Effects of Air Pollution on Lung Function Development and Asthma Occurrence

INTRODUCTION

A substantial body of evidence indicates that exposure to current levels of ambient air pollutants is associated with a wide spectrum of acute adverse health effects. The health effects of air pollution on children's respiratory health are of clinical, public health, and regulatory concern (Table 24.1). Although short-term effects of exposure to ambient pollutants are well documented, long-term effects of chronic exposures on lung development and adverse respiratory health events have only recently been extensively investigated. The lack of understanding of which pollutants are important for acute and chronic health effects and what levels of exposure are safe inhibits rational approaches for control. Although a large number of chemical species occur in ambient air, ozone, nitrogen dioxide (NO2) , acid vapors, respirable particulate matter (PM10 and PM2.5), sulfur dioxide (SO2) and acid aerosols have been identified as presenting the greatest hazard to human populations. 1

AMBIENT

AIR

POLLUTION

Air polluted with ozone, NO 2 and respirable particles is an important public health problem in many regions of the world. These pollutants are produced by fossil fuel combustion and subsequently undergo photochemical reactions in the atmospheric aerosol. The patterns of emission and photochemistry produce an aerosol that varies in composition and particle size distribution in a complicated manner over time and space. Photochemical reactions between NO 2 *To whom correspondence should be addressed. The Lung: Development, Aging and the Environment ISBN 0 12 324751 9

and hydrocarbons produce a diurnal ozone profile. Ozone levels rise in the late morning after heavy traffic and peak in the 10:00 a.m. to 6:00 p.m. period. 2 In the evening, scavenging of ozone (03) by NO titration in areas with heavy traffic reduces the ozone to levels below background levels at night. High ozone levels may occur in downwind communities later in the afternoon and evening, stemming from airborne transport in the setting of low NO levels in areas without heavy traffic. Ozone levels show systematic variation by day of week. High ozone areas have higher levels on weekends compared to weekdays, low ozone areas do not have higher weekend levels. Other pollutants have less pronounced diurnal variation. 2 SO 2 is produced by combustion of sulfur containing fuels, primarily coal-fired power plants and diesel engines. Because coal is a common source of fuel, SO 2 and acid aerosols are exposures of interest in many regions of the world. Acids, such as nitric, formic, and acetic acids, are also present in the gas phase of the atmosphere in some regions including southern California. Higher concentrations of pollutants in late afternoon influence exposure because children are most likely to be outdoors and physically active. The timing of high ozone levels may increase the exposure and dose for children relative to adults. Children spend more time outside during high ozone periods in the afternoon, on weekends, and during the summer months? Furthermore, children are more likely to engage in vigorous physical activity while outside, increasing the delivered dose of pollutants to the distal lung which is more sensitive to damage because it has thin or patchy respiratory extracellular lining fluid (RELF) as a protective barrier. Particulate pollution has received increased attention in recent years. PMlo levels show marked geographic variation. Annual average concentrations of PM2. 5 in southern Copyright 9 2004 Elsevier All rights of reproduction in any form reserved.

California during the 1994-1997 period ranged from 7 ~tg/m3 outside the Los Angeles air basin to 32 ].tg/m3 within the air basin. Of measured ions in PM2.5, nitrate is the most abundant, followed by ammonium, sulfate, and chloride. In addition, PM2.5 contains a number of transition metals and organic compounds that influence its toxicity. Based on associations with lung cancer and asthma outcomes, increased research attention has also been focused on bioaerosols, diesel exhaust particles and ultrafine particles (< 100 nm).

R E S P I R A T O R Y H E A L T H EFFECTS OF A M B I E N T AIR P O L L U T I O N Acute exposures to high levels of ambient pollutants have resulted in severe effects including substantial increases in morbidity and mortality as observed during pollution episodes in the Meuse Valley in 1930, Donora, Pennsylvania in 1948, and London in 1952. In the U.S. and Western Europe, regulatory efforts make such episodes a remote possibility; however, acute respiratory effects in children exposed at current ambient levels of ozone are welldocumented. 1 Acute respiratory effects from exposures to ambient levels of NO 2, SO2 and acids have been documented in studies of susceptible children and adults. Studies have established that adverse health effects occur in some groups of children exposed to ambient levels of ozone, particulates and N O 2 that occur in developed and developing nations, and have provided a limited amount of suggestive evidence for chronic health effects (Table 24.1). 1 Much of the research on the acute effects of air pollution has focused on shortterm exposures to ozone and NO 2. Studies of adults and children using controlled human exposures have documented that ozone inhalation of as little as 0.08 ppm for several hours is associated with reproducible dose-dependent (concentration, duration, and minute ventilation) effects that are enhanced by exercise. 1 NO 2 also has acute effects, but primarily at levels exceeding 2.0 to 4.0 ppm. 1 The effects

