ࡱ>  .0)*+,-3DE^q Rbjbjt+t+ 3AAG@](((T||||\p|p[ v"88r"<" "JVLVLVLVKVXZ$]^Z("!"^"""ZB8r BBB"l8:(r^N||"JVBBKM,(^Nr4 l#sO||?LN NITROGEN DIOXIDE: EVALUATION OF CURRENT CALIFORNIA AIR QUALITY STANDARDS WITH RESPECT TO PROTECTION OF CHILDREN Mark W. Frampton, M.D. Departments of Medicine and Environmental Medicine University of Rochester School of Medicine and Dentistry Rochester, NY 14642-8692 Prepared for California Air Resource Board California Office of Environmental Health Hazard Assessment September 1, 2000 1. EXTENDED ABSTRACT Nitrogen dioxide (NO2) is the most abundant and toxic of the nitrogen oxides formed from combustion of fossil fuels, and ambient concentrations are related to traffic density as well as point sources. Indoor NO2 levels may exceed those found outdoors. When inhaled, NO2 persists to the lung periphery because of its relatively low solubility. Greater than 60% of inhaled NO2 is deposited, predominantly in the centri-acinar region, and the fraction deposited increases with exercise. Epidemiological studies have found relationships between both outdoor and indoor NO2 levels and respiratory illness, decrements in lung function, and exacerbation of asthma, especially in children. Outdoor NO2 was associated with increased infant mortality and intrauterine mortality in Sao Paulo, Brazil. However, these studies are subject to exposure misclassification, and generally fail to consider a possible role of indoor and outdoor particle exposure as a confounding factor. NO2 may represent a marker for exposure to traffic- or combustion-related pollution in these epidemiological studies. Human clinical studies generally fail to show effects of exposure concentrations at or below the current California standard of 0.25 ppm, which supports the concept that NO2 is a marker of pollution rather than a cause of direct effects at ambient levels. However, exposure to NO2 at concentrations only slightly above 0.25 ppm appear to enhance responsiveness to allergen challenge in subjects with asthma. 2. BACKGROUND Combustion of fossil fuels results in the oxidation of nitrogen-containing compounds and the formation of nitrogen oxides. There are at least 7 species of nitrogen oxide compounds: nitric oxide (NO), nitrogen dioxide (NO2), nitrous oxide (N2O), nitrogen trioxide (NO3), dinitrogen trioxide (N2O3), dinitrogen tetroxide (N2O4), and dinitrogen pentoxide (N2O5). These species are largely interconvertible, and therefore referred to collectively as NOx. Nitrogen dioxide is the most abundant in the atmosphere, and represents the greatest risk to human health. The U.S. Environmental Protection Agency has established a National Ambient Air Quality Standard (NAAQS) for NO2 of 0.053 ppm (100 g/m3), measured as an annual arithmetic mean. The State of California has established only a short-term (1 hour) standard for NO2 of 0.25 ppm (470 g/m3). Nitrogen dioxide is considered an important outdoor pollutant not only because of potential health effects, but because it is an essential precursor in the formation of tropospheric ozone via photochemical reactions, and contributes to the formation of atmospheric acids and secondary particles. These issues will not be discussed in this review, which will focus on the health effects of exposure to NO2 itself. This review will not address the role of NO2 in ozone or acid formation via photochemical reactions, and will only briefly discuss the chemistry, sources, and dosimetry of NO2. A number of reviews of these topics are available. 3. PRINCIPAL SOURCES AND EXPOSURE ASSESSMENT The primary sources for NO2 are internal combustion engines, both gasoline and diesel powered, as well as point sources, especially power plants. U.S. emissions of NOx in 1996-1997 were approximately 23,000 short tons per year, with roughly 11,000 tons contributed by fuel combustion from non-transportation sources  QUOTE "(Office of Air and Radiation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ffice of Air and Radiation, 1998). In 1991, 8.9 million people resided in counties that exceeded the NAAQS for NO2, with the highest annual concentrations occurring in Southern California  QUOTE "(Bascom et al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ascom et al., 1996). National mean concentrations of NO2 decreased 14% from 1988 to 1997, to about 20 ppb, although NOx emissions decreased little during that time period, and increased 1% in 1996-1997  QUOTE "(Office of Air and Radiation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ffice of Air and Radiation, 1998). Since 1970, total NOx emissions have increased 11% and emissions from coal-fired power plants have increased 44%. During the past 5 years, all U.S. counties have been in compliance with the Federal NO2 standard. Compliance with the Federal NAAQS for NO2 does not preclude substantial short-term peak concentrations, and the California standard of 0.25 ppm for 1 hour continues to be exceeded, although with less frequency. In 1999, maximum one-hour values for NO2 were highest in the counties of Riverside (0.307 ppm) and Imperial (0.286), with annual mean concentrations of 0.022 and 0.035, respectively  QUOTE "(Office of Air and Radiation, 1998)"  ADDIN PROCITE 110591190200000023284F6666696365206F662041697220616E6420526164696174696F6E2C2031393938290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A01B0000040C0048656C7665746963610000001CE0153C0C683EA80C683B740C944E7C00000001020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C683910000000020C4895400C9450A40000002C0C9450A40C4FBE40D7100000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657304343536350101000400000400000000000000000000000000000000000000000000000000000000000000000000 (Office of Air and Radiation, 1998). Because NO2 concentrations are related to traffic density, commuters in heavy traffic may be exposed to higher concentrations of NO2 than those indicated by regional monitors. In one study of personal exposures by Los Angeles commuters  QUOTE "(Baker et al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aker et al., 1990), in-vehicle NO2 concentrations, averaged over 1 week of travel, ranged from 0.028 to 0.170 ppm, with a mean of 0.078 ppm. This was 50% higher than ambient concentrations measured at local monitoring sites. Indoor NO2 levels, in the presence of an unvented combustion source, may exceed those found outdoors. Natural gas or propane cooking stoves release NO2, as do kerosene heaters. Peak levels exceeding 2.0 ppm have been measured in homes with gas stoves  QUOTE "(Leaderer et al., 1984)"  ADDIN PROCITE 110591190200000017284C6561646572657220657420616C2E2C2031393834290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A00F0000040C0048656C766574696361004E9C0000002C1CCACBA00C4669700C944E7C0C466970020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C60AC0C000000020C4895400C9450A40000002C0C9450A40C4FBE40D6000000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573244C656164657265722C2053746F6C77696A6B2C20657420616C2E2031393834202332323001010024000004000000AE1C242A000840FFD5761400037098173DAC50000000290000000017348560 (Leaderer et al., 1984), and exposures during cooking have been measured as high as 0.6 ppm for up to 45 minutes  QUOTE "(Goldstein et al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oldstein et al., 1988). It is important to recognize that outdoor NO2 levels provide a background for the higher peaks that may occur indoors; thus higher outdoor levels may drive higher peaks indoors, with outdoor levels contributing approximately 50% to indoor levels  QUOTE "(Marbury et al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arbury et al., 1988). Distance of residences from roadways appears to influence indoor NO2 levels. In Tokyo, Japan, NO2 exposure among adult women, age 40-60 years, was determined at varying distances from the roadside, using personal monitoring and monitoring inside and outside the home  QUOTE "(Nakai et al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akai et al., 1995). The highest mean personal exposure levels were found in women living closest to the roadway at 63.4 ppb, compared with 55.3 ppb farthest from the roadway. Personal monitoring in homes with unvented combustion sources were less clearly correlated to distance from the roadway than homes without combustion sources. In another study in the Netherlands  QUOTE "(Roorda-Knape et al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oorda-Knape et al., 1999), NO2 levels in school classrooms were found to be significantly correlated with traffic density and distance of the school from the roadway. Concentrations of NO2 as high as 4 to 5 ppm have been measured inside ice hockey arenas, from operation of natural gas-fueled ice resurfacing machines in the presence of inadequate ventilation  QUOTE "(Hedberg et al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edberg et al., 1989). These exposures have been associated with epidemics of acute respiratory illness in exposed players and fans. 3.1 Dosimetry Nitrogen dioxide is an oxidant gas that dissolves in water to form nitric acid, and also reacts with lipids and proteins in cells. It likely reacts either within the lung epithelial lining fluid or in the epithelial cell membrane, and probably does not penetrate beyond the epithelium as an intact molecule  QUOTE "(Postlethwait et al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ostlethwait et al., 1990). Toxic effects are presumably related to the effects of NO2 and its reaction products on lung cells. Nitrogen dioxide is less reactive than ozone, and is relatively insoluble; therefore, removal of inhaled NO2 in the upper airway is limited. Dosimetric studies indicate that most inhaled NO2 is retained in the lungs and deposited primarily in peripheral airways, particularly the terminal bronchiolar region. Miller et al.  QUOTE "(Miller et al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iller et al., 1982) developed a dosimetric model for NO2 in the human which indicated that the NO2 dose to the transitional airways increased three- to four-fold compared with the more proximal airways, and then decreased again in the alveolar region. Using this model, increases in tidal volume from 500 to 1500 mL would increase lung uptake from 60% to 90%, primarily attributable to increased alveolar uptake. Approximately 15 times more NO2 would be delivered to pulmonary tissue at maximum tidal volume, as would occur during heavy exercise, than during rest. Data from a clinical study  QUOTE "(Bauer et al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auer et al., 1986) were supportive of these predictions. Fifteen asthmatic subjects were exposed to 0.3 ppm NO2 via mouthpiece for 20 minutes at rest, followed by 10 minutes of exercise. Expired NO2 concentrations were measured continuously. NO2 deposition was 722% at rest, increasing to 871% with moderate exercise. These findings indicate that the NO2 dose to the distal airways and alveolar space, and therefore toxic effects in this region, would be substantially increased by exercise. 4. DESCRIPTION OF KEY STUDIES The assessment of health risks of exposure to NO2 and other ambient pollutants depends on three types of investigations: epidemiological studies, human clinical studies, and animal exposure and toxicology studies. In addition, in vitro exposure of cells and tissues assist with determining mechanisms of effects. Traditionally, epidemiological studies have focused on symptoms, doctor visits, hospitalizations, medication use, pulmonary function measures, and mortality as health outcomes. Clinical studies have focused on symptoms, changes in pulmonary function (principally spirometry), and occasionally assessment of non-specific airways responsiveness, in part because these measurements are relatively simple, safe, and reproducible. More recently, innovative approaches have been used to examine pollutant effects on respiratory host defense, airway inflammation, cardiac effects, and systemic effects. This review will first summarize findings from epidemiological studies, followed by human clinical studies. Although animal and in vitro exposure studies per se will not be addressed in detail in this review, particularly relevant data from these approaches will be addressed in the appropriate context. Emphasis will be placed on relevant studies within the past 5 years, particularly those dealing with the health of children. 