb) or greater were associated with and odds ratio of 2.3 (95% CI: 1.7-4.8). Maeda et al. [1992] studied 305 children living at different distances from a busy road, and found that those living up to 20 meters from the road (which corresponded with the highest personal NO2 exposure, measured for adult subjects) had a significant increase in the prevalence of chronic phlegm. Sanyal and Maduna studied 1,820 children under the age of 14 and found that the prevalence of respiratory illness was higher for those living in residences where wood, coal and kerosene were used for cooking. Although Speizer et al. [1980] reported a significant association between gas stoves and respiratory illness before the age of two, no association was found between current exposure and prevalence of respiratory symptoms in the cohort. Other research has placed more emphasis on the direct relationship between measured NO2 exposures and respiratory health outcomes. Melia et al. [1982] further investigated the trends discussed above with a cross-sectional population of 5 and 6 year olds living in homes with gas stoves. Weeklong NO2 measurements were made in bedrooms and living rooms, and children were separated into three exposure categories: less than 38 ug/m3 (20 ppb), between 38 and 76 ug/m3 (20 and 40 ppb), and greater than 76 ug/m3 (40 ppb). For both sexes, the unadjusted prevalences of one or more respiratory conditions were positively associated with living room concentrations, but this relationship disappeared after adjusting for age, sex, social class, smokers in the household and humidity. The authors point out that NO2-related health effects might be difficult to detect in such a small population sample. Koo et al. [1990] conducted a similar cross-sectional study with 362 children (mean age 10) and collected samples every 24 hours instead of every 7 days, but no significant association was found between the measured NO2 levels and respiratory symptoms. Also in 1990 Dijkstra et al. published the results of a relatively large longitudinal study, in which 1,051 children aged 6 to 12 were followed for two years. Nitrogen dioxide concentrations between 11 and 33 ug/m3 (5.9 – 17.7 ppb) were recorded in homes with no indoor source, and between 11 and 67 ug/m3 (5.9 – 35.5 ppb) in homes with a source, but no association between these concentrations and the respiratory health of the children was found. Gomzi et al. [1999] monitored NO2 in conjunction with ammonia and particulate matter at two Croatian schools. No direct relationship between reported respiratory symptoms and mean concentrations of 8-12 ug/m3 (4-6 ppb) NO2 were found. In 1991, Neas et al. published a study reporting that a 28 ug/m3 (15 ppb) increase in annual household NO2 concentrations was associated with increased incidence of lower respiratory symptoms (OR = 1.4, 95% CI = 1.1-1.7). 1,567 children between 7 and 11 years of age participated, and this trend was more pronounced in girls than in boys. Pilotto et al. [1997] studied 388 subjects between 6 and 11 years of age living in homes Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  20  with unvented gas appliances. It was reported that NO2 concentrations greater than 150 ug/m3 (80 ppb) were positively associated with sore throats, colds and absences from school of 3 days or longer. Statistically significant dose-response relationships were found for rates of cough with phlegm, sore throat, and absences from school. Similarly, Shima and Adachi [2000] found a significant increase in the incidence of bronchitis, wheeze and asthma associated with indoor NO2 concentrations among 824 children aged 9 and 10. In three papers resulting from a prospective cohort study involving 172 6-yearold children, Mukala et al. [1996; 1999; 2000] reported an increased risk of cough with increasing NO2 exposure (RR = 1.5, 95% CI = 1.0-2.3), especially evident in the highest exposure group (greater than 27.2 ug/m3, or 14.5 ppb) in winter (RR = 3.6; 95% CI = 1.49.3). Finally, Roselund and Blumm [1999] compared a population of 99 adolescent hockey players exposed to high NO2 concentrations at an ice arena to 56 unexposed controls. Risk ratios for many respiratory symptoms were high. In order to determine what level of NO2 concentration was associated with these health effects, the investigators attempted to re-create the conditions in the arena at the time of exposure. Concentrations up to 2,400 ug/m3 (1,250 ppb) were recorded, but it is not certain that concentrations were in the same range at the time of exposure. While inconsistencies remain, the studies reviewed do provide some evidence that children, but not necessarily infants, are a population subgroup that may be susceptible to respiratory symptoms associated with NO2 exposure. The relatively large study conducted by Neas et al. [1991] indicated an increased risk of respiratory symptoms for 7-11 year old children associated with relatively small differences in long-term exposures to NO2. These findings are consistent with those of Melia et al. [1979], who compared children living in homes with gas versus electrical appliances. 3.4.2  Studies of Lung Function  Adults Five studies reported on pulmonary function in adults and NO2 exposure; two of these were conducted with subjects from sensitive sub-populations. In a study involving 16 asthmatics, Ng et al. [2001] investigated lung function response to NO2 exposure during use of gas-fired stoves. Short-term cooking resulted in concentrations between 0.03 and 490 ug/m3 (0.016 and 260 ppb) with a mean of 121 ug/m3 (64 ppb). These levels were associated with a mean decrease of 3.4% (95% CI = 0.8-5.9%) in peak expiratory flow rate (PEFR). The authors also noted that longer cooking times resulted in smaller changes in PEFR, but were associated with increased use of bronchodilators. Hackney et al. [1992] reported no significant association between NO2 and lung function in 26 COPD subjects. Two of the studies in healthy populations reported a significant decrease in lung function associated with NO2 exposure. Schindler et al. [1998] reported that a 10 ug/m3 (5 ppb) increase in long-term average NO2 exposure resulted in a decrease of 2.9% (95% CI = Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  21  2.1-3.8%) in forced vital capacity (FVC), though no significant change in forced expiratory volume (FEV1) was found. Considerable variability was observed in the measured personal exposures due to outdoor sources in some areas included in the study, and therefore exposure-related differences in lung function may be due, in part, to the presence of other air pollutants. Fisher et al. [1989] also showed a significant decrease in lung function associated with NO2 exposure although this finding was limited to those study subjects living in a rural area. Maeda et al. [1992] reported no association between NO2 exposure and lung function. Together these studies do not provide strong support for an association between indoor NO2 exposure and reduced pulmonary function. Children Eight studies reported on associations between NO2 exposure and children’s lung function. Three included asthmatic subjects, and all of these found a significant association between NO2 and reduced lung function. Quackenboss et al. [1991] (studying 30 asthmatic children aged 6 to 15 years) report a 40 L/min decrement in PEFR for every 20 ug/m3 (19 ppb) increase in NO2. Additional decrements of morning PEFR were seen in children whose bedrooms had high NO2 concentrations. Linaker et al. [2000] studied 114 asthmatic children (aged 7 to 12 years) and reported a dose-response relationship between the number of episodes of reduced PEFR and increasing NO2 exposure. Ponsonby et al. [2001] found that FEV1/FVC was reduced for children with higher NO2 exposures, for children living in homes with gas heaters, and for children who were not mite-sensitized. No differences between asthmatic and non-asthmatic subjects were reported. Of the remaining studies of healthy subjects, only Speizer et al. [1980] report a significant, but small, association between NO2 and lung function. Children living in homes with gas stoves were found to have slightly decreased FVC and FEV1 compared to children living in homes with electric stoves. Brunekreef et al. [1990], Dijkstra et al. [1990], Demissie et al. [1998] and Mukala et al. [1999] all found no association between NO2 exposure and pulmonary function in children. 3.4.3  Studies of Other Health Outcomes  Adults Bernard et al. [1997] studied 107 smoking adults (who smoked fewer than 10 cigarettes per day) and compared personal NO2 exposures to levels of plasma anti-oxidants. An inverse relationship was found between NO2 concentrations and levels of uric acid and glutathione (GSH), in men only. No correlation was found between NO2 and malondialdehyde (MDA) or B-carotene. Giroux et al. [1998] studied male nitrogen fertilizer workers and found that those most exposed to hydrogenated and oxygenated nitrogen compounds had the highest levels of serum nitrates. Norback et al. [2000] report that nasal patency decreased with NO2 exposure, while levels of lysozyme and eosinophil cationic protein (ECP) increased.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  22  Infants and Children Beyond the standard respiratory symptoms commonly studied, some investigators included other symptoms such as abdominal pain, diarrhoea, fever, dizziness, and headache. Of the four studies that reported on these symptoms [Quackenboss et al., 1991; Mukala et al., 1996 and 1999; Farrow et al., 1997; and Sanyal and Maduna, 2000], only Farrow et al. [1997] report significant findings. An increase in incidence of diarrhoea was associated with a doubling of indoor NO2 exposure (OR = 1.4, 95% CI = 1.1-1.7) in a cohort of 921 infants aged 3 to 12 months. In another study focussed on urinary excretion, Adgate et al. [1992] reported no relationship between NO2 and hydroxyproline to creatine ratios. 3.5 Studies of Controlled Human Exposures to NO2 3.5.1  Overview of Studies  A total of 34 controlled human exposure studies were reviewed, 32 of which were published between 1990 and 2001. Summaries of all these studies can be found in Table 3.6, located at the end of this report. The two pre-1990 studies [Orehek et al., 1976; Goings et al., 1989] were “classic” studies, frequently referred to in the literature. In Addition, two meta analyses [Folinsbee et al., 1992; Rasmussen et al., 1992] and one review article [Samet et al., 1990] which focused on pre-1990 studies were examined. Within the 34 studies, subjects ranged from 8 to 85 years of age. Most studies focussed on adults aged 18 to 50 years of age; only a few focussed on children or the elderly. Some or all of the subjects in about half of the studies had asthma of varying degrees of severity, and three studies included subjects diagnosed with chronic obstructive pulmonary disease (COPD). Other subjects were generally healthy non-smokers. In these studies, subjects were exposed to NO2 via mouthpieces or in environmental chambers of differing size and design. Nitrogen dioxide concentrations ranged from 94 to 5,640 ug/m3 (50 to 3,000 ppb), though most exposures were between 188 and 3,760 ug/m3 (100 and 2,000 ppb). In many of the studies, the subjects were exposed to NO2 as well as ambient, filtered, or clean air to provide baseline or control information. Subjects often performed light to moderate exercise, a strategy used to increase the amount of pollutant inhaled per unit time and to evaluate interactions between NO2 exposure and exercise (which can induce asthmatic episodes). Several physiological effects of inhaled NO2 were investigated. The primary focus of most studies was to monitor changes in lung function, through spirometric measurements such as forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and airway responsiveness through body plethysmography measuring specific airway resistance (SRaw). In many of the studies, subjects were exposed to NO2 and then “challenged” with an agent known to cause bronchoconstriction, such as carbachol, methacholine, histamine, or cold air. Some studies evaluated the effects of NO2 on the Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  23  characteristics of lung biochemical indicators collected with bronchoalveolar lavage (BAL), changes in cardiac output, alveolar permeability and whole blood and/or serum characteristics. 