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Review of the health risks associated with nitrogen dioxide and sulfur dioxide in indoor air Brauer, Michael 2008

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Reference Location Route of Exposure Number of Subjects Duration of Exposure SO2 Concentration Speizer and Frank, 1966 Boston, MA, USA Mouthpiece and Chamber 8 (8 male, 0 female) Healthy volunteers 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 Snell and Luchsinger, 1969 Washington, DC, USA 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. 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 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. 3 hours 5 ppm 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 Newhouse, Dolovich and Obminski, 1978 Albuquerque, NM, USA Chamber 10 (9 male, 1 female) 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 Jaeger, Tribble and Wittig, 1979 FL, USA Mouthpiece 80 (45 male, 35 female) 40 healthy non- smokers 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 von Nieding, Wagner et al., 1979 Germany Chamber 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 Table 4.5 Controlled Human Exposure Studies of the Health Effects of SO2 Subject Description Characteristics of Study #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 mid- expiratory 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. 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. Positive Results Null or Negative Results CommentsMain Comparison Reference Location Route of Exposure Number of Subjects Duration of Exposure SO2 Concentration Subject Description Characteristics of Study Sheppard, Wong et al., 1980 San Francisco, CA, USA Mouthpiece 21 (15 male, 6 female) 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. 10 minutes 1, 3, or 5 ppm Sheppard, Saisho et al., 1981 San Francisco, CA, USA Mouthpiece 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) Stacy, House et al., 1981 Chapel Hill, NC, USA 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 Kirkpatrick, Sheppard et al., 1982 San Francisco, CA, USA 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 Linn, Bailie et al., 1982 Downey, CA, USA 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 Bethel, Erle et al., 1983a San Francisco, CA, USA 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 Positive Results Null or Negative Results CommentsMain Comparison 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. The increases in SRaw produced by inhalation of SO2 were prevented by treatment with atropine in asthmatic and non-asthmatic subjects, suggesting that SO2- induced bronchoconstriction is mediated by parasympathetic pathways. 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. 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 Route of Exposure Number of Subjects Duration of Exposure SO2 Concentration Subject Description Characteristics of Study Bethel, Epstein et al., 1983b San Francisco, CA, USA Chamber 10 (8 male, 2 female) 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 Kagawa, 1983 Japan Chamber 7 (7 male, 0 female) Healthy subjects aged 19-23 years, one 4-year smoker, the rest non- smokers. 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 Koenig, Pierson et al., 1983 Seattle, WA, USA Mouthpiece 9 (6 male, 3 female) Adolescents with extrinsic asthma aged 12 to 16 years. Subjects were exposed via a mouthpiece with nose clips (orally) to 1 mg/m3 NaCl, 0.5 ppm SO2 and 1 mg/m 3 NaCl, or 1 ppm SO2 and 1 mg/m 3 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). 10 minutes 0.5 and 1 ppm Linn, Shamoo et al., 1983a Downey, CA, USA Mouthpiece 23 (15 male, 8 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. 10 minutes plus the time necessary for body plethys- mography, symptom questionnaires, and pulmonary function testing before and after exercise 0.75 ppm Linn, Venet et al., 1983b Downey, CA, USA Chamber 23 (13 male, 10 female) 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 post- exercise physiologic testing. 0.2, 0.4, and 0.6 ppm Sheppard, Epstein et al., 1983 San Francisco, CA, USA Mouthpiece 8 (4 male, 4 female) 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 Positive Results Null or Negative Results CommentsMain Comparison 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. The smoking subject appeared to experience smaller decreases in Gaw/Vtg with exposure, perhaps because his baseline value was the lowest of all subjects. 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 dose- response 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 SO2- induced 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 post- exposure 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 Route of Exposure Number of Subjects Duration of Exposure SO2 Concentration Subject Description Characteristics of Study Bedi, Folinsbee and Horvath, 1984 Santa Barbara, CA, USA Chamber 9 (9 male, 0 female) 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 Bethel, Sheppard et al., 1984 San Francisco, CA, USA Mouthpiece 7 (5 male, 2 female) Non-smoking asthmatic volunteers aged 24-36 years. Subjects were exposed to humidified room-temperature air, humidified room- temperature air containing SO2, cold dry air, and cold dry air containing SO2 on 4 separate randomized days at least 24 hours apart. 3 minutes 0.5 ppm Hackney, Linn et al., 1984 Downey, CA, USA 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 Kulle, Sauder et al., 1984 Baltimore, MD, USA Chamber 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 Linn, Avol et al., 1984a Downey, CA, USA Chamber 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 6- hour 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 Downey, CA, USA Chamber 8 (4 male, 4 female) Young asthmatics aged 19-29 years. Subjects were exposed to SO2- free 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 Downey, CA, USA Chamber 24 (19 male, 6 female) 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 Linn, Shamoo et al., 1984b Positive Results Null or Negative Results CommentsMain Comparison 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. IC = inspiratory capacity ERV = expiratory reserve volume 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 post- exposure 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 questionnaire- reported 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). 6 of 24 subjects are the same subjects cited in Linn WS et al (1984) n=8 entry. Reference Location Route of Exposure Number of Subjects Duration of Exposure SO2 Concentration Subject Description Characteristics of Study Linn, Shamoo et al., 1984c Downey, CA, USA 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 warm- up and cool down included). 0.3, 0.6 ppm Schachter, 1984 New Haven, CT, USA 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 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 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 doubling SO2 concentrations via a mouthpiece, performing voluntary eucapnic hyperpnea. Doubling concentrations were inhaled for 3 minutes, 6 times. started at 0.125 ppm Bethel, Sheppard et al., 1985 San Francisco, CA, 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 kilogram- meters/min exercise. The experiment was repeated at an exercise rate of 1000 kilogram- meters/min. 5 minutes 0.25 ppm Folinsbee, Bedi & Horvath, 1985 Santa Barbara, CA, USA 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 Koenig, Morgan et al., 1985 Seattle, WA, USA Mouthpiece 10 (5 male, 5 female) 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 Sheppard, Eschenbacher et al., 1984 Positive Results Null or Negative Results CommentsMain Comparison 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. 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. 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 dose- response relationship was evident for exercising asthmatics. 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. 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. 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. 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. Reference Location Route of Exposure Number of Subjects Duration of Exposure SO2 Concentration Subject Description Characteristics of Study Linn, Fischer et al., 1985a Downey, CA, USA Chamber 24 (15 male, 9 female) 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 Linn, Shamoo et al., 1985b 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. 5 minutes plus brief warm-up and cool-down periods 0.6 ppm Roger, Kehrl et al., 1985 Research Triangle Park, NC, USA Chamber 28 (28 male, 0 female) Non-smoking, mild asthmatic males with hypersensitivity to methacholine, aged 19- 34 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 Witek and Schachter, 1985a New Haven, CT, USA Chamber 8 (4 male, 4 female) 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 Witek, Schachter et al., 1985b New Haven, CT, USA Chamber 20 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 Positive Results Null or Negative Results CommentsMain Comparison 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. 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. 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.  (NOAEL 250 ppb) 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 non- asthmatics 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. 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 Route of Exposure Number of Subjects Duration of Exposure SO2 Concentration Subject Description Characteristics of Study Horstman, Roger et al., 1986 Research Triangle Park, NC, USA Chamber 27 (29 male, 0 female) 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 Balmes, Fine & Sheppard, 1987 San Francisco, CA, USA Mouthpiece 8 (6 male, 2 female) 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 Kehrl, Roger et al., 1987 Research Triangle Park, NC, USA Chamber 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. 1 ppm Linn, Avol et al., 1987 Downey, CA, USA Chamber 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 10- min exercise periods 0.2, 0.4, and 0.6 ppm Rondinelli, Koenig & Marshall, 1987 Seattle, WA, USA Mouthpiece 10 (10 male, 0 female) Healthy non-smokers aged 55-73 years. Subjects were exposed to 1 mg/m3 NaCl droplet aerosol alone, 1 mg/m3 NaCl droplet aerosol with 0.5 ppm SO2 (7 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. 30 minutes 0.5 and 1 ppm Horstman, Seal et al., 1988 Research Triangle Park, NC, USA Chamber 12 (12 male, 0 female) Non-smoking males aged 22-37 years with a history of physician- diagnosed asthma. 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 0 - 5 minutes 1 ppm Positive Results Null or Negative Results CommentsMain Comparison 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. The authors note that the effects of one minute exposure were mainly due to reaction of two 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. Reference Location Route of Exposure Number of Subjects Duration of Exposure SO2 Concentration Subject Description Characteristics of Study Bedi and Horvath, 1989 Santa Barbara, CA, USA Chamber 14 (7 male, 7 female) Healthy adults aged 20- 46 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 Sandstrom, Stjernberg et al., 1989a 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 Jorres and Magnussen, 1990 Germany 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 Koenig, Covert et al., 1990 Seattle, WA, USA Chamber 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 Linn, Shamoo et al., 1990 Downey, CA, USA 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 Magnussen, Jorres et al., 1990 Germany 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 Sandstrom, Stjernberg et al., 1989b Positive Results Null or Negative Results CommentsMain Comparison SO2 exposure and pulmonary function (FVC, FEV1, FEF25-75, and Raw) No association was observed between breathing 2 ppm SO2 and pulmonary function. 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. 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 pre- exposure levels. This article reports concentrations of "10 mg SO2/m 3 (4 ppm)" and "20 mg SO2/m 3 (8 ppm)." 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 non- significant 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. 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. NOTE: response curves for all patients are illustrated in the article. RT = total respiratory resistance Vmax50 = maximal flow 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. Post- exposure 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. Reference Location Route of Exposure Number of Subjects Duration of Exposure SO2 Concentration Subject Description Characteristics of Study Huang, Wang and Hsieh, 1991 Taipei, Taiwan Mouthpiece 6 (5 male, 1 female) 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 Islam, Neuhann et al., 1992 Germany Chamber 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 Devalia, Rusznak et al., 1994 London, U.K. Chamber 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 Heath, Koenig et al., 1994 Seattle, WA, USA Breathing inside head dome 22 (22 male, 0 female) 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 Gong, Lachenbruch et al., 1995 Downey, CA, USA 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). 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 Linn, Gong et al., 1997 Downey, CA, USA Chamber 41 (19 male, 22 female) 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 Nowak et al., 1997 Hamburg, northern Germany Mouthpiece 790 Adults aged 20 to 44 years. SO2 inhalation challenges were performed during isocapnic hyperventilation at a constant rate 3 minutes max 2 ppm Trenga, Koenig and Williams, 1999 Seattle, WA, USA Mouthpiece 47 (14  male, 33  female) Asthmatic adults aged 18-39 years. Subjects exposed during moderate exercise 10 minutes 0.5 ppm Positive Results Null or Negative Results CommentsMain Comparison 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.  Methacholine and allergen sensitivities of airways were not increased after polluted air was inhaled. 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 co- exposure 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. No ethnic differences in respiratory resistance, pulmonary or nasal measurements were observed. No significant changes in epithelial or white blood cell count were observed. 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). 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. 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%). Reference Location Route of Exposure Number of Subjects Duration of Exposure SO2 Concentration Subject Description Characteristics of Study Winterton, Kaufman et al., 2000 Seattle, WA, USA Mouthpiece 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 Tunnicliffe, Hilton et al., 2001 Birmingham U.K. Chamber 24 (12 male, 12 female) 12 normal (5 male, 7 female) adults aged 22- 49 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 Positive Results Null or Negative Results CommentsMain Comparison Genetic polymorphisms were compared for SO2 responders (FEV1 decreased by > 12% after SO2 exposure) and non- responders to determine which biomarkers indicated sensitivity to inhaled SO2. 13 of the 62 subjects were responders. Response to SO2 was associated with the wild- type allele of the TNF-a promoter polymorphism (12 of 12 responders vs. 28 of 46 non- responders, 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. Reference Year & Season of Study Location Exposure Source Study Design Number of Subjects Duration of Exposure Sorsa et al., 1982 (not reported) (not reported) investigators from Sweden Industrial (aluminum smelter) Cross-sectional 16 (8 plant workers and 8 clerks) Exposed: males with an average of 20 years at the foundry, including three smokers.  Controls: male clerks, including 5 smokers. All exposed employees complained of some symptoms, including cough, nose or eye irritation, and previous respiratory inflammation. 5 to 39 years of employment Kangas, Jappinen & Savolainen, 1984 (Year not reported)  Winter, Spring and Summer Finland Industrial (pulp mills) Cross-sectional 162 (81 sulfur exposed and 81 age and smoking-habit matched unexposed controls) Pulp mill workers with and without occupational exposure to organic and inorganic sulfides in 2 adjoining mills. (not reported) Englander, Sjoberg, et al., 1988 1961 - 1985 Sweden Industrial (sulfuric acid factory) Retrospective cohort 400 (all males) 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.  ≥ 6 months Meng & Zhang, 1990 (not reported) Taiyuan City, Northern China Industrial (sulfuric acid factory) Cross-sectional 82 (40 plant workers and 42 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) Yadav & Kaushik, 1996 (not reported) (not reported) investigators from Kurukshetra, India Industrial (fertilizer factory) Cross-sectional 84 (42 SO2 exposed and 42 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 Table 4.4  Epidemiological Studies of Other Health Outcomes of SO2 Exposure Special Characteristics of Study Subject Description 0.2 to 3 ppm (daily averages), mean = 1.0 ± 0.85 ppm Occurrence of genotoxic effects (sister chromatid exchanges and chromosome aberrations). 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. 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. Cause- specific 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), non- malignant 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 Workers were exposed to an average SO2 level of 41.7 mg/m 3 . (not known whether exposure levels subject specific) 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. Main Comparison Positive Results Null or Negative Results SO2 Concentrations Reference Year & Season of Study Location Exposure Source Study Design Number of Subjects Duration of Exposure Special Characteristics of Study SO2 Concentrations 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. Subjects lived near Mt. Sakurajima, one of the most active volcanoes in the world up to 28 days ambient seasonal averages from 0.010 to 0.013 ppm (ecological data) Main Comparison Positive Results Null or Negative Results Neonatal mortality was compared to SO2 monthly average and maximum hourly average concentrations, as well as to ash and suspended particulate concentrations. The monthly average SO2 concentration was positively associated with neonatal mortality. The maximum hourly average SO2 concentration, ash and particulate concentration were not associated with neonatal mortality. Reference Year & Season of Study Location Exposure Source Study Design Number of Subjects Kehoe et al, 1932 (not reported) Dayton, OH, USA Industrial (refrigerator manufacturing plant) Cross-sectional 200 (100 who worked with SO2 as a 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 Skalpe, 1964 (not reported) Norway Industrial (pulp mills) Cross-sectional 110 (54 exposed pulp mill 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. Ferris, Burgess & Worcester, 1967 1962, October Berlin, NH, USA Industrial (pulp mills) Cross-sectional 271 (147 exposed pulp mill workers and 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. Smith, Peters et al., 1977 1973 - 1974 Salt Lake City, UT, USA Industrial (copper smelter)  Cross-sectional (with longitudinal follow-up over one year) 113 (all males) Caucasian smelter workers aged 19- 64 years (mean age = 36). Smelter workers were chronically exposed to SO2 from the processing of copper sulfide concentrates. Archer & Gillam, 1978 (not reported) Garfield, UT, USA Industrial (copper smelter)  Cross-sectional 1,215 (953 smelter employees, and 262 mine truck maintenance shop employees, all males) Smelter workers: mean age = 41.3 years, 8.9% non-white, 9.9 cigarettes/day controls = 37.0 years, 13.5% non- white, 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). Lebowitz et al., 1979 1976 Salt Lake City, UT, USA Industrial (copper smelter)  Cross-sectional (with follow-up spirometry available for a subset of 244 subjects) 430 (all males) 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. Kangas, Jappinen & Savolainen, 1984 (Year not reported)  Winter, Spring and Summer Finland Industrial (pulp mills) Cross-sectional 162 (81 sulfur exposed and 81 age and smoking-habit matched unexposed controls) Pulp mill workers with and without occupational exposure to organic and inorganic sulfides in 2 adjoining mills. Table 4.3  Epidemiological Studies of Respiratory Effects of SO2 Exposure Subject Description Special Characteristics of Study Duration of Exposure Exposed workers mean = 4 years; Controls mean = 4.5 years 10 to 100 ppm, based on area sampling. 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. (not reported) 1.6 to 45 ppm (personal exposure measurements of study subjects) 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. (not reported) 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%). Some less than and others more than 20 years. 