4.1 Epidemiological Studies 4.1.1 Outdoor A number of epidemiological studies have sought evidence for health effects of exposure NO2 outdoors, along with other pollutants, in both adults and children. A selection of studies published since 1995 are summarized in Table 1. Several studies show significant relationships between ambient NO2 levels and health effects, including respiratory symptoms, episodes of respiratory illness, lung function, and even mortality. However, because NO2 shares sources with other pollutants, especially fine particles, epidemiological studies are often unable to distinguish the relative importance of NO2 in causing health effects. Particular caution is needed in interpreting the results of studies measuring ambient concentrations of NO2, but not particles. Indeed, many studies conducted over the past 10 years in a variety of locations around the world have observed a strong relationship between fine particle levels and both mortality and morbidity. That NO2 appears strongly correlated with health outcomes in a few of these studies is perhaps not surprising, given the close correlation between NO2 and particles. Beginning in the 1970s, epidemiological studies in Chattanooga, Tennessee examined the relation between respiratory illnesses and ambient levels of NO2. Shy and colleagues  QUOTE "(Shy et al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hy et al., 1970) ADDIN  tracked the respiratory symptoms of 871 families (4,043 individuals) selected from five schools situated near a munitions factory in Chattanooga. This factory emitted NO2 into surrounding areas. The ambient 24-hr mean NO2 levels were 0.083 ppm in the high exposure area, 0.063 ppm in the intermediate area, and 0.043 ppm in the low area. Total suspended particulate and sulfate concentrations were similar across the three areas. Biweekly questionnaires indicated that the rates of acute respiratory illness were higher among the families living in the relatively high exposure area, although the rates were not consistently associated with the exposure gradient among the three schools in the high exposure area. Differences in family size, income, or education did not explain the observed associations. Parental smoking habits did not appear to influence the illness rates among children. A subsequent study in the same Chattanooga community  QUOTE "(Pearlman et al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earlman et al., 1971) ADDIN  studied lower respiratory tract infections in 3,217 school children and infants. Physicians office records were used to validate the parental reports of illness. Episodes of bronchitis were reported more often for school children living two and three years in the high and intermediate ambient NO2 areas. This pattern was not observed in the infants, and no significant difference in incidence was observed between the high and intermediate areas. The incidence of croup and pneumonia did not differ significantly among the three exposure areas. Control for socioeconomic status and for parental smoking was not mentioned. In  ADDIN further collection and analyses of data and from the Chattanooga studies  QUOTE "(Love et al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ove et al., 1982), including improved estimates of environmental exposures data, there was an apparent increase in lower respiratory illness in children who resided in an area previously defined as having high exposure to NO2, although exposure levels at the time of the illnesses were comparable across the study region. The authors noted that the increased illnesses could not be attributed unequivocally to the atmospheric NO2. In analyses of another EPA database from Chattanooga, Harrington and Krupnick  QUOTE "(Harrington & Krupnick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arrington & Krupnick, 1985) ADDIN  found a statistically significant relationship between NO2 and reports of acute respiratory illness for children 12 years of age and younger. However, there was no clear exposure-response relationship. Braun-Fahrlander and colleagues  QUOTE "(Braun-Fahrlander et al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raun-Fahrlander et al., 1992)  ADDIN followed respiratory symptoms of 625 Swiss children in two cities using a daily symptom diary. Exposures to NO2 were estimated using passive samplers placed outside the residence location and inside in the room where the child spent the most time. The concentrations of NO2 indoors and outdoors were not associated with symptom incidence rates. The duration of symptom episodes was associated with outdoor but not indoor NO2 concentration. The Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA)  QUOTE "(Zemp et al., 1999; Schindler et al., 1998; Ackermann-Liebrich et al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emp et al., 1999; Schindler et al., 1998; Ackermann-Liebrich et al., 1997) QUOTE ""  ADDIN PROCITE 110591190200000000010000C7100000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657304343533340101000400000400000000000000000000000000000000000000000000000000000000000000000000  QUOTE ""  ADDIN PROCITE 110591190200000000010000D6100000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657304343536340101000400000400000000000000000000000000000000000000000000000000000000000000000000  examined the long-term effects of air pollution exposure in a cross-sectional and longitudinal study of 8 areas in Switzerland. Significant associations were observed between symptoms (chronic phlegm, chronic cough, breathlessness at rest, dyspnea on exertion) and both NO2 and particles  QUOTE "(Zemp et al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emp et al., 1999). In the cross-sectional component of the study  QUOTE "(Schindler et al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chindler et al., 1998), a significant negative correlation was observed between NO2 and both FVC (( = -0.0123, p<0.001) and FEV1 (( = -0.0070, p<0.001). NO2 levels correlated strongly with PM10 levels (r = 0.91), making it impossible to determine the role of specific pollutants in the observed associations. Frischer et al.  QUOTE "(Frischer et al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rischer et al., 1993) studied 423 Austrian school children living in 4 small towns with varying levels of outdoor NO2 levels. The children were assessed with spirometry and cold air inhalation challenge on two occasions 6 months apart. Lung function increased for the children coincident with an overall decrease in NO2 levels, and NO2 levels were found to be predictive for an increase in FVC. However, the study does not provide convincing evidence for causality in the relationship; the amount of lung function increase was consistent with that expected from increase in height during the interval. No measurements of ambient particles were reported. A population-based study in the Netherlands  QUOTE "(Boezen et al., 1998)"  ADDIN PROCITE 11059119020000001528426F657A656E20657420616C2E2C2031393938290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A00D0000040C0048656C766574696361004E9C0000002C1CCACBA00C4669700C944E7C0C466970020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C61DC88000000020C4895400C9450A40000002C0C9450A40C4FBE40B50F0000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657323426F657A656E2C205363686F7574656E2C20657420616C2E203139393820233431383701010023000004000000922C242A000840FFD6762400036A380CED449000000029000000000CB7B2B0 (Boezen et al., 1998) suggested that, in adults, airways hyperresponsiveness at baseline increased risk for respiratory symptoms from air pollution. Relationships were observed between exposure to NO2 and to PM10 with respiratory symptoms, only in the group with some measure of airway lability. Associations have also been observed between NO2 levels and emergency visits for asthma in Valencia, Spain  QUOTE "(Tenias et al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enias et al., 1998), in Barcelona  QUOTE "(Castellsague et al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astellsague et al., 1995), in Israel  QUOTE "(Garty et al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arty et al., 1998), and in Santa Clara County, California  QUOTE "(Lipsett et al., 1997)"  ADDIN PROCITE 110591190200000016284C69707365747420657420616C2E2C2031393937290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A00E0000040C0048656C766574696361004E9C0000002C1CCACBA00C4669700C944E7C0C466970020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C6204D4000000020C4895400C9450A40000002C0C9450A40C4FBE40CE100000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573224C6970736574742C204875726C65792C20657420616C2E203139393720233435343101010022000004000000922C242A000840FFD6762400036A380CED449000000027000000000CB7B2B0 (Lipsett et al., 1997). In these studies, NO2 effects may have been reflective of the pollutant mix rather than NO2 alone. Children with asthma appear to be more susceptible to the health effects of air pollution in general, although the specific role of NO2 exposure remains in question. McConnell et al  QUOTE "(McConnell et al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cConnell et al., 1999), reporting data from the Southern California Childrens Health Study, found positive associations between indices of air pollution, including NO2, PM10, and PM2.5, and respiratory symptoms in children with asthma. The strongest association was with NO2 (Figure 1). No association was seen for children without asthma. Particles, NO2, and acids were too highly correlated to allow estimation of individual pollutant effects. Krmer et al.  QUOTE "(Krmer et al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rmer et al., 2000) examined the relationship between NO2 exposure, as assessed by outdoor and personal monitors, and the prevalence of atopy and rhinitis in 9 year old children. Interestingly, a significant relationship for both endpoints was observed with outdoor NO2 levels, but not with levels obtained from personal monitoring. This suggests that a factor associated with outdoor air pollution, other than NO2, may be playing a causative role. A large study of visits to doctors offices in London for respiratory complaints  QUOTE "(Hajat et al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ajat et al., 1999) found different pollutant associations for children than for adults. Among children, positive associations were found between asthma visits and both NO2 and CO. The strongest relationship was during the summer, when the percentage change in asthma visits for a 10 to 90th percentile increase in 24-hour NO2, lagged by one day, was 13.2% (CI: 5.6-21.3%). For adults, the only significant association was for PM10. This finding suggests that children and adults may differ in their susceptibilities to components of the ambient pollutant mix. Associations between NO2 levels and mortality have been observed. A very brief report  QUOTE "(Garcia-Aymerich et al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arcia-Aymerich et al., 2000) examined mortality in a cohort of patients with chronic obstructive pulmonary disease in Barcelona. Significant relationships were found between mortality and increases in SO2, 1 hour maximum NO2, and 24 hour average NO2, but not black smoke. However, data for black smoke nearly missed significance, and it is likely that NO2 represents a surrogate for pollution in general in this study. Saldiva et al.  