3.5.2  Studies of Lung Function and Airway Responsiveness  Healthy Subjects Two of the ten studies that involved healthy subjects reported that NO2 exposure had some direct impact on lung function. Significant decreases in the mean FVC and FEV1 (0.17 and 0.11 L, respectively) were reported by Blomberg et al. [1999] after the first of four consecutive daily 4-hour exposures to 3,760 ug/m3 (2,000 ppb) of nitrogen dioxide. Similarly, “day of observation” was the only statistically significant factor affecting lung function in consecutive daily exposures conducted by Goings et al. [1989]. Subjects were exposed to 3,760 or 5,640 ug/m3 (2,000 or 3,000 ppb) NO2 for two hours, and a small (2%) decrease in FVC and FEV1 was seen between day 0 and day 1, but not between any of the other days. Of the remaining eight studies, two reported that exposure to NO2 (and NO2 in combination with other pollutants) had some impact on lung function performance in bronchial provocation challenges. Frampton et al. [1991] found a greater carbacholinduced decrease in FVC and FEV1 in subjects exposed to 2,820 ug/m3 (1,500 ppb) NO2 than in those exposed to 1,128 or 94 ug/m3 (600 or 50 ppb), but found no significant association between NO2 exposure alone and lung function. Hazucha et al. [1994] used a methacholine challenge to assess the effects of NO2 on subsequent O3-induced lung function response. Female subjects were exposed to air or 1,128 ug/m3 (600 ppb) NO2 followed by 590 ug/m3 (300 ppb) O3; the methacholine dose required to reduce the FEV1 by 10% was 1.7 mg/mL after the NO2/O3 combination. In comparison, the control (clean air) methacholine dose was 14.3 mg/mL and the dose for O3 alone was 5.6 mg/mL. These results suggest that a combined exposure NO2 and O3 is associated with bronchial hyperresponsiveness. Exposure to 1,128 ug/m3 NO2 alone had no significant impact on lung function or bronchial responsiveness. Rasmussen et al. [1990, 1992], Hackney et al. [1992], Morrow et al. [1992], Vagaggini et al. [1996] and Chambers and Ayers [2001] all reported no significant association between NO2 exposure and lung function in healthy adult volunteers. Asthmatic Subjects Seven of the seventeen studies involving asthmatic volunteers focussed on the direct impact of NO2 on lung function. Roger et al. [1990] found that a 75-minute exposure to 564 ug/m3 (300 ppb) NO2 with intermittent exercise resulted in significantly increased specific airway resistance (SRaw) (4.0 cmH2Osec for cases; 3.2 for controls) and decreased FEV1 (13% for cases; 7% for controls) in male subjects. Tunnicliffe et al. [1994] report that subjects exposed to 752 ug/m3 (400 ppb) for 1 hour via mouthpiece showed mean 4% decrease in FEV1, while those exposed to 188 ug/m3 (100 ppb) showed Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  24  no significant change. Jorres et al. [1995] report that asthmatic subjects had a small drop in mean FEV1 after a 3-hour exposure of 188 ug/m3 (100 ppb). Volunteers exposed to 564 ug/m3 (300 ppb) NO2 for three hours [Avol et al., 1992] showed a significant drop in lung function between hours 0 and 1, but not between hours 1 and 3. Studies conducted by Rasmussen et al. [1990], Jorres and Magnussen [1991] and Vagaggini et al. [1996] found no direct impact of NO2 on measures of lung function in asthmatic volunteers. The remaining ten studies assessed the effects of NO2 on subjects’ airway responsiveness to known allergens and bronchoconstrictors. Orehek et al. [1976] found that 1-hour exposures to 188 and 376 ug/m3 (100 and 200 ppb) enhanced the effects of carbachol in 13 of 20 volunteers. The mean dose necessary to induce a two-fold increase in airway resistance was reduced from 0.66 mg to 0.36 mg. Jorres and Magnussen [1990] reported that 30 minutes exposure to 470 ug/m3 (250 ppb) reduced the PV100SRaw (mean provocative ventilation necessary to increase SRaw by 100%) by 19%. Both Salome et al. [1996] and Strand et al. [1996] reported increased responsiveness to histamine during and after exposure to 1,128 and 488 ug/m3 (600 and 260 ppb) NO2, respectively. Similarly Strand et al. [1997, 1998] and Jenkins et al. [1999] found that exposure to NO2 in combination with allergen inhalation led to decreased lung function. Strand et al. [1997] report a 6.6% decrease in peak expiratory flow and a 4.4% decrease in late phase FEV1 [1998] for mild asthmatics exposed to 490 ug/m3 (260 ppb) NO2 for 30 minutes. Jenkins et al. [1999] found that mild, non-smoking asthmatics were not significantly impacted by exposure to 376 ug/m3 (200 ppb) NO2 for 6 hours, but that 752 ug/m3 (400 ppb) resulted in a significant decrease in the PD20FEV1 (dose of allergen necessary to decrease the baseline FEV1 by 20%) after 3 hours. Interestingly, Devalia et al. reported that a 6-hour exposure to 752 ug/m3 (400 ppb) NO2 in combination with 522 ug/m3 (200 ppb) SO2 produced in a significant decrease in the PD20FEV1, a result not seen when NO2 alone was administered. Huang et al. report that mite-sensitive asthmatic children exposed for 5 minutes to air from the Taipei Tunnel (183 to 313 ug/m3 SO2; 846 to 940 ug/m3 NO2) followed by methacholine and/or inhaled allergen showed no change in pulmonary function. Subjects with COPD Three studies investigated subjects with COPD to assess the possibility that these patients exhibit enhanced sensitivity to the effects of NO2 exposure. Vagaggini et al. [1996] studied 7 healthy, 8 asthmatic and 7 COPD (mean age 58 years) volunteers. All were exposed to 564 ug/m3 (300 ppb) NO2 for 1 hour with intermittent periods of moderate exercise. COPD patients showed a slight but significant decrease (3 %) in FEV1 2 hours after exposure. Morrow et al. [1992] studied 20 elderly normal and 20 COPD (mean age 60 years) volunteers exposed to 564 ug/m3 (300 ppb) NO2 for four hours, and found that the COPD subjects demonstrated progressive decrements in FVC and FEV1 (to 8.2 and 4.8%, respectively) over the four-hour period. Hackney et al. [1992] studied 26 volunteers with physician-diagnosed COPD (aged 45-70), a history of heavy smoking, and low FEV1. Subjects were exposed to ambient air or 564 ug/m3 (300 ppb) for four Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  25  hours with periods of intermittent exercise, and no significant association between lung function and NO2 exposure was observed. 3.5.3  Studies of Lavage Fluids  Studies of biochemical markers, in addition to providing information regarding the toxicological mechanism of action, may indicate sub-clinical effects of exposure. Nine of the eighteen studies published since 1994 looked for changes in the chemistry and cytology of lavage fluid, before and after exposure to NO2. Of these, seven involved only healthy volunteers, one included only asthmatic volunteers, and one included both. None of these studies were conducted with COPD subjects. Many of these studies have focused on the measurement of inflammatory mediators. Wang et al. [1995] reported that healthy subjects exposed to 752 ug/m3 (400 ppb) NO2 for 6 hours experienced a significant increase in the amount of eosinophil cationic protein (ECP) found in their nasal lavage fluid after an allergen challenge. NO2 did not directly affect levels of the other inflammatory mediators tested. Following a 4-hour exposure to 3,760 ug/m3 (2,000 ppb) NO2, Blomberg et al. [1997, 1999] reported significant increases in the neutrophils, IL-8 and myeloperoxidase (MPO), found in bronchial lavage fluid. Similarly, Solomon et al. [2000] studied subjects exposed to the same 4-hour concentration for three consecutive days. A significant increase in neutrophils and a significant decrease in T-helper cells were observed. Azadniv et al. [1998] studied BAL fluids 15 healthy subjects after 6 hours of exposure to 3,760 ug/m3 (2,000 ppb) NO2. In the first phase the BAL was taken 18 hours after the end of the exposure, and in the second phase it was taken immediately after the exposure. First phase results showed an increase in leukocytes (2.2 to 3.1%) and a small decrease in CD8T lymphocytes and in non CD4/non CD8 T lymphocytes. No significant changes were observed in the second phase of testing. Jorres et al. [1995] and Avissar et al. [2000] both found that exposure to lower concentrations of 1,880 and 2,820 ug/m3 (1,000 and 1,500 ppb) for 3 hours did not have significant effect on the differential cell counts in the BAL fluid of subjects, both healthy and asthmatic. Finally, Strand et al. [1996] reported an increase in the granulocyte expression of the Mac-1 adhesion molecule in mildly asthmatic subjects 30 minutes after a 30-minute exposure to 488 ug/m3 (260 ppb), but no significant changes in tryptase, ECP or MPO. Kelly et al. [1996] reported that significant decreases in the antioxidants uric and ascorbic acid were detected in both bronchial (upper respiratory tract) and bronchoalveolar (lower) fluid after a 4-hour exposure to 3,760 ug/m3 (2,000 ppb) NO2. A significant increase in bronchial GSH (reduced glutathione) was also observed. These results suggest an NO2-induced depletion of respiratory tract antioxidants. 3.5.4  Insight from Published Reviews of Controlled NO2 Exposures  In the studies described above, there is a great deal of variability in the levels of exposure at which responses are detected. In several cases, studies that are similar in design and Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  26  execution have produced discordant results. To more clearly understand and interpret this literature, two meta analyses and a key review paper were consulted for further information and insight. The review of Samet and Utell [1990] includes only two of the papers mentioned in this report [Orehek et al., 1976; Goings et al., 1989], however, it also describes inconsistent findings, in studies conducted pre-1990. Possible explanations for the inconsistencies found in pre-1990 papers, probably also relevant to the more recent studies, are discussed in detail. The authors suggest that following factors complicate the interpretation of experimental results: -  Small sample sizes that do not allow for the establishment of general patterns.  -  Differences in exposure protocols that make studies difficult to compare. For example, oronasal breathing (chamber exposures) versus oral breathing (mouthpiece exposures) and exercise versus no exercise protocols.  -  Failure to recognize normal exposure circumstances of subjects and, therefore, failure to account for possible pre-established tolerances.  -  Possible overemphasis on group mean responses. Lumping all individual study subjects into a mean analysis may result in some patterns and sensitivities being missed.  -  Although the major site of NO2 injury is the terminal bronchioles, most studies focus on tests of the upper airways, which may be relatively insensitive to any deleterious effects.  Despite these challenges to interpretation, Samet and Utell [1990] argue that that many of these studies have shown evidence that individual asthmatics and groups of asthmatics do respond to levels of NO2 that induce no response in healthy volunteers. Given the inconsistencies in responses to NO2 exposure in controlled experimental studies, two meta analyses were conducted in attempts to quantitatively assimilate the information derived from the various studies. In 1992 Folinsbee published a metaanalysis of 25 studies (published and unpublished) that asked the question “Does NO2 exposure increase airways responsiveness?” Raw data was collected for all of the study subjects (703 asthmatics; 131 health normal) so that individuals could be assessed on a case-by-case basis. Results of airway responsiveness tests before and after exposure to NO2 were reviewed, and cases were simply labelled as “increased” or “decreased”. If the results for a particular individual could not be assessed with confidence, the data was excluded from further analysis. The number of asthmatic and normal subjects that showed increased airway responsiveness was calculated and tested for statistical significance with a sign test. It was determined that 70% of asthmatics showed increased airway responsiveness during resting exposure, but only 50% showed an increase during exposure with intermittent exercise. 47% of normal subject had increased responsiveness Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  27  with exposures less than 1,880 ug/m3 (1,000 ppb), and 80% showed increased responsiveness with exposures to higher concentrations. This meta analysis confirmed the increased sensitivity of asthmatics and suggested that a significant proportion of nonasthmatic subjects also experience airway responsiveness at concentrations of approximately 1,880 ug/m3 (1,000 ppb.) Rasmussen and colleagues [1992] performed a similar meta-analysis on studies published between 1980 and 1989 that involved 10 or more subjects (healthy and/or asthmatics) and followed a randomized, blinded design. FEV1, SRaw and AR were used as indicators of NO2 impact. Significant effects were seen in the airway resistance and responsiveness of asthmatics at concentrations between 600 and 1,200 ug/m3 (320–638 ppb), and in the airway responsiveness of healthy subjects at concentrations greater than 2,000 ug/m3 (1,063 ppb). These findings are in good agreement with the metal analysis of Folinsbee [1992], again indicating adverse effects of exposures to concentrations above approximately 2,000 ug/m3, and the roughly 2- to 3-fold enhanced sensitivity of asthmatics. It is important to note that the controlled exposure studies described above have, by design, focused only on acute exposures and responses. Exposures have generally been for periods of 1-6 hours and outcomes were typically evaluated immediately postexposure. It is therefore not possible from these studies to determine the potential impacts of repeated exposures or the possibility of delayed or chronic responses. 