include decrements in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), cough and chest discomfort, lung injury and inflammation, and changes in airway responsiveness. 1 Changes in pulmonary function have also been observed in children at summer camp, military recruits, and athletes exposed to ambient air pollution during outside activities. 4 The ozone-induced acute changes in pulmonary function are reversible. The reversibility of the acute and sub-acute changes in lung function either with anesthetic or with time indicates this mechanism may not be responsible for chronic effects. 1 Airway hyperreactivity persists after ozone-induced changes in FEV 1 resolve and the degree of reactivity is not associated with the magnitude of spirometric changes, suggesting an independent mechanism for hyper-reactivity. Increased reactivity may be involved in the pathogenesis of chronic lung disease because increased airway reactivity to nonspecific stimuli such as methacholine is a characteristic of chronic respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). The inflammatory response involves increased numbers of macrophages, neutrophil infiltration, increased cellular protein permeability following the production of a broad range of inflammatory cytokines, and increased arachidonic acid metabolites. As with airway hyper-reactivity, the inflammatory response is not correlated with acute lung function decrements. In addition to the inflammatory response, some studies suggest that acute NO 2 exposure at commonly encountered ambient levels may adversely affect other aspects of immune function, including macrophage function resulting in decreased airway clearance and increased risk of infection. In the following sections the emerging evidence for chronic effects of ambient pollutants focusing on lung function development and decline and asthma incidence will be reviewed.

Chronic effects of air pollution on lung function Normal development and growth of the lungs is necessary for optimal gas exchange that is essential for aerobic life.

Alterations in lung structure during the life course can adversely affect lung function, resulting in an increased occurrence of respiratory-related morbidity and mortality. Lung function can be assessed using a broad array of tests that measure lung volume, airflow and gas diffusion. Spirometry measures how well the respiratory system functions in exhaling air. Maximal forced expiratory volume maneuvers and spirometers are used to assess FEV 1, maximum mid-expiratory flow (MMEF), and FVC. The information gathered using spirometry is useful in assessing airway obstruction and functional lung capacity. Spirometry does not measure total lung capacity or diffusion capacity. A number of insults including intrauterine growth retardation, viral infections, premature birth, inflammatory conditions, genetic mutations and environmental toxicants can disrupt lung development and growth leading to reduced lung function. Airborne environmental toxicants pose a unique threat to the development and maintenance of maximum attained lung function. Exposures to tobacco smoke and combustion-derived ambient air pollutants are common. Large volumes of air are inhaled daily, and in polluted environments substantial inhaled and deposited doses to airways and air exchange regions occur. If lung defenses are breached, normal developmental and homeostatic process can be disrupted leading to disruption of development and acute damage that can lead to chronic reduction in lung function.

Effects of environmental toxicants on lung function growth and decline

Normal growth of lung function Fig. 24.1 shows the change in lung function over the life course using FEV 1 as an example. Curve I shows the optimal growth and decline of FEV 1. Lung growth begins in the in utero period and continues until the late teens and early twenties. Lung function reaches a maximum by age 18-20 years in females and 22-25 years in males; 5 some males may show a small amount of lung function growth into the mid-20s. Among non-smokers, FEV1 and FVC show a plateau, without respiratory symptoms, that may

lmyor

. . . . . . .