QUOTE "(Saldiva et al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aldiva et al., 1994) studied mortality among children under age 5 in Sao Paulo, Brazil, a city with dense traffic, high pollution levels, and high infant mortality. Mortality due to congenital malformations, neonatal events, or prematurity was excluded. Mean NO2 (NOx) levels were 0.127 ppm. Only NO2, and not PM10, ozone, SO2, or CO, was associated with mortality in this study, with an estimated odds of 1.30, 95% CI: 1.17-1.43. The Sao Paulo group subsequently examined the influence of pollutant exposure on intrauterine mortality  QUOTE "(Pereira et al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ereira et al., 1998). Again, the strongest single-pollutant coefficient was for NO2 (0.0013/g/m3, p<0.01, Figure 2), with lesser coefficients for SO2 and CO. No significant relationship was seen for PM10 or ozone. An index combining the effects of NO2, SO2, and CO associated most strongly with fetal mortality. The authors postulated one mechanism may be formation of methemoglobin in the fetus; fetal hemoglobin is more easily oxidized than that in adults. Exposure to ambient fine particulate matter has been associated with increases in cardiovascular mortality. Peters and colleagues  QUOTE "(Peters et al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eters et al., 2000) used a novel approach to determine whether ambient pollution levels were associated with cardiac arrhythmias. The investigators obtained data from patients with implantable cardiac defibrillators, determining the number of times the defibrillator was activated in response to an arrhythmia, and correlating this with ambient concentrations of particles and gases. The strongest association was with NO2 , with a 1 to 2-day lag. For example, the odds ratio for having at least 10 defibrillator events in association with a 26 ppb increase in NO2 was 2.79, with 95% confidence intervals of 1.53-5.10. The concentration-response relationship was steeper for NO2 than for PM2.5 or black carbon (Figure 3). This is a potentially instructive study because NO2 levels were highest in the winter, and PM2.5 levels were highest in the summer. Correlation between NO2 and PM2.5 measurements were lower (r=0.57) than in many epidemiological studies, allowing some ability to attribute effects. The authors hypothesized that NO2 may be a marker for the more toxic emissions associated with local traffic-related pollution, rather than PM alone, which is a mixture of combustion and transported particles. The data are also consistent with toxicity related to NO2 as a component of the ambient pollutant mixture. 4.1.2 Indoor The indoor setting provides the potential for discrimination between NO2 and particle effects, because stoves burning natural gas emit primarily NOx. Many studies have examined the potential for health effects of indoor NO2 exposure, especially in children; many of these studies, and their methodological problems, have been reviewed  QUOTE "(Samet & Utell, 1990; Samet & Spengler,1991; Frampton et al., 1991b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amet & Utell, 1990; Samet & Spengler,1991; Frampton et al., 1991b) QUOTE ""  ADDIN PROCITE 110591190200000000010000FD060000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365731B53616D65742026205370656E676C657220313939312023313835310101001B000004000000922C242A000842FFD6762400036A380CC3971000000021000000000CB7B2B0  QUOTE ""  ADDIN PROCITE 11059119020000000001000062050000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573224672616D70746F6E2C2053616D65742C20657420616C2E203139393120233134333401010022000004000000922C242A000840FFD6762400036A380CC3971000000027000000000CB7B2B0 , and only selected studies will be mentioned here. Key studies published since 1995 are summarized in Table 2. Reports during the 1970s, from the United Kingdom  QUOTE "(Melia et al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elia et al., 1977) ADDIN and the U.S.  QUOTE "(Speizer et al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peizer et al., 1980),  ADDIN suggested that residence in a home with a gas stove increased the frequency of respiratory symptoms and of respiratory illness among children less than 2 years of age. Small sample size, inadequate control of potential confounding factors (e.g., presence of other children in the household, day care attendance, exposure to environmental tobacco smoke, and socioeconomic status) and potential misclassification of exposure and outcome limit the validity of these investigations. In particular, misclassification of exposure by using gas stoves as a surrogate for NO2 exposure, and small sample sizes, may tend to bias many of the studies toward no effect. In a pilot study, Goldstein and associates  QUOTE "(Goldstein et al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oldstein et al., 1988) ADDIN  monitored NO2 exposures for 5 days in asthmatic subjects with a portable continuous monitoring instrument held at breathing level before, during, and after they used a gas stove for cooking. The limited data suggested that at average NO2 levels below 0.3 ppm there were no consistent effects on lung function, while at concentrations above 0.3 ppm most of the asthmatic subjects showed a drop in forced vital capacity (FVC). To reduce the problem of small sample size, Hasselblad et al.  QUOTE "(Hasselblad et al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asselblad et al., 1992) reported a meta-analysis of 11 epidemiological studies of respiratory illness in children and residential NO2 exposure. The authors found an estimated 20% increase in risk of respiratory illness in children per 15 ppb increment in indoor NO2 exposure. A number of additional studies have been published since 1990, with continued mixed results. A prospective cohort study of infants conducted in Albuquerque, New Mexico  QUOTE "(Samet et al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amet et al., 1993) attempted to address many of the issues of previous studies related to sample size and exposure misclassification. Exposures to NO2 and respiratory illnesses were monitored prospectively from birth to 18 months of age in a cohort of 1,205 infants living in homes with gas and electric cooking stoves, without smoking. NO2 exposures were estimated from serial measurements of bedroom NO2 concentrations. Respiratory illnesses were quantified from reports of symptoms and illnesses from mothers and validated by home visits ADDIN . No consistent trends in incidence or duration of illness were observed by level of NO2 exposure at the time of illness or during the prior month, or by type of stove. However, indoor NO2 levels were very low in this study. Neas et al.  QUOTE "(Neas et al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eas et al., 1991)  ADDIN  reported that a composite measure of respiratory symptoms increased monotonically with measured annual average NO2 concentrations within the home, among children in the Harvard Six Cities study. Symptoms included shortness of breath with wheeze, chronic wheezes, chronic cough, phlegm, or bronchitis. Residential NO2 levels were not associated with pulmonary function. On the other hand, Dijkstra et al.  QUOTE "(Dijkstra et al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ijkstra et al., 1990)  ADDIN found no associations between chronic cough, persistent wheeze, or shortness of breath with wheeze with indoor NO2 measurements in the homes of children in the Netherlands. More recent studies have utilized personal monitoring methods in an attempt to improve exposure classification. Mukala et al.  QUOTE "(Mukala et al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ukala et al., 1999) prospectively studied personal exposure to NO2 for periods of 13 weeks among 163 preschool children in Helsinki, using individual passive diffusion monitors. Daily diaries of symptoms were kept by the parents, and in a subset of 53 children, peak expiratory flow rates were measured in the morning and evening. Co-variates considered in the model included allergy, education, smoking, stove type, and outdoor pollutant concentrations (NO, NO2, O3, SO2, and total suspended particles). The median personal NO2 exposure was 21.1 g/m3 (0.011 ppm), with a maximum of 99 g/m3 (0.05 ppm). An increased risk of cough was associated with increasing NO2 exposure (risk ratio = 1.52; 95% confidence interval 1.00-2.31). There were no significant effects on other respiratory symptoms or peak flow. In Australia, where unvented natural gas cooking and heating are common, Pilotto et al.  QUOTE "(Pilotto et al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ilotto et al., 1997) queried respiratory symptoms and school absences among 388 children from 6 to 11 years of age, and monitored indoor NO2 levels at their schools, which were chosen for having either unvented gas heating or electric heating. Classroom monitoring of NO2 levels was conducted intermittently over several months. A significant increase in sore throat, colds, and absences from school were found for children in environments with hourly peak levels e"80 ppb, compared with background levels of 20 ppb. Exposure-response relationships were evident for each outcome. However, no measurements of other pollutants, either indoor or outdoor, were provided. Caution must be used in interpreting the findings from cross-sectional studies, because many factors other than pollutant levels may influence differences between populations. In the Latrobe Valley of Australia  QUOTE "(Garrett et al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arrett et al., 1998), NO2 levels were monitored in eighty homes, on 5 separate occasions for 4 days each, and health questionnaires administered to the 148 children residing in those homes. 58 of the children were asthmatic, although the diagnostic criteria were not provided. Children underwent allergy prick testing and monitored their peak flow rates for a 2-week period in the winter and spring. The indoor median NO2 concentration was 6.0 ppb, with a maximum of 128 ppb. Respiratory symptoms were more common in children exposed to a gas stove (odds ratio 2.3, CI 1.00-5.2), even after adjusting for NO2 levels (odds ratio 2.2, CI 1.0-4.8). Atopic children tended to have a greater risk than non-atopic children. NO2 concentration was not a significant risk factor for symptoms. The authors conclude that gas stoves may pose a risk apart from NO2. However, the relative paucity of NO2 monitoring data for each home may have provided insufficient statistical power to demonstrate an association. More important weaknesses in the study are the inclusion of homes with cigarette smokers, and the failure to monitor other pollutants, either inside or outside the home. These factors may have confounded the findings. Jarvis et al.  QUOTE "(Jarvis et al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arvis et al., 1996) studied symptoms, lung function, and atopy in 15,000 adults aged 20-44 years in Britain, as part of the European Community Respiratory Health Survey. Women, but not men, who reported cooking with gas had an increased risk for symptoms consistent with asthma, such as wheezing (odds ratio (OR) 2.07, CI 1.41-3.05), waking with shortness of breath (OR 2.32, CI 1.25-4.34), and asthma attacks (OR 2.60, CI 1.20-5.65). Lung function was measured in a subset of subjects, and FEV1 was reduced 3.1% of predicted for women cooking with gas compared to those using other means, after adjusting for age, smoking, and town of residence. Total and specific IgE levels were not associated with gas stove use. There was no protective effect associated with use of an exhaust fan. The authors boldly concluded from their estimate of the population attributable risk fraction that the prevalence of wheeze with breathlessness in young women would be reduced by between 8% and 48% if cooking with gas were abandoned. Although studies such as this are limited by the potential for exposure misclassification and the influence of other environmental and biological factors, the findings are consistent with women spending more time at cooking than men, and with reports of increased responsiveness to allergen challenge following NO2 exposure (see below). Taken together, studies of the health effects of exposure to NO2 indoors fail to make a convincing case for association with respiratory illness in either children or adults. The findings of the Hasselblad meta-analysis  QUOTE "(Hasselblad et al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asselblad et al., 1992) must be interpreted with caution because the 11 studies used in the analysis employed varying methodologies and study populations. Small sample size, potential for misclassification, inclusion of smokers in many of the studies, and failure to consider potential effects of outdoor pollution, or other indoor pollutants, may bias many of the studies. For example, burning of natural gas in gas stoves emits ultrafine particles in addition to NO2, and the cooking process is also a source of particles. It is possible that observed health effects associated with gas stove use may represent health effects of particle exposure, or of particles combined with NO2. This may explain why Garrett et al.  