3.6 Discussion of LOAELs for Chronic and Acute Exposure to NO2 3.6.1  Chronic Exposure  Epidemiological studies are best suited to evaluate the impact of chronic exposures and to serve as the basis for chronic exposure guidelines. The epidemiological studies that were reviewed largely fail to indicate associations between NO2 exposure and a wide range of heath outcomes, although there are several notable exceptions that allow broad conclusions to be made. Overall, the epidemiological studies support the results from chamber studies indicating that asthmatics exhibit increased susceptibility to the effects of NO2 exposure. While asthma may be exacerbated by NO2 exposure, there is little evidence to support a relationship between NO2 exposure and development of asthma. For example, a large infant birth cohort study designed specifically to evaluate the association between respiratory illness incidence and NO2 exposure from gas stove use showed no association [Samet et al., 1993]. One exception is a Canadian study in which asthma incidence was associated with exposure to NO2 in a small subset of the study population in which exposures were measured [Infante-Rivard, 1993]. In contrast there is more consistent evidence associating NO2 exposure with respiratory symptom prevalence in children, but not specifically in infants. This relationship is noteworthy since children were not frequently studied in the controlled exposure investigations.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  28  Given the inconsistencies in results amongst the studies, we focus on the larger studies with measured exposures to recommend a LOAEL. In one of the larger prospective cohort studies of childhood respiratory illness, Neas et al. [1991] report that a 15 ppb increase in long-term NO2 exposure was significantly associated with a 40% increase in the increased cumulative incidence of lower respiratory symptoms (shortness of breath, wheeze, chronic cough, chronic phlegm, bronchitis). Based on this relationship, the results of other studies reporting associations between long term exposure to NO2 and similar lower respiratory symptoms in children, and supported by acute impacts observed in controlled exposure studies, a LOAEL for chronic exposures of 25 ppb (47 ug/m3) is recommended. This value is based upon the increased indoor N02 concentrations associated with major indoor sources for which health effects have been observed in epidemiological studies. Application of this LOAEL as a standard will be complicated in locations where ambient NO2 concentrations are close to or exceed 25 ppb. This LOAEL is somewhat lower than the World Health Organization (WHO) air quality guideline (40 ug/m3) and the North American outdoor air standard (the U.S. National Ambient Air Quality Standard and the Canadian Maximum Acceptable Air Quality Guideline), an annual mean of 53 ppb (100 ug/m3). 3.6.2  Acute Exposure  To address an acute exposure LOAEL, the numerous controlled exposure studies provide insight and several relatively consistent findings are evident. As with the epidemiological literature, the review of controlled exposure studies suggests that asthmatics exhibit enhanced sensitivity to the effects of NO2 exposure. Whereas healthy adults experience bronchial hyperresponsiveness following 3-hour exposures to approximately 1,000 ppb (1,880 ug/m3) NO2, there is a relatively consistent asthmatic response to levels as low as 300 ppb (564 ug/m3) for 1-hr exposures, with a limited number of studies reporting reduced lung function (3-hr exposure) or bronchial hyperresponiveness (1-hr exposure) to concentrations as low as 100 ppb (188 ug/m3). These findings are also supported by two meta-analyses. There are some suggestions that individuals with COPD also exhibit enhanced susceptibility to the effects of NO2, although this has only been explored in a limited number of studies and findings were inconsistent. The studies of clinical indicators of response are supported by numerous studies demonstrating associations between NO2 exposure and production of a (sub-clinical) enhanced inflammatory response. None of the studies of biochemical and cytological markers were conducted at exposures below those of the studies with lung function or bronchial responsiveness as endpoints. Therefore it is not possible to determine whether sub-clinical responses are measurable at even lower levels of exposure. Despite the inability of others to reproduce their findings, Orehek and colleagues [1976] found that 13 of 20 asthmatic volunteers were prone to increased airway responsiveness after a 1-hour exposure to 188 ug/m3 (100 ppb) NO2. Considering the variable degree of respiratory impairment between asthmatic subjects and the consequent variability in responses to NO2, the more consistent findings of effects at 300 ppb (564 ug/m3) and the evidence of responses in at least some study subjects to 1-hour exposures of 188 ug/m3  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  29  (100 ppb), a concentration of 200 ug/m3 (106 ppb) is suggested as an acute exposure LOAEL. This level is consistent with the WHO Air Quality Guideline of 200 ug/m3 (1 hour) and only slightly lower than the 1-hour ambient quality standard for Australia (229 ug/m3). The recommended LOAEL is somewhat lower than the Canadian 1-hour Maximum Acceptable Ambient Air Quality Guideline value of 400 ug/m3 (212 ppb) and the California 1-hour of standard of 480 ug/m3 (255 ppb). There is no short-term NO2 ambient air quality standard for the U.S.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  30  4 SULFUR DIOXIDE (SO2) 4.1 Properties and Sources Information in this section has been drawn from the following sources: Agency for Toxic Substances and Disease Registry (ATSDR). “Toxicological Profile for Sulfur Dioxide”, http://www.atsdr.cdc.gov/toxprofiles/tp116.html. [2002] ChemInfo. “Sulfur Dioxide” ChemInfo Record #714, http://ccinfoweb.ccohs.ca/cheminfo. [2002]  Sulfur dioxide is a colourless gas with a pungent, irritating odour characteristic of burning sulfur. This very reactive weak acid exists as a gas at normal ambient temperatures and pressures. It exists as a colourless liquid below -10°C. Contact with water forms sulfurous acid. The pH of an aqueous solution is slightly acidic. Certain metals and organic substances glow, burn or explode in SO2 atmospheres. Table 4.1 summarizes the physical and chemical properties of this compound. Table 4.1 Summary of the Chemical and Physical Properties of Sulfur Dioxide PROPERTY CAS #  7446-09-5  Synonyms  bisulfite; sulfur oxide; sulfurous oxide; sulfurous acid anhydride; sulfurous anhydride  Molecular Formula  SO2  Structural Formula  O=S=O  Molecular Weight Air Concentration Units Conversion Colour  64.06 g/mol 3  1 mg/m = 0.38 ppm at 101.3 kPa Colourless in both liquid and gaseous forms.  Odour  Pungent, irritating odour, similar to burning sulfur. Odour thresholds of 0.1-5 ppm have been reported.  Melting Point  -72.2°C at 101.3 kPa  Boiling Point  -10.0°C at 101.3 kPa  Critical Temperature  157.6°C  Vapour Pressure  339 kPa at 21.1°C  Vapour Density  2.26 (air = 1)  Specific Gravity  Liquid: 1.43 at 0°C (water = 1)  Solubility in Water  Very soluble in water (11.28 g/100 mL at 20°C). Rapidly converted to sulfurous acid (H2SO3), which is a dibasic acid with pH less than 3.  Solubility in Other Liquids  Acetone and other ketones, methanol, ethanol, acetic acid, diethyl ether, chloroform and sulfuric acid.  Stability  Extremely stable in heat – up to 2000°C. Complex reactions of SO2 occur in the atmosphere.  Flammability  Does not burn.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  31  4.1.1  Sources of SO2  The average atmospheric residence time for SO2 is 1-5 days. Ambient air concentrations of SO2 range from 1-5 ug/m3 in remote areas to 400 ug/m3 in polluted urban areas. Volcanoes and geysers are sporadic but possibly significant natural sources of SO2. It is also thought that hydrogen sulfide from the natural decay of vegetation on land and in the oceans is oxidized to SO2 within hours. Most of the sulfur in fossil fuel is converted into SO2 during combustion, and fossil fuel combustion accounts for the greatest proportion of anthropogenic releases globally. Petroleum refining, metal smelting, paper manufacturing and the fabrication of rubber products are other major anthropogenic sources. Unvented kerosene space heaters and coal burning are significant indoor sources of SO2. Atmospheric SO2 can be oxidized photochemically or catalytically to SO3 then react with water vapour to form sulphuric acid (H2SO4). Other substances can react with sulfate ions to form salts which are washed out by rain. Although wet deposition is a significant route of removal from the atmosphere, direct surface uptake of SO2 is the most significant removal process. The global sulfur cycle involves an atmospheric flux of 140-350 x 106 tons per year, approximately 40-60 x 106 tons of which are from anthropogenic sources in the form of SO2, sulfuric acid and sulfate. In the US, 65% of anthropogenic emissions are from coal combustion, and 13% are from oil combustion. 4.2 Toxicologic Characteristics Section 4.5 reviews the large number of clinical experiments which have exposed human volunteers to sulfur dioxide. As for NO2, human exposure trials are considered more relevant to human health outcomes than animal studies, therefore the toxicology literature is only briefly summarized here using the following reviews as a basis. Amdur, MO (1986). Air Pollutants. In: Klaassen, CD, Amdur, MO & Doull J (eds). rd Casarett and Doull’s Toxicology: The Basic Science of Poisons (3 edition). New York, NY: Macmillan Publishing Company, 801-824. ATSDR – Agency for Toxic Substances and Disease Registry (1997) Toxicological Profile for Sulfur Dioxide. Available from: http://www.atsdr.cdc.gov/toxprofiles/tp116.html; Accessed October 2002. Lippmann, M (2000). Sulfur Oxides: Acidid Aerosols and SO2. In: Lippmann M (ed). nd Environmental Toxicants (2 edition). New York, NY: Wiley-Interscience, 771-809. Petruzzi, S, Musi, B & Bignami, G (1994). Acute and chronic sulphur dioxide exposure: an overview of its effects on humans and laboratory animals. Annali dell Istituto Superiore di Sanita 30 (2): 151-156. Schlensinger, RB (1999). Toxicology of Sulfur Oxides. In: Holgate, ST, Samet, JM et al. (eds). Air Pollution and Health. San Diego, CA: Academic Press, 585-602.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  32  Once again, emphasis has been placed on the results of experimental animal studies conducted at exposure concentrations considered to be most relevant to human populations, 5 ppm (13,000 ug/m3) or less. 4.2.1  Absorption and Biochemistry  The ready solubility of sulfur dioxide in water forms the basis for its physiological and toxicological effects. Gaseous SO2 dissolves in fluids found in the upper respiratory tract to form bisulfite, sulfite, and hydrogen ions that are quickly absorbed by the blood and distributed throughout the body. Studies have shown that the efficiency of this process is affected by the concentration of inhaled SO2, where high concentrations (≥ 100 ppm) result in absorption of ≥ 90% of the pollutant, and low concentrations (≤ 2 ppm) result in 5-40% absorption. Inspiratory rate and route of inhalation further affect efficiency such that exercising individuals engaged in oronasal breathing absorb more SO2 (≥ 80%) than those at rest. Once absorbed, sulfite ions in the blood can be oxidized to sulfates and excreted in the urine, or they can react with proteins to form S-sulfonate, which has been found at elevated levels in the plasma and aorta of SO2-exposed experimental animals. The biochemical significance of these findings is not yet understood, but they provide evidence for the possibility of toxicological effects in non-pulmonary target organs. Once absorbed, bisulfite ions in the blood might be responsible for inducing the bronchoconstriction generally associated with sulfur dioxide exposure. By disrupting the disulfude bonds present in tissue proteins, bisulfite may lead to the alteration of neurotransmitter receptors and the subsequent contraction of smooth muscle tissue in the lungs. 