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. No associations were found between FVC, FEV1, ratio and exposure to air contaminants  in cross-sectional comparisons. (not reported) 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. No differences in respiratory symptoms found. Main Comparison Positive Results Null or Negative Results SO2 Concentrations Reference Year & Season of Study Location Exposure Source Study Design Number of Subjects Subject Description Special Characteristics of Study Dodge, Solomon et al., 1985 1978-1982 Morenci, Kingman and San Manuel, AZ, USA Ambient (in smelter town) Cross-sectional (with longitudinal follow-up for 3 years) 678 (3rd to 5th grade children) 343 children in Morenci, a smelter town, 134 children from San Manuel, another smelter town, and 201 children from Kingman a non- industrial 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. Rom, Wood, et al., 1986 1980, 1980 - 1983 Salt Lake City, UT, USA Industrial (copper smelter)  Cross-sectional (longitudinal follow-up of previous study, and additional 3- year follow-up) 66 in 1980, 48 of these participated in 1983, as well as 15 additional workers (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. Englander, Sjoberg et al., 1988 1961 - 1985 Sweden Industrial (sulfuric acid factory) Retrospective cohort 400 (all males) 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. Broder, Smith et al., 1989 June-November 1985 Sudbury, ON, Canada Industrial (nickel smelter) 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%). Osterman, Greaves, et al., 1989 1980 to 1983 Quebec, Canada Industrial (silicon carbide plant) Cross-sectional 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. Duration of Exposure Main Comparison Positive Results Null or Negative Results SO2 Concentrations (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 (chi- square = 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. 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.  = 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. Cause- specific standardized mortality/morbidity ratios (SMRs) were calculated. Deaths from respiratory tumours elevated (5 observed vs. 2.5 expected), but not statistically significant. No increase in non-malignant respiratory disease. 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. 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. 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) 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 Year & Season of Study Location Exposure Source Study Design Number of Subjects Subject Description Special Characteristics of Study Froom, Sackstein et al., 1998 (not reported) Tel Aviv, Israel Industrial (electric power generating station) Cross-sectional 72 (38 exposed power station technicians and 34 unexposed technicians) Power station operators who were exposed worked near burning chambers, unexposed controls worked near burning chambers under negative pressure. SO2 from burning chambers Donoghue & Thomas, 1999 1993-1996 Mount Isa, Australia Ambient (in a city of 25,000 with a copper smelter and a lead smelter) Time series (not reported) 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. Wang, Peng et al., 1999 1995 Chongqing, China Ambient (city with several steel, iron and power plants, industry and residences mainly use coal for energy) Cross-sectional 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. Smith-Sivertsen, Bykov et al., 2001 May 1994 to April 1995 Sor-Varanger, Norway and Nikel, Russia Ambient (in small cities, one with a nickel smelter and the other nearby) Cross-sectional 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). Duration of Exposure Main Comparison Positive Results Null or Negative Results SO2 Concentrations 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. 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. (not reported) Concentrations ranged from "zero" to 8700 ug/m3.  The maximum (5- minute 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. No association found between peak SO2 exposure and hospital presentations or admissions for asthma, wheeze or shortness of breath. (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. FVC and FEV1 based on pulmonary function measurements were compared for areas of different SO2 concentration. 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. (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, 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. 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. Biersteker, de Graaf & Nass, 1965 1964, January to March Rotterdam, the Netherlands Indoor and Outdoor (residential) 60 Homes representative of bungalows, multistoried houses, flats, and high rise apartments. indoor samples taken in living room, outdoor samples taken outside same house ~14 to 22/site; half indoors and half outdoors 24 hours Drechsel bottle with hydrogen peroxide solution, analyzed by titration of total acidity Stock, Kotchmar et al., 1985 May to October, 1981 Sunnyside and Clear Lake neighbourhoods of Houston, TX Indoor and Outdoor (residential) 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 1) 6-8 am 2) 9-11 am 3) 1-3 pm 4) 6-8 pm Sampler Used Number of Measurements not reported Flame photometric continuous gas analyzer Table 4.2  Studies of Indoor and Outdoor Exposures to SO2 20 minutes Pararosanaline 1 week Indoor and Outdoor (residential) Indoor (residential) Indoor and Outdoor (office) 30 homes/city: 15 coal-burning; 15 gas-burning 15 units in each of 2 staff quarters:  Tsim Sha in a heavy traffic area; and Shatin in a low traffic, but industrial area 1 ground floor office in naturally ventilated building, and 1 third floor office in mechanically ventilated building. 2 ~ 2000 records/site (recorded every 5 minutes over sampling period) 1996, Winter Hong Kong 4 cities in Eastern China: Chengde Shenyang Shanghai Wuhan Birmingham, UK Yuhui, Xiaoming et al., 1991 Lee, 1997 Kukadia & Palmer, 1998 1996, January to March 1987, June to August 1987 - 1988, December to February Tedlar bag and pump   (1 L/min), analysis by pulsed fluorescence SO2 analyzer 30 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 16 per site: 4 samples per day, 2 days in summer and 2 in winter, in the kitchen and bedroom at breathing level. 120 Data logging continuous gas analyzer 2 hours Reference Year & Season of Study Location Type of Exposure Number of Sites Duration Indoor and Outdoor (residential or public facilities) ~ 60 Spengler, Ferris & Dockery, 1979 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. (year not reported) one-year period 6 cities in USA: Kingston/ Harriman TN; Portage WI; Steubenville OH; St. Louis MO; Topeka KS; Watertown MS Site Description 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) Méranger and Brulé, 1987 (year not reported) March and April Antigonish, Nova Scotia Indoor and Outdoor (residential) ug/m3  I/O Ratio ~0.20 Indoor 0 Outdoor 73 Indoor 246 Outdoor 384 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 indoor outdoor indoor outdoor indoor outdoor Kingston, TN 1 12 0 4 1 12 Portage, WI 6 8 5 7 10 10 Steubenville,OH 22 52 16 35 26 59 St. Louis, MO 10 40 10 28 26 60 Topeka, KS 1 2 0 1 2 5 Watertown, MS 8 25 0 11 10 31 ppb indoor 5.1 outdoor 2.8 Indoor 5.3 Outdoor 5.0 Despite higher indoor than outdoor SO2 levels, authors caution that this result may be confounded by differences between homes and diurnal patterns. 2 - 10 3 - 16 0 - 30 SUMMER Chengde Shenyang Shanghai Wuhan Kitchen/coal 71 75 694 174 Bedroom/coal 60 51 334 67 Kitchen/gas 47 74 53 76 Bedroom/gas 39 53 33 87 WINTER Chengde Shenyang Shanghai Wuhan Kitchen/coal 482 860 173 Bedroom/coal 274 502 87 Kitchen/gas 163 65 70 Bedroom/gas 140 37 41 indoor outdoor I/O Ratio I/O I/O indoor outdoor Tsim Sha 4.3 6.0 0.72 0.54 0.85 1.4 2.5 Shatin 3.9 4.3 0.91 0.86 0.97 1.0 1.3 Nat Vent Mech Vent Outdoor Nat. Mech. Mean 4.4 3.9 11 10.6 13.4 I/O Ratio 0.4 0.4 0.3 0.3 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. nL/L (ppb) ppb Mean Standard Deviation 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. ug/m3 Units Measured Concentration of SO2 Minimum Maximum indoors in town Outdoor levels greater than indoor. No distinction between natural and mechanical ventilation with regards to indoor air quality, Results ug/m3 Indoor concentrations consistently and significantly lower than outdoor. Differences between cities significant. ug/m3 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). outdoors in town outdoors control Sampler Used Number of Measurements Reference Year & Season of Study Location Type of Exposure Number of Sites DurationSite Description 5 hours 2 per site: indoors (in most densely occupied area) and outdoors (near fresh air intake during peak hours) at each 20 minutes 2 to 4 weeks (not reported) Teflon bag and pump (1 L/min), analysis by pulsed fluorescence SO2 analyzer Indoor (residential) Houses, none with chimneys, some with no paraffin use, some with use of paraffin for heating, lighting, and/or cooking 72 (not reported) Venice, Italy Indoor and Outdoor (public places) Diffusion monitor with glass fibre filter coated with sodium bicarbonate, analysis by ion chroma- tography 48 hours 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 25 4 per site: 2 indoors in main living area  near kitchen and 2 outdoors under rain shelter 36 test runs under various conditions inside and outside clamshell. Sampling probes positioned close to breathing zone of a sleeping person. 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) 7 days Boyle and Sherwood Park, Alberta Hong Kong (not reported: possibly New Mexico, US, based on authors' location) Hong Kong (not reported: possibly South Africa, based on acknowledge- ment) South Africa 1996 - 1997, October to March Bailie, Pilotto et al., 1999 Camuffo, Brimble- combe et al., 1999 Lee, Chan & Chui, 1999 1996, February and August Winter (year not reported) 1 Indoor (tent) Indoor (residential) Correr museum: 3 outdoor sites around the museum and 6 rooms indoors 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 Indoor and Outdoor (museum) 14 115 1 6 per site: 3 days per site (fall, spring and winter), twice per day (once in the morning and once in the afternoon) 8 per site: 4 outdoors by fresh air intake of air- conditioning unit, 4 in middle of living area Diffusion tubes, with stainless steel mesh coated with potassium hydroxide, analysis by ion chroma- tography 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 Exotox 75 continuous gas analyzer Apartments of non-smokers in different areas of city, 20 -140 m2, 2 - 5 occupants and from 2nd to 35th floors 50 very low income households, 40 low income households, and 25 middle income households; in cooking and living areas of each home Zhou & Cheng, 2000 Chao, 2001 (not reported) 1997, May to June 1995 - 1996, February to December Sanyal & Maduna, 2000 Draeger Multi- gas Multiwarn II continuous gas analyzer Kindzierski & Sembaluk, 2001 1998, Late Fall Indoor and Outdoor (residential) 10 Indoor and Outdoor (residential) Exotox 75 continuous gas analyzer 6 hours Ogawa PS-100 passive samplers Mean Standard Deviation Units Measured Concentration of SO2 Minimum Maximum Results 0.54 0 6.8 OUTDOORS Feb. Aug. 40 25.8 34.2 19.9 16.8 INDOORS 5.8 <6 5.9 4.8 <6 4.4 5.0 5.6 <6 <6 Indoor Outdoor restaurant 1 0.006 0.006 restaurant 2 0.006 0.007 restaurant 3 0.003 0.003 rural library 1 0.006 0.007 library 2 0.003 0.003 rural recreation site 1 0.005 0.005 recreation site 2 0.003 0.003 recreation site 3 0.012 0.009 shopping mall 1 0.003 0.009 shopping mall 2 0.003 0.003 shopping mall 3 0.008 0.008 sports centre 1 0.006 0.006 sports centre 2 0.003 0.003 rural car park 0.003 0.005 June - Sept Oct - Dec March - May Very low income 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 Indoor 6.3 2.6 10.4 2.2 Outdoor 8.1 2.6 15.7 3.8 I/O Ratio 1.01 0.25 3 0.78 (MEDIANS) Boyle Sherwood Boyle Sherwood Boyle Sherwood Indoor 0.5 1.4 0.2 0.9 2.3 5.2 Outdoor 4.3 9.9 3.7 8.2 5.6 13 I/O 0.13 0.13 0.05 0.08 0.52 0.4 Indoor levels much lower than outdoor. Higher indoor and outdoor (2x) levels in Sherwood Park than Boyle due to increased traffic and industrial emissions. Lotto Room 2 diesel machine outside site Site Comments ppb 0 - 1.5 depending on heater, fuel, and air exchange rate ppm Lotto Room 3 Lotto Room 4 Outdoor concentrations higher than indoor. Higher levels than those recorded at the V&A Museum in London and at the Residenz in Wurzburg. Piazza San Marco Enclosed Courtyard 1 Bellini Room 1 Bellini Room 2 Enclosed Courtyard 2 After electricity, paraffin was the most commonly used fuel (69% of households and 64%, respectively). Fuel use not associated with SO2 levels. 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 Lotto Room 1 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. SO2 values significantly higher in kitchen than in living room from June- September  (winter in South Africa). ppm ug/m3 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. uL/L (ppm) mg/m3 ug/m3 Reference Location Study Design Number of Subjects Duration of Exposure NO2 Concentration Orehek, Massari et al., 1976 Single-blind 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. 1 hour 0, 0.1 ppm, 0.2 ppm (4 subjects only) Goings, Kulle et al., 1989 Baltimore, USA Placebo- controlled, randomized double-blind 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. Exposure in the chamber was for 2 hours on three consecutive days. Year one: ambient air or 2 ppm NO2; Year two: ambient air or 3 ppm NO2; Year three: ambient air, 1 or 2 ppm NO2 Jorres & Magnussen, 1990 Germany Crossover 14 (10 male, 4 female) 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 Rasmussen, Kjaergaard & Petersen, 1990 Denmark Randomized double-blind 40 (24 male, 16 female) 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 Roger, Horstman et al., 1990 North Carolina, USA Crossover 34 (all male) in two separate studies Non-smoking asthmatic Caucasian males (aged 19- 35 years).  13 in preliminary experiment and 21 in concentration- response 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. Concentration- response 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. Rubinstein, Bigby, et al., 1990 Chamber 9 (4m, 5f) 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 Table 3.6  Controlled Human Exposures to NO2 Subject Description Characteristics of Study NO2 and direct bronchomotor effects (specific airway resistance, with carbachol and without) in asthmatics. 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. 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. 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). Difference between SRaw and FEV1 in first hour (no exposure) and 3rd hour (after two hours of exposure). Asthmatic versus controls. 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. FEV1 following exercise in NO2 versus clean air. 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 (concentration- response).  NO2 exposure and enhanced airway responsiveness from increasing SO2 exposure. 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. CommentsNull or Negative ResultsPositive ResultsMain Comparison Reference Location Study Design Number of Subjects Duration of Exposure NO2 Concentration Subject Description Characteristics of Study Frampton, Morrow et al., 1991 Rochester, New York Experimental Group 1 9 (7 male, 2 female); Group 2 15 (11 male, 4 female); Group 3 15 (12 male, 3 female) 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. Huang, Wang & Hsieh, 1991 Taipei, Taiwan Crossover 6 (5 male, 1 female) Mite-sensitive asthmatic children with mean age 12 years. Moderate severity, given no asthmatic medications for at least 7 days. Taipei road tunnel air or ambient air administered via mouthpiece. 5 minutes 70-120 ppb SO2 and 450- 500 ppb NOX (NO2 and NO) combined. Jorres & Magnussen, 1991 Hamburg, Germany 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 Kim, Koenig et al., 1991 Seattle, Washington, USA Crossover 9 Healthy men from 19-23 years of age who were actively involved in intercollegiate cross- country 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 Sandstrom, Stjernberg et al., 1991 Sweden Experimental (not crossover) 18 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 Avol, Linn et al., 1992 Downey, California, USA Crossover 34 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 0.01- 0.26 ppm (ambient) Hackney, Linn et al., 1992 Los Angeles, CA, USA Chamber 26 (15 male, 11 female) 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. 4 hour exposures. Exercise periods lasted 7 minutes. Ambient air or 0.3 ppm NO2. Morrow, Utell et al., 1992 Rochester, NY, USA Double-blind Crossover 40 (COPD = 13 male, 7 female; 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 Rasmussen, Kjaergaard, et al., 1992 Denmark Double-blind Crossover 14 (10 male, 4 female) 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 CommentsNull or Negative ResultsPositive ResultsMain Comparison NO2 exposure and pulmonary function (SGaw, PEFR, MEFR, FVC and FEV1) and airway reactivity. 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. 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 never- smokers 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 Study Design Number of Subjects Duration of Exposure NO2 Concentration Subject Description Characteristics of Study Devalia, Rusznak, et al., 1994 Experimental 8 (4 male, 4 female) Non-smoking, mild asthmatic adults aged 18- 45 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. Hazucha, Folinsbee et al., 1994 Chapel Hill, NC, USA Double-blind Crossover 21 (all female) 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 Tunnicliffe, Burge & Ayers, 1994 Double-blind  10 (4 male, 6 female) 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. Drechsler-Parks, 1995 Santa Barbara, CA, USA 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. 2 hours 0.60 ppm NO2 or 0.60 ppm NO2 and 0.45 ppm O3 Jorres, Nowak et al., 1995 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 Wang, Duddle et al., 1995 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. Kelly, Blomberg et al., 1996 Single-blind 44 Non smoking, asymptomatic male and female volunteers (19- 45yrs) 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 CommentsNull or Negative ResultsPositive ResultsMain Comparison 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). 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. 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 Duration of Exposure NO2 Concentration Subject Description Characteristics of Study 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 by- products. 60 minutes 0.3 or 0.6 ppm Strand, Salomonsson et al., 1996 Huddinge, Sweden Crossover 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) Vagaggini, Paggiaro et al., 1996 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. One hour exposure with moderate intermittent exercise (10 minutes every 15 minutes). Ambient air and/or 0.3 ppm NO2 Blomberg, Krishna et al., 1997 Umea, Sweden Crossover 30 (18 male, 12 female) Healthy adults aged 20-30 years (mean 35). Randomized exposure to air or NO2 via chamber. Alternate 15- minute periods of rest and exercise. Exposures separated by > 3 weeks. 4 hours 2.0 ppm Strand, Rak et al., 1997 Huddinge, Sweden Crossover 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. 30 minutes 490 ug/m3 Azadniv, Utell, et al., 1998 Rochester, NY, USA 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). 6 hours 2.0 ppm Strand, Svartengren et al., 1998 Experimental 16 (10 male, 6 female) Non-smoking, mild asthmatic adults aged 21- 52 years with allergy to pollen. Subjects were exposed to NO2 and/or ambient filtered air in an exposure chamber, at least four weeks apart. 30 minute exposures over four subsequent days. Ambient air and/or  500 ug/m3 NO2 CommentsNull or Negative ResultsPositive ResultsMain Comparison 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 by- products 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. 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. 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, B- cells, 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. Results indicate that "short exposure to an ambient level of NO2 followed several hours later by allergen inhalation enhances allergen-induced late asthmatic reaction." 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). Note:  the authors state that there was an increase in early phase response after a single NO2 exposure (p=0.03). Reference Location Study Design Number of Subjects Duration of Exposure NO2 Concentration Subject Description Characteristics of Study Blomberg, Krishna et al., 1999 Umea, Sweden Crossover 12 (8m, 4f) Mean age of 26 years. Exposure once to filtered air and on 4 consecutive days to NO2 via chamber. Intermittent exercise. 