QUOTE "(Garrett et al., 1998)"  ADDIN PROCITE 110591190200000016284761727265747420657420616C2E2C2031393938290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A00E0000040C0048656C766574696361004E9C0000002C1CCACBA00C4669700C944E7C0C466970020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C6391EC000000020C4895400C9450A40000002C0C9450A40C4FBE40020F0000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657304333934300101000400000400000000000000000000000000000000000000000000000000000000000000000000 (Garrett et al., 1998), found a significant relationship between respiratory symptoms in children and gas stove use, but not indoor NO2 levels. The Samet et al. study of infants in Albuquerque  QUOTE "(Samet et al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amet et al., 1993) provides convincing evidence that indoor NO2, at the very low concentrations found in that study, are not associated with respiratory illnesses in children under 18 months of age. 4.2 Clinical Studies 4.2.1 Studies with Healthy Subjects Effects on Pulmonary Function: Studies examining responses of healthy volunteers to acute exposure to NO2  ADDIN have generally failed to show alterations in lung mechanics of healthy volunteers  QUOTE "(Hackney et al., 1978; Kerr et al., 1979; Frampton et al., 1991a; Azadniv et al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ackney et al., 1978; Kerr et al., 1979; Frampton et al., 1991a; Azadniv et al., 1998) QUOTE ""  ADDIN PROCITE 110591190200000000010000DA000000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365731D4B6572722C204B756C6C652C20657420616C2E203139373920233232340101001D000004000000AE1C242A000844FFD57614000370981744CEE0000000230000000017348560  QUOTE ""  ADDIN PROCITE 1105911902000000000100004B030000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573224672616D70746F6E2C204D6F72726F772C20657420616C2E2031393931202338363301010022000004000000AE1C242A000848FFD57614000370981744CEE0000000270000000017348560  QUOTE ""  ADDIN PROCITE 110591190200000000010000820D0000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657321417A61646E69762C205574656C6C2C20657420616C2E203139393820233335353101010021000004000000AE1C242A000848FFD57614000370981744CEE0000000270000000017348560 . Exposures ranging from 75 minutes to 3 hours at concentrations up to 4.0 ppm NO2  QUOTE "(Linn et al., 1985b; Mohsenin, 1987b; Mohsenin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inn et al., 1985b; Mohsenin, 1987b; Mohsenin, 1988) QUOTE ""  ADDIN PROCITE 110591190200000000010000F2060000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573134D6F6873656E696E203139383720233138333901010013000004000000AE1C242A00084AFFD57614000370981744CEE0000000190000000017348560  QUOTE ""  ADDIN PROCITE 11059119020000000001000097000000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573124D6F6873656E696E2031393838202331353601010012000004000000AE1C242A000848FFD57614000370981744CEE0000000170000000017348560   ADDIN did not alter pulmonary function. Curiously, Bylin and associates  QUOTE "(Bylin et al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ylin et al., 1985)  ADDIN found increased airway resistance after a 20-minute exposure to 0.25 ppm NO2 and decreased airway resistance after a 20-minute exposure to 0.5 ppm NO2, but no change in airway responsiveness to aerosolized histamine challenge in the same subjects. Overall, there is little convincing evidence that exposure of healthy volunteers to NO2 at levels as high as 4.0 ppm alters airway mechanics, as measured by spirometry or flow resistance. Several observations indicate that NO2 exposures in the range of 1.5-2.0 ppm cause small but significant increases in airway responsiveness. Mohsenin  QUOTE "(Mohsenin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ohsenin, 1988)  ADDIN found that a 1-hour exposure to 2 ppm NO2 increased responsiveness to methacholine, as measured by changes in specific airway conductance, without directly affecting lung function. Furthermore, pretreatment with ascorbic acid prevented the NO2-induced increase in airway responsiveness  QUOTE "(Mohsenin, 1987b)"  ADDIN PROCITE 110591190200000011284D6F6873656E696E2C203139383762290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A0080000040C0048656C7665746963610000001CE0153C0C63CDE40C63CC880C944E7C00000001020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000050000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C63CA24000000020C4895400C9450A40000002C0C9450A40C4FBE40F2060000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573134D6F6873656E696E203139383720233138333901010013000004000000AE1C242A00084AFFD57614000370981744CEE0000000190000000017348560 (Mohsenin, 1987b) ADDIN  ADDIN . A mild increase in responsiveness to carbachol was observed following a 3-hour exposure to 1.5 ppm NO2, but not to intermittent peaks of 2.0 ppm  QUOTE "(Frampton et al., 1991a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rampton et al., 1991a) ADDIN  ADDIN . Few human clinical studies of NO2 have included elderly subjects. Morrow et al.  QUOTE "(Morrow et al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orrow et al., 1992) ADDIN  studied the responses of 20 healthy volunteers, 13 smokers and 7 nonsmokers of mean age 61 years, following exposure to 0.3 ppm NO2 for 4 hours with light exercise. There was no significant change in lung function related to NO2 exposure for the group as a whole. However, the 13 smokers experienced a slight decrease in FEV1 during exposure, and their responses were significantly different from the 7 nonsmokers (% change in FEV1 at end of exposure: 2.25 vs. +1.25%, p = 0.01). Effects on Host Defense: Clinical studies have attempted to address the question of whether NO2 exposure increases susceptibility to infection. Goings et al.  QUOTE "(Goings et al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oings et al., 1989) ADDIN  exposed healthy volunteers to either 1-3 ppm NO2 or to air for 2 hours per day for 3 consecutive days. A live, genetically engineered influenza A vaccine virus was administered intranasally to all subjects after exposure on day 2. Infection was determined by virus recovery from nasal washings, a 4-fold or greater increase in antibody titer, or both. The findings of this study were inconclusive, in part because of limitations in sample size. In addition, the attenuated, cold-adapted virus used in the study was incapable of infecting the lower respiratory tract, where NO2 may have its greatest impact on host defense. Another approach has been to obtain lavaged cells from NO2-exposed individuals and examine their handling of infectious virus in vitro. Several NO2 exposure scenarios, including continuous low-level exposure or intermittent peak exposures have been examined  ADDIN  QUOTE "(Frampton et al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rampton et al., 1989) ADDIN . Alveolar macrophages obtained by BAL 3 1/2 hours after a 3-hour continuous exposure to 0.60 ppm NO2 tended to inactivate influenza in vitro less effectively than cells collected after air exposure. The effect was observed in cells from 4 of the 9 subjects studied; alveolar macrophages from these 4 subjects increased release of interleukin-1 after exposure to NO2, whereas cells from the remaining 5 subjects decreased release of interleukin-1 following exposure. However, in a subsequent study  QUOTE "(Azadniv et al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zadniv et al., 1998) involving 2.0 ppm NO2 exposures for 6 hours with intermittent exercise, no effect on alveolar macrophage function or inactivation of influenza virus was observed, either immediately or 18 hours after exposure. Airway Inflammation: Unlike ozone exposure, NO2 exposure at near-ambient levels (i.e., less than 2.0 ppm) does not cause a significant influx of polymorphonuclear leukocytes (PMN) into the airways and alveoli  QUOTE "(Frampton et al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rampton et al., 1989). NO2 appears to be much less potent than ozone in eliciting a neutrophilic inflammatory response. However, prolonged exposure to NO2 at concentrations only slightly above peak levels occurring indoors can cause mild airway inflammation. Healthy volunteers exposed to 2.0 ppm NO2 for 6 hours with intermittent exercise  QUOTE "(Azadniv et al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zadniv et al., 1998) showed a slight increase in the percentage of PMN obtained in bronchoalveolar lavage fluid 18 hours after exposure (air: 2.20.3%; NO2: 3.10.4%). In a separate group of subjects, no effects of this exposure protocol were found on alveolar macrophage phenotype or expression of the adhesion molecule CD11b or receptors for IgG when assessed immediately after exposure  QUOTE "(Gavras et al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avras et al., 1994). Blomberg et al.  QUOTE "(Blomberg et al., 1997)"  ADDIN PROCITE 11059119020000001728426C6F6D6265726720657420616C2E2C2031393937290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A00F0000040C0048656C766574696361004E9C0000002C1CCACBA00C4669700C944E7C0C466970020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C642568000000020C4895400C9450A40000002C0C9450A40C4FBE40000D0000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657324426C6F6D626572672C204B726973686E612C20657420616C2E203139393720233334323001010024000004000000922C242A000840FFD6762400036A380CBF019000000029000000000CBC7810 (Blomberg et al., 1997) reported that 4-hour exposures to 2.0 ppm NO2 resulted in an increase in interleukin-8 and PMN in the proximal airways of healthy subjects, although no changes were seen in bronchial biopsies. This group also studied the effects of repeated 4-hour exposures to 2 ppm NO2 on 4 consecutive days, with BAL, bronchial biopsies, and BAL fluid antioxidant levels assessed 1.5 hours after the last exposure  QUOTE "(Blomberg et al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lomberg et al., 1999). The bronchial wash fraction of BAL fluid showed a two-fold increase in PMN and a 1.5-fold increase in myeloperoxidase, indicating persistent mild airway inflammation with repeated NO2 exposure. Interestingly, small but significant decrements in FVC and FEV1 were observed after the first exposure, which returned to baseline following subsequent exposures. There is evidence from both animal and human studies that exposure to NO2 may alter lymphocyte subsets in the lung and possibly in the blood. Lymphocytes, particularly cytotoxic T cells and NK cells, play a key role in host defense against respiratory viruses by eliminating infected host cells. Richters and colleagues  QUOTE "(Damji & Richters, 1989)"  ADDIN PROCITE 1105911902000000182844616D6A6920262052696368746572732C2031393839290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A0100000040C0048656C7665746963610000001CE0153C0C643F500C643B6C0C944E7C00000001020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C643998000000020C4895400C9450A40000002C0C9450A40C4FBE4053040000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365731B44616D6A69202620526963687465727320313938392023313133300101001B000004000000922C242A000842FFD6762400036A380CBF019000000021000000000CBC7810 (Damji & Richters, 1989)  QUOTE "(Richters & Damji, 1988; Richters & Richters, 1989; Kuraitis & Richters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ichters & Damji, 1988; Richters & Richters, 1989; Kuraitis & Richters, 1989) QUOTE ""  ADDIN PROCITE 11059119020000000001000046030000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365731D52696368746572732026205269636874657273203139383920233835380101001D000004000000922C242A000840FFD6762400036A380CBF019000000023000000000CBC7810  QUOTE ""  ADDIN PROCITE 11059119020000000001000047030000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365731D4B757261697469732026205269636874657273203139383920233835390101001D000004000000922C242A000840FFD6762400036A380CBF019000000023000000000CBC7810   ADDIN showed that mice exposed to NO2 at levels as low as 4 ppm for eight hours demonstrate reductions in populations of CD8+ (cytotoxic/suppressor) lymphocytes in the spleen. In humans, Sandstrom et al.  