4.2.2  Pulmonary Effects  The primary physiological response to sulfur dioxide exposure is bronchial constriction leading to increased airway resistance and decreased pulmonary function. Acute exposures to SO2 at concentrations greater than 1 ppm (2630 ug/m3) have led to increased airway resistance (8.5-150%) in resting laboratory animals, while effects in exercising animals have been seen at concentrations as low as 0.5 ppm. No significant increases in airway resistance have been reported for animals chronically (> 26 weeks) exposed to sulfur dioxide concentrations between 0.13-5.7 ppm (340-15,000 ug/m3). This result appears to be congruent with the rapid recovery of pulmonary function reported in studies of acute exposure. On the other hand, chronic exposure in the same range of concentrations has resulted in significant thickening of the tracheal mucous layer, which dampens the effect of ciliary beating and slows mucociliary clearance. Removal of foreign materials from the respiratory tract becomes less efficient as a result, and the primary defence against inhaled infectious agents is compromised. These symptoms, similar to those of chronic  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  33  bronchitis in humans, faded over a period of 1 to 3 months after the discontinuation of exposure. As with nitrogen dioxide, SO2 has been shown to disrupt the structure and function of the cilia and of alveolar macrophages. These effects have only been seen in animals at concentrations significantly higher than those generally associated with ambient air pollution (> 5 ppm), and are not considered relevant to this review. However, it should be noted that humans with hyperreactive airway conditions are known to be much more sensitive to the effects of SO2 than those with normal lung function, and that animal study results may need to be considered in a different light when extrapolated to sensitive populations. 4.2.3  Immune Response  The literature investigating how SO2 affects the immune response of exposed individuals is limited. Significant depression of antibody production has been observed at concentrations of 5 ppm (13,150 ug/m3) and greater, but not at concentrations of 0.5 ppm (1,300 ug/m3) or less. It is important to note that these results may be linked to the doseabsorption relationship discussed above, and that absorption efficiency may have some impact the magnitude of the immune response. 4.2.4  Other Effects  The oxidative effects of sulfur dioxide on red blood cells have been demonstrated in numerous animal studies. Reduced erythrocyte flexibility has been associated with SO2 concentrations ranging from 0.9-10 ppm (2400-26300 ug/m3), which can lead to increased fragility and decreased lifespan of mature cells. Although the experimental results of well designed studies have been consistent, further study is needed to understand the health implications of this outcome. Very few studies have investigated the carcinogenicity of sulfur dioxide in animals and, due to poor study design, the results have been inconclusive. Chronic exposure to concentrations of 500 ppm (1,300 mg/m3) and greater have been associated with increased incidence of lung tumours, but small study populations bring the statistical significance of the results into question. There is no evidence to support the possible carcinogenicity of SO2 at ambient concentrations, and the International Agency for Research on Cancer (IARC) has placed it in Group 3: Unclassifiable as to carcinogenicity to humans. 4.3 Indoor Exposure to SO2 4.3.1  Overview of Studies  Table 4.2 (located at the end of this report) summarizes the results of 14 studies reporting concentrations of SO2 in non-industrial indoor conditions. All reported results of area Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  34  (stationary) sampling; none reported personal exposure monitoring. Most included measurements made inside and outside homes [Biersteker et al., 1965; Spengler et al., 1979; Stock et al., 1985; Méranger and Brulé, 1987; Yuhui et al., 1991; Lee et al., 1997; Bailie et al., 1999; Sanyal and Maduna 2000; Chao, 2001; Kiendzierski and Sembaluk, 2001], including an army tent [Zhou and Cheng, 2000], and a few included measurements in offices and public places such as recreation or entertainment facilities and shopping malls [Spengler et al., 1979; Kulkadia and Palmer 1998; Camuffo et al., 1999; Lee et al., 1999]. Although the studies spanned the years 1964 to 1998, all but 5 were conducted in the last 10 years. Four studies were conducted in China (including three in Hong Kong), two in South Africa, three in Europe (Britain, Italy and the Netherlands), and five in North America (three in the US and two in Canada). 4.3.2  SO2 Concentrations Indoors  Concentrations of SO2 were reported in various units: mg/m3, ug/m3, ppm (or uL/L), and ppb (or nL/L). In Table 4.2, these are listed as reported in the articles, but in this discussion, to facilitate comparisons, all measurements are converted to ug/m3. The concentrations reported in the South African studies were extremely high, with mean levels in the range of 9,500 to 60,000 ug/m3 in living and cooking areas of very low to middle income homes [Sayal and Maduna, 2000], and of 1,400 ug/m3 in homes with no chimneys [Bailie et al., 1999]. The only other study reporting such high levels was an experiment conducted in an army tent, attempting to simulate living conditions of US Gulf War soldiers [Zhou and Cheng, 2000]. Here the highest levels measured were about 4,000 ug/m3 with tent flaps closed and after several hours of burning kerosene or jet fuel in convection heaters. Two other studies reported indoor concentrations over 100 ug/m3. A study in eastern China in 1987-8 measured high levels in kitchens using coal as fuel (71 to 860 ug/m3) and in some kitchens using gas in the winter time (65 to 163 ug/m3) [Yuhui et al., 1991] . In a study in the Netherlands in 1964 where coal and high-sulfur gas was used for heating some homes, seven of 60 homes had average concentrations greater than 100 (up to 246 ug/m3) [Biersteker et al., 1965]. In the remaining studies, mean indoor SO2 concentrations ranged from 0.5 to 32 ug/m3, over the most recent 20 years and throughout locations in North America, Europe and Asia [Spengler et al., 1979; Stock et al., 1985; Méranger and Brulé, 1987; Lee et al., 1997; Kulkadia and Palmer 1998; Camuffo et al., 1999; Lee et al., 1999; Chao, 2001; Kiendzierski and Sembaluk, 2001]. North American studies are the most relevant to the Canadian situation because of the common heating methods (usually central heating using gas or oil furnaces and water or forced-air heat circulation) and cooking practices (usually electric, with some gas, usually vented) used in this area of the world. Spengler et al. [1979] reported results from about 60 locations in 6 eastern to mid-western US cities, taken over a one-year period. Indoor levels ranged from “zero” to 26 ug/m3, generally following the pattern of concentrations outdoors in these locales. Stock et al. [1985] measured SO2 concentrations in 12 houses, and found an average of 5.1 ug/m3 (standard deviation = 5.3). Méranger and Brulé [1987] Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  35  studied the effects of outdoor air on indoor air quality in one house in central Antigonish, Nova Scotia. Levels indoors were usually less than 10 ug/m3, with an average of about 8 ug/m3 over the 8 weeks of sampling. Indoor SO2 did not appear to correlate with outdoor sulphate episodes. In the most recent study, Kendzierski and Sembaluk [2001] studied indoor SO2 levels in one urban and one rural Alberta community in winter and summer. Indoor concentrations of SO2 ranged from 0.2 to 2.3 ug/m3 in the rural community and from 0.9 to 5.2 ug/m3 in the urban community, reflecting the relative levels of outdoor concentrations. 4.3.3  Factors Associated with SO2 Indoors  Many of the studies compared SO2 concentrations indoors and outdoors. Most found that indoor levels were lower than levels outdoors, with indoor:outdoor ratios ranging from about 0.1 to 0.9 [Biersteker et al., 1965; Spengler et al., 1979; Méranger and Brulé, 1987; Lee et al., 1997; Kulkadia and Palmer 1998; Camuffo et al., 1999; Lee et al., 1999; Kiendzierski and Sembaluk, 2001]. Four studies found situations in which indoor levels were higher, though the average indoor:outdoor ratios were all below 1.8 and most were still below 1 [Biersteker et al., 1965; Stock et al., 1985; Lee et al., 1999; Chao, 2001]. Results of several studies suggested that indoor concentrations tracked outdoor concentrations, but with lower levels indoors, suggesting that a source of indoor exposure is outdoor pollution and that materials indoors act as a sink for the gas [Biersteker et al., 1965; Spengler et al., 1979; Kiendzierski and Sembaluk, 2001]. Only one study conducted inferential analyses of the factors related to indoor SO2 levels. Biersteker et al. [1965] used multiple regression to examine potential determinants of exposure. They found that concentrations increased in older homes, with oil, coal and gas heating (in increasing order), with increasing smoking in the home, and with increasing SO2 outdoors. Only the first factor was statistically significant. The descriptive statistics reported in other studies are suggestive. Coal heating and cooking appear to be associated with increased SO2 [Yuhui et al., 1991]. Lack of venting of cooking and heating sources appears to increase concentrations [Biersteker et al., 1965; Bailie et al., 1999; Zhou and Cheng, 2000]. Similarly, season may affect indoor levels. In the winter, when windows are closed and use of heaters increases, higher indoor levels were measured [Yuhui et al., 1991; Sanyal and Maduna, 2000]. In one South African study, SO2 levels increased with decreasing socio-economic status [Sanyal and Maduna, 2000]. 4.3.4  Factors Associated with SO2 Outdoors  Given that indoor levels appeared to be associated with outdoor levels in these studies, it is useful to consider potential sources of outdoor sulfur dioxide. Note that the literature on outdoor sources was not independently reviewed; these observations are drawn from the indoor studies reported here.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  36  The highest outdoor SO2 concentrations reported were measured in European cities: from 73 to 384 ug/m3 in Rotterdam in 1964 [Biersteker et al., 1965]; and from 52 to 105 ug/m3 in Venice in 1996 [Camuffo et al., 1999]. Two cities (Steubenville, Ohio and St. Louis, Missouri) in the US six-cities study had levels in the range of 28 to 60 ug/m3 [Spengler et al., 1979]. Other studies in Canada, the US, UK, and Hong Kong reported levels ranging from “zero” to 30 ug/m3 [Spengler et al., 1979; Stock et al., 1985; Méranger and Brulé, 1987; Lee, 1997; Kukadia and Palmer, 1998; Lee et al., 1999; Chao, 2001; Kindzierski and Sembaluk, 2001]. Three studies measured outdoor levels in urban and rural areas of the same country [Spengler et al., 1979; Lee et al., 1999; Kendzierski and Sembaluk, 2001]. All found that more densely populated urban areas had higher outdoor SO2 levels. Industrial, home heating, and vehicular traffic emissions are potential sources related to population density. Chao [2001] reported that ambient levels in Hong Kong have been reduced considerably since the introduction of government restrictions on sulfur content in fuel. 4.3.5  Limitations  Surprisingly few studies have examined SO2 concentrations in indoor air, perhaps because non-industrial indoor levels are usually (though not always) lower than ambient concentrations outdoors. Studies conducted to date have used a wide array of sampling and analytical methods; the comparability of these methods is difficult to assess, since many of the reports describe the methods used very briefly and without reference to standard quality assurance techniques, including limits of detection, calibration, and use of blanks. Some of the studies collected an impressive number of samples under widely varying conditions (e.g., different seasons, building types, population densities, heating types, socioeconomic conditions, and levels of tobacco smoking) and collected descriptive information about these conditions [Biersteker et al., 1965; Spengler et al., 1979; Yuhui et al., 1991; Lee et al., 1997; Bailie et al., 1999; Sanyal and Maduna 2000; Chao, 2001; Kiendzierski and Sembaluk, 2001]. Unfortunately, only the earliest study [Biersteker et al., 1965] included inferential analyses to allow reasonable confidence in the interpretation of which factors influence SO2 concentrations after adjusting for other potential determinants. 