I

1..........

last up to 10 years for males and shorter for females before beginning a slow decline. Impaired prenatal or postnatal lung growth may result from exposure to environmental toxicants including tobacco smoke and ambient air pollutants. The temporal patterns of exposures and lung function growth and development may be important in understanding the long-term adverse effects of exposures. Effects of active and passive tobacco smoke exposure have been extensively investigated, although recent studies show in utero effects of maternal smoking are important. 6'7 Reduced prenatal or postnatal growth rates result in lungs that do not reach their developmental potential, reaching a reduced level resulting in symptoms at an earlier age with normal age-related decline in function or acute respiratory conditions. The effects of toxicants on postnatal growth may be permanent; however, it is unknown whether 'catch-up' or prolonged growth occurs during late adolescence resulting in normal attained lung function levels. Normal or reduced lung function growth rates may also be followed by a shorter plateau phase and/or a period of accelerated decline that produces an early onset of chronic respiratory diseases. Superimposed on these lifetime patterns are acute episodes of reversible airflow obstruction. For a given amount of obstruction, symptoms may be more severe depending on baseline function.

l

I

I

............I..........

40

50

60

70

]

Based on studies of occupational groups and model systems, it has become recognized that a large number of toxicants have the potential to adversely affect lung function growth and decline. In order to understand the effects of environmental toxicants on lung function growth and decline, the timing of exposure must be considered. Critical windows of susceptibility occur during the fetal and childhood periods of growth and development. Exposure during these periods may have larger long-term consequences than exposure at the same level during the adulthood phase of decline. Furthermore, exposures during later life-course periods are often correlated with exposure in earlier periods. For example, active smoking, exposure to environmental tobacco smoke (ETS) and in utero exposure to maternal smoking are highly correlated. If the temporal correlation of in utero and ETS exposure during childhood are not accounted for, the effects of in utero exposure could be incorrectly ascribed to ETS exposure during childhood. 6'7 Lastly, toxicants can induce disease states that affect later exposure or recall of previous exposure history, suggesting that prospective studies may be necessary to clarify the temporal relationships between exposures and adverse respiratory outcomes.

! ............ . . . . . . . . . . . . . . . . . .

Birth

10

20

30

80

Age (years)

Fig. 24.1. Schematic representation of the life course of forced expiratory volume (not to scale). I=normal growth and decline, II=impaired prenatal or postnatal growth, Ill=normal growth but accelerated decline, IV = episodes of reversible airflow obstruction.

Tobacco smoke and lung function growth during childhood Tobacco smoke is a prototypic toxicant because its effects on lung function have been most extensively studied over the life course. 8-1~ A detailed account of the effects of

early-life tobacco smoke is given in Chapter 20. In brief, in utero exposure to maternal smoking is associated with

decreased lung function at birth, which persists into adolescence and adulthood. The effects of in utero exposure are largest in children who also develop childhood asthma. 11 Because in utero exposure also increases the risk for asthma, in utero exposure affects lung function directly during the in utero period and indirectly through increased occurrence of childhood asthma. A large number of studies have investigated the role of ETS exposure on lung function in children and ETS exposure is prospectively associated with lung function growth; however, most studies have not assessed the effects of the highly correlated exposure of maternal smoking during pregnancy. Tobacco smoke exposure affects the length of the plateau and rate of decline in lung function. Smoking and ETS exposure are associated with a shorter plateau and an accelerated decline in susceptible smokers that may lead to an early onset of disability and death from chronic lung diseases. Smoking cessation results in a rate of decline in lung function similar to that in non-smokers, even after the onset of disability.

Ambient air pollution and childhood lung function growth The fetal period appears to be a critical window for the effects of toxicants on lung function. The effects of ambient air-pollutant exposure during the in utero period on lung function at birth or during childhood have yet to be established. Recent studies showing that current levels of ambient air pollution increase the risk for low birth weight and pre-term birth suggest that lung function could be adversely affected by air pollution exposure during the fetal period. 12'13 Studies of air pollution during specific age periods and lung function levels in newborns as well as lung function growth in children will be required to address this important issue. Long-term exposure to outdoor air pollutants has been associated with reductions in the growth of lung function. ~4'15 We studied the effects of air pollution on lung function growth over a 4-year period in school children residing in 12 communities in Southern California with varying levels of air pollutants. Significant deficits in growth of lung function (FEV 1, FVC, and MMEF) were associated with exposure to particles with NO 2, PM10, PM2.5, PM10-PM2.5, and inorganic acid vapor (p < 0.05). Our results showing an association of NO 2 with lung function growth in the 12 communities are depicted in Fig. 24.2. The associations for both PM and acids were similar to those for NO2, indicating that exposures associated with mobile sources (NO x and PM) are important. The independent effects of these pollutants could not be identified due to their high degree of correlation across communities. No significant associations were observed with ozone in the cohort of fourth graders. The deficits were generally larger for children spending more time outdoors. In an analysis of a second cohort of fourth graders recruited four years later in the same 12 Southern California

i

12.61 12.4 12.2 12 11.8 11.6

9 LM

9

IR =-o61 I ]p = 0.02]