QUOTE "(Sandstrom et al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andstrom et al., 1991)  ADDIN observed a significant, dose-related increase in lymphocytes and mast cells recovered by BAL 24 hours after a 20-minute exposure to NO2 at 2.25 - 5.5 ppm. Rubinstein et al.  QUOTE "(Rubinstein et al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ubinstein et al., 1991)  ADDIN  ADDIN found that a series of 4 daily 2-hour exposures to 0.60 ppm NO2 resulted in a small increase in NK cells recovered by BAL. In contrast, repeated exposures to 1.5 or 4 ppm NO2 for 20 minutes every 2nd day on six occasions resulted in decreased CD16+56+ and CD19+ cells in BAL fluid, 24 hours after the final exposure  QUOTE "(Sandstrom et al., 1992b; Sandstrom et al., 1992a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andstrom et al., 1992b; Sandstrom et al., 1992a) QUOTE ""  ADDIN PROCITE 11059119020000000001000078090000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365732653616E647374726F6D2C2048656C6C656461792C20657420616C2E203139393220233235303601010026000004000000922C242A00084CFFD6762400036A380CBF01900000002B000000000CBC7810 . No effects were seen on PMN or total lymphocytes. Finally, Azadniv et al.  QUOTE "(Azadniv et al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zadniv et al., 1998) ADDIN  observed a small but significant reduction in CD8+ T lymphocytes in peripheral blood, but not BAL, 18 hr following single 6 hour exposures to 2.0 ppm NO2. Differing exposure protocols and small numbers of subjects among these studies may explain the varying and conflicting findings. Furthermore, the clinical significance of transient, small changes in lymphocyte subsets is unclear. However, even small changes in susceptibility to respiratory viruses resulting from exposure to NO2 may have a significant public health impact because of the large number of individuals exposed in the home, both to NO2 and to respiratory viruses. However, clinical studies provide little evidence for effects on lung function, airway inflammation, or host defense impairment in healthy subjects at outdoor ambient exposure concentrations. Induction of Emphysema: Clinical emphysema in humans has been linked with deficient proteinase inhibitor activity in the lung, presumably via inactivation by cigarette smoke. One mechanism by which chronic NO2 exposure may result in structural lung injury is through inactivation of lung proteinase inhibitors. Animal models involving prolonged exposure to relatively high levels of NO2 have found pathological changes of emphysema  QUOTE "(Evans et al., 1976; Lafuma et al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vans et al., 1976; Lafuma et al., 1987) QUOTE ""  ADDIN PROCITE 110591190200000000010000B9000000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365731E4C6166756D612C20486172662C20657420616C2E203139383720233139310101001E000004000000922C242A000844FFD6762400036A380CBF019000000023000000000CBC7810 . Mohsenin and Gee (Mohsenin and Gee, 1987)  ADDIN exposed healthy volunteers to 3 or 4 ppm NO2 for 3 hours and observed a 45% decrease in the functional activity of (1-proteinase inhibitor in BAL fluid. Supplementation with vitamins C and E prior to exposure abrogated the effect of 4.0 ppm NO2 on elastase inhibitory capacity of the alveolar lining fluid  QUOTE "(Mohsenin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ohsenin, 1991) ADDIN  ADDIN . In contrast, Johnson et al.  QUOTE "(Johnson et al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ohnson et al., 1990) ADDIN  found no effect of exposure for 3 hours to continuous 1.5 ppm or intermittent peaks of 2.0 ppm NO2 on either the concentration (immunoassay) or functional activity of (1-proteinase inhibitor in BAL fluid. The absence of an effect in the Johnson study may reflect the lower exposure levels used. Frampton et al.  QUOTE "(Frampton et al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rampton et al., 1989) ADDIN  observed a 47% increase in a2macroglobulin, a metalloproteinase inhibitor released by alveolar macrophages, in BAL fluid 3 and 1/2 hours following 3-hour exposures to 0.60 ppm NO2. This protein may have local immunoregulatory effects as well as provide local protection against proteinases. Its increase following NO2 exposure suggests a protective response. However, no change in BAL fluid levels of a2-macroglobulin were observed following similar exposures to 1.5 ppm NO2  QUOTE "(Frampton et al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rampton et al., 1989) ADDIN  ADDIN . 4.2.2 Studies of People with Asthma Orehek and colleagues  QUOTE "(Orehek et al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rehek et al., 1976) were the first to report that relatively brief exposures of asthmatics to low-level NO2 (0.1 ppm) might enhance subsequent responsiveness to challenge with a broncho-constricting drug. Although NO2 alone caused an increase in airway resistance in only 3 of 20 asthmatics, bronchial responsiveness to carbachol increased in 13 of these 20 subjects. However, this report was challenged because of the retrospective separation of responding from non-responding subjects. Hazucha and colleagues  QUOTE "(Hazucha et al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azucha et al., 1983) ADDIN  failed to confirm these results in a study of 15 asthmatic subjects. Although there were some differences in techniques and patient selection between the Orehek and Hazucha studies, it seems likely that the findings of Orehek and coworkers reflect a retrospective stratification of subjects into responder and non-responder groups that was not justified a priori. Other investigators have also been unable to confirm effects of 0.1-0.2 ppm NO2 on lung function in either asthmatic adolescents  QUOTE "(Koenig et al., 1985; Koenig et al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oenig et al., 1985; Koenig et al., 1988) QUOTE ""  ADDIN PROCITE 110591190200000000010000FE070000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573224B6F656E69672C2050696572736F6E2C20657420616C2E203139383820233231323201010022000004000000AE1C242A000840FFD5761400037098173E0CB0000000270000000017348560   ADDIN or in mildly asthmatic adults  QUOTE "(Koenig et al., 1985; Bauer et al., 1986; Orehek et al., 1976; Bylin et al., 1985; Hazucha et al., 1983; Koenig et al., 1988; Kleinman et al., 1983; Linn et al., 1986; Mohsenin & Gee, 1987; Morrow & Utell, 1989; Roger et al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oenig et al., 1985; Bauer et al., 1986; Orehek et al., 1976; Bylin et al., 1985; Hazucha et al., 1983; Koenig et al., 1988; Kleinman et al., 1983; Linn et al., 1986; Mohsenin & Gee, 1987; Morrow & Utell, 1989; Roger et al., 1990) QUOTE ""  ADDIN PROCITE 110591190200000000010000DB000000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365731E42617565722C205574656C6C2C20657420616C2E203139383620233232350101001E000004000000AE1C242A000844FFD57614000370981744CEE0000000230000000017348560  QUOTE ""  ADDIN PROCITE 110591190200000000010000D1000000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573214F726568656B2C204D6173736172692C20657420616C2E2031393736202332313501010021000004000000AE1C242A000840FFD57614000370981744CEE0000000270000000017348560  QUOTE ""  ADDIN PROCITE 110591190200000000010000D7000000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365732142796C696E2C204C696E6476616C6C2C20657420616C2E2031393835202332323101010021000004000000AE1C242A000848FFD57614000370981744CEE0000000270000000017348560  QUOTE ""  ADDIN PROCITE 110591190200000000010000CE000000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365732348617A756368612C2047696E73626572672C20657420616C2E2031393833202332313201010023000004000000AE1C242A00084AFFD57614000370981744CEE0000000290000000017348560  QUOTE ""  ADDIN PROCITE 110591190200000000010000FE070000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573224B6F656E69672C2050696572736F6E2C20657420616C2E203139383820233231323201010022000004000000AE1C242A000840FFD57614000370981744CEE0000000270000000017348560  QUOTE ""  ADDIN PROCITE 110591190200000000010000DC000000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573224B6C65696E6D616E2C204261696C65792C20657420616C2E2031393833202332323601010022000004000000AE1C242A000848FFD5761400037098173E0CB0000000270000000017348560  QUOTE ""  ADDIN PROCITE 110591190200000000010000B6040000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365731D4C696E6E2C2041766F6C2C20657420616C2E20313938362023313233390101001D000004000000AE1C242A000840FFD57614000370981744CEE0000000230000000017348560  QUOTE ""  ADDIN PROCITE 1105911902000000000100003B010000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573184D6F6873656E696E2026204765652031393837202333323301010018000004000000AE1C242A00084EFFD57614000370981744CEE00000001D0000000017348560  QUOTE ""  ADDIN PROCITE 1105911902000000000100002B000000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573174D6F72726F772026205574656C6C20313938392023343401010017000004000000AE1C242A00084EFFD57614000370981744CEE00000001D0000000017348560  QUOTE ""  ADDIN PROCITE 11059119020000000001000072030000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657321526F6765722C20486F7273746D616E2C20657420616C2E2031393930202339303301010021000004000000AE1C242A000848FFD57614000370981744CEE0000000270000000017348560 . Kleinman and colleagues  QUOTE "(Kleinman et al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leinman et al., 1983)  ADDIN evaluated the response of lightly exercising asthmatic subjects to inhalation of 0.2 ppm NO2 for 2 hours, during which resting minute ventilation was doubled. Although NO2 did not cause alterations in flow rates or airways resistance, approximately two-thirds of the subjects experienced increased responsiveness to methacholine after inhalation of NO2 compared with clean air, as assessed by specific airway resistance. In view of the inconclusive findings at 0.1 and 0.2 ppm NO2, Bauer and colleagues  QUOTE "(Bauer et al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auer et al., 1986)  ADDIN studied the effects of mouthpiece exposure to 0.3 ppm NO2 for 30 minutes (20 minutes at rest followed by 10 minutes of exercise at approximately 40 L/min) in 15 asthmatics. At this level, NO2 inhalation produced significant decrements in forced expiratory flow rates after exercise, but not at rest. Furthermore, after airway function was allowed to return to baseline during a 1-hour recovery period, isocapneic cold-air hyperventilation elicited increased airway responsiveness in the asthmatics who had earlier been exposed to NO2. Roger and coworkers  QUOTE "(Roger et al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oger et al., 1990), in a comprehensive, concentration-response experiment, were unable to confirm the results of  ADDIN a previous pilot study suggesting airway responses in asthmatic subjects. Twenty-one male asthmatics exposed to NO2 at 0.15, 0.30, and 0.60 ppm for 75 minutes did not experience significant effects on lung function or airway responsiveness compared with air exposure. Bylin and coworkers  QUOTE "(Bylin et al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ylin et al., 1985)  ADDIN found significantly increased bronchial responsiveness to histamine challenge compared with sham exposure in 8 atopic asthmatics exposed to 0.30 ppm NO2 for 20 minutes. Five of 8 asthmatics demonstrated increased reactivity, while 3 subjects showed no change, as assessed by specific airway resistance. Mohsenin  QUOTE "(Mohsenin, 1987a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ohsenin, 1987a)  ADDIN reported enhanced responsiveness to methacholine in eight asthmatic subjects exposed to 0.50 ppm NO2 at rest for 1 hour; airway responsiveness was measured by partial expiratory flow rates at 40% vital capacity, which may have increased the sensitivity for detecting small changes in airway responsiveness. Strand et al.  