4.4 Epidemiological Studies of Populations Exposed to SO2 4.4.1  Overview of Studies  No epidemiological studies of the effects of non-industrial indoor exposures to SO2 were found. Our review therefore focussed on two groups of epidemiological investigations:  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  37  ß  Studies of employees at work sites where SO2 was identified as a major contaminant, and where exposure measurements were available.  ß  Studies of populations exposed to ambient air pollution, also where exposure measurements were available. This category was further limited to exclude studies in which the air pollution was likely to include a wide array of other co-pollutants (e.g., typical urban air pollution from vehicle traffic), since the levels of these pollutants tend to be highly correlated, making it difficult or impossible to distinguish the independent effects of SO2 [Moolgavkov and Luebeck, 1996]. We limited the review to studies of ambient air pollution in which special sources of SO2 were identified.  Twenty epidemiological studies which met the above criteria were identified. Fifteen focused on SO2-exposed populations in occupational settings including copper, lead and nickel smelters, pulp mills, sulfuric acid plants, a refrigerator manufacturer, a power station, a silicon carbide plant, an aluminum foundry, and a fertilizer factory [Kehoe et al., 1932; Skalpe, 1964; Ferris et al., 1967; Smith et al., 1977; Archer and Gillam, 1978; Lebowitz et al., 1979; Sorsa et al., 1982; Kangas et al., 1984; Rom et al., 1986; Englander et al., 1988; Broder et al., 1989; Osterman et al., 1989; Meng and Zhang, 1990; Yadav and Kaushik, 1996; Froom et al., 1998]. Five studies investigated populations exposed to ambient SO2, one in a city in which high sulfur coal was the predominant energy source and the others in areas with point sources – including an active volcano and metal smelters [Dodge et al., 1985; Donaghue and Thomas, 1999; Shinkura et al., 1999; Wang et al., 1999; Smith-Sivertsen et al., 2001]. Most of the studies focussed on respiratory health [Kehoe et al., 1932; Skalpe, 1964; Ferris et al., 1967; Smith et al., 1977; Archer and Gillam, 1978; Lebowitz et al., 1979; Kangas et al., 1984; Dodge et al., 1985; Rom et al., 1986; Englander et al., 1988; Broder et al., 1989; Osterman et al., 1989; Froom et al., 1998; Donaghue and Thomas, 1999; Wang et al., 1999; Smith-Sivertsen et al., 2001]. A few examined other health outcomes, including absenteeism, cardiovascular and neurological symptoms, all cause and cancer mortality, neonatal mortality, and genotoxicity [Sorsa et al., 1982; Kangas et al., 1984; Englander et al., 1988; Meng and Zhang, 1990; Yadav and Kaushik, 1996; Shinkura et al., 1999]. 4.4.2  Studies of Respiratory Symptoms, Lung Function and Other Respiratory Outcomes  Table 4.3 (located at the end of this report) summarizes the results of epidemiological studies examining respiratory health in relation to sulfur dioxide exposure. Most were cross-sectional in design, and examined respiratory symptoms using standardized questionnaires and lung function measurements, usually including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). This group of studies will be discussed first. The first published account of the effects of SO2 exposure included interviews and physical examinations of 100 refrigerator manufacturing workers who used the gas as a Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  38  refrigerant and were exposed to very high concentrations: 10 to 100 ppm (26,300 to 263,000 ug/m3) [Kehoe et al., 1932]. In comparison to 100 controls of similar age from other areas of the same plant, these men experienced more pharyngitis, tonsillitis, dyspnea on exertion, increased sensitivity to other irritants, fatigue, abnormal reflexes, and altered senses of smell and taste. Four studies examined copper smelter employees. In a cross-sectional study, Archer and Gillam [1978] compared 953 smelter workers exposed to 0.4 to 3 ppm SO2 (1,000 to 6,000 ug/m3) as well as low concentrations of arsenic, copper, manganese and iron, to 262 employees of the nearby mine truck maintenance shop. They found higher frequencies of cough, phlegm, dyspnea, chest tightness, and chronic bronchitis. FVC and FEV1 were significantly lower in the exposed group, an effect that increased with duration of exposure, after controlling for smoking. Early retirements were also twice as frequent in the smelter group, suggesting that employees with respiratory difficulties selfselected out of exposure. Lebowitz et al. [1979] examined 430 smelter employees ranked according to differing levels of SO2 (from less than 2.5 ppm to more than 5 ppm) and dust exposure. They found a slight increase in chronic obstructive pulmonary disease among highly SO2-exposed smokers, and reductions in FEV1 (compared to earlier spirometry results) related to exposure among those with less than 20 years in the plant, but no other appreciable differences in lung function among exposed employees.. Smith et al. [1977] and Rom et al. [1986] reported on changes in pulmonary function among workers in the same Utah copper smelter. The first study included repeated lung function testing of 113 employees in 1973 and 1974, the second followed a subset of 66 and 48 of the first study’s subjects in 1980 and 1983, respectively. The earlier study measured personal exposures of the subjects, and found levels in the most exposed group ranging from 1.6 to 45 ppm (4,208 to 118,000 ug/m3). A decline in FEV1 and in FEV1/FVC ratio was associated with exposures greater than 1 ppm SO2, which remained after controlling for respirable dust exposures. The later study did not include personal monitoring, but reported exposure data from company records in the intervening time period of 0.1 to 6.5 ppm (262 to 17,000 ug/m3). Workers who were exposed to greater than 1 ppm SO2 in 1973-74 as well as workers whose initial FEV1 was less than 90% predicted displayed improvements in lung function in 1980. No accelerated decline in lung function was observed between 1980 and 1983. Rom et al. [1986] attributed the differences in results to short expiratory times in the original pulmonary function tests. In another smelter study, in Sudbury, Broder et al. [1989] compared lung function and respiratory symptoms of 143 nickel smelter workers and 117 civic labourers. Smelter workers’ exposures to SO2 were 40 times those of the controls, averaging 0.67 ppm (1,750 ug/m3), based on personal measurements of study subjects. They were also exposed to metal fumes, including iron, nickel and copper. Smelter employees reported a history of pneumonia more frequently than controls, and had decreased FEV1 and forced expiratory flow rates at 50% and 75% of vital capacity, however these decrements were no longer significant after adjusting for age, height, smoking status, duration of employment, and mask wearing (the latter adjustment factor was associated with exposure). Civic workers, 19% of whom were former smelter workers, had more Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  39  shortness of breath. The investigators concluded that there was little evidence of chronic effects of SO2 exposure, but cautioned that based on data about prior employees, the smelter workers studied may constitute healthy workers able to remain in the job. Three studies examine pulp and paper workers. Skalpe [1964] examined 54 workers from 4 Norwegian pulp mills, exposed to SO2 at levels between 2 and 36 ppm (5,200 – 94,000 ug/m3), and 56 unexposed controls who worked in a local paper mill. The pulp mill workers reported more cough, expectoration and dyspnea on exertion than controls, especially among those younger than 50. Maximal expiratory flow rate was lower among exposed workers under age 50, nut not in older employees. There were no differences in vital capacity between the groups. In a similar study in the US, Ferris et al. [1967] compared 147 pulp mill workers (some exposed to chlorine and some to SO2) to 124 paper mill workers. SO2 levels ranged from the limit of detection of 4 ppm to 31 ppm (10,500 to 81,300 ug/m3). Pulp mill workers had slightly higher rates of obstructive lung disease, but not of chronic bronchitis. Pulp mill workers who were smokers had higher rates of lung disease than paper workers who smoked. The investigators noted that many of the paper mill workers had previously worked in the pulp department, but had transferred to avoid the pulp mill exposures. Kangas et al. [1984] conducted a crosssectional study of 162 Finnish pulp mill employees, with estimated exposures from 0.07 to 7.4 ppm (180 to 19,400 ug/m3). No differences in respiratory symptoms were reported by workers considered exposed to organic and inorganic sulfides. Osterman et al. [1989] studied respiratory symptoms in 145 Quebec silicon carbide plant workers with 3 to 41 years of employment, and with average exposures to SO2 of 0.12 ppm (315 ug/m3), with levels as high as 1.5 ppm (3,900 ug/m3). Employees were also exposed to respirable silica, carbon monoxide, and polycyclic aromatic hydrocarbons. Employees were assigned quantitative measures of cumulative exposure and exposure intensity to dust and SO2, based on measurements in each job. Phlegm, wheeze, and dyspnea increased with increasing SO2, but not dust, exposure (cumulative and average intensity), after controlling for age and current smoking. A synergistic effect of smoking and SO2 exposure was observed for most symptoms. Froom et al. [1998] conducted a cross-sectional study of 72 power station employees. About half were exposed to SO2, with concentrations from “zero” to 15 ppm (0 to 39,000 ug/m3) with an average of 0.7 ppm (1,800 ug/m3), and half were not exposed, because the burning chamber they worked with was under negative pressure. Cough, sputum and shortness of breath were elevated in the exposed group, and those with dyspnea had significant decrements in FEV1, FVC, and expiratory flow rates. However, there were no differences in pulmonary function overall between the exposed and unexposed workers. There appeared to be a synergistic effect on cough of smoking and SO2 exposure. Three of the cross-sectional studies were large studies of residents of areas with high levels of ambient SO2. Wang et al. [1999] studied 420 men and 676 women (all nonsmokers and non-coal users) in China’s largest city, Chongqing. Mean urban SO2 levels were 0.08 ppm (213 ug/m3). High sulfur coal was the main fuel used in the city’s industries and homes. Rural SO2 levels in the region were about half the urban levels at Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  40  0.04 ppm (103 ug/m3). Though particulate levels were also high, there was little difference between urban and rural concentrations. FVC, FEV1, and FEV1/FVC ratio were significantly reduced in subjects living within one km of the two urban air monitoring stations, compared to those living within the same radius of the rural station. The differences remained after removing those with occupational exposures from the analysis. More recently, Smith-Sivertsen et al. [2001] examined lung function and respiratory symptoms in about 1,600 residents of a nickel smelter town in Russia, and of 3,400 residents of a nearby Norwegian town. Monthly average PM10 particulate levels were less than 0.008 ppm (20 ug/m3) in both places. Monthly average SO2 levels were less than 20 ug/m3 in the Norwegian town, but from 0.008 to 0.06 ppm (20 to 150 ug/m3) in the Russian town. No differences in lung function were observed with ambient exposures to SO2 on the day before or the day of screening. Russian subjects reported exposureassociated persistent cough and phlegm, but the analysis did not control for cigarette smoking (which was also somewhat associated with exposure) or employment at the smelter (~11% of male subjects and ~3% of females). Dodge et al. [1985] conducted repeated measurements 3 years apart of 678 3rd to 5th grade children living in areas near an Arizona smelter town with varying mean ambient SO2 levels: from a low of less than 0.002 ppm (< 4 ug/m3) to a high of 0.04 ppm (103 ug/m3). Cough prevalence was significantly associated with SO2 concentration, but no other respiratory symptoms or lung function measures were related to exposure. Two studies examined respiratory effects other than lung function and respiratory symptoms. Englander et al. [1988] conducted a small retrospective cohort study of 400 sulfuric acid factory workers followed for up to 24 years. This study found an excess of respiratory cancers (5 observed compared to 2.5 expected, p = 0.11), but no increase in non-malignant respiratory disease. The median SO2 concentration in the breathing zone of the workers was estimated to be 1.4 ppm (3,600 ug/m3). Donoghue and Thomas [1999] conducted a time series analysis of presentations and admissions to hospital for asthma-related complaints in a small Australian city with copper and lead smelters. No association with peak SO2 exposures measured at any of the 10 monitoring stations, and ranging from “zero” to 3.3 ppm (8,700 ug/m3), was detected. The effects of other pollutants (particulates, metals, ozone, and nitrogen oxides) were not examined. 