SM

9 RV E UP 9 AT 9 LN

i 11.2 11.4 10.8 , 0

~~...,=~ 9 ML

5

10

15

20

25

9 SD 30

35

40

45

NO=(pp~)

Fig. 24.2. Average growth rate in forced expiratory volume in one second (FEV1) vs. community N O 2 exposure in the Children's Health Study, fourth grade cohort, 1993-1997.

communities, reduced FEV 1 and MMEF growth was most strongly associated with vapor acids, NO2, PM2.5, and elemental carbon levels, a marker for diesel exhaust. The estimated growth rate for children in the most polluted of the communities as compared with the least polluted was predicted to result in a cumulative reduction of 3.4% in FEV 1 and 5.0% in MMEF over the 4-year study period. Across cohorts and lung function measures, we observed significant associations with both particles and gaseous pollutants. Although the correlations among pollutants were high, fine particles (PM2.5) and the elemental carbon portion of PM showed stronger associations with lung function growth than PM10 or the organic carbon portion of particulates. Two other studies, one conducted in Austria 16 and the other in Poland 17, have also reported associations between ambient air pollutants and lung function growth in children. The long-term effect of exposure to ambient air pollution on children's lung function was investigated in nine Austrian cities over a 3-year period. ~6 Repeated spirometry in a cohort of 1150 children showed significant deficits in FVC, FEV 1, and MMEF associated with ozone levels and some evidence that SO 2 and NO 2 were associated with deficits in MMEF growth. In the Polish study, lung function growth (FVC and FEV1) over 2-year period was compared for 1001 children living in two regions of Krakow with different levels of particulate air pollution. Lung function growth was significantly slower in the high pollution area. Collectively, these prospective studies strengthen earlier evidence from cross-sectional studies that long-term exposure to elevated levels of air pollution during childhood can produce deficits in lung function growth. Whether the deficits in growth result in decreased maximum attained lung function in adulthood is an active area of research. Cross-sectional studies in adults have provided some evidence that air pollution is associated with lung function level. 1 For example, a study in Switzerland reported that NO2, SO2, and PM10 were associated with deficits in FVC and FEV~, but the results for ozone were inconsistent, is

In a follow-up study of the effects of NO 2 on lung function in the same population, average home outdoor and personal exposure within a community showed a deficit in average F V C . 19 The investigators were unable to determine which, if any of the single pollutants accounted for the observed associations. There have been few truly longitudinal studies of the effects of air pollution on lung function decline and the findings have been inconsistent. 2~ In a longitudinal study of subjects living in two regions in Southern California with high and low ozone exposure, three follow-up measurements were conducted between 1977 and 1987. Lung function decline in non-smokers did not vary by chronic exposure to air pollution. This study could not separate the effects of individual pollutants. In this study, acute responses to laboratory ozone exposure were not correlated with individual long-term changes in FEV1, suggesting that acute decrements from ozone exposure may not be related to long-term effects. However, the hyper-responsiveness and acute inflammatory response to ozone is not correlated with acute decrements in FEV 1, and any chronic effects of ozone are likely to involve repeated inflammatory insults. 22 In contrast, a second study of residents of three southern Californian communities with varying levels of air pollutants, long-term exposure to polluted air was associated with decline in FEV1. 21 Again, this study could not identify the effects of individual pollutants. Associations between lung function and 20-year average concentrations of respirable particles, suspended sulfates, SO 2, ozone, and indoor particles were examined in a cohort of 1391 non-smokers. 2~ The number of days that PM10 levels exceeded 100ktg/m 3 and average ozone levels were associated with decrement in FEV 1 in males with a family history of asthma and allergy and mean SO 4 concentration was associated with FEV 1 in all males. 2~ Although effects of mixtures of ambient pollutants on lung function development and decline have been reported, these studies have not clearly identified the constituent or characteristic of the air-pollution mixture that accounts for the associations. The lack of understanding of which pollutants are important and what levels of exposure are safe inhibits rational approaches for control. Although a large number of chemical species occur in ambient air, ozone, NO 2, acid vapors, respirable particulates (PM10 and PM2.5) , SO 2, and acid aerosols have been identified as candidate pollutants for adverse effects on lung function. 1 Evidence for effects of each of these pollutants on lung function growth and decline are reviewed next.