4 hours 2.0 ppm 11 Mild atopic asthmatic volunteers, non-smokers, aged 18-45 years. 6 hours 0, 100 ppb O3, 200 ppb NO2, and 100 ppb O3 + 200 ppb NO2 10 Mild atopic asthmatic volunteers, non smokers, aged 18-45 years. 3 hours 200 ppb O3, 400 ppb NO2, and 200 ppb O3 + 400 ppb NO2 Avissar, Reed et al., 2000 Single-blind 21 (12 male, 9 female) Aged 18-40 years, non- smokers with normal spirometry and no symptoms of upper respiratory infection at least 6 weeks prior to study. Controlled exposure via special chamber. Separated by 3 weeks. 3 hours 0, 0.6 ppm and 1.5 ppm 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. Chambers & Ayres, 2001 Birmingham, UK 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 Jenkins, Devalia et al., 1999 Randomized, single-blind Controlled exposure via chamber. CommentsNull or Negative ResultsPositive ResultsMain Comparison 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. 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 post- exposure 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. Exposure to NO2 and O3 on response to inhaled allergen in exercising mild atopics. Reference Year & Season of Study Location Exposure Type Study Design Number of Subjects Melia, Florey & Chinn, 1979 1973 - 1977 England and Scotland, UK Indoor (residential) Cohort 4827 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. Speizer, Ferris et al., 1980 1977 - 1978 Watertown, MA; Kingston, TN; St. Louis, MO; Steubenville, OH; Portage, WI; Topeka, KS, USA Indoor (residential) Prospective Cohort 8866 School children aged 6 to 10 years. Indoor measurements were taken in several homes within the different exposure groups (gas stoves / electric). Melia, Florey et al., 1982 January to March Middlesbrough, England, UK Indoor (residential) Cross- sectional 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). Hoek, Brunekreef et al., 1984 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. Weekly indoor averages in each home were collected using Palmes diffusion tubes in the kitchen, living room and bedroom. Ogston, Florey & Walker, 1985 1980 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. Berwick, Leaderer et al., 1989 1983 New Haven, CT, USA Personal and Indoor (residential) 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. Fischer, Brunekreef et al., 1989 1982 - 1985, Winters Vlaardingen and Vlagtwedde, Netherlands Personal and Indoor (residential) Longitudinal (not reported) Women living in rural (Vlagtwedde) and urban (Vlaardingen) areas. Personal and indoor measurements were taken using passive diffusion samplers. Table 3.5  Epidemiological Studies of the Health Effects Associated with NO2 Exposure Subject Description Characteristics of Study 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 1- year 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). Note: exposures were only measured in a subset of the study population, and the authors state that some of the measurements may be from non- study homes. 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. 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). 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. 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. 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= 1.69- 4.79). Exposure data were based on monitoring in 93% of the subjects' homes. NO2 was measured during a one week period. 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. 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. Main Comparison Null or Negative Results Comments Duration of Sampling Positive Results Reference Year & Season of Study Location Exposure Type Study Design Number of Subjects Subject Description Characteristics of Study Brunekreef, Houthuijs et al., 1990 1985 - 1986, January and December Netherlands Indoor (residential) Cross- sectional 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. Dijkstra, Houthuijs et al., 1990 1985 - 1987 Netherlands Indoor (residential) Longitudinal 1051 Non-smoking Dutch children aged 6 -12 years (mean = 9.1 years). Indoor exposure to NO2. Measurements collected by Palmes' diffusion tubes in kitchen, living room and bedroom. 362 Primary school children, mean age 10.0 years. 319 Mothers of the children in the study, mean age 37.9 years. Neas, Dockery et al., 1991 1983-1988 Watertown, MA; Kingston, TN; St. Louis, MO; Steubenville, OH; Portage, WI; Topeka, KS, USA Indoor (residential) Cohort 1567 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. Quackenboss, Krzyzanowski & Lebowitz, 1991 1986 - 1988, May to November Tucson, AZ, USA Indoor (residential) Cross- Sectional 30 (17 male, 13 female) Asthmatic children between 6 and 15 years of age. Sampling done in kitchens, living rooms, bedrooms and outdoors at each home. Koo, Ho et al., 1990 1985 Hong Kong Indoor (residential, in an industrial area) Cross- sectional Ambient NO2 levels from various sources (smoking, gas cooking, etc.), measured using passive badge samplers. Main Comparison Null or Negative Results Comments Duration of Sampling Positive Results Weekly averages. 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, 41- 60 ug/m3, and >60 ug/m3). 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 1 week NO2 level and respiratory health (cough, wheeze, asthma, FVC, FEV1, PEF, MMEF) 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. 1 week 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. Weekly averages. 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 = 1.04- 2.49) for asthmatics and OR = 1.17 (95%CI = 1.04-1.37) for non-asthmatics per 10 ug/m3 increase in NO2. No effects found in non- asthmatic children. Measured NO2 level and level of reported respiratory symptoms (allergic rhinitis, asthma, bronchitis, chronic chough, chronic sputum, pneumonia, runny nose, tuberculosis and wheeze). Samples were taken over 24 hours. Reference Year & Season of Study Location Exposure Type Study Design Number of Subjects Subject Description Characteristics of Study Adgate, Reid et al., 1992 North Carolina, USA Personal and Indoor (residential) Cross- sectional 20 (13 male, 7 female; 8 African American, 12 Caucasian) Preschool children aged 3 months to 5.5 years who were enrolled day- care. Personal, indoor and school NO2 measurements were taken using active chemiluminescent monitors, Bendix process instruments and passive diffusion monitors. Hackney, Linn et al., 1992 Fall and Winter Los Angeles, CA, USA Personal ? 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 305 3 - 6 year olds who have lived within the survey area for > 1 year Samet, Lambert et al., 1992 1988 - 1991 Albuquerque, NM, USA Indoor (residential) Prospective Cohort 411 Infants (followed from birth for first 2 years). Personal exposures in the home. Infante-Rivard, 1993 1988 - 1990 Montreal, Canada Indoor Case-control 61 cases and 79 controls Cases: newly confirmed asthmatic children aged 3-4  Controls: age matched non-asthmatic children Ambient indoor NO2 levels measured by passive diffusion badges Samet, Lambert et al., 1993 1988 - 1990 Albuquerque, NM, USA Indoor (residential) Prospective Cohort 1205 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. Cross- sectional Maeda, Nitta & Nakai, 1992 1987 - 1990 Three areas in Tokyo, Japan Personal, Indoor and Outdoor (residential) Personal, indoor and outdoor exposures were obtained by passive diffusion badges in each zone. Main Comparison Null or Negative Results Comments Duration of Sampling Positive Results Measurements were taken over one week during the heating season. NO2 exposure level and urinary excretion of hydroxyproline and desmosine. 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). 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. 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. 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. Samples were taken over 48 hours. Reference Year & Season of Study Location Exposure Type Study Design Number of Subjects Subject Description Characteristics of Study Mukala, Pekkanen et al., 1996 Mukala, Pekkanen et al., 1999 Mukala, Alm et al., 2000 Farrow, Greenwood et al., 1997 1993 Bristol, England Indoor Cross- sectional 921 Infants aged 3-12 months born and enrolled in ongoing cohort. Indoor exposure to NO2 in infant bedrooms, using Palmes monitoring tubes. Pilotto, Douglas et al., 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). Personal exposures (children living in homes with unflued gas appliances) and exposures at school (41 classrooms) were monitored. For dose- response, children allocated to <40 ppb, 40- 60 ppb, 60-80 ppb, 80- 100 ppb and >100 ppb groups. Smedje, Norback & Edling, 1997 1993 Uppsala, Enkoping, and other small communities in Sweden Indoor (school) Cross- sectional 627 627 schoolchildren aged 13 to 14 years (includes 40 asthmatics). Schoolchildren exposed to existing levels during school hours. Bernard, Saintot et al., 1997 1994 Montpellier, France Personal Cross- sectional 107 (40 male, 67 female) 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. Demissie, Ernst et al., 1998 1990 - 1992 Montreal, Canada Indoor (gas stoves) Case-control 989 Schoolchildren on Montreal Island (78% caucasian) aged 5-13 years. Living in homes with different cooking fuels. Helsinki, Finland1991 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) Main Comparison Null or Negative Results Comments Duration of Sampling Positive Results 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 No significant relationship was seen between current asthma and NO2. 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). 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) Not given. FEV1 and FVC versus type of cooking and heating fuels used in the home. 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. 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. Reference Year & Season of Study Location Exposure Type Study Design Number of Subjects Subject Description Characteristics of Study Garrett, Hooper et al., 1998 1994 - 1995 Victoria, Australia Indoor (residential) Longitudinal 148 (74 male, 74 female) Asthmatic and non- asthmatic 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. Giroux & Ferrieres, 1998 (not reported) Toulouse, France Indoor (industrial) Cross- sectional 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). Magnus, Nafstad et al., 1998 Oslo, Norway Indoor (residential) Nested case- control 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. Schindler, Ackermann- Liebrich et al., 1998 1990 - 1993, Various seasons 8 cities in Switzerland (Aarau, Basel, Davos, Geneva, Lugano, Montana, Payerne and Wald) Personal Cross- sectional 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. Main Comparison Null or Negative Results Comments Duration of Sampling Positive Results Badges in place for 4 days. 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). 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 = 1.13- 4.49) 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 symptoms (>20 ug/m3 versus <10 ug/m3; OR = 3.62; 95%CI = 1.08-12.08; p=0.09). 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. 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. 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). 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. 2 weeks The measured NO2 levels were compared between children who experienced bronchial obstruction and those who didn't. 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. NO2 exposure level (communities and zones of residences) and  lung function (FEV and FVC). 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 Year & Season of Study Location Exposure Type Study Design Number of Subjects Subject Description Characteristics of Study Gomzi, 1999 1990 - 1991, December to June Croatia Indoor (school) Cross- sectional 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). Rosenlund & Bluhm, 1999 1994, December 4th Stockholm, Sweden Indoor (ice rink) Cross- sectional 155 99 exposed hockey players aged  8 to 28 years (median =13) and 56 non-exposed hockey players aged 12-19 years (median = 14 ). 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. Linaker, Coggon et al., 2000 Southampton, England Personal Longitudinal 63 boys and 51 girls Asthmatic children (7 to 12 years) from non- smoking homes. Weekly personal exposures. Norback, Walinder et al., 2000 1993 Uppsala, Sweden Indoor (school) Cross- sectional 234 School Personnel Passive Sampling in schools. Sanyal & Maduna, 2000 1995 - 1996 Ku-Ntselamanzi Township, South Africa Indoor Longitudinal 1820 Children under the age of 14 from three different socio- economic 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. Shima & Adachi, 2000 1991 - 1993 7 different communities in Japan  (Chiba, Funabashi, Ichikawa, Kashiwa, Eirakudia, Ichihara and Tateyama) Indoor Prospective Cohort 842 (434 boys, 408 girls) Fourth grade pupils aged 9-10. Indoor exposures in subjects homes. Samples taken using passive diffusion badges. Smith, Nitschke et al., 2000 South Australia Personal Cross- Sectional 125 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 Main Comparison Null or Negative Results Comments Duration of Sampling Positive Results 24 hour measurements, colorimetric method (Levaggi modification of Jacob-Hocheiser method). 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). Measured air pollutants only had a slight effect on respiratory health of children. No specific results for NO2 exposure mentioned. 40 hours of monitoring during simulations designed to re- create the conditions that triggered the incident. 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 = 3- 175.8); 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. 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. Six hour area samples were taken three times over a 23 month period  (June- September, October- December, 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. 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. Approximately 22- 26 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. 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. 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. 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 Cross- sectional 202 Four-year-old asthmatic children from south Australia. Indoor exposures were measured with passive- diffusion 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. Ng, Seet et al., 2001 Singapore Indoor (kitchen) Cross- sectional 16 38-62 year-old female persistent asthmatics (6 mild asthma, 3 moderate asthma, 7 severe asthma). Exposure to gas hobs (cooking). Ponsonby, Glasgow et al., 2001 1999 Canberra, Australia Personal and Indoor (school) Cross- Sectional 344 Children 8-9 years old, 33% with asthma. Personal passive samples (separated by home characteristics) and school samples. Main Comparison Null or Negative Results Comments Duration of Sampling Positive Results Two samples were taken for each child for 2 to 12 hours. Relationship between NO2 exposure and chest tightness, breathlessness on exertion, and daytime asthma attacks. Higher levels of NO2 were found in homes with children with asthma than in homes without children with asthma. 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. 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. 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. 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. Longer cooking duration lowered exposures. 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. Kerosene heat+gas Kerosene heater only Gas stove only No NO2 Source Unvented geyser Vented geyser No geyser No Geyser Vented Geyser Dijkstra, Houthuijs et al., 1990 Unvented Geyser Kitchen Living Room Bedroom Outdoor Personal All No Geyser Vented Geyser Unvented Geyser Kitchen Living Room Bedroom Outdoor Classroom Outdoor (school) New Haven, CT, USA Netherlands Netherlands Netherlands London 1977 - 1978, May to April 1982, November and December 1983, Winter 1984 Watertown, MA; Kingston, TN; St. Louis, MO; Steubenville, OH; Portage, WI; Topeka, KS, USA 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 1985 & 1987, January 1987 - 1988, December to January 1985 & 1987, January ug/m3 N/A 1 set of measurements (kitchen, living room, child's bedroom and outdoor) per site. Personal (weekly and peak), Indoor (residential, weekly and peak), Indoor (classroom) and Outdoor (school) 1 week Palmes ppb 23 Housewives 1988, February 1984, April, October and December Indoor and Outdoor (residential) 29 4 homes with electric cookers, 20 with gas cookers, and 5 with gas cookers and kerosene heaters N/A Indoor (residential) Personal Personal, Indoor and Outdoor (residential) 11 homes in Taipei City (urban) and 12 homes in Central Taiwan (rural). 1 week 1 week Palmes ug/m3 Palmes ug/m3 ppb 1 week for Palmes tubes and 2 days for badges. 1 set of measurements (kitchen, living room and bedroom) per site. N/A 56 23 1 measurement per child. N/A N/A N/A 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. 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. Palmes tubes and badges. 1 sample (taken in the living room) every 6 days for 1 year. 1 set of measurements (kitchen, bedroom and living room) per site. At least 1 set of measurements (kitchen, living room and bedroom) per home. 1 set or measurements (personal, kitchen, living room, bedroom and outdoor) per participant. 313 in homes in rural areas and 299 homes in urban areas. Table 3.3  Studies Measuring Personal, Indoor and Outdoor concentrations of NO2 Noy, Brunekreef et al., 1990 Speizer, Ferris et al., 1980 Remijn, Fischer et al., 1985 Berwick, Leaderer et al., 1989 Fischer, Brunekreef et al., 1989 Brunekreef, Houthuijs et al., 1990 Houthuijs, Dijkstra et al., 1990 Melia, Chinn & Rona, 1990 Chan, Yanagisawa & Spengler, 1990 Vlagtwedde and Vlaardingen, Netherlands Taipei and Central Taiwan Veenendaal, Netherlands 612 612 Homes of children participating in the study. Women 876 Indoor (residential) Indoor (residential) Indoor (residential) Personal, Indoor and Outdoor (residential) (not reported) N/A N/A 152 N/A N/A Homes representative of the overall population being studied. Homes of non-smoking, adult women 62 Residential homes N/A N/A 24 hours Bubbler ug/m3 1 week Palmes ug/m3 2 weeks Palmes ug/m3 1 week Palmes ug/m3 110 107 homes and 3 schools 193 107 mothers and 86 children Reference Year & Season of Study Location Exposure Measured # of Sites Duration Sampler Used UnitsSite Description # of People Subject Description Number of Measurements Median 95%ile Electric Gas Electric Gas Electric Gas Portage 3.6 14.7 2.13 1.02 17.6 39.3 Topeka 19.4 31.6 1.26 41.6 73.6 Kingston 10.9 1.43 29.8 St. Louis 17.1 40.8 2.01 1.42 63.3 79.3 Steubenville 21.9 27.4 2.59 2.24 74.5 103.9 Watertown 41.4 54.3 1.14 1.21 95.2 116.3 Kitchen 79 2.2 391 9 Living Room 39 2 241 9 Bedroom 23 1.5 66 8 n Kitchen Living  Bedrm Average 6 89.5 76 105 90 49 41 43 38 71 13 41 25 29 31 4 6.4 6.2 5.2 5.9 Urban Rural Urban Rural Kitchen 120 143 55 60 Living 55 51 24 30 Bedroom 39 23 17 11 Personal 58 55 21 17 Kitchen 71 60 53 38 Living 43 34 26 21 Bedroom 35 15 27 6 Personal 43 41 43 26 Kitchen 49 32 30 24 Living 32 23 23 19 Bedroom 23 11 8 4 Personal 36 23 19 17 n indoor 75%ile 25%ile 597 23.6 24 14 135 40.3 50 24 144 61.7 73 46 Palmes Badges Palmes Badges Palmes Badges Palmes Badges 34.4 25.6 24.5 24.7 9.1 9.3 6.6 10.9 32.1 22.6 20.4 18.8 9.6 8.4 5.9 7 29.7 20.5 17.5 15.4 9 6.5 5 6.5 40.1 25.7 23.5 20.3 9.6 10.5 6.3 5.9 30.8 22.3 19.9 17.3 5.7 6.1 6.4 6.6 1995 1997 1995 1996 1995 1997 1995 1997 29.9 27.6 11.3 13 22.6 21.2 6.1 8.6 42.2 46 14.7 11 27.9 25.3 7.8 8.8 40 40 14 10 43.3 39.6 8.3 14.1 54.8 66 24.6 17 overall kerosene gas 34.7 36.9 19.2 23.3 37.8 24.4 13.7 23.5 65.9 24.1 12.9 21.4 Apr. Oct. Dec. Apr. Oct. Dec. Apr. Oct. Dec. 12 14 12 Per. 25 24 24 1.6 1.6 1.6 34 40 51 Per. (child) 22 22 22 1.5 1.4 1.5 Kitchen 28 30 30 2.2 2 2.1 Living Room 22 24 24 2 1.9 2 Bedroom 16 17 16 1.5 1.4 1.5 Peak 144 614 10 Peak (child) 139 767 7 Peak 209 2509 35 Peak (living) 129 1182 19 Values collected used to estimate personal exposures ranging from 11 to 139 ug/m3, with a geometric mean of 39 ug/m3. 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. Unvented water heaters a major source of NO2 in Dutch homes.  Inconclusive differences between urban and rural results. 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. 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. 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. Taipei City Central Taiwan Good test/retest correlation between 1985 and 1987 indoor results (results not shown), showing excellent reproducibility. Central TaiwanTaipei City 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 24- hour standard.  