4.4.3  Studies of Other Health Outcomes  Most of the five studies which examined other health effects of SO2 investigated different effects, so do not form a body of evidence about any of the outcomes. A summary of the studies is presented in Table 4.4 (located at the end of this report). The following presents a brief outline of each study, in order of their appearance in the table.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  41  In their cross-sectional study of 162 Finnish pulp mill employees, Kangas et al. [1984] found that workers considered exposed to organic and inorganic sulfides reported significantly more headaches and had a greater number of sick leaves in the previous year. Self-reported neurological symptoms and difficulty in concentrating were also elevated in the exposed group, though not significantly so. There were no differences in cardiovascular symptoms reported. SO2 exposures of pulp mill workers measured by these investigators ranged from 0.07 to 7.4 ppm (180 – 19,400 ug/m3); measurements of hydrogen sulfide and mercaptans were also reported, but not other pulp mill exposures. In the retrospective cohort study of 400 sulfuric acid factory workers by Englander et al. [1988], standardized mortality ratios (based on local rates in their Swedish county) showed excess overall mortality. The excesses were primarily due to deaths from violence and intoxication, gastrointestinal illnesses, and cardiovascular diseases. There was also a significant excess of bladder tumours, but not other cancers. The observed excesses did not appear to be related to duration of employment. The study had very low power to examine any but the most common causes of death, or to examine subgroups. The median SO2 concentration was 1.4 ppm (3,600 ug/m3). Meng and Zhang [1990] also studied sulphuric acid factory workers, in Taiyuan City, China. They examined chromosomal abberations and sister-chromatid exchanges in 40 plant employees, exposed to 0.13 to 4.6 ppm (340 to 11,970 ug/m3) SO2, and in 42 controls from Shanxi University, matched on age, sex, and smoking habits. Both markers were significantly elevated in the exposed workers, including all types of chromosomal aberrations. The increases were not associated with increasing duration of employment in the factory. Yadav and Kaushik [1996] conducted a similar cross-sectional study of 42 fertilizer factory workers, compared to 42 unexposed controls with unspecified employment. The fertilizer plant employees were exposed to average SO2 concentrations of 16 ppm (41,700 ug/m3) for up to 20 years. This group had significantly increased levels of all the markers of genotoxicity studied, including chromosomal aberrations, sister chromatid exchanges, satellite association, and mitotic index. Chromosomal aberrations and sister chromatid exchanges increased with exposure duration, but mitotic index decreased. The markers were also related to smoking and alcohol consumption. Although these lifestyle factors were a basis for matching, there were more smokers and fewer drinkers in the factory employee group. Sorsa et al. [1982] did not find any differences in the frequency of chromosomal aberrations or sister chromatid exchanges among 8 aluminum foundry workers exposed to lower concentrations of SO2, 0.2 to 3 ppm (500 to 7,900 ug/m3), in comparison to 8 clerks of similar age. Shinkura et al. [1999] examined neonatal mortality in the first 28 days of life among all live births (~ 30,000) in a 10-year period in the health region near Mt. Sakurajima, one of the most active volcanoes in the world. Mortality rate was positively associated with average SO2 concentrations in the month after birth, but not with ash, particulate or maximum hourly SO2 concentrations. Pollutant levels were measured at a single ambient monitoring station and were very low in comparison to industrial levels or levels in some polluted cities, averaging 0.01 ppm (26 ug/m3). Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  42  4.4.4  Limitations  The advantage of epidemiological studies is their potential to measure health effects in subjects who span a range of ages and susceptibilities, and who are exposed over a period of time in actual living or working conditions. Unfortunately, the shortcomings described below mean that the epidemiological data about SO2 can only support limited conclusions for standard setting purposes. There was a paucity of epidemiological studies of the health effects of sulfur dioxide which met our inclusion criteria. The only studies which examined similar outcomes, thus allowing consideration of the weight of evidence, were cross-sectional studies of respiratory disease symptoms and lung function. Cross-sectional studies are the weakest epidemiological study design, because of the difficulty of determining the temporal relationship between exposure and disease. Those with longitudinal follow-up have the opportunity to examine changes over time, but none of the studies reported here quantitatively addressed the issue of the healthy worker effect by tracing and testing those who left employment in the intervening period. Most of the cross-sectional studies, and the retrospective cohort study, had small study populations, precluding effective analyses by exposure subgroups. Most of the studies reviewed were conducted in occupational workforces in industrial settings. Most of these studies were conducted among male adults in North American and European communities likely to have baseline health status similar to such populations in Canada. However, it is known that such work groups are likely to be healthier than the population at large, which includes both children and the elderly outside of the working age range, as well as less healthy individuals either unable to work altogether, or unsuitable for industrial employment. Most of the occupational studies reported here involved exposures 10 to 100-fold higher than indoor non-industrial exposures in North America (in exposure studies, the latter ranged from about 0.2 to 30 ug/m3). The exposures in community-based epidemiological studies had SO2 levels closer to those indoors in North America, though still about 3 to 7-fold higher. Unfortunately two of these were conducted in countries where baseline health status may not be comparables to Canada’s, i.e., China and Russia. To meet our inclusion criteria, epidemiological studies had to use measurements to assign subjects’ exposures. Only a few of the studies (all occupational) included subject-specific measurements. Other occupational studies reported work site measurements which were used to crudely classify workers as exposed or unexposed. Studies of populations exposed to SO2 air pollution always used data from ambient monitoring stations to classify exposures of subjects or time periods. Most of the studies grouped subjects into two groups, one less exposed than the other. Without health outcome data over a range of exposure levels, it is difficult or impossible to ascertain an exposure level at which no effect is observed. Occupational studies tended to examine groups with exposures much higher than those expected in the indoor nonindustrial environment. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  43  Though we attempted to isolate the independent effects of SO2 by excluding air pollution studies in which exposures to co-pollutants were likely to be highly correlated, the communities of the air pollution studies included in the review still had other potential exposures. In addition, most of the occupational studies were conducted in work sites where other important exposures are likely to occur, but many of these were not measured or accounted for in the analysis. In these cases it is difficult to determine whether observed outcomes are attributable to the independent effect of SO2, to other exposures, or to the joint effects of SO2 and the other agents. 4.5 Studies of Controlled Human Exposures to SO2 4.5.1  Overview of Studies  Sixty-two controlled human exposure studies were located; these are summarized in Table 4.5 (located at the end of this report). Of these, most (41) were published in the period from 1980 to 1989, with 14 published after 1989 and 7 prior to 1980. The vast majority (50) were conducted in North America. Ten studies were conducted in Europe and two in Asia. The majority of the studies involved exposing human subjects to specified concentrations of SO2 in an environmental chamber. Forty involved unencumbered breathing of test air, 21 involved breathing test air through a mouthpiece or facemask, and one study required subjects to breathe within a head dome. The studies reviewed were almost exclusively of the crossover design, i.e., subjects crossed from one exposure condition to another, so that they served as their own controls. The ages of subjects ranged from 12 to 73 years. Most of the studies focussed on nonsmoking adults, but five focussed on children under the age of 18, and two involved both adults and children. 41 studies included asthmatic subjects, including all five whose focus was children. Of the studies of asthmatics, 10 also included healthy and/or atopic subjects. One study involved healthy and atopic individuals, while 18 focussed on healthy subjects only. One study investigated individuals with chronic obstructive pulmonary disease (COPD), and one study did not provide a subject description. Outcomes of interest included spirometry parameters (such as FEV1, FVC, and expiratory flow rates), airway resistance, respiratory symptoms and various other measures of response. The concentrations of SO2 to which subjects were exposed ranged from 0.07 to 28 ppm (180 – 73,000 ug/m3). Four studies involved exposures above 5 ppm (13,000 ug/m3), 14 involved exposures between 1 and 5 ppm (2,600 and 13,000 ug/m3), 13 involved exposures up to 1 ppm, and a further 33 involved exposures of 0.75 ppm (2,000 ug/m3) or less. Durations of exposure ranged from 1 minute to 6 hours, but most (48) involved exposures lasting 1 hour or less.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  44  The following sections describe the results, first for adults, then for children. Studies of adults are further categorized by the health outcomes investigated and by the health status of the subjects. 4.5.2  Adults: Studies of Pulmonary Function  Thirty controlled exposure studies investigated pulmonary function effects of SO2 exposure using typical spirometric measures including FVC, FEV1, and expiratory flow rates [Speizer and Frank, 1966; Snell and Luchsinger, 1969; Wolff et al., 1975; Kreisman et al., 1976; Newhouse et al., 1978; Jaeger et al., 1979; von Neiding et al., 1979; Stacy et al., 1981; Linn et al., 1982, 1983a, 1983b, 1984b, 1985b, 1987, 1990; Kagawa, 1983; Bedi et al., 1984; Hackney et al., 1984; Kulle et al., 1984; Schachter et al., 1984; Folinsbee et al., 1985; Witek and Schachter, 1985; Rondinelli et al., 1987; Bedi and Horvath, 1989; Devalia et al., 1994; Heath et al., 1994; Gong et al., 1995; Nowak et al., 1997; Trenga et al., 1999; Tunnicliffe et al., 2001]. In studies of both healthy and asthmatic individuals, oral exposure was observed to have a greater effect on lung function than oronasal or nasal exposure [Snell and Luchsinger, 1969; Linn et al., 1983a]. Healthy Subjects 19 controlled exposure studies investigating effects of SO2 exposure on pulmonary function involved healthy adult subjects. Among these, eleven tested SO2 concentrations of 1 ppm or more, most with very small sample sizes of between 8 and 20 subjects. Three of these studies revealed no change in lung function (FEV1, FVC, expiratory flow rates, or functional residual capacity) following exposure to 1 or 2 ppm (2,600 or 5,200 ug/m3) SO2 with exposures and exercise for 30 minutes to 4 hours [Bedi et al., 1984; Kulle et al., 1984; Bedi and Horvath, 1989]. Newhouse et al. [1978] found small but statistically nonsignificant differences in FEV1 following 2-hour oral exposure to 5 ppm SO2 with intermittent exercise. von Neiding et al. [1979] measured small but non-significant decreases in respiratory gas exchange on exposure to 5 ppm SO2. A mouthpiece study of healthy older subjects (aged 55 to 73) exposed to 1 ppm SO2 revealed significant reductions in FEV1 following SO2 in combination with NaCl droplet aerosol as compared to exposure to NaCl droplet aerosol alone [Rondinelli et al., 1987]. Speizer and Frank [1966] found that exposures to 15 ppm (39,000 ug/m3) had inconsistent effects on functional residual capacity. Three studies showed significant changes in maximal expiratory flow rates after 5 minutes to 3 hours of at-rest exposure to 1 and 5 ppm SO2 [Snell and Luchsinger, 1969; Wolff et al., 1975; Kreisman et al., 1976]. Snell and Luchsinger [1969] identified a dose-response relationship between SO2 and MEF50, and found that changes in pulmonary function parameters following nasal exposure were smaller than those following oral exposure to SO2. In the one large study, Nowak et al. [1997] gave 3-minute exposures of 2 ppm SO2 via isocapnic hyperventilation to 790 subjects aged 22 to 44 years and found that 3.4% of subjects were hypersensitive to SO2 (i.e., the exposure resulted in FEV1 decrements of more than 20%). Of subjects who responded to methacholine, 22.4% were also hypersensitive to SO2.