QUOTE "(Strand et al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trand et al., 1996) found increased responsiveness to histamine among 19 asthmatic subjects 5 hours after a 30 minute exposure to 0.26 ppm NO2, with intermittent exercise. The inconsistent results of these studies have not been satisfactorily explained. It is evident that a wide range of responses occur among asthmatics exposed to NO2. This variation may in part reflect differences in subjects and exposure protocols: mouthpiece vs. chamber, obstructed vs. non-obstructed asthmatics, sedentary vs. exercise, and requirements for medication. Identification of factors that predispose to NO2 responsiveness requires further investigation. These studies have typically involved volunteers with mild asthma; data are needed from more severely affected asthmatics who may be more susceptible. Overall, there is little convincing evidence that short-term exposures to NO2 at outdoor ambient concentrations significantly alter lung function or non-specific airway responsiveness in most people with mild asthma. However, outdoor levels influence indoor concentrations, which may reach peak levels that are clinically important for some adults and children with asthma. Effects on Allergen Responsiveness: The potential for NO2 exposure to enhance responsiveness to allergen challenge in asthmatics deserves special mention. Several recent studies, summarized in Table 3, have reported that low-level exposures to NO2 ,both at rest and with exercise, enhance the response to specific allergen challenge in mild asthmatics. Tunnicliffe et al.  QUOTE "(Tunnicliffe et al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unnicliffe et al., 1994) reported exposures of 8 subjects with asthma to 400 ppb NO2 for only 1 hour at rest, and found increased responsiveness to a fixed dose of allergen, both during the early and late phases of the response. No significant effect was seen at 100 ppb, but the data suggested an exposure-response relationship. Davies group from the U.K., in two reports  QUOTE "(Devalia et al., 1994; Rusznak et al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evalia et al., 1994; Rusznak et al., 1996) QUOTE ""  ADDIN PROCITE 11059119020000000001000090080000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573235275737A6E616B2C20446576616C69612C20657420616C2E203139393620233435363801010023000004000000A6CC242A000840FFD6762400036B380CB9F6F000000029000000000CB05200 , described an effect of exposure to the combination of 400 ppb NO2 and 200 ppb SO2, but not either pollutant alone, on subsequent allergen challenge in mild asthmatics. Strand and colleagues  QUOTE "(Strand et al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trand et al., 1998) from Sweden demonstrated increases in both the early and late phase responses to allergen following 4 daily repeated exposures to 260 ppb NO2 for 30 minutes, at rest. Finally, Jenkins et al.  QUOTE "(Jenkins et al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enkins et al., 1999) exposed asthmatic subjects to NO2, ozone, and their combination using two different protocols that varied time of exposure and gas concentration, but kept the total exposure constant. All three exposures of the high concentration regimen (200 ppb ozone, 400 ppb NO2, and the combination for 3 hours), but not the low concentration regimen, enhanced subsequent responsiveness to allergen. Additional data from both animal exposure and in vitro exposure studies provide support for enhancement of allergen responsiveness by NO2 exposure. Gilmour  QUOTE "(Gilmour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ilmour, 1995) has reviewed the evidence in animal models. Of particular interest is a rat model of house-dust-mite sensitivity in which a 3-hour exposure to 5 ppm NO2, after a priming injection and pulmonary challenge with antigen, increased the specific immune response and immune-mediated pulmonary inflammation. NO2 exposure also enhanced lymphocyte proliferation responses to allergen in both the spleen and mediastinal lymph nodes. Schierhorn et al.  QUOTE "(Schierhorn et al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chierhorn et al., 1999) observed increased histamine release by cultured human nasal mucosa from surgical resections in response to exposure to NO2 at 200 and 800 g/m3 (106 and 424 ppb) for 24 hours. The magnitude of the effect was more pronounced than for ozone. These recent studies involving allergen challenge appear relatively consistent in demonstrating effects at concentrations that occur indoors, and suggest that NO2 may enhance both allergen sensitization and its associated inflammatory response. Confirmation of these findings is needed from other centers. However, the rising incidence, prevalence, and mortality from asthma makes these observations particularly important and timely. Additional work is needed in understand more completely the exposure-response characteristics, effects of exercise, relationship to severity of asthma, role of asthma medications, and other clinical factors. Animal and in vitro studies are needed to establish the precise mechanisms involved. 4.2.3 Chronic Obstructive Pulmonary Disease Few studies have examined responses to NO2 in subjects with chronic obstructive pulmonary disease (COPD). In a group of 22 subjects with moderate COPD, Linn and associates  QUOTE "(Linn et al., 1985a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inn et al., 1985a) ADDIN  found no pulmonary effects of 1-hour exposures to 0.5, 1.0, and 2.0 ppm NO2. In a study by Morrow and colleagues  QUOTE "(Morrow et al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orrow et al., 1992), 20 subjects with COPD were exposed for 4 hours to 0.3 ppm NO2 in an environmental chamber, with intermittent exercise. Although progressive decrements in lung function occurred during the exposure, significant decreases were not found for FVC until the end of the exposure. The decrement in lung volume occurred without changes in flow rates. The difference in results between the Linn and Morrow studies may reflect the difference in duration of exposure. It is worth noting that changes in lung function were typical of the restrictive pattern seen with ozone rather than the obstructive changes described by some with NO2 exposure in asthmatics. 5. INTERACTIONS Environmental exposures to NO2 do not occur singly, but rather as a complex mixture of pollutants, and failure to consider the presence of other pollutants may confuse interpretation of the observed effects. Recent data suggest exposure to low concentrations of NO2 at rest may enhance the response to allergen inhalation in subjects with asthma (see section 4.2.2). When considering mixtures of anthropogenic pollutants, It may be impossible to separate the effects of one component from those of other components, particularly with the possibilities of synergistic or antagonistic interactions. In considering the health effects of mixtures, potential causal pathways should be carefully delineated. For example, some reports have suggested that HONO may contribute to the health effects attributed to indoor NO2  QUOTE "(Spengler et al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pengler et al., 1990) ADDIN  ADDIN . Efforts have been made to study effects of NO2-ozone mixtures on pulmonary function. These studies have generally revealed no interactive effects; the observed pulmonary function decrements appear to reflect the ozone component of the mixtures. Hazucha et al.,  QUOTE "(Hazucha et al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azucha et al., 1994) ADDIN  ADDIN  found that pre-exposure of healthy women to 0.6 ppm NO2 for 2 hours enhanced the development of nonspecific airway responsiveness induced by a subsequent 2-hour exposure to 0.3 ppm ozone, with intermittent exercise. Relatively high-level, prolonged (6 hours/day, up to 90 days) exposure to NO2 (14.4 ppm) and ozone (0.8 ppm) results in a syndrome of progressive pulmonary fibrosis in rats  QUOTE "(Rajini et al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ajini et al., 1993), associated with a sustained increase in procollagen gene expression in the central acini  QUOTE "(Farman et al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arman et al., 1999). This does not occur with either gas alone, indicating a true synergistic effect. The relevance of this observation for human ambient exposures is not clear, given the high exposure concentrations used in the study, and absence of evidence for alveolar fibrosis or restrictive lung disease in epidemiological studies. Bermudez et al.  QUOTE "(Bermudez et al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ermudez et al., 1999) examined DNA strand breaks in BAL cells from rats exposed to ozone (0.3 ppm), to NO2 (1.2 ppm), and the combination. Ozone and the combination exposure increased DNA strand breaks to a similar degree compared with air exposure, but NO2 alone had no effect. The effects of NO2 exposure on SO2-induced bronchoconstriction have been examined, but with inconsistent results. Jorres and Magnussen  QUOTE "(Jorres & Magnussen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orres & Magnussen, 1991)  ADDIN found an increase in airways responsiveness to SO2 in asthmatic subjects following exposure to 0.25 ppm NO2 for 30 minutes, yet Rubinstein et al.  QUOTE "(Rubinstein et al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ubinstein et al., 1990)  ADDIN found no change in responsiveness to SO2 inhalation following exposure of asthmatics to 0.30 ppm NO2 for 30 minutes. Overall, there are little definitive data suggesting that NO2 interacts with other pollutants in causing human health effects. However, human clinical studies have not systematically addressed the effects of pollutant combinations containing NO2, in part because of the complexity of the experimental design and the difficulty in studying the most susceptible subjects. 6. CONCLUSIONS Evidence for human health effects of exposure to ambient NO2 derives from epidemiological, human clinical, and animal exposure studies. This review has focused primarily on epidemiological and human exposure studies; those studies published since 1995 that appear most relevant to the current re-evaluation of the California air quality standard for NO2 are indicated with an asterisk in the first column of Tables 1-3. Many studies have found an increased incidence of respiratory illness in children associated with indoor NO2 exposure, and a meta-analysis indicates that a long-term increase in exposure to NO2 of 15 ppb is associated with an increase in illness odds of approximately 20% in children but not in adults. However, these studies are subject to exposure misclassification, and generally fail to consider a possible role of indoor and outdoor particle exposure as a confounder. Several recent epidemiological studies examining health outcomes related to outdoor pollutant exposure have found the strongest indicator of health effects to be NO2. Because outdoor NO2 concentrations correlate strongly with fine particles, and because a substantial body of evidence now exists associating exposure to fine particles with increased morbidity and mortality, NO2 is presumed to be a marker for traffic-related pollution, rather than a direct cause of the observed effects. Epidemics of respiratory illness described in ice hockey arenas with a poorly functioning Zamboni, which emit NO2, would suggest that exposure to NO2 at levels of 4 to 5 ppm, with exercise, can cause significant acute respiratory illness in some people. However, natural gas combustion also emits ultrafine particles (less than 100 nm in diameter), and it is possible that these particles were present and contributed in causing the observed episodes of respiratory illness. Taken together, the epidemiological evidence would indicate that traffic- and combustion-related pollutant exposure has adverse health effects, and that NO2 is an important atmospheric marker of exposure. We cannot exclude the possibility that NO2, as part of that ambient mixture, plays an important role in causing the observed health effects. 