Peak levels in excess of 1100 ug/m3 occurred regularly. Results Median/Geometric Mean Maximum Geometric Standard Deviation Minimum Standard DeviationMean Measured Concentrations of NO2 Reference Year & Season of Study Location Exposure Measured # of Sites Duration Sampler Used UnitsSite Description # of People Subject Description Number of Measurements 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 St. Louis Steubenville Portage Topeka All Gas Stove Smoker Controls Kerosene heater Gas stove Smoker Controls Overall Summer 1998 Winter 1988-1989 Summer 1989 Winter 1989-1990 Summer 1990 Winter 1990-1991 Japan Hong Kong Tucson, AZ, USA Lambert, Samet et al., 1992 Liao, Baconshone & Kim, 1991 Quackenboss, Krzyzanowski & Lebowitz, 1991 Madany & Danish, 1991 1985, Winter 1990, July to September 1983, Winter and Summer 1986 - 1988, May to November Winter and Summer 1989 1988-1991: October to March N/A 1657 Residences of subjects participating in the study. 2 sets of measurements (kitchen, living room, bedrooms and outdoor) per site. Watertown, MA; Kingston, TN; St. Louis, MO; Steubenville, OH; Portage, WI; Topeka, KS, USA Indoor (residential) Chapel Hill, NC, USA Los Angeles, CA, USA Albuquerque, NM, USA Indoor (residential) N/A 1 set of measurements (kitchen and living room) per site. 3 days Homes built between 1980 and 1984 with wood frame construction. 13 Homes evenly distributed throughout the country. 1 set of measurements in each home (kitchen, living room and main hallway). 1 set of measurements (indoor and outdoor) per site. ppb 20 mothers and 20 children, aged 0 to 5 years. SUMMER WINTER20 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 ppb Yoshino, Matsumoto et al., 1990 Adgate, Reid et al., 1992 Hackney, Linn et al., 1992 Neas, Dockery et al., 1991 Samet, Lambert et al., 1992 Samet, Lambert et al., 1993 Schwab, McDermott et al., 1994 Bahrain, Persian Gulf Indoor (residential) uL/LN/A 35 shops (opening directly on to street) and 35 offices (serving 20+ employees). 4 to 12 hours Badges ug/m3 Badges 70 Indoor and Outdoor (shops and offices) N/A N/A ug/m3 (not reported) Indoor (residential) 32 N/A 7 days Palmes N/A 2 weeks Palmes 2 sets of measurements per home (kitchen, living room and bedroom) per site.  1 in summer and 1 in winter. ppb 657 446 homes with gas cookers and 211 homes with electric cookers. Indoor and Outdoor (residential) N/A 1 week Palmes ug/m3 N/A N/A Personal and Indoor (residential) 1 week Continuous monitoring done with a chemiluminesce nt analyzer. Passive and personal samples done with Palmes tubes. Personal N/A N/A 26 15 men and 11 women aged 47-69 with history of heavy smoking. 24 hours 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. ug/m3 653 Residential homes. N/A N/A 2 weeks Palmes Badge 14 per subject (consecutive 24- hour measurements for 2 weeks). At least 1 set of measurements (kitchen, living room and bedroom) for each summer and winter season between 1988 and 1991. Results Median/Geometric Mean Maximum Geometric Standard Deviation Minimum Standard DeviationMean Measured Concentrations of NO2 22 29 470 420 10 18 63 49 7 12 13 21 11 11 31 60 10 11 20 29 11 9 9 11 4 25 mean median 65 59 142 29 79 69 161 39 20 16 94 5 108 84 1000 14 15.2 6.1 26.5 4.5 22.1 10.4 54.3 10 52.3 28.4 141.2 14.5 26 8.6 47 16.7 1.2 0.6 3 0.4 n annual winter summer No 63 12.5 10.2 15.9 Yes 162 27.9 31.5 25.5 No 173 6.1 7.3 5.9 Yes 91 11 23.1 5.9 No 69 16 15.4 17.7 Yes 208 31.3 35.5 29 No 148 11.4 11.7 12.3 Yes 93 24.2 31 12.3 No 194 5.7 5.9 6.1 Yes 110 17.2 20.1 15.5 No 169 7.4 8.4 7.5 Yes 87 16.7 21.4 14.2 No 816 8.6 8.9 9.2 Yes 751 23.5 28.7 20.9 Electric Gas Elec. Gas Elec. Gas Kitchen 13.6 36.8 19.4 58.5 9.2 26 Living Room 13.2 31.3 18.5 47.2 9.1 24 Bedrooms 11.5 26.4 17.7 34.3 7.5 19 Outdoors 19.4 25.8 28.5 34.1 13 18.9 Contin. n Contin. Palmes Child Mother Contin. Palmes Child Mother 6 13 19 10.5 14.4 5.6 10.7 5.6 4.4 7 6.5 7.3 10 7.6 2.6 4 5.3 2.5 7 3.8 5 6 6.2 2.8 5.1 3.8 2.3 n Contin. Palmes Child Mother Contin. Palmes Child Mother 5 70 71.4 50.6 44.1 81.2 73.2 41.6 41.1 175 5 22.4 26.5 19.3 23.8 15 14.2 17.8 17 37 5 12 14.7 16.3 16.9 12.2 14.6 13.2 14.4 30 5 6.4 4.6 9.5 6.8 3.6 3.2 3.5 1 11 101 13 235 59 20.32 11.7 7.97 (217) 11.6 6.16 5.11 18.1 10.84 6.39 28.58 19.76 7.85 (415) 26.33 23.3 11.77 22.89 15.33 5.75 15.25 9.03 7.35 (662) 8.31 4.92 5.69 13.66 8.07 6.15 27.72 16.92 7.3 (578) 24.81 16.61 5.01 22.01 13.88 6.27 14.8 9.24 6.95 (591) 9.57 4.54 3.87 13.29 8.44 5.97 20.87 (1001) 15.01 (994) 6.29 (321) 13.02 12.84 4.32 17.33 12.42 5.59 NO2 source? 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. 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. Principal source of NO2 in homes with asthmatic children was outdoor air.  Only 5 came from homes with gas ranges. 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. 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. SUMMER WINTER 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. Gas stove with pilot No Pilot Electric Gas with pilot No pilot Electric Gas stove with pilot No pilot Electric Reference Year & Season of Study Location Exposure Measured # of Sites Duration Sampler Used UnitsSite Description # of People Subject Description Number of Measurements 1-hour (both sets) 24-hour March 24-hour June 24-hour September 24-hour December Personal Indoor Outdoor Gas appliances No gas appliances Gas Stove No Gas Stove 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 Urban Rural 0% fresh air (4.5 days) 100% fresh air (1 day) 50% fresh air (1 day) 0% fresh air (1 day) Reported here with the mean concentrations.  Measurements taken under different ventilation conditions. Bergland, Braback et al., 1994 New England, USA 41 Sundsvall, Sweden 70 Ice skating rinks Indoor and Outdoor (ice rink) Montreal, Canada Sega, Fugas & Kalinic, 1992 1990-1991, February to February Tokyo, Japan Zagreb, Croatia 1990, March to December 1987-1990, Fall to Winter 1992, January (not reported) N/A 32 Children playing hockey and 9 rink personnel. Badge Japan Sundsvall, Sweden ug/m 3 ppm Athens, Greece 1 old ice rink and 1 new ice rink. Personal and Indoor (ice rink) 2 1991, January Winter 1991, February Vermont, USA Indoor (recreational) 9 Enclosed Skating Rinks N/A Gastec monitor 8 at each site during one hockey game. 1 month for each set. 1 N/A Personal N/A 1 week Palmes ug/m390 Residential homes N/A Housewives ug/m3 ug/m3 54 (not reported) Badges for personal, residential and school samples. Continuous chemi- luminiscent analyzers at fixed stations. 24 hours N/A 24 urban and 30 rural homes; 1 urban and 1 rural school Personal and Indoor (residential) 85 85 (76 male, 9 female) Personal, Indoor and Outdoor (residential), Indoor and Outdoor (school) and Outdoor (fixed ambient stations) 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. 2 sets of measurements (kitchen and living room) per site.  1 taken in winter and 1 taken in summer. 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. Argiriou, Asimako- poulos et al., 1994 Infante-Rivard, 1993 Loizidou, Lagoudi & Petrakis, 1992 Brauer & Spengler, 1994 Nakai, Nitta & Maeda, 1995 Maeda, Nitta & Nakai, 1992 Kawamoto, Matsuno et al., 1993 Paulozzi, Spengler et al., 1993 Near surgery rooms in the basement of the building 56 1988 - 1990, January to December Indoor and Outdoor (hospital) N/A Continuous chemi- luminescent analyzer. 62 2 sets (indoor and outdoor) of 1- hour averages; 4 sets (indoor and outdoor) of 24-hour averages. 62 2 days Badges 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). Personal, Indoor and Outdoor (residential) Indoor (residential) 140 Children.  61 cases with asthma and 79 healthy controls.  20% subset of a larger study population. N/A 24 hours Badge Residential apartment units. 20 with oil heaters; 17 with kerosene heaters; 1 with a gas fan heater; 47 with electric or "clean" heaters. 1 personal and indoor measurement per subject/site. 1 week Badge University students aged 21-34 years.  21 smokers and 64 non- smokers. ppb1 per child ppb School children followed from 5th (1990) to 6th (1991) grade. N/A Reported here with mean concentrations.  Ideally, 1 set of measurements (bench, rink side, resurfacer and outdoor) per site. 7 days PalmesN/A ppb ug/m3 12 hours for rinkside measurements and 1 hour for personal measurements. Results Median/Geometric Mean Maximum Geometric Standard Deviation Minimum Standard DeviationMean Measured Concentrations of NO2 indoor outdoor I/O ratio indoor outdoor indoor outdoor indoor outdoor 34.8 100 13.26 53.02 127 404 5 22 51.8 123.3 0.42 8.1 35 65 180 39 53 51.1 139.6 0.37 8.1 33.4 67 198 38 80 46.6 127.3 0.37 6.9 32 62 184 34 55 49.3 104.4 0.47 7.1 20.1 62 131 32 64 Zone A Zone B Zone C Zone A Zone B Zone C 44 36.8 28.7 17.5 13.4 9.3 45.8 39.6 35.3 19.1 17.8 18.9 43.3 35.9 19.7 8.3 4.9 1.9 Living Kitchen Winter Summer Winter Summer Winter 39 97 204 89 6 8 Summer 35 65 Winter 22 26 Summer 24 28 n mean 6 17.6 8.26 134 9.2 7.57 295 11.3 13.7 13.5 55.7+/- 51.7+/- 21.8+/-8.1 20.5+/- 219 474 290 (estimate) 1 2 3 0 0.05 1 0.02 0.3 0.25 0.65 0.4 0.3 0.35 0 0.22 <0.1 <0.1 0.38 0.5 0.05 0.31 <0.5 0 0 0 0 1 1.38 1.28 1.22 0 0 0.25 0.32 0.32 0.36 Week 1 Week 2 Week 3 Week 4 Week 1 Week 2 Week 3 Week 4 Week 1 Week 2 Week 3 Week 4 Bed. 8 3.3 18 4 Out. (h) 13 5.3 28 8 Class. 15 13 18 22 Out. (s) 14 11 20 23 Pers. 20 24 14 30 55 46 4.7 69 11 13 13 14 551 25 Fixed 40 29 41 44 11 12 8.9 17 82 13 Bedrm 5 2.7 10 1 Out. (h) 5 1.8 11 3 Class. 8 3 6 8 Out. (s) 5 4 9 6 Pers. 24 8 6 8 82 7.2 5.6 5.5 8 6 6 6 561 2 Rink Side Personnel Player Rink Side Player Rink Player Rink Player 256 199 (9) 315 (10) 4557 (16) 4368 (10) 95 164 2170 2553 Old Rink 461 Old Rink 73 84 (4) 64 (2) <100 (2) 2501 (2) 18 Old 339 Old 81 127 (4) 61 (2) <100 (1) 350 (4) 749 (4) 52 152 505 Old Player 526 Old <100 167 (4) 112 (2) 123 (1) 1189 (4) 2027 (2) 58 441 New Rink 7000 New 207 New Player 7946 New Player 283 n mean Outdoor 54 17.6 2.4 193 0.44 Resurfacer 57 128 3.6 1428 3.11 Bench 57 169 4 2141 3.11 Rinkside 53 168 4 2470 1.76 27 221.1 3.2 30 134 4.6 25 214 3.3 31 140 4.3 Enclosed 58 169.5 4 Open Rink 9 16.2 1.57 7 329.7 3.7 51 154.7 4 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. Cat. Converter on No Ventilation Ventilation System 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. Levels up to 60 times higher than the 24- hour 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. Old Arena New Arena Game Average 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. 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). 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? 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. PERIOD No noticeable difference between cases and controls with regard to prevalence of other emission sources. No significant differences in exposure levels between smokers and non- smokers (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. No Cat. Converter Propane-Fuelled Gasoline-Fuelled Old Arena New Arena Reference Year & Season of Study Location Exposure Measured # of Sites Duration Sampler Used UnitsSite Description # of People Subject Description Number of Measurements Rink # 1 (enclosed) 2 (enclosed) 3 (enclosed) 4 (enclosed) 5 (enclosed) 6 (enclosed) 7 (enclosed) 8 (outdoor) 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) (during work hours) Building 1 Building 2 Building 3 Building 4 Reference No Gas Used Natural Gas Propane-Butane Convection Kerosene Reflection Kerosene Kerosene Fan Town Gas Propane Gas Electric Winter Fall Spring Massachusetts, USA (not reported) 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. 8 sets of measurements (kitchen, living room, master bedroom and outdoor) per home.  1 for each season of the study. ppb Continuous chemi- luminescent analyzer. ppb Winter Winter Boston, MA, USA Residential homes Goteborg, Sweden 4 office buildings in high traffic areas, and 1 reference site in a low traffic area. 90 1987 - 1988, May to May Indoor and Outdoor (office) 5 nL/L 4 days Los Angeles, CA, USA ppb 14 hours Badges Badges Length of hockey game (approximately 1.5 hours). N/A N/A N/A N/A 1 set of indoor (taken at the building exhaust) and outdoor (taken at the building intake) measurements per site. Palmes Room measuring 20m2 and 45m3. N/A N/A 2 weeks 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. Continuous chemi- luminescent analyzer. ppm Maximum of 3 sets of measurements (indoor and outdoor) per site.  One in each of winter, summer and fall. 3 hours for each measurement (plus 3 hours pre- burning and 3 hours post- burning) Lee, Yanagisawa & Spengler, 1994b Lee, Yanagisawa et al., 1994a Spengler, Schwab et al., 1994 Lee, Yanagisawa et al., 1996 Ekberg, 1995 Sega, 1995 Lee, Yanagisawa et al., 1995 Arashidani, Yoshikawa et al., 1996 1993, September 1984 - 1986, November to October Summer and Winter 1984 - 1996, Winter, Summer and Fall (not reported) Boston, MA, USA Palmes ug/m3 8 7 enclosed ice rinks and 1 outdoor ice rink. 48 hours for the main study and 24 hours for the micro study. Badge ppb 517 Residential homes 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. Indoor and Outdoor (ice rink) N/A Indoor and Outdoor (ice rink) 1 N/A 2 weeks Palmes Personal, Indoor and Outdoor (residential) 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. 482 Residential homes 752+ 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. Adults.  682 participated in the main study, and 70+ participated in a more focussed micro study. N/A Indoor and Outdoor (residential) N/A N/A N/A N/A 1 measurement (living room) per site. 1 week Emission from space heaters Zagreb, Croatia Japan 1 Indoor (residential) 550 Indoor and Outdoor (residential) 192 single dwelling units (SDUs);  207 small multi- dwelling units (SMDUs); 131 large multi-dwelling units (LMDUs) Results Median/Geometric Mean Maximum Geometric Standard Deviation Minimum Standard DeviationMean Measured Concentrations of NO2 Rink Outdoor Rink Outdoor 538 49 1 68 342 59 934 2 46 688 42 13 752 33 3 35 2729 12 4 325 2676 28 368 1531 38 547 38 5 97 752 6 83 807 7 93 37 N/A 8 13 day 1 day 2 day 3 day 4 day 5 684 564 306 406 52 671 640 346 412 45 673 637 300 400 41 699 657 292 421 48 718 137 234 437 55 665 618 288 394 31 678 645 365 387 103 679 614 332 416 47 689 291 383 50 415 289 177 226 31 318 198 153 186 31 645 610 291 271 39 24 36 12 26 25 n mean median max 25%ile 661 38.14 17.95 36.4 162.4 25.2 669 37.19 19.36 33.6 197.4 23.8 682 37.57 17.45 35.2 137.4 25.4 648 27.23 16.14 24.6 153.9 16.7 660 38.26 20.91 35.8 137.5 23 intake exhaust intake exhaust 26 22 33 24 20 14 37 24 18 12 46 30 20 40 34 64 10 Summer Winter Summ. winter summer winter sum. winter 26 22.2 12.1 7.9 62 33 8 8 36.4 39.5 19.6 35.5 83 204 5 4 38.6 39.3 16.6 37.3 71 141 9 11 0.36 0.1 0.07 0.27 0.04 0.03 0.53 0.12 0.16 0.12 0.02 0.03 0.28 0.06 0.05 SDU SMDU LMDU Single Small M Large M Indoor 17 28.9 26.8 10.8 14.9 20 Outdoor 17 23 23.6 6.2 6.8 9.6 I/O 1.08 1.29 1.54 Indoor 17.8 30.2 25.4 11.9 19.3 22.1 Outdoor 18.4 25.1 25.4 4 6.9 5.4 I/O 0.97 1.28 0.97 Indoor 17.3 28.7 29.1 7.9 7.9 17 Outdoor 15.9 23.7 24.5 6.3 6.9 9.7 I/O 1.16 1.18 1.03 Outdoor levels contribute more to indoor levels in the summer than the winter, due to better ventilation (open windows). Fuel type influences exposure. 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. 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. 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. #3#1 #2 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. 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. Reference Year & Season of Study Location Exposure Measured # of Sites Duration Sampler Used UnitsSite Description # of People Subject Description Number of Measurements Home A B C D E F G H I J K L Propane Gasoline Electric/Outdoor Residential Office Restaurant Canada Finland Norway Slovakia Japan China USA Czech Denmark Outside Kitchen Living Room Bedroom Kitchen Living Room Bedroom 1994, Fall 1 indoor and outdoor measurement at each site. Simultaneous indoor and outdoor tests were done at 6 residences, 6 offices and 6 restaurants in both cities. 18 enclosed ice rinks and 1 outdoor ice rink. Indoor and Outdoor (ice rink) ug/m3 Boston, MA, USA Seoul and Taegu, Korea 36 Indoor/Outdoor (residential, office and restaurant) Indoor and Outdoor (ice rink) 19 ug/m3 PalmesChildren 9-11 years of age. 46 15 measurements per child (7 weeks in winter and 8 in summer). 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. Preschool children aged 3-6 years. Residential homes N/A Personal N/A N/A 172 N/A Indoor and Outdoor (residential) 12 Huddersfield, England 40 Indoor and Outdoor (residential) Palmes 3 consecutive sets of measurements (kitchen, living room, bedroom and outdoor) for each site. 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 2 weeks Baek, Kim & Perry, 1997 Cotterill & Kingham, 1997 Ross, 1996 Yoon, Lee et al., 1996 Mukala, Pekkanen et al., 1996 Linaker, Chauhan et al., 1996 Brauer, Lee et al., 1997 Southampton, England Helsinki, Finland Southern England 1991, Winter and Summer International 1993 - 1994, May to May 1994 - 1995, November to February 1994, January to March 1994 - 1995, Summer and Winter 1994, Winter 1 set per rink.  Includes 2 indoor measurements and 1 outdoor. 1 week Palmes 1 week Palmes and continuous. 1 week 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. N/A N/A ppb N/A 4 sets of 2 measurements at each rink. 1 week Palmes nL/L 1 set of measurements (kitchen, living room, bedroom and outdoor) per site.  Palmes tubes and continuous monitors were used simultaneously. N/A 24 hours Advantech badge ppb 1 week Palmes ppb332 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 N/A N/A ug/m3 Results Median/Geometric Mean Maximum Geometric Standard Deviation Minimum Standard DeviationMean Measured Concentrations of NO2 n mean Personal 97 36 257 11 Kitchen 95 52 447 14 Living Room 95 40 315 14 school 1 school 2 57 54 63 77 27 23 16 24 all 21 45.8 11 urban 27.4 suburban 18.2 Fuel Kitchen Living Bedrm Gas 38 / 215 16 / 70 Gas 22 / 259 14 / 120 18 / 180 Gas 21 / 282 15 / 102 16 / 115 Gas 18 / 125 15 / 100 11 / 41 Some 13 / 53 9 / 37 4 / 34 Electric 12 / 44 8 / 28 Electric 3 / 13 0 / 5 3 / 19 Gas 32 / 293 25 / 295 15 / 305 Gas 22 / 320 13 / 191 10 / 250 Gas 17 / 100 10 / 56 2 / 16 Gas 25 / 169 11 / 49 Some Electric 33 / 211 21 / 115 n Nov. Dec. Jan. Feb. Nov. Dec. Jan. Feb. Nov. Dec. Jan. Feb. 5 443 93 212 190 221 21 280 146 447 74 72 100 724 56 12 55 64 46 55 26 39 22 42 46 44 33 34 146 17 2-Jan 37 36 22 20 37 21 Indoor Outdoor Indoor Outdoor Indoor Outdoo Indoor Outdoor Indoor Outdoor 33 32 22 14 24 29 96 67 9 12 22 31 10 13 19 29 58 73 9 10 58 42 22 14 56 40 105 77 21 19 Bench Rink End Outdoor I/O ratio Bench Rink Outdoor I/O ratio Bench Rink Bench Rink End Bench Rink End 333 325 14 19.5 125 117 12 9.2 3.9 3.9 2680 3175 5 5 173 173 9 41.4 81 75 7 13.4 3.7 3.9 1023 998 1 1 97 88 12 7.8 51 46 9 4.5 3.2 3 659 566 6 8 53 43 12 4.4 41 33 12 3.5 2.1 2 140 137 12 11 123 129 24 5.9 85 90 22 3.8 2.4 2.4 462 405 25 29 12 14 11 0.985 14 17 9 0.8 1.9 1.6 23 26 1 1 342 262 25 11.2 137 108 22 5.8 3.5 3 1768 1046 21 22 35 29 9 3 13 15 6 2.4 2.6 2 323 194 1 5 250 287 24 4.5 70 66 20 2.2 5.7 6.4 1131 1504 7 8 period 1 period 2 period 3 overall period 1 period 2 period 3 overall overall overall 37 44 39 40 4 5 6 6 55 25 41 44 46 44 32 34 37 34 175 7 23 25 27 25 13 14 20 16 118 4 17 18 18 18 9 8 8 8 52 5 gas electrical 68 19 33 17 22 14 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. Significant difference between urban and suburban exposures attributable to automobile traffic. 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. 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. 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. 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. 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. Playground Week 1 Playground Week 2 Classroom Week 1 Classroom Week 2 Reference Year & Season of Study Location Exposure Measured # of Sites Duration Sampler Used UnitsSite Description # of People Subject Description Number of Measurements TSTE ST Personal Kitchen Living Room Outdoor (home) 1 2 3 4 5 (winter average) School 1 School 2 School 3 School 4 5 Gas Stoves 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 1993, Spring 1990 - 1991, Winter and Spring 1993, March 1996, January to February 1993-1994, Winter 1992, April to September October in 1994; April, May and June in 1995 Raaschou-Nielsen, Skov et al., 1997 Bernard, Saintot et al., 1998 Colbeck, 1998 Lee, 1997 Lolova, Uzunova et al., 1997 Pilotto, Douglas et al., 1997 Pennanen, Salonen et al., 1997 ppb 1994, March to October 1994, November to March Indoor arenas of different sizes, with different heating, ventilation and resurfacing technology. Classrooms in 8 different schools.  