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  45  Eight controlled studies investigating pulmonary function parameters in healthy subjects involved exposures of 0.75 ppm (2,000 ug/m3) or less. Five of these studies reported no change in pulmonary function parameters (FVC, FEV1, expiratory flow rates) in response to SO2 concentrations of 0.75, 0.6, 0.5, 0.25, and 0.2 ppm SO2 [Jaeger et al., 1979; Stacy et al., 1981; Schachter et al., 1984; Linn et al., 1987; Tunnicliffe et al., 2001]. Three studies reported statistically non-significant SO2-induced impacts on lung function (FVC, FEV1, expiratory flow rates) [Snell and Luchsinger, 1969; Kreisman et al., 1976; Rondinelli et al., 1987]. Asthmatic Subjects In the 16 studies that examined asthmatic adults, effects were more pronounced than in healthy subjects and were evident at lower concentrations. In one mouthpiece study, 23 asthmatic subjects had non-significant decreases in FEV1, FVC, and peak expiratory flow rate in response to SO2 concentrations of 0.75 ppm (2,000 ug/m3) [Linn et al., 1983a]. In a similar study of 40 asthmatic subjects FEV1 decreased following oral exposure to SO2 concentrations ranging from 0.2 to 0.6 ppm (520 to 1,600 ug/m3), increasing with exposure level [Linn et al., 1987]. Jaeger et al. [1979] also found decreases in midmaximal expiratory flow in mouthpiece breathing asthmatics exposed to 0.5 ppm. Asthmatic subjects exposed to concentrations of 0.75 ppm or higher in an environmental chamber, with exercise for 10 minutes to 3 hours had significant decrements in expiratory flow and FEV1 [Hackney et al., 1984; Schachter et al., 1984; Witek and Schachter, 1985; Heath et al., 1994]. Two studies observed significant decrements in pulmonary function (FVC, FEV1, peak expiratory flow rate) at somewhat lower concentrations, 0.5 and 0.6 ppm (1,300 to 1,600 ug/m3) [Linn et al, 1983b; Trenga et al., 1999]. Gong et al. [1995] observed significant dose-response in FEV1 in asthmatic subjects with 10 minutes of heavy exercise over a concentration range from 0.5 to 1 ppm. Five studies involving adult asthmatics exposed to 0.1-0.25 ppm SO2 [Linn et al., 1982, 1983b, 1990: Devalia et al., 1994; Tunnicliffe et al., 2001], and 1 study of adults with COPD exposed to 0.4 ppm SO2 [Linn et al.., 1985b] revealed no changes in pulmonary function attributable to SO2. 4.5.3  Adults: Studies of Airway Resistance  Forty-two studies of adults used a body plethysmograph to achieve sensitive measures of changes in airway resistance over SO2 concentrations ranging from 0.1 to 28 ppm [Speizer and Frank, 1966; Snell and Luchsinger, 1969; von Neiding et al., 1979; Sheppard et al., 1980, 1981, 1983, 1984a, 1984b; Stacy et al., 1981; Linn et al., 1982, 1983a, 1983b, 1984a, 1984b, 1984c, 1985a, 1985b, 1987, 1990; Kirkpatrick et al., 1982; Bethel et al., 1983a, 1983b, 1984, 1985; Bedi et al., 1984; Hackney et al., 1984; Kulle et al., 1984; Schachter et al., 1984; Folinsbee et al., 1985; Roger et al., 1985; Horstman et al., 1986, 1988; Balmes et al., 1987; Kehrl et al., 1987; Rondinelli et al., 1987; Bedi and Horvath, 1989; Jorres and Magnussen, 1990; Magnussen et al., 1990; Islam et al., 1992;  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  46  Gong et al., 1995]. Because of the specialized equipment required for such studies, all were relatively small in size with 6 to 85 subjects (median = 14). Healthy Subjects In healthy subjects, airway resistance studies did not display a consistent pattern, though most often no changes in resistance were observed. Exposure of healthy, exercising adults up to 1 ppm in five studies, and 2 ppm in one study revealed no significant changes in airway resistance [Kulle et al., 1984; Schachter et al., 1984; Folinsbee et al., 1985; Linn et al., 1987; Rondinelli et al., 1987; Bedi and Horvath, 1989]. Studies of healthy subjects at rest revealed no change in pulmonary resistance after either a 10-minute exposure to 0.5 ppm or a 2-hour exposure to 5 ppm SO2 [von Neiding et al., 1979; Magnussen et al., 1990]. Other investigators found increases in resistance at SO2 concentrations similar to or lower than the previously cited group. A significant increase in airway resistance was seen following exposure of healthy adults to 1 ppm during exercise [Bedi et al., 1984]. Another study revealed significant changes in airway resistance after 2-hour exposures to 0.75 ppm SO2 during exercise [Stacy et al., 1981]. Airway resistance was also increased following mouthpiece exposures to 0.5 ppm, 5 ppm or 15 ppm SO2 at rest [Speizer and Frank, 1966; Snell and Luchsinger, 1969; Sheppard et al., 1980]. Exercising Asthmatic Subjects Of the 22 studies that examined airway resistance in exercising asthmatics, all but one revealed increases in airway resistance in association with exposure to SO2 concentrations ranging from 0.2 to 1 ppm and exposure durations ranging from 5 minutes to 6 hours [Sheppard et al., 1981; Kirkpatrick et al., 1982; Linn et al. 1983a., 1983b, 1984a, 1984b, 1984c, 1985a, 1987, 1990; Bethel et al. 1983a., 1983b, 1985; Schachter et al., 1984; Hackney et al., 1984; Roger et al., 1985; Horstman et al., 1986, 1988; Kehrl et al., 1987; Gong et al., 1995]. Twelve of these studies involved exposure to SO2 concentrations of 0.5 ppm or less. In one, exposure to 0.1 ppm SO2 for 10 minutes significantly increased airway resistance in the 2 most responsive subjects [Sheppard et al., 1981]. Numerous studies showed dose-response relationships between SO2 concentration and airway resistance [Linn et al., 1983b, 1984b, 1984c, 1987; Schachter et al., 1984; Horstman et al., 1986; Gong et al., 1995]. One study of asthmatics exercising intermittently found no variation in airway resistance with separate exposures to 0.25 and 0.5 ppm SO2 for 1 hour. [Linn et al., 1982] At-Rest Asthmatic Subjects Similar to studies of healthy adults, studies of asthmatics at-rest were not consistent. Some showed increased airway resistance with concentrations in the range of 0.5 to 1 ppm SO2 [Sheppard et al., 1980, 1984b; Balmes et al., 1987; Magnussen et al., 1990], but others did not [Sheppard et al., 1981; Bethel et al., 1984; Schachter et al., 1984]. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  47  Sheppard et al. [1980] found that in asthmatic individuals at rest, airway resistance increased after 10 minutes of exposure to 1 ppm SO2, with greater changes at concentrations of 5 ppm. Interestingly, two studies indicated that repeated exposure to SO2 over a short period induces tolerance to the bronchomotor effects of SO2 [Sheppard et al., 1983; Linn et al., 1984a]. The effect was seen in exposures separated by 30-minute intervals in one study and on successive days in the other. Duration of exposure was also observed to influence the impact of SO2 on airway resistance [Horstman et al., 1988]. At 1 ppm SO2, bronchoconstriction was significantly increased after 2- and 5-minute exposures, but not after exposures of shorter duration. Eucapnic Hyperventilation Four studies involving eucapnic hyperventilation of SO2 revealed increases in airway resistance at 0.5 ppm SO2 for 10-, 9- and 3-minute durations, and at 0.6 ppm SO2 for 5 minutes [Sheppard et al., 1981, 1983; Balmes et al., 1987; Islam et al., 1992]. Subjects were healthy and asthmatic adults and sample sizes ranged from 6 to 26 subjects. Temperature and Humidity Another study of eucapnic hyperventilation of SO2 revealed that dry, cold air increased the effect of SO2 on airway resistance [Sheppard et al., 1984b]. Airway resistance increased from baseline by 100% at 0.51 ± 0.2 ppm in dry cold air, at 0.60 ± 0.41 ppm in dry warm air, and at 0.87 ± 0.41 ppm in dry humidified air, following 3 minute exposures. These findings are supported by other studies of adult asthmatics exposed to SO2 [Bethel et al., 1984; Linn et al., 1984c, 1985a]. In one, high temperature and humidity mitigated the bronchoconstriction induced by SO2 exposure [Linn et al., 1985a]. In another study, of exposures from 0.3 to 0.6 ppm SO2 at temperatures ranging from -6 to 21 ºC, the effects of decreasing temperature and increasing SO2 were additive [Linn et al., 1984c]. The limits of the effect of cold are illustrated by the study of Linn et al. [1984b] which found that decreases in temperature from room temperature to 5 °C only slightly increased airway response to SO2. 4.5.4  Adults: Studies of Respiratory Symptoms  Many of the studies of spirometry and/or airway resistance outcomes also recorded changes in various symptoms. These were generally subject-reported and included respiratory symptoms such as taste, odour, nasal congestion or discharge, cough, sputum production, wheeze, shortness of breath, sore throat, substernal irritation, sore chest, and chest tightness, as well as non-respiratory symptoms including heart rate variability. Twenty-one studies included an examination of respiratory symptoms [Speizer and Frank, 1966; Kreisman et al., 1976; Stacy et al., 1981; Kagawa, 1983; Linn et al., 1982; 1983a, 1983b, 1984a, 1984b,1984c, 1985a, 1985b, 1987; Kulle et al., 1984; Witek et al., 1985; Hackney et al., 1984; Witek et al., 1985; Horstman et al., 1988; Gong et al., 1995; Tunnicliffe et al., 2001]. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  48  Healthy Subjects Few changes in respiratory symptoms were observed in healthy subjects at low SO2 concentrations (< 1 ppm). Four studies found no increases in symptoms in 7-31 exercising or at-rest adults exposed to 0.15-0.75 ppm SO2 for 1-2 hours [Stacy et al., 1981; Kagawa, 1983; Linn et al., 1987; Tunnicliffe et al., 2001]. A study of 10 healthy subjects revealed increasing numbers and severity of symptoms with increasing exposure from 0.25 to 1 ppm [Witek et al., 1985]. A study of 4-hour exposures of 20 healthy, exercising adults to 1 ppm revealed SO2-induced symptoms that were most pronounced when SO2 was administered in combination with (NH4)2SO4 [Kulle et al., 1984]. Studies of 8 and 18 healthy individuals exposed to between 3 and 28 ppm (7,900 and 74,000 ug/m3) SO2 for 1 to 10 minutes, revealed symptoms associated with increasing SO2 concentration [Speizer and Frank, 1966; Kreisman et al., 1976]. The earlier study reported that symptoms were more common during oral rather than nasal exposure. Asthmatic Subjects Respiratory symptoms were observed more consistently among asthmatics than healthy subjects. Of 13 investigations of exercising asthmatic subjects, 11 revealed increased respiratory symptoms in association with SO2 exposure [Linn et al., 1983a, 1983b, 1984a, 1984b,1984c, 1985a; Hackney et al., 1984; Witek et al., 1985; Horstman et al., 1988; Gong et al., 1995], while 2 reported no consistent changes. [Linn et al., 1987; Tunnicliffe et al., 2001] SO2 concentrations exhibiting no effect ranged from 0.2-0.6 ppm but concentrations ranging from 0.2 to 1 ppm resulted in increased symptoms. The shortest duration of exposure revealing increased symptomatology was 5 minutes (at 0.6 ppm in 2 studies and 1 ppm in another). Three of the studies reporting SO2-induced increases in symptoms reported that changes tended to be transient, disappearing 1 hour or 1 day following exposure. [Linn et al., 1983b, 1984a; Hackney et al., 1984] One study indicated that the combination of SO2 and exercise had a synergistic effect on respiratory symptoms [Gong et al., 1995]. In a study of 10 healthy and 10 asthmatic individuals, asthmatics tended to complain of lower respiratory complaints with increasing SO2 concentration, whereas the healthy subjects complained more frequently of upper airway symptoms [Witek et al., 1985]. 