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Am J Epidemiol. 134:204-219. Office of Air and Radiation, U. S. Environmental Protection Agency. 1997 National Air Quality: Status and Trends. Six principal pollutants - nitrogen dioxide (NO2). 98. U.S. Environmental Protection Agency. Orehek, J., Massari, J.P., Gayrard, P., Grimaud, C., and Charpin, J. (1976). Effect of short-term, low-level nitrogen dioxide exposure on bronchial sensitivity of asthmatic patients. J Clin Invest. 57:301-307. Pearlman, M.E., Finklea, J.F., Creason, J.P., Shy, C.M., Young, M.M., and Horton, R.J.M. (1971). Nitrogen dioxide and lower respiratory illness. Pediatrics. 47:391-398. Pereira, L. A. A., Loomis, D., Conceicao, G. M. S., Braga, A. L. F., Arcas, R. M., Kishi, H. S., Singer, J. M., Bohm, G. M., and Saldiva, P. H. N. (1998). Association between air pollution and intrauterine mortality in Sao Paulo, Brazil. Environ Health Perspect. 106:325-329. Pershagen, G., Rylander, E., Norberg, S., Eriksson, M., and Nordvall, S. L. (1995). Air pollution involving nitrogen dioxide exposure and wheezing bronchitis in children. Int J Epidemiol. 24:1147-1153. Peters, A., Liu, E., Verrier, R. L., Schwartz, J., Gold, D. R., Mittleman, M., Baliff, J., Oh, J. A., Allen, G., Monahan, K., and Dockery, D. W. (2000). Air pollution and incidence of cardiac arrhythmia. Epidemiology. 11:11-17. Pilotto, L. S., Douglas, R. M., Attewell, R. G., and Wilson, S. R. (1997). Respiratory effects associated with indoor nitrogen dioxide exposure in children. Int J Epidemiol. 26:788-96. Postlethwait, E. M., Langford, S. D., and Bidani, A. (1990). Reactive absorption of nitrogen dioxide by pulmonary epithelial lining fluid. J Appl Physiol. 68:594-603. Rajini, P., Gelzleichter, T. R., Last, J. A., and Witschi, H. (1993). Alveolar and airway cell kinetics in the lungs of rats exposed to nitrogen dioxide, ozone, and a combination of the two gases. Toxicol Appl Pharmacol. 121:186-192. Richters, A.and Damji, K.S. (1988). Changes in T-lymphocyte subpopulations and natural killer cells following exposure to ambient levels of nitrogen dioxide. J Toxicol Environ Health. 25:247-256. Richters, A.and Richters, V. (1989). Nitrogen dioxide (NO2) inhalation, formation of microthrombi in lungs and cancer metastasis. Journal of Environmental Pathology and Toxicology. 9:45-51. Roger, L.J., Horstman, D.H., McDonnell, W., Kehrl, H., Ives, P.J., Seal, E., Chapman, R., and Massaro, E. (1990). Pulmonary function, airway responsiveness, and respiratory symptoms in asthmatics following exercise in NO2. Toxicol Ind Health. 6:155-171. Roorda-Knape, M. C., Janssen, N. A., de Hartog, J., Van Vliet, P. H., Harssema, H., and Brunekreef, B. (1999). Traffic related air pollution in city districts near motorways. Sci Total Environ. 235:339-341. Rubinstein, I., Bigby, B.G., Reiss, T.F., and Boushey, H.A.Jr. (1990). Short-term exposure to 0.3 ppm nitrogen dioxide does not potentiate airway responsiveness to sulfur dioxide in asthmatic subjects. Am Rev Respir Dis. 141:381-385. Rubinstein, I., Reiss, T.F., Bigby, B.G., Stites, D.P., and Boushey, H.A.Jr. (1991). Effects of 0.60 PPM nitrogen dioxide on circulating and bronchoalveolar lavage lymphocyte phenotypes in healthy subjects. Environ Res. 55:18-30. Rusznak, C., Devalia, J. L., and Davies, R. J. (1996). The airway response of asthmatic subjects to inhaled allergen after exposure to pollutants. Thorax. 51:1105-1108. Saldiva, P. H. N., Lichtenfels, A. J. F. C., Paiva, P. S. O., Barone, I. A., Martins, M. A., Massad, E., Pereira, J. C. R., Xavier, V. P., Singer, J. M., and Bohm, G. M. (1994). Association between air pollution and mortality due to respiratory diseases in children in Sao Paulo, Brazil: a preliminary report. Environ Res. 65:218-225. Samet, J. M., Lambert, W. E., Skipper, B. J., Cushing, A. H., Hunt, W. C., Young, S. A., McLaren, L. C., Schwab, M., and Spengler, J. D. (1993). Nitrogen dioxide and respiratory illnesses in infants. Am Rev Respir Dis. 148:1258-1265. Samet, J. M.and Spengler, J. D. (1991). in Indoor air pollution, Johns Hopkins University Press, Baltimore, Maryland. Samet, J.M.and Utell, M.J. (1990). The risk of nitrogen dioxide: What have we learned from epidemiological and clinical studies? Toxicol Ind Health. 6:247-262. Sandstrom, T., Helleday, R., Bjermer, L., and Stjernberg, N. (1992a). Effects of repeated exposure to 4 ppm nitrogen dioxide on bronchoalveolar lymphocyte subsets and macrophages in healthy men. Eur Respir J. 5:1092-1096 . Sandstrom, T., Ledin, M.C., Thomasson, L., Helleday, R., and Stjernberg, N. (1992b). Reductions in lymphocyte subpopulations after repeated exposure to 1.5 ppm nitrogen dioxide. Br J Ind Med. 49:850-854. Sandstrom, T., Stjernberg, N., Eklund, A., Ledin, M. C., Kolmodin-Hedman, B., Lindstrom, K., Rosenhall, L., and Angstrom, T. (1991). Inflammatory cell response in bronchoalveolar lavage fluid after nitrogen dioxide exposure of healthy subjects: a dose-response study. Eur Respir J. 4:332-339. Schierhorn, K., Zhang, M., Matthias, C., and Kunkel, G. (1999). Influence of ozone and nitrogen dioxide on histamine and interleukin formation in a human nasal mucosa culture system. Am J Respir Cell Mol Biol. 20:1013-9. Schindler, C., Ackermann-Liebrich, U., Leuenberger, P., Monn, C., Rapp, R., Bolognini, G., Bongard, J. P., Brandli, O., Domenighetti, G., Karrer, W., Keller, R., Medici, T. G., Perruchoud, A. P., Schoni, M. H., Tschopp, J. M., Villiger, B., and Zellweger, J. P. (1998). Associations between lung function and estimated average exposure to NO2 in eight areas of Switzerland. The SAPALDIA Team. Swiss Study of Air Pollution and Lung Diseases in Adults. Epidemiology. 9:405-411. Shy, C. M., Creason, J. P., Pearlman, M. E., McClain, K. E., and Benson, F. B. (1970). The Chattanooga schoolchildren study: effects of community exposure to nitrogen dioxide. II. Incidence of acute respiratory illness. J Air Poll Contr Assoc. 20:582-588. Speizer, F.E., Ferris, B.Jr., Bishop, Y.M.M., and Spengler, J. (1980). Respiratory disease rates and pulmonary function in children associated with NO2 exposure. Am Rev Respir Dis. 121:3-10. Spengler, J.D., Brauer, M., and Koutrakis, P. (1990). Acid air and health. Environ Sci Technol. 24:946-956. Strand, V., Rak, S., Svartengren, M., and Bylin, G. (1997). Nitrogen dioxide exposure enhances asthmatic reaction to inhaled allergen in subjects with asthma. Am J Respir Crit Care Med. 155:881-887. Strand, V., Salomonsson, P., Lundahl, J., and Bylin, G. (1996). Immediate and delayed effects of nitrogen dioxide exposure at an ambient level on bronchial responsiveness to histamine in subjects with asthma. Eur Respir J. 9:733-740. Strand, V., Svartengren, M., Rak, S., Barck, C., and Bylin, G. (1998). Repeated exposure to an ambient level of NO2 enhances asthmatic response to a nonsymptomatic allergen dose. Eur Respir J. 12:6-12. Studnicka, M., Hackl, E., Pischinger, J., Fangmeyer, C., Haschke, N., Kuhr, J., Urbanek, R., Neumann, M., and Frischer, T. (1997). Traffic-related NO2 and the prevalence of asthma and respiratory symptoms in seven year olds. Eur Respir J. 10:2275-2278. Tenias, J. M., Ballester, F., and Rivera, M. L. (1998). Association between hospital emergency visits for asthma and air pollution in Valencia, Spain. Occup Environ Med. 55:541-547. Tunnicliffe, W. S., Burge, P. S., and Ayres, J. G. (1994). Effect of domestic concentrations of nitrogen dioxide on airway responses to inhaled allergen in asthmatic patients. Lancet. 344:1733-1736. Wang, J. H., Devalia, J. L., Duddle, J. M., Hamilton, S. A., and Davies, R. J. (1995a). Effect of six-hour exposure to nitrogen dioxide on early-phase nasal response to allergen challenge in patients with a history of seasonal allergic rhinitis. J Allergy Clin Immunol. 96:669-676. Wang, J. H., Duddle, J., Devalia, J. L., and Davies, R. J. (1995b). Nitrogen dioxide increases eosinophil activation in the early-phase response to nasal allergen provocation. Int Arch Allergy Immunol. 107:103-105. Zemp, E., Elsasser, S., Schindler, C., Kunzli, N., Perruchoud, A. P., Domenighetti, G., Medici, T., Ackermann-Liebrich, U., Leuenberger, P., Monn, C., Bolognini, G., Bongard, J. P., Brandli, O., Karrer, W., Keller, R., Schoni, M. H., Tschopp, J. M., Villiger, B., and Zellweger, J. P. (1999). Long-term ambient air pollution and respiratory symptoms in adults (SAPALDIA study). Am J Respir Crit Care Med. 159:1257-66. FIGURE LEGENDS Figure 1. Association between ambient NO2 concentrations in (ppb) and production of phlegm in the Childrens Health Study. A concentration-response relationship was seen for children with asthma. Adapted from Figure 2 in  QUOTE "(McConnell et al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cConnell et al., 1999. Figure 2. Relative risk of intrauterine mortality for increasing concentrations of NO2 (quintiles of the 5-day moving average, in (/m3). Adapted from Figure 4 in  QUOTE "(Pereira et al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ereira et al., 1998. Figure 3. Associations between defibrillator discharges and quintiles of 2-day lagged values of PM2.5, black carbon, and NO2, adjusted for season, minimum temperature, humidity, trend, and day of the week. Adapted from Figure 2 in  QUOTE "(Peters et al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eters et al., 2000.    Table 1. Epidemiological studies of outdoor NO2 exposure (since 1995). * Indicates particular relevance to Standard. ReferenceLocationParticipantsApproach & MethodsExposure Levels (ppb)Findings QUOTE "(Boezen et al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oezen et al., 1998)Netherlands288 adults age 48-73 yrs, with and without respiratory symptoms. Time series, respiratory symptoms24-h means: Urban, 46; Rural, 27Group with airways hyperresponsiveness or peak flow lability experienced increased symptoms with exposure to NO2 or PM10  QUOTE "(Castellsague et al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astellsague et al., 1995)BarcelonaAsthmatics age >14 visiting emergency departmentsTime series24-h means: Summer, 55; Winter, 53Relative risk for asthma visits associated with both black smoke and NO2. QUOTE "(Garcia-Aymerich et al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arcia-Aymerich et al., 2000)BarcelonaPatients with COPDTime series mortalityNot givenAssociations between mortality and NO2, but black smoke not significant. QUOTE "(Garty et al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arty et al., 1998)Israel1076 Children age 1-18 yrs presenting to ED with asthma attackTime seriesWeekly means ~50-250Emergency department visits correlated with concentrations of NO2 and SO2. * QUOTE "(Hajat et al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ajat et al., 1999)London, UKPatients with respiratory complaints visiting physicians officesTime series analysis of Dr visits for asthma and lower respiratory diseasesAnnual Mean 33.6, SD 10.5Significant associations between asthma consultations and NO2 for children, PM10 for adults QUOTE "(Krmer et al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rmer et al., 2000)Germany317 children age 9 yrsTime series, with both outdoor and personal monitoringWeekly means: Outdoors, 84-116; Personal, 43-50Atopy related to outdoor NO2 levels (OR=1.81) but not personal NO2 exposure. No measurements of other pollutants.