4 with unflued gas heating and 4 with electric heating. Sydney, Australia Bulgaria Finland Bristol, England Badges ppb Badges 1 week Montpellier, France Colchester, England Personal and Indoor (residential) (not reported) Homes of study participants. Indoor (shops) and Car Parks Farrow, Greenwood et al., 1997 Smedje, Norback & Edling, 1997 Alm, Mukala et al., 1998 Mukala, Pekkanen et al., 1999 Mukala, Alm et al., 2000 Helsinki, Finland Copenhagen and surrounding rural areas, Denmark. Uppsala and Enkoping, Sweden (not reported) Hong Kong Indoor and Outdoor (ice rink) Classrooms in two high schools. Homes of participating children.  97 located within 10 km of Copenhagen city centre; 99 located 30 to 50 km away from Copenhagen city limits. Indoor (classroom) 41 Personal and Indoor (classroom) 28 Personal, Indoor and Outdoor (residential) 196 5 ppbInfants aged 3 to 12 months. 1 set of measurements (personal, infant's bedroom and outdoor) per participant. 2 weeks Palmes Indoor and Outdoor (residential) 921 Homes of infants participating in the study. 921 Indoor/Outdoor (staff quarters) 15 units in each of 2 staff quarters buildings.  TSTE = Tsim Sha Tsui East and ST = Shatin N/A N/A 20 minutes nL/L30 4 sets of measurements (indoor and outdoor) at each site. Teflon bag and pump (1 L/min) Children aged 10-12 years. Homes of participating children: 5 in Lulin; 5 in Al. Stamboliiski; 5 in Vrasta; 5 in Assenovgrad 1 set of measurements (personal, kitchen, living room and outdoor) per child/site. Personal, Indoor and Outdoor (home) 20 20 N/A N/A 2 days of measurements at each site. 1 measurement per classroom. N/A Children between 4 and 12 years of age. 12 days Palmes ug/m3 Day 1= 5 hours during regular rink usage;  Day 2 = 3 hours during a hockey game Continuous chemi- luminescent analyzer. ug/m3 ug/m3Badges 121 6 hours for the classroom measurements, and up to 4 hours for the evening personal measurements. 3 per day in each classroom for 9 weeks.  4 evening measurements for each of the 121 children. Children attending the 8 schools.  Only those exposed to gas appliances (and no tobacco smoke) at home were chosen for personal monitoring. N/A 196 1 week 1 set of measurements (personal, child's bedroom and outdoor) for each child/home. Personal, Indoor and Outdoor (day care) 8 4 urban (U) and 4 suburban (S) daycare centres. 219 Preschool children  Palmes ug/m3 Reported here with the median concentrations.  Measurements made of 6 consecutive weeks in winter and 7 consecutive weeks in spring. 1 week 107 40 adult men and 67 adult women. Reported here with the mean concentrations.  1 set (personal and kitchen) per participant. 2 weeks Palmes ug/m3 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. N/A N/A 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. 1 week Palmes ug/m3 Results Median/Geometric Mean Maximum Geometric Standard Deviation Minimum Standard DeviationMean Measured Concentrations of NO2 median gmean Indoor 6.8 6.9 86 0.6 Outdoor 12.6 12.2 46 1.7 indoor outdoor I/O indoor outdoor I/O I/O 44.8 57.6 0.78 15.1 13 0.87 0.7 29.3 29.8 0.97 16.1 13 1.03 0.89 Lulin Al. Stam. Vrasta Assen. 14.5 59.2 4.1 7.7 116 1.91 55.8 154 5.1 35.3 405 2.29 7.1 66.1 5 6.8 125 3.33 9.5 109.5 10.5 16.6 208 4.51 DAY 1 Mean Mean 1-hour 15-min resurf. 350 590 610 640 propane 130 210 320 320 gasoline 10 9 10 10 electric 6090 7310 7440 7530 propane 6230 2100 2320 2500 propane Gas Electric 50.4 22 74.4 13.8 24.8 11.2 103.6 7.8 Urban FD ~ 19 ~ 31 ~ 6.5 Rural FD ~ 5 ~ 10.5 ~ 2.5 Urban BR ~ 6.5 ~ 13 ~ 2 Rural BR ~ 2.5 ~ 8.5 ~ 1 Urban P ~ 8 ~ 21.5 ~ 4.5 Rural P ~ 4 ~ 7.5 ~ 1 9 2 n winter spring winter spring Personal (U) 658 25 28 1.4 1.4 Personal (S) 829 17 17 1.5 1.4 Indoor (U) 46 36 46 1.2 1.5 Indoor (S) 41 29 25 1.2 1.4 Outdoor (U) 45 40 49 1.3 1.6 Outdoor (S) 36 27 25 1.5 1.5 n Kitchen Pers. Kitchen Pers. 81.4 11.5 Men 14 30.3 31.6 17 9.8 Women 15 37.6 37 15 19.4 Both 29 34.1 34.4 16.2 15 Men 13 18.7 31.2 14 12.6 Women 14 16.4 23.3 5.8 5 Both 27 17.5 27.1 10.5 10 24.5 34 13 25.6 38 17 90 58 60 43 51.3 78 54 56 42 49.4 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. 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. 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. Though kitchen values varied considerably between those with gas cookers and those without, personal exposures were not significantly different. For shops, indoor/outdoor ratios - 0.34- 0.54, avg. 0.44. 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. DAY 2 No correlation between CO and NO2 levels.  High levels in rinks with propane resurfacers.  No correlation between indoor and outdoor NO2. Car parks had similar NO2 concentrations as those measured at curbside.  Concentrations in payment booths higher than those in shops. 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. 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. Reference Year & Season of Study Location Exposure Measured # of Sites Duration Sampler Used UnitsSite Description # of People Subject Description Number of Measurements No NO2 Source Gas Stove Gas Heater Smoking Multiple Personal Indoor Outdoor 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 original5 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. Levy, Lee et al., 1998 Pennanen, Salonen et al., 1998 Magnus, 1998 Levy, 1998 Schindler, Ackermann-Liebrich et al., 1998 Monn, Brandli et al., 1998 Garrett, Abramson et al., 1998 1994 - 1995, March to February 1996: Winter (not reported) 1992 - 1995 1993 - 1994, Winter and Summer Homes and workplaces of all participants. 568 N/A 37 Finland 306 Indoor (ice rink) 16 Personal, Indoor (daycare), Indoor and Outdoor (residential). Personal, Indoor and Outdoor (residential) Urban, rural and alpine regions of Switzerland Oslo, Norway 3 personal, 3 indoor and 12 outdoor measurements for each participant. 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) Children less than 2 years of age. Reported here with mean concentrations.  1 set of measurements (personal, kitchen, bedroom, living room, outdoor and daycare) for each participating child. 2 weeks Palmes ug/m3 International. 18 cities in 15 countries. Indoor (residential) Personal and Indoor (ice rink) Personal, Workplace, Indoor and Outdoor (residential) Latrobe Valley, Australia Boston, MA, USA Hong Kong Mumbai, India 80 Residential homes Indoor and Outdoor (residential) Badge ppb Personal, Indoor and Outdoor (residential) 37 Residences of study participants. 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. 2 days Badge Leung, Lam et al., 1998 Kulkarni & Patil, 1998 Garrett, Hooper & Hooper, 1999 1996, February and April 1994 - 1997, Winters 1994 - 1996, Winter 21 participated in winter study and 22 participated in summer study.  Six subjects participated in both winter and summer. N/A 4 days Modified Badge ug/m3 6 sets of measurements (kitchen, living room, bedroom and outdoor) for each household. Palmes ppb 19 Enclosed Skating Rinks (not reported) Resurfacer drivers 1 week in 1994- 1995; 7 to 17 hours in 1995- 1997 Palmes in 1993- 1994; Badges in 1995-1997. ppb 1 set of measurements (kitchen, living room and bedroom) per site. > 570 1 week 4 per site in winter 1993-1994.  3 per site in winter 1995-1996.  5 per site in winter 1996-1997. 40 High-rise apartment units. N/A N/A Adults Reported here with the mean concentrations.  1 set of measurements (personal, home and office) for each participant. Palmes ug/m3560 2 days Home of children participating in the study 306 N/A 1 week Homes of participants. 1 week 2 for resurfacers retrofitted with ECT, and 3 for resurfacers with original ECT. Palmes ug/m3N/A ppb Results Median/Geometric Mean Maximum Geometric Standard Deviation Minimum Standard DeviationMean Measured Concentrations of NO2 n Bedroom Living Kitchen 15 5.8 7.2 7.3 17.7 <0.7 15 12.1 12.8 15.3 46.1 <0.7 14 9.6 13.1 14 50.1 <0.7 7 10.8 11.5 12.6 52.9 1.8 29 21.3 27.7 20.5 246 1.8 Winter Summer Winter Summer Winter Summer 43.7 23.6 16.0 2.9 87.5 42.9 40.8 26.2 17.1 12.2 80.9 51.2 38.7 21.5 13.7 3.2 77.2 48.4 30.9 69.1 10.1 31.7 73.7 6.5 48.7 157.9 20.5 prop. gas. elec. Year 1 (1994-132 42 33 Year 2  117 85 29 Year 3 (1996-164 107 34 n Indoor Outdoor Work Personal Indoor Outdoor Work Pers. 29 10.7 21.3 14.3 15.7 6.4 6.7 1.5 5.6 44 25.4 35 24.8 27.5 14.2 10.2 5.6 9.4 15 16.8 30.5 26.1 24.1 5.8 5.2 6.3 5.8 31 5.5 14 24.1 15.1 3.2 5.3 4.7 2.8 31 12.3 37.2 26 20.5 7 8.2 8.4 4.1 33 9 15 20.2 17.5 5.6 6.7 11.1 12.8 21 40.8 38.7 46.3 43.7 17.1 13.7 45.3 16 59 23.1 22 26.9 28.3 14.1 13.8 10.4 14.2 30 41.9 16.4 26.4 41.2 42 7 10.6 23.9 33 43.2 52.2 35 47.9 14.8 20 16.1 15.5 40 38.7 41.7 51.9 50 18.2 16.2 40.3 28.5 30 62.7 37.7 106.1 41.6 24.4 15 13.1 9.5 30 7.8 13.8 19.9 12.9 4.4 8.2 2.9 2.8 15 34.4 48.5 56.2 51.5 12.9 10 18.6 16.4 15 23.4 25 30 25.8 11.3 11.5 8.8 6.5 33 8.3 11.9 10.6 11 6.3 5.5 3 5 61 21.5 35.1 34.2 25 12.5 10.3 10.9 7.3 20 19.2 33.7 26.2 28 15.8 20.1 9.1 10.7 n mean 306 15.5 7 59 <2 80 14.9 6.6 38 5 296 14.7 6.5 43 2 79 13.2 5.4 33 5 302 25.3 10.9 60 5 141 16.9 9.5 60 <2 personal indoor outdoor pers. indoor outdoor personal pers. pers. 39.6 35 46.9 15 15 21 37 78 19 30.3 25 39.7 13 12 19 31 98 4 35.3 33 46.8 13 14 21 35 84 8 26.4 17 30.8 10 7 14 24 89 3 21.6 16 24.4 8 6 12 21 48 8 21.4 13 19.9 8 5 9 20 62 7 20.7 12 20.2 8 5 9 20 37 4 20.1 12 15.8 7 5 7 18 49 5 1994 1995 1996 1994/1995 1996 1994/19 95 1996 650 147 1750 400 100 20 125 69 161 275/150 300 25/25 75 NO2 exposure higher than reported by Koo et al.  Indoor levels generally lower than outdoor levels, with the exception of the kitchen. 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. 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. 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. 10 samples exceeded the Australian 24- hour ambient guideline of 115 ug/m3.  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. 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 on personal exposure (2 to 6 ug/m3). Testing done at 69 arenas, but results only reported with respect to ECT. Reference Year & Season of Study Location Exposure Measured # of Sites Duration Sampler Used UnitsSite Description # of People Subject Description Number of Measurements hourly 15 Indoor 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 Indoor (public buildings) Indoor (ice rink) N/A N/A 1996, Winter and Summer Rosenlund & Bluhm, 1999 Nayebzadeh, Cragg- Elkouh et al., 1999 Bailie, Pilotto et al., 1999 Camuffo, Brimble- combe et al., 1999 Lee, Chan & Chui, 1999 Gomzi, 1999 1990 - 1991, December to June 1996 - 1997, October to March 1994 - 1995, October to December Enclosed Courtyard 1 Enclosed Courtyard 2 Lotto Room 1 Bellini Room 1 Bellini Room 2 Teflon bag and pump (1 L/min) nL/L Piazza San Marco ppb ug/m3 1 continuous measurement under changing rink conditions. At least 16 week-long measurements per child. 1 indoor and 1 outdoor measurement at each site. 20 minutes 1994, December 1 Ice rink N/A 46 hoursN/A Shima & Adachi, 1998 Shima & Adachi, 2000 Correr museum, Venice, Italy (Not reported. Possibly Australia given location of the authors.) Hong Kong Montreal, Quebec, Canada Zagreb, Croatia Southampton, England Winter 1993, Winter and Summer 1996, February and August Stockholm, Sweden 24 hours 114 measurements in winter and 82 measurements in spring. Continuous analyzer ug/m 3 2 to 4 weeks Passive ppb Lotto Room 3 Lotto Room 2 Lotto Room 4 1 at three of the sites, 2 at 6 of the sites Indoor (residential) Residential homes.  83 up to 49 m from a major road; 499 > 50 m from a major road; 125 suburban; 243 rural. 950 ppbChiba, Japan N/A 24 hours BadgesN/A 2 measurements per site, taken in the living room.  1 during the heating season and 1 during the non-heating season. Indoor (residential) 72 Residential homes N/A N/A 1 measurement per home, taken in the living room. 24 hours Continuous Indoor and Outdoor (museum) 1 3 outdoor sites 6 indoor sites around the museum. N/A Indoor (school) 3 2 schools in industrial areas and 1 in a rural area. N/A Palmes Indoor and Outdoor (public places) 14 N/A N/A 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 N/A 114 Asthmatic children between 7 and 12 years of age. 1 week Linaker, Coggon et al., 2000 Linaker, Chauhan et al., 1999 Personal and Outdoor (ambient) N/A 2 Building A - Urban. Train station and shopping complex attached on ground floor; Building B - Urban.  No train station or shopping complex. N/A N/A 3 sets in building A and 1 set in building B. 5 days (only during working hours) Pump and Tube ug/m3 Continuous ug/m3 Results Median/Geometric Mean Maximum Geometric Standard Deviation Minimum Standard DeviationMean Measured Concentrations of NO2 unvent. vented unheat. 0-49m to major road 73 20 18 unvented 172 5 > 50m to major road 66 21 16 vented 112 6 Suburban 73 19 15 unheat. 47 2 Rural 64 19 11 hourly hourly 24 0 Feb. Aug. 25.9 16.2 25.9 21 12.1 11.1 10.7 8.2 9.6 10.7 8.7 10.6 10.3 11.8 10.5 Industrial Rural Indust. Rural Indust. Rural Indust. Rural Winter 12 8 7 6 55 30 0 1 Spring 8 14 7 7 4 30 3 5 Winter 16 13 10 7 46 48 2 3 Spring 16 17 4 9 23 38 1 5 indoor outdoor 40 52 63 82 11 20 rural 33 43 12 20 rural 54 62 37 73 37 44 25 44 38 63 47 22 26 39 8 19 rural 42 63 mean median Personal 17 11 496 0.7 Ambient 12.3 12.8 29.8 4.3 A Feb. May Februar May Occupied Grnd 161 90 1.46 1.34 11 97 64 1.51 1.44 19 65 82 1.42 1.29 Unoccupied 10 68 56 1.65 1.19 28 88 68 1.13 1.2 Roof 61 40 1.24 1.31 June June Building A Ent. 91.5 1.57 Recep. 60.2 1.35 Hall 81 1.23 Building B Ent. 71 1.23 Recep. 78.7 1.23 2358 450 2294 1018 242 172 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 non- heating 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. Site Comments Only slight differences seen between pollution levels in rural and industrial districts. 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. 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. 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. 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 (R 2 = 0.921 and 0.919 respectively).  R2 for NO2 = 0.59. 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. Should replace propane fuelled ice- resurfacing machines with electric ones diesel machine outside site Increased exhaust pipe, 2h after use, vent on 2hrs after use of resurfacing machine Peak NO2 after 0.5hr use of machine Catalytic converter, vent off Increased exhaust pipe, 2h after use Reference Year & Season of Study Location Exposure Measured # of Sites Duration Sampler Used UnitsSite Description # of People Subject Description Number of Measurements All participants (n = 60) Subset (n = 12) Home Indoor Home Outdoor Workplace Personal I/O Ratio Day 1 (Jan 12) Day 2 (Jan 13) Day 3 (Jan 14) Overall Group 1 Group 2 Group 3 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 Grenoble, Toulouse & Paris Sanyal & Maduna, 2000 Smith, Nitschke et al., 2000 Ciuk, Volkmer & Edwards, 2001 Gauvin, 2001 Levesque, Allaire et al., 2000 Norback, Walinder et al., 2000 Brisbane, Australia Quebec City, Canada Chao & Law, 2000 Uppsala, Sweden Cyrys, Heinrich et al., 2000 1995 - 1996, June to November 1997, Summer Personal, Indoor and Outdoor (home) One sampler located in mid- section of the rink (west side) and one sampler in upper section of the rink (west side). ppm Adult office workers. 2 days ppb 1 set of measurements (personal, office, living room and outdoor) for each participant. Passive filter badges Indoor (arena during monster truck rally) N/A N/A 2 samplers operation during 3 monster truck shows. 36 minuets to 197 minutes Toxilog Indoor and Outdoor (residential) 1 personal measurement daily per participant for six 1-week periods Fixed ambient monitoring stations in geographically distinct areas of Port Adelaide. 1 per classroom and 1 per subject. Gas cooking and heating ppb From arrival home after completion of day's activities to bedtime (mean = 4.5 hours) 1993 Adelaide, Australia Self-reported, regularly medicated asthmatics. Indoor (residential) Homes of 4-year-old children participating in study. N/A 125 Badges ug/m3 1995 - 1996, February to December South Africa 1993, All year Indoor (residential) Continuous ug/m3 (not reported) Personal and Outdoor (ambient) 3 1999, March and December 1998, April to October Port Adelaide, Australia Lee, Yang & Bofinger, 2000 Hamberg, West Germany and Erfurt, East Germany 1996, January 12 - 14 1999, June Hong Kong 1 3 Fixed ambient monitoring stations in French cities. 2 randomly chosen classrooms in each of 12 schools. Households of study participants. 115 193 63 Homes of the 57 participants and the 6 office buildings they were working in at the time of the study. Residential homes. 201 in Hamberg and 204 in Erfurt. 305 Dennekamp, Howarth et al., 2001 1 personal sample for each child. 5 to 75 minutes Continuous chemi- luminescent analyzer. ppbAberdeen, UK 12 Residences of a 20% subset of the total study population. 60 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 N/A 1 week 6 hoursN/A N/A 3 days of sampling at each site (fall, spring and winter), 2 samples per day. 2 sets of measurements (living room, bedroom and outdoor) at each home.  1 in winter and 1 in summer. Palmes Occupational (classroom) 24 234 School personnel 1 week Badge 57 Personal, Indoor (office), Indoor and Outdoor (residential) N/A Badges Passive badges for personal sample, and continuous chemiluminesce nt analyzers at ambient sites. 79 Children 4 to 14 years: 24 in Grenoble; 32 in Toulouse; 23 in Paris. 2 days for the personal samples; 18 to 24 days for the ambient data. Non-vented gas stove with 4 rings and 1 oven. N/A 2 to 12 hours Personal and Outdoor (ambient) Emission from a gas range. N/A N/A N/A 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. ug/m3 ug/m3 ug/m3 ppb Results Median/Geometric Mean Maximum Geometric Standard Deviation Minimum Standard DeviationMean Measured Concentrations of NO2 Pers. Living Rm Kitchen Bedrm Outdoor Pers. Living Kitchen Bedrm Out. Pers. Kitchen Pers. Kitchen 46 10.9 73.1 26.6 47.3 53.8 61 50.9 71.8 10 21 22.4 12.2 15 67.3 96.1 30.8 24.4 (median) Erfurt Hamb. 95%ile E 95%ile H 5%ile E 5%ile H living room 15 17 33 37 8 8 bedroom 15 18 36 34 8 8 outdoor 29 31 49 52 15 15 10.5 5.6 31.1 1.2 14.5 5.8 35 2 18.2 5 23.3 10.1 15 5.2 31.3 5.7 0.78 0.55 3.62 3.52 Time (min) TWA 1 197 <0.5 0.8 2 110 1 180 <0.5 0.7 2 36 1 183 <0.5 0.6 2 183 5.1 11 2 June October March kitchen 18 16.5 21.5 living 57.5 37.5 46 kitchen 17.5 13 13 living 9 9 17.5 kitchen 10 8 8 living 8.5 8 11.5 28.7 20 32 12 67 23 Overall 10.3 2.7 155.6 (7h) 0.1 (6h) Gas apps. 17.1 2 No gas apps. 8.3 2.5 Winter 13.6 2.4 Summer 7.8 3.1 473 219 310 52 584 13 996 139 184 52 92 5 104 19 230 13 296 52 373 70 30.7 7.7 19.3 1.8 personal ambient pers. ambient 32.3 9.9 48.9 1.2 46 40.8 17 5.8 25 11 43.8 1.5 59 75.9 17 31.8 50 44.2 8 8.7 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 NO2 levels quite high, also contributing to personal exposures. 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. 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). Highest NO2 levels measured in schools situated near roads with heavy traffic Concentrations of NO2 higher in living areas than in cooking areas for group 1 only.  Also higher concentrations during winter for this group. Gas cooking and heating No NO2 associated with electrical cooking as evidenced by no change from the baseline readings.  Gas stove produces no NO2 when off.  Higher NO2 levels found in homes with lower socio-economic status (~ 4ppb difference). Highest NO2 levels measured in homes with unvented gas appliances. Gren. - amb. Paris - ambient Crude correlations between ambient air conc and personal exposures were poor for all 3 cities (R2 = 0.009 Grenoble, R2 = 0.04 in Toulouse and R2 = 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. Toul. - amb. Grenoble - personal Paris - personal Toulouse - personal Grenoble - ambient Paris - ambient Toulouse - ambient Reference Year & Season of Study Location Exposure Measured # of Sites Duration Sampler Used UnitsSite Description # of People Subject Description Number of Measurements Indoor Outdoor Workplace Personal Classroom Personal Non-School Time-weighted Total 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 Indoor Outdoor I/O ratio Southern California, USA Basel, Switzerland; Helsinki, Finland; Prague, Czech Republic Singapore Canberra, Australia Utrecht, Netherlands 1996, April and May Metropolitan Helsinki, Finland Lee, Xue et al., 2002 Kousa, Monn et al., 2001 Ng, Seet et al., 2001 Ponsonby, Glasgow et al., 2001 Rijinders, Janssen et al., 2001 Rotko, Kousa et al., 2001 ug/m 3 Adult participants in the EXPOLIS study: 201 from Helsinki; 35 from Prague; 50 from Basel 1996 - 1997 Personal N/A Heating Traffic Volume Nearby Work Location Gas Stove Season Reported here with the mean concentrations. 48 hours Palmes (not reported) Personal 16 1999, July to September Schools.  