4.5.5  Adults: Studies of Other Measures of Response  Other measures of response which have been investigated include lung clearance, respiratory inflammatory response, genetic sensitivity to asthmatic response, and heart rate. Lung Clearance Wolff et al. [1975] and Newhouse et al. [1978] examined bronchial clearance in 9 and 10 healthy adults exposed to 5 ppm SO2. In at-rest subjects exposed to SO2 for 3 hours, there was little change in clearance with exposure [Wolff et al, 1975]. Among exercising Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  49  subjects exposed to SO2 for 2.5 hours, clearance was significantly faster compared to baseline [Newhouse et al., 1978]. Cellular Inflammatory Response in the Respiratory System Bronchoalveolar lavage (BAL) to recover mast cells, macrophages, and lymphocytes has recently been used to examine inflammatory responses to inhalation exposures. Sandstrom et al. [1989a, 1989b, 1989c] were the first to report such investigations for SO2. They exposed 12 healthy, exercising adults to 4 or 8 ppm SO2 for 20 minutes, and 24 hours later found increased numbers of inflammatory cells in BAL fluid, which increased with increasing exposure levels, and decreased to near normal numbers after 3 days. A subsequent study found very similar results in 22 healthy, at-rest adults exposed to 4, 5, 8, and 11 ppm SO2 for 10 minutes [Sandstrom et al., 1989b]. A third study included BAL 4, 8, 24, and 72 hours post-exposure; it confirmed that the peak response was 1 day after exposure [Sandstrom et al., 1989c] Genetic Susceptibility Winterton et al. [2000] investigated five genetic polymorphisms linked to asthma to determine whether any might be associated with hypersensitivity to SO2 among asthmatics. They exposed 62 adult at-rest asthmatics to 0.5 ppm SO2 for 10 minutes; of these, 12 were hypersensitive (i.e., they had a decline in FEV1 greater than 12%). All of the sensitive responders had the wild-type allele of the TNF-a gene promoter polymorphism, vs. only 61% of the non-sensitive subjects. No other polymorphism was associated with the SO2 hypersensitivity. Heart Rate Another new train of investigation related to air pollutants is cardiac arrhythmias. Linn et al. [1990] exposed moderate to severe asthmatic subjects to 0.3 and 0.6 ppm SO2 during 10 minutes of exercise and found no change in heart rate. Tunnicliffe et al. [2001] exposed 12 healthy and 12 asthmatic subjects to 0.2 ppm for 1 hour at rest and also found no change in heart rate during exposure. They did find changes in the frequency domains of the electrocardiograms (in opposite directions for healthy and asthmatic subjects), which led them to initial hypotheses about effects on vagal tone induced by bronchoconstriction and bronchodilation of lung airways. 4.5.6  Studies of Children  Seven studies included children and adolescents, in the age range of 9 to 18 years [Koenig et al., 1983, 1985, 1990; Huang et al., 1991; Magnussen et al., 1990; Islam et al., 1992; Linn et al., 1997]. No studies of children under 9 or of infants were found. Because the studies of Magnussen et al. [1990] and Islam et al. [1992] included adults and did not entail separate analyses by age, the results of these studies are reported in the previous sections.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  50  Two studies by Koenig et al. [1983, 1985] of asthmatic adolescents exposed at rest or during exercise to 0.5 and 1 ppm for 10 or 50 minutes found significant decrements in pulmonary function (FEV1, expiratory flow rates), despite the small numbers of subjects in the studies (9 and 10, respectively). Results of both studies also suggested that exposures by mouth exacerbate the effect of SO2, as they do in adults. In a study of 13 adolescents, Koenig et al. [1990] examined the joint effect of very low levels of SO2 (0.1 ppm) and ozone (at 0.12 ppm), and found that this combination resulted in significant decrements in FEV1, where exposures to either gas alone did not. Two other studies examined the effect of gases in combination. Huang et al. [1991] exposed 6 asthmatic children to road tunnel air with SO2 and NO2 concentrations 6 and 20 times (respectively) higher than those of ambient air. Very slight non-significant decrements in FVC, FEV1, and expiratory flow were observed after 105 breaths of the polluted air. Linn et al. [1997] exposed 26 asthmatic and 15 healthy children to 0.1 ppm SO2, 0.1 ppm ozone, and 100 ug/m3 sulphuric acid aerosol for 4 hours, with intermittent exercise. They found little change in spirometric measures after the simulated “acid haze” exposures. 4.5.7  Limitations  The controlled human experiments had several advantages compared to the epidemiological studies of the health effects of SO2. The experimental conditions allowed the exact exposure concentration to be controlled and known. Co-exposures could be eliminated or given under controlled circumstances, so that the independent and joint effects of SO2 could be more confidently assessed. Of course, controlled exposures are also less realistic, considering the complex mixtures which may occur in ambient or indoor air; a few investigators attempted to reconstruct such exposures in their chambers. Clinical exposures were always of short duration, ideal for assessing the acute changes which can result from exposure episodes of minutes to hours, but not for assessing the results of chronic low level exposures. This limitation coincides with the fact that the lowest exposures offered to clinical study subjects were about 0.1 ppm (260 ug/m3) considerably higher than levels typically observed in North American homes or ambient air. Acute exposures also limit the range of health outcomes which can be observed; long-term health effects such as cancer, chronic obstructive pulmonary disease, and systemic effects cannot be endpoints in experimental studies of humans, for both practical and ethical reasons. Another limitation of clinical studies is the very small number of subjects typically included, such that changes in lung function that were not statistically significant may have resulted from power problems. Small studies also limit investigators’ ability to identify at-risk subsets of the population, although asthmatics were certainly considered. Age groups that are often cited as most at risk, infants and the elderly, were not. Only two studies examined subjects beyond middle age, and the eldest was 73 years of age.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  51  4.6 Discussion of LOAELs for Chronic and Acute Exposures to SO2 4.6.1  Chronic Exposure  Standard setting to protect against chronic exposure to SO2 is best addressed by the epidemiological literature on the respiratory health of exposed subjects. This literature usually reported long-term averages of 24-hour measurements from ambient monitoring stations or of shift-long (likely 8-hour) measurements of occupational exposures. Although not always explicitly expressed, the outcomes examined tended to be effects expected to develop over a period of years, such as decrements in lung function, or chronic respiratory symptoms. The only study [Kehoe et al., 1932] which examined truly independent exposures to SO2 found increases in almost all respiratory symptoms in employees using the gas as a refrigerant; they were exposed to very high concentrations in the range of 10 to 100 ppm. The studies in smelters, pulp mills, and silicon carbide plants which examined average exposures of 0.5 ppm and higher usually found decrements in FEV1, as well as increases in cough, phlegm, dyspnea, and chronic obstructive pulmonary disease in exposed workers. Many reported anecdotal evidence of workers who chose to avoid exposure by either transferring to less exposed jobs or retiring early. Some, but not all of these studies controlled for co-exposures such as dust. Among studies of populations residing near special ambient sources of SO2, the study in Chongqing, China [Wang et al., 1999] showed the most convincing difference between the exposed and unexposed group, with significant decrements in lung function with long-term average exposures of 0.08 vs. 0.04 ppm, and little difference in particulate exposure. The study of the smelter city of Nikel, Russia and its region [Smith-Sivertsen et al., 2001], where the highest monthly means were 0.06 ppm showed no differences in lung function related to daily average exposure, but increased cough and phlegm in the more exposed Russian population. However, there was no control for differences in smoking and occupational exposures. Finally, in the Arizona smelter region [Dodge et al., 1985], again no lung function or asthma differences were associated with exposure, but children with the highest exposures (0.02 to 0.04 ppm) had a higher prevalence (but not cumulative incidence) of cough. There was no control for concurrent particulate exposures which did differ between the study groups, but not to the same extent as SO2 exposures. This evidence suggests that SO2 has a chronic effect on lung function and respiratory symptoms and disease. The lowest observable adverse effect level (LOAEL) for lung function decrements appears to be about 0.08 ppm, averaged over about one year. The LOAEL for cough may be lower (0.02 to 0.04 ppm), but other explanations for the evidence in this regard cannot be ruled out. Table 4.6 lists current exposure guidelines set in North America and by the World Health Organization (WHO). The annual air quality guidelines are in the range of the more tenuous LOAELs reported above: 0.01 to 0.03 ppm. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  52  The epidemiological data reviewed in this report does not adequately address asthmatics, children, or the elderly as potential susceptible sub-populations. In occupational studies, several investigators noted an excess risk of respiratory disease or symptoms among SO2exposed subjects who were also smokers, implying a synergistic relationship between these two exposures. The three studies which examined chromosomal damage and the one which found excess bladder and lung cancer risk, all included subjects exposed at levels higher than the above LOAELs. Genetic changes including cancer is a research area which deserves ongoing attention, as does the emerging area of reproductive outcomes and infant mortality. To date, most studies of the latter outcomes have been conducted in regions where the source of SO2 exposure is typical mixed urban air pollution. 4.6.2  Acute Exposure  The studies of controlled human exposures provide the best evidence about the doserelated acute effects of SO2. In healthy adults, few studies found changes in lung function or symptoms at exposures below 1 ppm, although bronchorestriction did result at concentrations in the range of 2 to 5 ppm. Among the exceptions was a study of older adults (55 to 73 year of age) which found decrements in FEV1 after exposure to 0.5 and 1 ppm for 30 minutes with exercise [Rondinelli et al., 1987]. Asthmatic adults and children were considerably more likely to react to lower concentrations of SO2, with exposures over 0.5 ppm consistently resulting in decrements in FEV1. Increases in airway resistance were consistently observed in exercising asthmatics, at even lower concentrations, including exposure-duration combinations as low as 0.2 ppm for 5 minutes and 0.1 ppm for 10 minutes. Reductions in FEV1 were also observed at these low levels when adolescents and adults were exposed to SO2 either during or after exposure to similar concentrations of ozone. This evidence suggests that asthmatics, especially when breathing through the mouth, are sensitive to low concentrations of SO2 even with very short durations of exposure. The lowest observable adverse effect level (LOAEL), though not consistently replicated, was 0.1 ppm during 10-minute exposures. Among the acute exposure guidelines set in Canada, the US and the WHO (Table 4.6, overleaf), only the WHO guideline recognizes the potential speed of asthmatic response to this gas, with a 10-minute guideline of 0.175 ppm.  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  53  Table 4.6 Ambient Air Standards for SO2 (in ppm) Canadian Air Quality Objectives Type of Standard  Maximum Desirable  Maximum Acceptable  Annual  0.011  0.023  24 hours  0.057  0.115  3 hours 1 hour  Maximum Tolerable  0.306  United States  World Health Organization  National Ambient Air Quality Standards  Health-Based Guidelines  0.030  0.020  0.140  0.040  0.500 0.172  0.344  10 minutes  Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene  0.175  54  5 REFERENCES Adgate, JL, Reid, HF, et al. (1992). Nitrogen dioxide exposure and urinary excretion of hydroxyproline and desmosine. Archives of Environmental Health 47(5): 376-384. Agency for Toxic Substances and Disease Registry. 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