* QUOTE "(Lipsett et al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ipsett et al., 1997)Santa Clara County, CaliforniaAsthmatics making visits to ED. Time series, ED visits for asthma at 3 hospitals. ED visits for gastroenteritis were control population.Mean 1-h peak, 69, SD 28Significant PM10 risk, dependent on temperature. NO2 also significant but not when PM10 factored in. * QUOTE "(McConnell et al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cConnell et al., 1999)Southern California4th, 7th, and 10th grade children with or without asthma in 12 suburban communitiesCross-sectional24 h means: 21.9, range 2.7-42.6"Bronchitis" symptoms in children with asthma associated with NO2 and PM10 levels. Effects of PM10, NO2, and acid inseparable because all were closely correlated.  Table 1 (continued) ReferenceLocationParticipantsApproach & MethodsExposure Levels (ppb)Findings* QUOTE "(Moolgavkar et al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oolgavkar et al., 1997)Minneapolis-St. Paul & BirminghamElderly adults hospitalized for pneumonia and chronic obstructive pulmonary diseaseTime series24 h means: 16.3; 10-90th percentile, 7.9-25.3NO2 associated with hospital admissions in Minneapolis-St. Paul, but ozone gave strongest association, and other pollutants were inseparable.* QUOTE "(Pereira et al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ereira et al., 1998)Sao Paulo, BrazilUnborn childrenTime series, intrauterine mortality24-h means 296, SD 153NO2 showed strongest association with fetal mortality* QUOTE "(Peters et al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eters et al., 2000)Boston, MAPatients with implantable cardiac defibrillatorsTime series24 h means 23; 5-95th percentile, 11-37Increased risk of defibrillator discharge associated with 1-2 day lagged NO2 levels QUOTE "(Pershagen et al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ershagen et al., 1995)Stockholm, Sweden204 infants age 4-48 mos. hospitalized for wheezing bronchitis (cases), 409 controls.Case-control study; model estimates of outdoor NO2 concentrations at home address1-h values, mean ~100, range 38-660Increased risk of hospitalization related to NO2 exposure in girls, RR = 2.7 (p=0.02), but not boys. NO2 levels considered a surrogate for air pollution in general. QUOTE "(Schindler et al., 1998)"  ADDIN PROCITE 11059119020000001828536368696E646C657220657420616C2E2C2031393938290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A0100000040C0048656C766574696361004E9C0000002C1CCACBA00C4669700C944E7C0C466970020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C661750000000020C4895400C9450A40000002C0C9450A40C4FBE40C7100000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657330536368696E646C65722C2041636B65726D616E6E2D4C696562726963682C20657420616C2E203139393820233435333401010030000004000000DD1C242A000840FFD6762400036A380CBF612000000035000000000CB6E700 (Schindler et al., 1998)Switzerland (SAPALDIA)ChildrenCross-sectional, pulmonary functionAnnual means 17-109. Estimated average personal exposure: 24-93Negative correlation between NO2 and both FVC and FEV1. NO2 levels correlated strongly with PM10 levels (r=0.91), QUOTE "(Studnicka et al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tudnicka et al., 1997)AustriaChildren age 7 yrsCross-sectional, 8 non-urban communities with varying pollution from traffic.Overall means: 6-17Prevalence of asthma significantly associated with long-term NO2 exposure. No particle measurements QUOTE "(Tenias et al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enias et al., 1998)Valencia, SpainAsthmatics age >14 identified from emergency department (ED) visitsEcological time series, ED visits1 h means 189, 5-95th percentiles 134-288Relative risk for ED visit significant for NO2 24 hour mean, NO2 1 hour maximum, and ozone 1 hour maximum. Not significant for SO2 or black smoke. QUOTE "(Zemp et al., 1999)"  ADDIN PROCITE 110591190200000013285A656D7020657420616C2E2C2031393939290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A00B0000040C0048656C766574696361004E9C0000002C1CCACBA00C4669700C944E7C0C466970020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C6635B8000000020C4895400C9450A40000002C0C9450A40C4FBE40D20F0000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573215A656D702C20456C7361737365722C20657420616C2E203139393920233432323101010021000004000000922C242A000848FFD6762400036A380CFD1FC000000027000000000CB7B2B0 (Zemp et al., 1999)Switzerland9,651 adults age 18-60 yrs (SAPALDIA study)Time series, respiratory symptomsAnnual mean 67, range 17-109Significant associations between symptoms (chronic phlegm, chronic cough, breathlessness at rest, dyspnea on exertion) and both NO2 and particles. Effects of NO2 and particles could not be distinguished. Table 2. Epidemiological studies of indoor NO2 exposure (since 1995). * Indicates particular relevance to Standard. ReferenceLocationParticipantsApproach & MethodsFindings QUOTE "(Garrett et al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arrett et al., 1998)AustraliaHealthy and asthmatic children 7-14 yr.Prospective. Intermittent monitoring in homes with and without gas stoves. Respiratory symptoms, peak flow, skin prick testing. Smoking homes included, no measurements of other pollutants.Relationship between gas stove, but not NO2 levels, and respiratory symptoms. * QUOTE "(Jarvis et al., 1996)"  ADDIN PROCITE 110591190200000015284A617276697320657420616C2E2C2031393936290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A00D0000040C0048656C766574696361004E9C0000002C1CCACBA00C4669700C944E7C0C466970020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C5E98D4000000020C4895400C9450A40000002C0C9450A40C4FBE40B5100000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657304343534340101000400000400000000000000000000000000000000000000000000000000000000000000000000 (Jarvis et al., 1996)East Anglia, UKAdults age 20-44 yrsCross-sectional, questionnaire, lung function and IgE levels on a subsetGas stove use associated with Increased symptoms and decreased lung function in women, but not men QUOTE "(Magnus et al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agnus et al., 1998)Oslo, NorwayOslo birth cohort: Children age <2 yrs who developed e"2 episodes of bronchial obstruction or 1 episode lasting >4 months.Case-control study; personal and home monitoringNo effect of NO2  QUOTE "(Moran et al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oran et al., 1999)U.K.National Child Development Study, cohort born in 1958 (age 34-35 yrs at time of study). 1449 examined, 1119 with chest disease and 330 controls.Retrospective cohort study. Gas or electric cooking, health status, lung function, skin tests.No association between gas cooking in childhood or adulthood and incidence of asthma, respiratory symptoms, or allergic sensitization. Slightly lower FEV1 associated with gas cooking in men only.* QUOTE "(Mukala et al., 1999)"  ADDIN PROCITE 110591190200000015284D756B616C6120657420616C2E2C2031393939290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A00D0000040C0048656C766574696361004E9C0000002C1CCACBA00C4669700C944E7C0C466970020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C6632D4000000020C4895400C9450A40000002C0C9450A40C4FBE40C0100000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E63657304343535310101000400000400000000000000000000000000000000000000000000000000000000000000000000 (Mukala et al., 1999)HelsinkiPre-school children in day care, 3-6 yr. No information on baseline health status.Prospective. Personal monitoring of NO2 exposure and respiratory symptoms, peak flow in a subset of subjects.Relationship between NO2 exposure and cough* QUOTE "(Pilotto et al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ilotto et al., 1997)AustraliaSchool children 6-11 yr. No information on baseline health status.Prospective. Fixed monitoring in homes and schools with electric versus gas heating. Respiratory symptoms and school absences. No measurements of other pollutants.Hourly peak levels e"80 ppb associated with increased sore throat, colds, and absences Table 3. Effects of NO2 exposure on response to inhaled allergen. * Indicates particular relevance to Standard. ReferenceLocationParticipantsApproach & MethodsFindings* QUOTE "(Devalia et al., 1994; Rusznak et al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evalia et al., 1994; Rusznak et al., 1996) QUOTE ""  ADDIN PROCITE 11059119020000000001000090080000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E636573235275737A6E616B2C20446576616C69612C20657420616C2E203139393620233435363801010023000004000000922C242A00084AFFD6762400036A380CCCAB2000000029000000000CBC7810 United KingdomMild asthmatics6 h exposures to combination of 400 ppb NO2 and 200 ppb SO2. Increased allergen responsiveness to combination of NO2 and SO2, but not to individual gases. Effect persists 48 h, maximal at 24 h.* QUOTE "(Jenkins et al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enkins et al., 1999)United Kingdom11 patients with mild asthma1) 6-h exposures to air, 100 ppb ozone, 200 ppb NO2, and combination followed by allergen challenge; 2) 3-h exposures to air, 200 ppb ozone, 400 ppb NO2, and combination; all with intermittent exercise.All of the second exposure scenarios (ozone, NO2, and combination), but none of the first exposure scenarios, resulted in enhanced responsiveness to allergen. Authors conclude that response may have a concentration threshold. * QUOTE "(Strand et al., 1997)"  ADDIN PROCITE 11059119020000001528537472616E6420657420616C2E2C2031393937290105000100000400000094509400000041000000020C4895400C9450A40000002C0C9450A4000000A00D0000040C0048656C766574696361004E9C0000002C1CCACBA00C4669700C944E7C0C466970020000040000000000000040697C0C944D14010000000C944D1C000000000C944CEC00000000040000040C0048656C766574696361000338010000000C944D14000000001CCACBA00000000001000004000000CE2EC00C686FA0000000020C4895400C9450A40000002C0C9450A40C4FBE40AF0C0000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365731E537472616E642C2052616B2C20657420616C2E20313939372023333333390101001E000004000000922C242A000844FFD6762400036A380CCCAB2000000023000000000CBC7810 (Strand et al., 1997)Sweden18 patients with mild asthma, age 18-50 yrsExposure to 490 g/m3 NO2 (260 ppb) for 30 min at restLate phase, but not early phase, response to allergen enhanced by NO2.* QUOTE "(Strand et al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trand et al., 1998)Sweden16 patients with mild to moderate asthma, age 21-52 yrs4 daily repeated exposures to 260 ppb NO2 for 30 min at restSignificant increases in both early and late phase response to allergen after 4th day of exposure.* QUOTE "(Tunnicliffe et al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unnicliffe et al., 1994)United Kingdom10 nonsmoking mild asthmatics age 16-60 yrs. 8 subjects completed.Exposure to air, 100 ppb, and 400 ppb NO2 for 1 hr at rest, separated by at least 1 week, followed by allergen challenge.Post-challenge reduction in FEV1 after 400 ppb NO2 was greater than after air, for both the early (p<0.009) and late (p<0.02) responses. No difference in nonspecific airway responsiveness.  QUOTE "(Wang et al., 1995b; Wang et al., 1995a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ang et al., 1995b; Wang et al., 1995a) QUOTE ""  ADDIN PROCITE 1105911902000000000100000D0C0000474D6163696E746F73682048443A4170706C69636174696F6E733A50726F43697465203420466F6C6465723A44617461626173653A4672616D70746F6E207265666572656E6365732057616E672C20446576616C69612C20657420616C2E203139393520233331373501010020000004000000922C242A000846FFD6762400036A380CCCAB2000000025000000000CBC7810 United Kingdom2 groups of 8 subjects with allergic rhinitisExposure to 400 ppb NO2 (at rest?) for 6 h followed by nasal allergen challenge and nasal lavageIncrease in myeloperoxidase and eosinophil cationic protein in nasal lavage fluid following allergen challenge.  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