3 government-run and 1 private. 344 Personal and Indoor (classroom) N/A 176 Adults between 25 and 55 years 2 days.  Personal measurements done only in non- school hours (18 hours/day). 1 measurement for each child and each classroom. ppb Home Location Home Type Exposed to ETS Commuting Time Windows Open Age of Home Floor Area 1997 - 1998 1996 - 1997, October to December N/A N/A 4 (not reported) Homes and workplaces of all participants. 286 Adult female asthmatics Children with mean age of 9.1 years Personal, Workplace, Indoor and Outdoor (residential) 48 hours 1 set per participant, including 2 consecutive 1-week measurements and 1 peak measurement while cooking. 1 week; Between 30 and 60 minutes for peak. N/A Personal, Outdoor (residential), Indoor and Outdoor (school) 2426 Schools: 1 very urban (VU); 1 fairly urban (FU); 1 non- urban (NU); 1 near to a busy highway (VB); 1 near to a fairly busy highway (FB); and 1 on a non-busy road (NB) 111 Residential homes: 56 in Upland (valley site) and 55 in San Bernardino (mountain) Indoor and Outdoor (residential) N/A School children between 6 and 12 years of age. 1 set of measurements (living room and outdoor) per site. 6 days Badges Badge 1 week 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. ug/m3 258 indoor; 237 outdoor; 188 workplace; 261 personal ug/m 3 Palmes Palmes Palmes for 1- week; Pump for peak. ug/m3 ppb Results Median/Geometric Mean Maximum Geometric Standard Deviation Minimum Standard DeviationMean Measured Concentrations of NO2 Helsinki Prague Basel Helsinki Prague Basel Hels. Prag. Basel 24 61 36 21.2 57 32.3 1.8 1.5 1.6 18 43 27 14.7 37.7 22.8 2.1 1.9 2.2 27 30 3 22.8 25.9 32.3 2.2 1.8 1.6 25 43 30 22.6 40.7 28.4 1.7 1.5 1.4 2 week 130 36 Peak 490 0 Ambient 135 36 10.1 4.9 75%ile 25%ile 10.4 11.1 8.3 11.1 6.8 10.1 8.6 autumn winter spring summer 20.9 29.4 22.9 19 8 16 13.4 12.4 9.3 12.4 12.5 9.6 19.1 33.5 25.3 19.2 11.9 16 17.1 12.5 8.5 19.3 16.9 13 31.6 59 32.4 24.8 27.6 41.6 29.2 20.5 26.7 33.2 26.8 15.7 82.3 36.8 21.8 57 37.1 17.3 35.1 46.7 32.3 19.5 25.9 42.1 33.3 19.7 163.1 9.2 18.7 23.4 19.6 17.8 58.9 4.7 14.2 19.1 15.8 14.8 30.8 7.2 26.1 36 29.2 15.6 82.6 6 19.2 29.7 25 15.1 46.8 6.4 19.1 25.1 18.2 17.9 59.9 6.4 29.8 49 38.1 25.6 71.4 12.9 27 41.5 29.8 21.3 49.5 8.3 24.7 36.1 22.6 16 43.5 6.1 38 58.3 39.3 15.7 67.2 9.6 31.9 56.1 34.9 82.1 24 34 44.9 26.9 66.9 13.5 n AM median 95%ile Downtown 41 30.2 11.4 28 46.6 Suburban 135 23.4 10.2 21.9 44.7 High Rise 107 26.8 10.5 24.7 46.1 House 65 21.7 10.5 21.2 41.3 <1970 62 29.6 11.6 27.2 47.3 >1970 114 22.5 9.6 21.6 41.3 <60m2 63 26.9 10.5 23.8 45.3 >60m2 110 24 11.1 21.8 45.9 No Extra 152 24.7 10.6 22.9 45.3 Oil/Wood 24 26.5 12.5 24.1 47.3 Low/Mod 138 23.5 10.6 21.7 44.7 Heavy 38 30.1 10.4 27 46.6 Downtown 40 30.1 10.3 30.6 47 Suburban 126 23.7 10.6 22.4 44.3 Summer 107 26.3 12 23.8 46.1 Winter 69 22.8 8.6 21.4 38.6 No 167 24.5 10.5 22.4 45.9 Yes 9 32.9 15.5 33.5 60.5 <20/48 h 117 23 9.9 21.9 41.3 >20/48 h 57 28.8 12 25.9 50.6 Yes 54 27.5 11.1 26.2 45.9 No 122 23.8 16.6 21.9 45.9 <1 h 96 25.4 11.1 23.4 46.6 >1 h 65 24.6 10.2 22.2 44.3 n mean median max 95%ile min 92 28 12.6 28.9 52 49.3 4.3 88 20.1 14 17.4 47.8 42.1 3.2 87 2.08 1.69 1.33 10.62 5.41 0.22 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 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. 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. 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. 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. 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 Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene TABLE OF CONTENTS 1 INTRODUCTION 1 2 METHODS 2 2.1 LITERATURE SEARCH..........................................................................2 2.2 INCLUSION AND EXCLUSION CRITERIA ..................................................3 2.3 CATEGORIES OF STUDIES....................................................................5 3 NITROGEN DIOXIDE (NO2) 6 3.1 PROPERTIES AND SOURCES ................................................................6 3.1.1 Anthropogenic Sources of NO2 .................................................................... 7 3.1.2 Indoor Sources of NO2.................................................................................. 7 3.1.3 Indoor Nitrogen Oxides Chemistry ............................................................... 8 3.2 TOXICOLOGIC CHARACTERISTICS .........................................................8 3.2.1 Biochemistry .................................................................................................. 8 3.2.2 Pulmonary Effects ......................................................................................... 9 3.2.3 Immune Response ........................................................................................ 9 3.2.4 Other Effects................................................................................................ 10 3.3 PERSONAL AND INDOOR EXPOSURE TO NO2.......................................10 3.3.1 Indoor Sources of NO2................................................................................ 11 3.3.2 Outdoor Sources of NO2 ............................................................................. 13 3.3.3 NO2 Exposure in Ice Rinks ......................................................................... 15 3.3.4 Summary ..................................................................................................... 15 3.4 EPIDEMIOLOGICAL STUDIES OF POPULATIONS EXPOSED TO NO2 .........16 3.4.1 Studies of Respiratory Symptoms and Disease ........................................ 17 3.4.2 Studies of Lung Function ............................................................................ 21 3.4.3 Studies of Other Health Outcomes............................................................. 22 3.5 STUDIES OF CONTROLLED HUMAN EXPOSURES TO NO2......................23 3.5.1 Overview of Studies .................................................................................... 23 3.5.2 Studies of Lung Function and Airway Responsiveness ............................ 24 3.5.3 Studies of Lavage Fluids............................................................................. 26 3.5.4 Insight from Published Reviews of Controlled NO2 Exposures................. 26 3.6 LOAELS FOR CHRONIC AND ACUTE EXPOSURE TO NO2 .....................28 3.6.1 Chronic Exposure........................................................................................ 28 3.6.2 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) 31 4.1 PROPERTIES AND SOURCES ..............................................................31 4.1.1 Sources of SO2............................................................................................ 32 4.2 TOXICOLOGIC CHARACTERISTICS .......................................................32 4.2.1 Absorption and Biochemistry...................................................................... 33 4.2.2 Pulmonary Effects ....................................................................................... 33 4.2.3 Immune Response ...................................................................................... 34 4.2.4 Other Effects................................................................................................ 34 4.3 INDOOR EXPOSURE TO SO2 ..............................................................34 4.3.1 Overview of Studies .................................................................................... 34 4.3.2 SO2 Concentrations Indoors ....................................................................... 35 4.3.3 Factors Associated with SO2 Indoors......................................................... 36 4.3.4 Factors Associated with SO2 Outdoors...................................................... 36 4.3.5 Limitations.................................................................................................... 37 4.4 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 Overview of Studies .................................................................................... 44 4.5.2 Adults: Studies of Pulmonary Function ...................................................... 45 4.5.3 Adults: Studies of Airway Resistance......................................................... 46 4.5.4 Adults: Studies of Respiratory Symptoms.................................................. 48 4.5.5 Adults: Studies of Other Measures of Response....................................... 49 4.5.6 Studies of Children...................................................................................... 50 4.5.7 Limitations.................................................................................................... 51 4.6 LOAELS FOR CHRONIC AND ACUTE EXPOSURES TO SO2....................52 4.6.1 Chronic Exposure........................................................................................ 52 4.6.2 Acute Exposure ........................................................................................... 53 5 REFERENCES 55 Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 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 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 2 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 3 - 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 Group 1 AND Group 4 Combination #2 Group 2 AND Group 4 Combination #3 Group 1 AND Group 3 AND Group 4 Combination #4 Group 2 AND Group 3 AND Group 4 Combination #5 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. Pre- 1990 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 4 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 NO2 SOx NO(sub)x cook heat sulphur dioxide SO2 NO(sub)2 SO(sub)x gas combustion sulfur dioxide NOx SO(sub)2 burn 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 asthma exposure hospital occupation pulmonary allergy domestic health indoor office respiratory arena effect home lung pollut 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 5 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 Includes all clinical and experimental studies on human subjects. 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. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 6 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 46.01 g/mol Air Concentration Units Conversion 1 mg/m3 = 0.53 ppm at 101.3 kPa 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. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 7 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 8 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 (2nd 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/m 3) 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 9 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/m 3). 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 (940- 11,280 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 10 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 extra- pulmonary 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 11 Table 3.2 Numbers of Studies of Personal and Indoor NO2 Exposure, by Continent and Country LOCATION NUMBER OF STUDIES North America 19 United States 16 Canada 3 Europe 38 United Kingdom 8 The Netherlands 7 Finland 5 Croatia 3 France 2 Sweden 5 Germany 1 Greece 1 Italy 1 Bulgaria 1 Switzerland 1 Norway 1 Denmark 1 Switzerland, Finland, Czechoslovakia 1 Asia 14 Taiwan 1 Japan 5 Hong Kong 5 Korea 1 India 1 Singapore 1 Australia 6 Middle East (Bahrain) 1 Africa (South Africa) 1 International Studies 2 Unspecified 2 3.3.1 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 12 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 13 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/m 3 (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 14 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/m 3) 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 15 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 16 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 17 Table 3.4 Numbers of Epidemiological Studies of NO2, by Study Design and Characteristics VARIABLE NUMBER OF STUDIES Cohort 9 Case-Control 5 Cross-sectional 18 Longitudinal 5 Panel 3 Other 1 Study Design Asia 4 Australia 5 North America 10 Western Europe 20 Other 2 Location Adults 12 Children 31 Study Population* COPD 1 Identified Asthmatics 10 Not Specified 30 Health Status of Study Population Lung Function 13 Respiratory Symptoms, Illnesses and Diseases 33 Measured Outcome* Other 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 cross- sectional 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 18 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 19 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/m 3 (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 age- and location-matched controls (n = 103), Hoek et al. [1984] found no significant association between residential NO2 concentrations (ranging from 110 to 789 ug/m 3 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 20 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 21 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-year- old 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 = 1.4- 9.3). 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/m 3 (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 22 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 23 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 24 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 carbachol- induced decrease in FVC and FEV1 in subjects exposed to 2,820 ug/m 3 (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/m 3 (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 25 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/m 3 (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/m 3 (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/m 3 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/m 3 (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 26 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 27 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 meta- analysis 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 28 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 non- asthmatic 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 post- exposure. 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 29 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/m 3) 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 30 (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 31 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 64.06 g/mol Air Concentration Units Conversion 1 mg/m3 = 0.38 ppm at 101.3 kPa Colour 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 32 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/m 3 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). Casarett and Doull’s Toxicology: The Basic Science of Poisons (3rd 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). Environmental Toxicants (2nd 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 33 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/m 3) 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 34 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 dose- absorption 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 35 (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/m 3, 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/m 3, 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 36 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/m 3 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 37 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 38 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 39 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 self- selected 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 40 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 cross- sectional 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 non- smokers 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 41 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 exposure- associated 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/m 3) 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 42 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/m 3). 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 43 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 non- industrial environment. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 44 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 non- smoking 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 45 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 non- significant 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 46 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/m 3) [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 mid- maximal 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 47 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 48 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 49 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 50 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 51 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/m 3 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 52 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 53 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 SO2- exposed 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 dose- related 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 54  Table 4.6 Ambient Air Standards for SO2 (in ppm) Canadian Air Quality Objectives United States World Health Organization Type of Standard Maximum Desirable Maximum Acceptable Maximum Tolerable National Ambient Air Quality Standards Health-Based Guidelines Annual 0.011 0.023 0.030 0.020 24 hours 0.057 0.115 0.306 0.140 0.040 3 hours 0.500 1 hour 0.172 0.344 10 minutes 0.175 Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 55 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. (2002) Toxicological Profile for Sulfur Dioxide http://www.atsdr.cdc.gov/toxprofiles/tp116.html. Alm, S, Mukala, K, et al. (1998). Personal NO2 exposures of preschool children in Helsinki. Journal of Exposure Analysis and Environmental Epidemiology 8(1): 79-100. Amdur, MO (1986). Air Pollutants. In: Klaassen, CD, Amdur, MO & Doull J (eds). Casarett and Doull’s Toxicology: The Basic Science of Poisons (3rd Ed.). New York, NY: Macmillan Publishing Company, 801-824. Arashidani, K, Yoshikawa, M, et al. (1996). Indoor pollution from heating. Industrial Health 34(3): 205-215. Archer, VE and Gillam, JD (1978). Chronic sulfur dioxide exposure in a smelter – Part 2 Indices of chest disease. Journal of Occupational Medicine 20(2): 88-95. Argiriou, A, Asimakopoulos, D, et al. (1994). On the energy consumption and indoor air quality in office and hospital buildings in Athens, Hellas. Energy Conversion and Management 35(5): 385-394. 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. Avissar, NE, Reed, CK, et al. (2000). Ozone, but not nitrogen dioxide, exposure decreases glutathione peroxidases in epithelial lining fluid of human lung. American Journal of Respiratory and Critical Care Medicine 162(4 Part 1): 1342-1347. Avol, EL, Linn, WS, et al. (1992). Experimental exposures of young asthmatic volunteers to 0.3 ppm nitrogen dioxide and to ambient air pollution. Journal of Clean Technology and Environmental Sciences 2(2): 113-122. Azadniv, M, Utell, MJ, et al. (1998). Effects of nitrogen dioxide exposure on human host defence. Inhalation Toxicology 10(6): 585-601. Baek, SO, Kim, YS and Perry, R (1997). Indoor air quality in homes, offices and restaurants in Korean urban areas Indoor/outdoor relationships. Atmospheric Environment 31(4): 529- 544. Bailie, RS, Pilotto, LS, et al. (1999). Poor urban environments: Use of paraffin and other fuels as sources of indoor air pollution. Journal of Epidemiology and Community Health 53(9): 585-586. Balmes, J, Fine, J and Sheppard, D (1987). Symptomatic bronchoconstriction after short term inhalation of sulfur dioxide. American Review of Respiratory Disease and Critical Care Medicine 136(5): 1117-21. Bedi, JF and Horvath, SM (1989). Inhalation route effects on exposure to 2.0 parts per million sulfur dioxide in normal subjects. Journal of the Air and Waste Management Association 39(11): 1448-1452. Bedi, JF, Folinsbee, LJ and Horvath, SM (1984). Pulmonary function effects of 1.0 and 2.0 parts per million sulfur dioxide exposure in active young male nonsmokers. Journal of the Air Pollution Control Association 34(11): 1117-1121. Berglund, M, Braback, L, et al. (1994). Personal NO2 exposure monitoring shows high exposure among ice skating schoolchildren. Archives of Environmental Health 49(1): 17-24. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 56 Bernard, N, Saintot, M, et al. (1998). Personal exposure to nitrogen dioxide pollution and effect on plasma antioxidants. Archives of Environmental Health 53(2): 122-8. Berwick, M, Leaderer, BP, et al. (1989). Lower respiratory symptoms in children exposed to nitrogen dioxide from unvented combustion sources. Environment International 15(1 6): 369-373. Bethel, RA, Epstein, J, et al. (1983b). Sulfur dioxide induced bronchoconstriction in freely breathing exercising asthmatic subjects. American Review of Respiratory Disease and Critical Care Medicine 128(6): 987-990. Bethel, RA, Erle, DJ, et al. (1983a). Effect of exercise rate and route of inhalation on sulfur dioxide induced bronchoconstriction in asthmatic subjects. American Review of Respiratory Disease and Critical Care Medicine 128(4): 592-6. Bethel, RA, Sheppard, D, et al. (1984). Interaction of sulfur dioxide and dry cold air in causing bronchoconstriction in asthmatic subjects. Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology 57(2): 419-23. Bethel, RA, Sheppard, D, et al. (1985). Effect of 0.25 parts per million sulfur dioxide on airway resistance in freely breathing heavily exercising asthmatic subjects. American Review of Respiratory Disease and Critical Care Medicine 131(4): 659-661. Biersteker, K, de Graaf, H, and Nass, CAG. (1965) Indoor air pollution in Rotterdam homes. International Journal of Air and Water Pollution 9: 343-350 Blomberg, A, Krishna, MT, et al. (1997). The inflammatory effects of 2 ppm NO2 on the airways of healthy subjects. American Journal of Respiratory and Critical Care Medicine 156(2 Part 1): 418-424. Blomberg, A, Krishna, MT, et al. (1999). Persistent airway inflammation but accommodated antioxidant and lung function responses after repeated daily exposure to nitrogen dioxide. American Journal of Respiratory and Critical Care Medicine 159(2): 536-43. Brauer, M and Spengler, JD (1994). Nitrogen dioxide exposures inside ice skating rinks. American Journal of Public Health 84(3): 429-433. Brauer, M, Koutrakis, P, et al. (1991). Indoor and outdoor concentrations of inorganic acidic aerosols and gases. Journal of the Air and Waste Management Association 41(2): 171- 81. Brauer, M, Lee, K, et al. (1997). Nitrogen dioxide in indoor ice skating facilities: An international survey. Journal of the Air and Waste Management Association 47(10): 1095-1102. Broder, I, Smith, JW, et al. (1989). Health status and sulfur dioxide exposure of nickel smelter workers and civic laborers. Journal of Occupational Medicine 31(4): 347-353. Brunekreef, B, Houthuijs, D, et al. (1990). Indoor nitrogen dioxide exposure and childrens’ pulmonary function. Journal of the Air and Waste Management Association 40(9): 1252- 1256. Camuffo, D, Brimblecombe, P, et al. (1999). Indoor air quality at the Correr Museum, Venice, Italy. Science of the Total Environment 236(1 3): 135-52. Chambers, DC and Ayres, JG (2001). Effects of nitrogen dioxide exposure and ascorbic acid supplementation on exhaled nitric oxide in healthy human subjects. Thorax 56(10): 774- 778. Chan, CC, Yanagisawa, Y and Spengler, JD (1990). Personal and indoor outdoor nitrogen dioxide exposure assessments of 23 homes in Taiwan. Toxicology and Industrial Health 6(1): 173-182. Chao, CYH (2001). Comparison between indoor and outdoor air contaminant levels in residential buildings from passive sampler study. Building and Environment 36(9): 999-1007. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 57 Chao, CYH and Law, A (2000). Study of personal exposure to nitrogen dioxide using passive samplers. Building and Environment 35(6): 545-553. ChemInfo. (2002) Nitrogen Dioxide ChemInfo Record #748, http://ccinfoweb.ccohs.ca/cheminfo. ChemInfo. (2002) Sulfur Dioxide ChemInfo Record #714, http://ccinfoweb.ccohs.ca/cheminfo. Ciuk, J, Volkmer, RE and Edwards, JW (2001). Domestic nitrogen oxide exposure, urinary nitrate, and asthma prevalence in preschool children. Archives of Environmental Health 56(5): 433-438. Colbeck, I (1998). Nitrogen dioxide in the workplace environment. Environmental Monitoring and Assessment 52(1-2): 123-130. Cotterill, A and Kingham, S (1997). Nitrogen dioxide in the home: Cooking, double glazing or outdoor air. Indoor and Built Environment 6(6): 344-349. Cyrys, J, Heinrich, J, et al. (2000). Sources and concentrations of indoor nitrogen dioxide in Hamburg (West Germany) and Erfurt (East Germany). Science of the Total Environment 250(1 3): 51-62. Demissie, K, Ernst, P, et al. (1998). The role of domestic factors and day care attendance on lung function of primary school children. Respiratory Medicine 92(7): 928-935. Dennekamp, M, Howarth, S, et al. (2001). Ultrafine particles and nitrogen oxides generated by gas and electric cooking. Occupational and Environmental Medicine 58(8): 511-516. Devalia, JL, Rusznak, C, et al. (1994). Effect of nitrogen dioxide and sulfur dioxide on airway response of mild asthmatic patients to allergen inhalation. Lancet 344(8938): 1668-1671. Dijkstra, L, Houthuijs, D, et al. (1990). Respiratory health effects of the indoor environment in a population of Dutch children. American Review of Respiratory Disease and Critical Care Medicine 142(5): 1172-8. Dodge, R, Solomon, P, et al. (1985). A longitudinal study of children exposed to sulfur oxides. American Journal of Epidemiology 121(5): 720-36. Donoghue, AM and Thomas, M (1999). Point source sulphur dioxide peaks and hospital presentations for asthma. Occupational and Environmental Medicine 56(4): 232-6. Drechsler Parks, D (1995). Cardiac output effects of O3 and NO2 exposure in healthy older adults. Toxicology and Industrial Health 11(1): 99-109. Ekberg, LE (1995). Concentrations of NO2 and other traffic related contaminants in office buildings located in urban environments. Building and Environment 30(2): 293-298. Englander, V, Sjoberg, A, et al. (1988). Mortality and cancer morbidity in workers exposed to sulfur dioxide in a sulfuric acid plant. International Archives of Occupational and Environmental Health 61(3): 157-162. Farrow, A, Greenwood, R, et al. (1997). Nitrogen dioxide, the oxides of nitrogen, and infants' health symptoms. Archives of Environmental Health 52(3): 189-194. Ferris, BG, Burgess, WA and Worcester, J (1967). Prevalence of chronic respiratory disease in a pulp mill and a paper mill in the United States. British Journal of Industrial Medicine 24(1): 26-37. Fischer, P, Brunekreef, B, et al. (1989). Effects of indoor exposure to nitrogen dioxide on pulmonary function of women living in urban and rural areas. Environment International 15(1 6): 375-381. Folinsbee, LJ (1992). Does nitrogen dioxide exposure increase airways responsiveness? Toxicology and Industrial Health 8(5): 273-283. Folinsbee, LJ, Bedi, JF and Horvath, SM (1985). Pulmonary response to threshold levels of sulfur dioxide (1.0 ppm) and ozone (0.3 ppm). Journal of Applied Physiology 58(6): 1783-7. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 58 Frampton, MW, Morrow, PE, et al. (1991). Effects of nitrogen dioxide exposure on pulmonary function and airway reactivity in normal humans. American Review of Respiratory Disease and Critical Care Medicine 143(3): 522-527. Froom, P, Sackstein, G, et al. (1998). The effect of exposure to SO2 on the respiratory system of power station workers. Work 11(3): 325-329. Garrett, MH, Abramson, MJ, et al. (1998). Indoor environmental risk factors for respiratory health in children. Indoor Air International Journal of Indoor Air Quality and Climate 8(4): 236- 243. Garrett, MH, Hooper, MA and Hooper, BM (1999). Nitrogen dioxide in Australian homes: levels and sources. Journal of the Air and Waste Management Association 49(1): 76-81. Garrett, MH, Hooper, MA, et al. (1998). Respiratory symptoms in children and indoor exposure to nitrogen dioxide and gas stoves. American Journal of Respiratory and Critical Care Medicine 158(3): 891-5. Gauvin, S (2001). Relationship between Nitrogen dioxide person exposure and ambient air monitoring measurements among children in three French metropolitan areas: VESTA Study. Archives of Environmental Health 56(4): 336-341. Giroux, M and Ferrieres, J (1998). Serum nitrates and creatinine in workers exposed to atmospheric nitrogen oxides and ammonia. Science of the Total Environment 217(3): 265-269. Goings, SA, Kulle, TJ, et al. (1989). Effect of nitrogen dioxide exposure on susceptibility to influenza A virus infection in healthy adults. American Review of Respiratory Disease and Critical Care Medicine 139(5): 1075-81. Gomzi, M (1999). Indoor air and respiratory health in preadolescent children. Atmospheric Environment 33(24): 4081-4086. Gong, HJ, Lachenbruch, PA, et al. (1995). Comparative short term health responses to sulfur dioxide exposure and other common stresses in a panel of asthmatics. Toxicology and Industrial Health 11(5): 467-487. Hackney, JD, Linn, WS, et al. (1984). Time course of exercise induced bronchoconstriction in asthmatics exposed to sulfur dioxide. Environmental Research 34(2): 321-7. Hackney, JD, Linn, WS, et al. (1992). Exposures of older adults with chronic respiratory illness to nitrogen dioxide a combined laboratory and field study. American Review of Respiratory Disease and Critical Care Medicine 146(6): 1480-1486. Hazucha, MJ, Folinsbee, LJ, et al. (1994). Lung function response of healthy women after sequential exposures to NO2 and O3. American Journal of Respiratory and Critical Care Medicine 150(3): 642-647. Health Canada. (2002) Health and Air Quality Regulations: National Ambient Air Quality Objectives http://www.hc sc.gc.ca/hecs secs/air_quality/naaqo.htm. Accessed May 29. Heath, SK, Koenig, JQ, et al. (1994). Effects of sulfur dioxide exposure on African American and Caucasian asthmatics. Environmental Research 66(1): 1-11. Hoek, G, Brunekreef, B, et al. (1984). Indoor nitrogen dioxide pollution and respiratory symptoms of schoolchildren. International Archives of Occupational and Environmental Health 55(1): 79-86. Horstman, D, Roger, LJ, et al. (1986). Airway sensitivity of asthmatics to sulfur dioxide. Toxicology and Industrial Health 2(3): 289-98. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 59 Horstman, DH, Seal, E, et al. (1988). The relationship between exposure duration and sulfur dioxide induced bronchoconstriction in asthmatic subjects. American Industrial Hygiene Association Journal 49(1): 38-47. Houthuijs, D, Dijkstra, L, et al. (1990). Reproducibility of personal exposure estimates for nitrogen dioxide over a two year period. Atmospheric Environment 24(2): 435-437. Huang, JL, Wang, SY and Hsieh, KH (1991). Effect of short term exposure to low levels of SO2 and NOx on pulmonary function and methacholine and allergen bronchial sensitivities in asthmatic children. Archives of Environmental Health 46(5): 296-299. Infante Rivard, C (1993). Childhood asthma and indoor environmental risk factors. American Journal of Epidemiology 137(8): 834-844. Islam, MS, Neuhann, HF, et al. (1992). Bronchomotoric effect of low concentration of sulfur dioxide in young healthy volunteers. Fresenius Environmental Bulletin 1(8): 541-546. Jaeger, MJ, Tribble, D and Wittig, HJ (1979). Effect of 0.5 ppm sulfur dioxide on the respiratory function of normal and asthmatic subjects. Lung 156(2): 119-27. Jenkins, HS, Devalia, JL, et al. (1999). The effect of exposure to ozone and nitrogen dioxide on the airway response of atopic asthmatics to inhaled allergen: dose and time dependent effects. American Journal of Respiratory and Critical Care Medicine 160(1): 33-9. Jorres, R and Magnussen, H (1990). Airways response of asthmatics after a 30 min exposure, at resting ventilation, to 0.25 ppm NO2 or 0.5 ppm SO2. European Respiratory Journal 3(2): 132-137. Jorres, R and Magnussen, H (1991). Effect of 0.25 ppm nitrogen dioxide on the airway response to methacholine in asymptomatic asthmatic patients. Lung 169(2): 77-85. Jorres, R, Nowak, D, et al. (1995). The Effect of 1 ppm nitrogen dioxide on bronchoalveolar lavage cells and inflammatory mediators in normal and asthmatic subjects. European Respiratory Journal 8(3): 416-424. Kagawa, J (1983). Respiratory effects of two hour exposure with intermittent exercise to ozone, sulfur dioxide and nitrogen dioxide alone and in combination in normal subjects. American Industrial Hygiene Association Journal 44(1): 14-20. Kangas, J, Jappinen, P and Savolainen, H (1984). Exposure to hydrogen sulfide, mercaptans and sulfur dioxide in pulp industry. American Industrial Hygiene Association Journal 45(12): 787-90. Kawamoto, T, Matsuno, K, et al. (1993). Personal exposure to nitrogen dioxide from indoor heaters and cooking stoves. Archives of Environmental Contamination and Toxicology 25(4): 534-538. Kehoe, R, Machle, W, et al. (1932). On the effects of prolonged exposure to sulphur dioxide. The Journal of Industrial Hygiene 14: 159-173. Kehrl, HR, Roger, LJ, et al. (1987). Differing response of asthmatics to sulfur dioxide exposure with continuous and intermittent exercise. American Review of Respiratory Disease and Critical Care Medicine 135(2): 350-5. Kelly, FJ, Blomberg, A, et al. (1996). Antioxidant kinetics in lung lavage fluid following exposure of humans to nitrogen dioxide. American Journal of Respiratory and Critical Care Medicine 154(6): 1700-1705. Kilpelainen, M, Koskenvuo, M, et al. (2001). Wood stove heating, asthma and allergies. Respiratory Medicine 95(11): 911-916. Kim, SU, Koenig, JQ, et al. (1991). Acute pulmonary effects of nitrogen dioxide exposure during exercise in competitive athletes. Chest 99(4): 815-819. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 60 Kindzierski, W and Sembaluk, S (2001). Indoor outdoor relationship of SO2 concentrations in a rural and an urban community of Alberta. Canadian Journal of Civil Engineering 28: 163- 169. Kirkpatrick, MB, Sheppard, D, et al. (1982). Effect of the oronasal breathing route on sulfur dioxide induced bronchoconstriction in exercising asthmatic subjects. American Review of Respiratory Disease and Critical Care Medicine 125(6): 627-31. Koenig, JQ, Covert, DS, et al. (1990). Prior exposure to ozone potentiates subsequent response to sulfur dioxide in adolescent asthmatic subjects. American Review of Respiratory Disease and Critical Care Medicine 141(2 I): 377-380. Koenig, JQ, Morgan, MS, et al. (1985). The effects of sulfur oxides on nasal and lung function in adolescents with extrinsic asthma. Journal of Allergy and Clinical Immunology 76(6): 813- 8. Koenig, JQ, Pierson, WE, et al. (1983). Effects of inhaled sulfur dioxide (SO2) on pulmonary function in healthy adolescents: exposure to SO2 alone or SO2 + sodium chloride droplet aerosol during rest and exercise. Archives of Environmental Health 37(1): 5-9. Koo, LC, Ho, JHC, et al. (1990). Personal exposure to nitrogen dioxide and its association with respiratory illness in Hong Kong. American Review of Respiratory Disease and Critical Care Medicine 141(5): 1119-1126. Kousa, A, Monn, C, et al. (2001). Personal exposures to NO2 in the EXPOLIS study: Relation to residential indoor, outdoor and workplace concentrations in Basel, Helsinki and Prague. Atmospheric Environment 35(20): 3405-3412. Kreisman, H, Mitchell, CA, et al. (1976). Effect of low concentrations of sulfur dioxide on respiratory function in man. Lung 154(1): 25-34. Kukadia, V and Palmer, J (1998). The effect of external atmospheric pollution on indoor air quality: A pilot study. Energy and Buildings 27(3): 223-230. Kulkarni, MM and Patil, RS (1998). Factors influencing personal exposure to nitrogen dioxide in an Indian metropolitan region. Indoor and Built Environment 7(5 6): 319-332. Kulle, TJ, Sauder, LR, et al. (1984). Sulfur dioxide and ammonium sulfate effects on pulmonary function and bronchial reactivity in human subjects. American Industrial Hygiene Association Journal 45(3): 156-61. Lambert, WE, Samet, JM, et al. (1992). Classification of residential exposure to nitrogen dioxide. Atmospheric Environment Part a General Topics 26(12): 2185-2192. Lebowitz, MD, Burton, A and Kaltenborn, W (1979). Pulmonary function in smelter workers. Journal of Occupational Medicine 21(4): 255-259. Lee, K, Xue, XP, et al. (2002). Nitrous acid, nitrogen dioxide, and ozone concentrations in residential environments. Environmental Health Perspectives 110(2): 145-149. Lee, K, Yanagisawa, Y, et al. (1994a). Carbon monoxide and nitrogen dioxide exposures in indoor ice skating rinks. Journal of Sports Sciences 12(3): 279-283. Lee, K, Yanagisawa, Y, et al. (1996). Classification of house characteristics in a Boston residential nitrogen dioxide characterization study. Indoor Air International Journal of Indoor Air Quality and Climate 6(3): 211-216. Lee, K, Yang, W and Bofinger, ND (2000). Impact of microenvironmental nitrogen dioxide concentrations on personal exposures in Australia. Journal of the Air and Waste Management Association 50(10): 1739-1744. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 61 Lee, KY, Yanagisawa, Y and Spengler, JD (1994b). Reduction of air pollutant concentrations in an indoor ice skating rink. Environment International 20(2): 191-199. Lee, KY, Yanagisawa, Y, et al. (1995). Classification of house characteristics based on indoor nitrogen dioxide concentrations. Environment International 21(3): 277-282. Lee, SC (1997). Comparison of indoor and outdoor air quality at two staff quarters in Hong Kong. Environment International 23(6): 791-797. Lee, SC, Chan, LY and Chiu, MY (1999). Indoor and outdoor air quality investigation at 14 public places in Hong Kong. Environment International 25(4): 443-450. Leung, R, Lam, CWK, et al. (1998). Indoor environment of residential homes in Hong Kong Relevance to asthma and allergic disease. Clinical and Experimental Allergy 28(5): 585- 590. Levesque, B, Allaire, S, et al. (2000). Air quality monitoring during indoor monster truck and car demolition shows. Journal of Exposure Analysis and Environmental Epidemiology 10(1): 58-65. Levy, JI (1998). Impact of residential nitrogen dioxide exposure on personal exposure: An international study. Journal of the Air and Waste Management Association 48(6): 553- 560. Levy, JI, Lee, K, et al. (1998). Determinants of nitrogen dioxide concentrations in indoor ice skating rinks. American Journal of Public Health 88(12): 1781-1786. Liao, SST, Baconshone, J and Kim, YS (1991). Factors influencing indoor air quality in Hong Kong measurements in offices and shops. Environmental Technology 12(9): 737-745. Linaker, CH, Chauhan, AJ, et al. (1996). Distribution and determinants of personal exposure to nitrogen dioxide in school children. Occupational and Environmental Medicine 53(3): 200- 3. Linaker, CH, Chauhan, AJ, et al. (1999). Personal exposures of children to nitrogen dioxide relative to concentrations in outdoor air. Occupational and Environmental Medicine 57(7): 472-6. Linaker, CH, Coggon, D, et al. (2000). Personal exposure to nitrogen dioxide and risk of airflow obstruction in asthmatic children with upper respiratory infection. Thorax 55(11): 930-3. Linn, WS, Avol, EL, et al. (1984a). Asthmatics' responses to 6 hr sulfur dioxide exposures on two successive days. Archives of Environmental Health 39(4): 313-9. Linn, WS, Avol, EL, et al. (1987). Replicated dose response study of sulfur dioxide effects in normal, atopic, and asthmatic volunteers. American Review of Respiratory Disease and Critical Care Medicine 136(5): 1127-34. Linn, WS, Bailey, RM, et al. (1982). Respiratory responses of young adult asthmatics to sulfur dioxide exposure under simulated ambient conditions. Environmental Research 29(1): 220-32. Linn, WS, Fischer, DA, et al. (1985a). Controlled exposures of volunteers with chronic obstructive pulmonary disease to sulfur dioxide. Environmental Research 37(2): 445-51. Linn, WS, Gong, H, Jr., et al. (1997). Chamber exposures of children to mixed ozone, sulfur dioxide, and sulfuric acid. Archives of Environmental Health 52(3): 179-187. Linn, WS, Shamoo, DA, et al. (1983a). Respiratory effects of 0.75 ppm sulfur dioxide in exercising asthmatics: influence of upper respiratory defences. Environmental Research 30(2): 340- 8. Linn, WS, Shamoo, DA, et al. (1984b). Comparative effects of sulfur dioxide exposures at 5 degrees C and 22 degrees C in exercising asthmatics. American Review of Respiratory Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 62 Disease and Critical Care Medicine 129(2): 234-9. Linn, WS, Shamoo, DA, et al. (1984c). Combined effect of sulfur dioxide and cold in exercising asthmatics. Archives of Environmental Health 39(5): 339-46. Linn, WS, Shamoo, DA, et al. (1985b). Effects of heat and humidity on the responses of exercising asthmatics to sulfur dioxide exposure. American Review of Respiratory Disease and Critical Care Medicine 131(2): 221-5. Linn, WS, Shamoo, DA, et al. (1990). Responses to sulfur dioxide and exercise by medication dependent asthmatics: Effect of varying medication levels. Archives of Environmental Health 45(1): 24-30. Linn, WS, Venet, TG, et al. (1983b). Respiratory effects of sulfur dioxide in heavily exercising asthmatics. A dose response study. American Review of Respiratory Disease and Critical Care Medicine 127(3): 278-83. Lippmann, M (2000). Sulfur Oxides: Acidid Aerosols and SO2. In: Lippmann M (ed). Environmental Toxicants (2nd ed.). New York, NY: Wiley-Interscience, 771-809. Loizidou, M (1992). Nitrogen dioxide levels in the indoor environment of a hospital. Fresenius Environmental Bulletin 1(10): 676-681. Lolova, D, Uzunova, E, et al. (1997). Indoor air quality in Bulgaria. Indoor and Built Environment 6(4): 237-240. Madany, IM and Danish, S (1991). Indoor residential nitrogen dioxide concentrations in Bahrain. Environment International 18(1): 95-101. Maeda, K, Nitta, H and Nakai, S (1992). Exposure to nitrogen oxides and other air pollutants from automobiles. Public Health Reviews 19(1 4): 61-72. Magnus, P, Nafstad, P, et al. (1998). Exposure to nitrogen dioxide and the occurrence of bronchial obstruction in children below 2 years. International Journal Of Epidemiology 27(6): 995-999. Magnussen, H, Jorres, R, et al. (1990). Relationship between the airway response to inhaled sulfur dioxide, isocapnic hyperventilation, and histamine in asthmatic subjects. International Archives of Occupational and Environmental Health 62(7): 485-491. Melia, RJ, Florey, C, et al. (1982). Childhood respiratory illness and the home environment. II. Association between respiratory illness and nitrogen dioxide, temperature and relative humidity. International Journal of Epidemiology 11(2): 164-9. Melia, RJW, Chinn, S and Rona, RJ (1990). Indoor levels of NO2 associated with gas cookers and kerosene heaters in inner city areas of England. Atmospheric Environment Part b Urban Atmosphere 24(1): 177-180. Melia, RJW, Flourey, CDV and Chinn, S (1979). The relation between respiratory illness in primary school children and the use of gas for cooking 1. Results from a national survey. International Journal of Epidemiology 8(4): 333-338. Meng, Z and Zhang, L (1990). Cytogenetic damage induced in human lymphocytes by sodium bisulfite. Mutation Research 298(2): 63-69. Meranger, JC, Brule, D, et al. (1987). Indoor outdoor levels of nitrogen and sulphur species and their relation to air flow in Antigonish, Nova Scotia. International Journal of Environmental Analytical Chemistry 29(1 2): 61-72. 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. Monn, C, Brandli, O, et al. (1998). Personal exposure to nitrogen dioxide in Switzerland. Science of the Total Environment 215(3): 243-251. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 63 Moolgavkar, S and Luebeck, E (1996). A critical review of the evidence on particulate air pollution and mortality. Epidemiology 7: 420-428. Morrow, PE, Utell, MJ, et al. (1992). Pulmonary performance of elderly normal subjects and subjects with chronic obstructive pulmonary disease exposed to 0.3 ppm nitrogen dioxide. American Review of Respiratory Disease and Critical Care Medicine 145(2): 291-300. Mukala, K, Alm, S, et al. (2000). Nitrogen dioxide exposure assessment and cough among preschool children. Archives of Environmental Health 55(6): 431-438. Mukala, K, Pekkanen, J, et al. (1996). Seasonal exposure to NO2 and respiratory symptoms in preschool children. Journal of Exposure Analysis and Environmental Epidemiology 6(2): 197-210. Mukala, K, Pekkanen, J, et al. (1999). Personally measured weekly exposure to NO2 and respiratory health among preschool children. European Respiratory Journal 13(6): 1411- 7. Nakai, S, Nitta, H and Maeda, K (1995). Respiratory health associated with exposure to automobile exhaust. II. Personal NO2 exposure levels according to distance from the roadside. Journal of Exposure Analysis and Environmental Epidemiology 5(2): 125-36. Nayebzadeh, A, Cragg Elkouh, S, et al. (1999). Sources of indoor air contamination on the ground floor of a high rise commercial building. Indoor and Built Environment 8(4): 237- 245. Neas, LM, Dockery, DW, et al. (1991). Association of indoor nitrogen dioxide with respiratory symptoms and pulmonary function in children. American Journal of Epidemiology 134(2): 204-219. Newhouse, MT, Dolovich, M, et al. (1978). Effect of threshold limit value levels of sulfur dioxide and sulfuric acid on bronchial clearance in exercising man. Archives of Environmental Health 33(1): 24-32. Ng, TP, Seet, CSR, et al. (2001). Nitrogen dioxide exposure from domestic gas cooking and airway response in asthmatic women. Thorax 56(8): 596-601. Norback, D, Walinder, R, et al. (2000). Indoor air pollutants in schools: nasal patency and biomarkers in nasal lavage. Allergy 55(2): 163-70. Nowak, D, Jorres, R, et al. (1997). Airway responsiveness to sulfur dioxide in an adult population sample. American Journal of Respiratory and Critical Care Medicine 156(4 I): 1151-1156. Noy, D, Brunekreef, B, et al. (1990). The assessment of personal exposure to nitrogen dioxide in epidemiologic studies. Atmospheric Environment Part a General Topics 24(12): 2903- 2909. Ogston, SA, Florey, CD and Walker, CH (1985). The Tayside infant morbidity and mortality study: effect on health of using gas for cooking. British Medical Journal Clinical Research Ed. 290(6473): 957-60. Orehek, J, Massari, JP, et al. (1976). Effect of short term, low level nitrogen dioxide exposure on bronchial sensitivity of asthmatic patients. Journal of Clinical Investigation 57(2): 301-7. Osterman, JW, Greaves, IA, et al. (1989). Respiratory symptoms associated with low level sulfur dioxide exposure in silicon carbide production workers. British Journal of Industrial Medicine 46(9): 629-635. Paulozzi, LJ, Spengler, RF, et al. (1993). A survey of carbon monoxide and nitrogen dioxide in indoor ice arenas in Vermont. Journal of Environmental Health 56(5): 23-25. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 64 Pennanen, AS, Salonen, RO, et al. (1997). Characterization of air quality problems in five Finnish indoor ice arenas. Journal of the Air and Waste Management Association 47(10): 1079- 1086. Pennanen, AS, Salonen, RO, et al. (1998). Two year follow up study of nonregulatory recommendations for better air quality in indoor ice arenas. Environment International 24(8): 881-887. 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. Pilotto, LS, Douglas, RM, et al. (1997). Respiratory effects associated with indoor nitrogen dioxide exposure in children. International Journal of Epidemiology 26(4): 788-96. Ponsonby, A L, Glasgow, N, et al. (2001). The relationship between low level nitrogen dioxide exposure and child lung function after cold air challenge. Clinical and Experimental Allergy 31(8): 1205-1212. Quackenboss, JJ, Krzyzanowski, M and Lebowitz, MD (1991). Exposure assessment approaches to evaluate respiratory health effects of particulate matter and nitrogen dioxide. Journal of Exposure Analysis and Environmental Epidemiology 1(1): 83-107. Raaschou Nielsen, O, Skov, H, et al. (1997). Front door concentrations and personal exposures of Danish children to nitrogen dioxide. Environmental Health Perspectives 105(9): 964- 970. Rasmussen, TR, Brauer, M, et al. (1995). Effects of nitrous acid exposure on human mucous membranes. American Review of Respiratory Disease and Critical Care Medicine 151(5): 1504-11. Rasmussen, TR, Kjaergaard, SK and Pedersen, OF (1990). Effects among asthmatic and healthy subjects of short term exposure to nitrogen dioxide in concentrations comparable to indoor peak concentrations. INDOOR AIR '90, Toronto, Ont. (Canada). Rasmussen, TR, Kjaergaard, SK, et al. (1992). Delayed effects of NO2 exposure on alveolar permeability and glutathione peroxidase in healthy humans. American Review of Respiratory Disease and Critical Care Medicine 146(3): 654-659. Remijn, B, Fischer, P, et al. (1985). Indoor air pollution and its effect on pulmonary function of adult non smoking women 1. Exposure estimates for nitrogen dioxide and passive smoking. International Journal of Epidemiology 14(2): 215-220. Rijnders, E, Janssen, NAH, et al. (2001). Personal and outdoor nitrogen dioxide concentrations in relation to degree of urbanization and traffic density. Environmental Health Perspectives 109: 411-417. Roger, LJ, Horstman, DH, et al. (1990). Pulmonary function, airway responsiveness, and respiratory symptoms in asthmatics following exercise in NO2. Toxicology and Industrial Health 6(1): 155-171. Roger, LJ, Kehrl, HR, et al. (1985). Bronchoconstriction in asthmatics exposed to sulfur dioxide during repeated exercise. Journal of Applied Physiology 59(3): 784-91. Rom, WN, Wood, SD, et al. (1986). Longitudinal evaluation of pulmonary function in copper smelter workers exposed to sulfur dioxide. American Review of Respiratory Disease and Critical Care Medicine 133(5): 830-3. Rondinelli, RC, Koenig, JQ and Marshall, SG (1987). The effects of sulfur dioxide on pulmonary function in healthy nonsmoking male subjects aged 55 years and older. American Industrial Hygiene Association Journal 48(4): 299-303. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 65 Rosenlund, M and Bluhm, G (1999). Health effects resulting from nitrogen dioxide exposure in an indoor ice arena. Archives of Environmental Health 54(1): 52-7. Ross, D (1996). Continuous and passive monitoring of nitrogen dioxide in UK homes. Environmental Technology 17(2): 147-155. Rotko, T, Kousa, A, et al. (2001). Exposures to nitrogen dioxide in EXPOLIS Helsinki: microenvironment, behavioral and sociodemographic factors. Journal of Exposure Analysis and Environmental Epidemiology 11(3): 216-23. Rubinstein, I, Bigby, BG, et al. (1990). Short term exposure to 0.3 ppm nitrogen dioxide does not potentiate airway responsiveness to sulfur dioxide in asthmatic subjects. American Review of Respiratory Disease and Critical Care Medicine 141(2 I): 381-385. Salome, CM, Brown, NJ, et al. (1996). Effect of nitrogen dioxide and other combustion products on asthmatic subjects in a home like environment. European Respiratory Journal 9(5): 910-8. Samet, JM and Utell, MJ (1990). The risk of nitrogen dioxide: what have we learned from epidemiological and clinical studies? Toxicology and Industrial Health 6(2): 247-62. Samet, JM, Lambert, WE, et al. (1992). A study of respiratory illnesses in infants and nitrogen dioxide exposure. Archives of Environmental Health 47(1): 57-63. Samet, JM, Lambert, WE, et al. (1993). Nitrogen dioxide and respiratory illnesses in infants. American Review of Respiratory Disease and Critical Care Medicine 148(5): 1258-1265. Sandstrom, T, Stjernberg, M, et al. (1989a). Is the short term limit value for sulfur dioxide exposure safe?: Effects of controlled chamber exposure investigated with bronchoalveolar lavage. British Journal of Industrial Medicine 46(3): 200-203. Sandstrom, T, Stjernberg, N, et al. (1989b). Cell response in bronchoalveolar lavage fluid after exposure to sulfur dioxide: A time response study. American Review of Respiratory Disease and Critical Care Medicine 140(6): 1828-1831. Sandstrom, T, Stjernberg, N, et al. (1991). Inflammatory cell response in bronchoalveolar lavage fluid after nitrogen dioxide exposure of healthy subjects: A dose response study. European Respiratory Journal 4(3): 332-339. Sanyal, DK and Maduna, ME (2000). Possible relationship between indoor pollution and respiratory illness in an Eastern Cape community. South African Journal of Science 96(2): 94-96. Schachter, EN (1984). Effects of sulfur dioxide on airway function. American Review of Respiratory Disease and Critical Care Medicine 125(1): 125-6. Schindler, C, Ackermann Liebrich, U, et al. (1998). Associations between lung function and estimated average exposure to NO2 in eight areas of Switzerland. Epidemiology 9(4): 405-411. 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. Schlensinger, RB (2000). Nitrogen Oxides. In: Lippmann M (ed). Environmental Toxicants (2nd ed.). New York, NY: Wiley-Interscience, 595-638. Schwab, M, McDermott, A, et al. (1994). Seasonal and yearly patterns of indoor nitrogen dioxide levels Data from Albuquerque, New Mexico. Indoor Air International Journal of Indoor Air Quality and Climate 4(1): 8-22. Sega, K (1995). Distributions of long term household exposure of different population groups to nitrogen dioxide. Journal of Exposure Analysis and Environmental Epidemiology 5(1): 35- 43. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 66 Sega, K, Fugas, M and Kalinic, N (1992). Indoor concentration levels of selected pollutants and household characteristics. Journal of Exposure Analysis and Environmental Epidemiology 2(4): 477-85. Sheppard, D, Epstein, J, et al. (1983). Tolerance to sulfur dioxide induced bronchoconstriction in subjects with asthma. Environmental Research 30(2): 412-9. Sheppard, D, Eschenbacher, WL, et al. (1984). Magnitude of the interaction between the bronchomotor effects of sulfur dioxide and those of dry (cold) air. American Review of Respiratory Disease and Critical Care Medicine 130(1): 52-5. Sheppard, D, Saisho, A, et al. (1981). Exercise increases sulfur dioxide induced bronchoconstriction in asthmatic subjects. American Review of Respiratory Disease and Critical Care Medicine 123(5): 486-491. Sheppard, D, Wong, WS, et al. (1980). Lower threshold and greater bronchomotor responsiveness of asthmatic subjects to sulfur dioxide. American Review of Respiratory Disease and Critical Care Medicine 122(6): 873-8. Shima, M and Adachi, M (1998). Indoor nitrogen dioxide in homes along trunk roads with heavy traffic. Occupational and Environmental Medicine 55(6): 428-433. Shima, M and Adachi, M (2000). Effect of outdoor and indoor nitrogen dioxide on respiratory symptoms in schoolchildren. International Journal of Epidemiology 29(5): 862-870. Shinkura, R, Fujiyama, C and Akiba, S (1999). Relationship between ambient sulfur dioxide levels and neonatal mortality near the Mt. Sakurajima volcano in Japan. Journal of Epidemiology (Japan) 9(5): 344-349. Skalpe, IO. (1964). Long-term effects of sulphur dioxide exposure in pulp mills. British Journal of Industrial Medicine 21: 69-73 Smedje, G, Norback, D and Edling, C (1997). Asthma among secondary schoolchildren in relation to the school environment. Clinical and Experimental Allergy 27(11): 1270-1278. Smith, BJ, Nitschke, M, et al. (2000). Health effects of daily indoor nitrogen dioxide exposure in people with asthma. European Respiratory Journal 16(5): 879-885. Smith, TJ, Peters, JM, et al. (1977). Pulmonary impairment from chronic exposure to sulfur dioxide in a smelter. American Review of Respiratory Disease and Critical Care Medicine 116(1): 31-40. Smith Sivertsen, T, Bykov, V, et al. (2001). Sulphur dioxide exposure and lung function in a Norwegian and Russian population living close to a nickel smelter. International Journal of Circumpolar Health 60: 342-359. Snell, RE and Luchsinger, PC (1969). Effects of sulfur dioxide on expiratory flow rates and total respiratory resistance in normal human subjects. Archives of Environmental Health 18(4): 693-8. Solomon, C, Christian, DL, et al. (2000). Effect of serial day exposure to nitrogen dioxide on airway and blood leukocytes and lymphocyte subsets. European Respiratory Journal 15(5): 922-928. Sorsa, M, Kolmodin Hedman, B and Jarventaus, H (1982). No effect of sulphur dioxide exposure, in aluminum industry, on chromosomal aberrations or sister chromatid exchanges. Hereditas 97: 159-161. Speizer, FE and Frank, NR (1966). A comparison of changes in pulmonary flow resistance in healthy volunteers acutely exposed to SO2 by mouth and by nose. British Journal of Industrial Medicine 23(1): 75-9. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 67 Speizer, FE, Ferris, B, et al. (1980). Respiratory disease rates and pulmonary function in children associated with NO2 exposure. American Review of Respiratory Disease and Critical Care Medicine 121(1): 3-10. Spengler, J, Schwab, M, et al. (1994). Personal exposure to nitrogen dioxide in the Los Angeles Basin. Air and Waste Management Association 44(1): 39-47. Spengler, JD, Ferris, BG, Jr., et al. (1979). Sulfur dioxide and nitrogen dioxide levels inside and outside homes and the implications of health effects research. Environmental Science and Technology 13(10): 1276-1280. Stacy, RW, House, D, et al. (1981). Effects of 0.75 parts per million sulfur dioxide on pulmonary function parameters of normal human subjects. Archives of Environmental Health 36(4): 172-178. Stock, TH, Kotchmar, DJ, et al. (1985). The estimation of personal exposures to air pollutants for a community based study of health effects in asthmatics design and results of air monitoring. J Air Pollut Control Assoc 35(12): 1266-1273. Strand, V, Rak, S, et al. (1997). Nitrogen dioxide exposure enhances asthmatic reaction to inhaled allergen in subjects with asthma. American Journal of Respiratory and Critical Care Medicine 155(3): 881-887. Strand, V, Salomonsson, P, et al. (1996). Immediate and delayed effects of nitrogen dioxide exposure at an ambient level on bronchial responsiveness to histamine in subjects with asthma. European Respiratory Journal 9(4): 733-740. Strand, V, Svartengren, M, et al. (1998). Repeated exposure to an ambient level of NO2 enhances asthmatic response to a nonsymptomatic allergen dose. European Respiratory Journal 12(1): 6-12. Trenga, CA, Koenig, JQ and Williams, PV (1999). Sulphur dioxide sensitivity and plasma antioxidants in adult subjects with asthma. Occupational and Environmental Medicine 56(8): 544-547. Tunnicliffe, WS, Burge, PS and Ayres, JG (1994). Effect of domestic concentrations of nitrogen dioxide on airway responses to inhaled allergen in asthmatic patients. Lancet 344(8939 4): 1733-1736. Tunnicliffe, WS, Hilton, MF, et al. (2001). The effect of sulphur dioxide exposure on indices of heart rate variability in normal and asthmatic adults. European Respiratory Journal 17(4): 604-608. US Environmental Protection Agency, Office of Air Quality Planning and Standards. (2002) National Ambient Air Quality Standards (NAAQS), http://www.epa.gov/airs/criteria.html. accessed May 29 US Environmental Protection Agency. (2002). Indoor Air Quality (IAQ): Nitrogen Dioxide http://www.epa.gov/iaq/no2.html. Vagaggini, B, Paggiaro, PL, et al. (1996). Effect of short term NO2 exposure on induced sputum in normal, asthmatic and COPD subjects. European Respiratory Journal 9(9): 1852-1857. von Nieding, G, Wagner, HM, et al. (1979). Controlled studies of human exposure to single and combined action of NO2, O3, and SO2. International Archives of Occupational and Environmental Health 43(3): 195-210. Wang, B, Peng, Z, et al. (1999). Particulate matter, sulfur dioxide, and pulmonary function in never smoking adults in Chongqing, China. International Journal of Occupational and Environmental Health 5(1): 14-9. Review of the Health Risks associated with NO2 and SO2 in Indoor Air University of British Columbia School of Occupational and Environmental Hygiene 68 Wang, JH, Duddle, J, et al. (1995). Nitrogen dioxide increases eosinophil activation in the early phase response to nasal allergen provocation. International Archives of Allergy and Immunology 107(1 3): 103-105. Winterton, DL, Kaufman, J, et al. (2001). Genetic polymorphism as biomarkers of sensitivity to inhaled sulfur dioxide in subjects with asthma. Annals of Allergy, Asthma, and Immunology 86(2): 232-238. Witek, TJ and Schachter, EN (1985a). Airway responses to sulfur dioxide and methacholine in asthmatics. Journal of Occupational Medicine 27(4): 265-8. Witek, TJ, Schachter, EN, et al. (1985b). Respiratory symptoms associated with sulfur dioxide exposure. International Archives of Occupational and Environmental Health 55(2): 179- 83. Wolff, RK, Dolovich, M, et al. (1975). Sulfur dioxide and tracheobronchial clearance in man. Archives of Environmental Health 30(11): 521-7. World Health Organization. (1999). Guidelines for Air Quality Health Based Guidelines WHO:Geneva http://www.who.int/environmental_information/Air/Guidelines/Chapter3.htm. Accessed May 29, 2002. Yadav, JS and Kaushik, VK (1996). Effect of sulphur dioxide exposure on human chromosomes. Mutation Research 359(1): 25-29. Yoon, DW, Lee, K, et al. (1996). Surveillance of indoor air quality in ice skating rinks. Environment International 22(3): 309-314. Yoshino, H, Matsumoto, H, et al. (1990). Investigation of indoor thermal environment, air quality, and energy consumption in new detached houses of wood frame construction in a small city in Japan. Environment International 16(1): 37-52. Yuhui, Q, Zhang, XM, et al. (1991). Indoor air pollution in four cities in China. Biomedical and Environmental Sciences 4(4): 366-72. Zhou, Y and Cheng, YS (2000). Characterization of emissions from kerosene heaters in an unvented tent. Aerosol Science and Technology 33(6): 510-524.

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