Ozone and lung function development The acute effects of ozone on lung function, airway hyperresponsiveness, and airway inflammation in humans and animal models have led to the hypothesis that living in regions with high levels of ambient ozone is associated with chronic deficits in lung function by reducing growth and speeding lung function decline. 23 Much of the evidence derives from cross-sectional studies of attained lung function and retrospectively assessed lifetime exposure. 24-28

The effects of air pollution on lung function have been studied in a cross-sectional analysis of children and youths aged 6 to 24 years. 25 In these subjects, community ozone level was associated with decrements in FVC and FEV 1. In another study, the effects of ozone exposure on lung function level were analyzed in 130 college students using a residence-based exposure assignment for ozone; 27 a strong relationship was observed between lifetime ambient ozone exposure and mid- and end-expiratory flows. No association with FEV 1 and FVC was found, which is consistent with biologic models of chronic effects of ozone in the small airways. In a study of another group of college students using a similar design, lung function was lower in the group with high ozone exposures. 28'29 Deficits were observed for FEV 1 [-3.1%; 95% confidence interval (CI),-0.2 to-5.9%] and M M E F (-8.1%; C I , - 2 . 3 to-13.9%). However, after considering the effects of PM10 exposure, the authors concluded that living for 4 or more years in regions of the country with high levels of ozone and related co-pollutants was associated with lower lung function, but that the effects were more strongly associated with PM10 levels than ozone levels. 28'29 Cross-sectional analysis of the Children's Health Study has also found an effect of ozone on peak expiratory flow rate (PEFR, r =-0.75, p < 0.005), and an effect of PM2. 5 on M M E F (r=-0.80, p < 0.005). Ozone exposure was associated with a decreased FVC and FEV 1 in girls with asthma, and an association found between peak ozone exposures and lower FVC and FEV 1 in boys spending more time outdoors. 3~ The effects of ozone were larger for exposures earlier in life. The cross-sectional studies suggest that high lifetime ozone exposure is associated with deficits in small airway function. The effects of ozone on children's lung function growth was prospectively investigated by Austrian researchers. 16 Using repeated pulmonary function tests over a three-year period from children in nine Austrian cities, they reported associations between ozone and reduced lung function growth, although the ozone findings may be confounded by contemporaneous exposure to other pollutants. In the Children's Health Study, we did not observe significant effects of ozone on growth of FVC, FEV1, or M M E F among school aged children. However, in the second cohort of fourth graders, we found that ozone was associated with reduced growth of PEF and some evidence for reduced growth in FVC and marginally with FEV 1 (p =0.053) in the more-outdoors group of children. 15 Putting the results of longitudinal and cross-sectional studies together, the evidence is consistent with an age-dependent effect of ozone on growth of small airway function that is largest during preschool ages. N O 2 and lung function development Because NO 2 is a common indoor air pollutant arising from natural gas combustion, the effect of NO 2 on lung function has been examined free from the effects of the mixture of other ambient pollutants. 1 In a prospective study of Dutch children who were followed over a 2-year period with serial

lung function measurements, NO 2 exposure showed a weak, negative association with MMEF, but there was no consistent relationship between growth of lung function and a single measurement of indoor NO2 .31 In early analyses of data from the Six Cities studies, lower levels of FEV 1 and FVC were observed in children living in homes with gas stoves, 32'33 but in subsequent analysis there was no evidence that lung function growth was correlated with gas stove exposure. 34 In a subsample of children from the Six Cities study for whom indoor NO 2 was measured in homes, there was no effect of NO 2 on lung function level. 35 Other studies of the effect of indoor sources of NO 2 on lung function in children have also been inconsistent. 1 The data from these studies, the Children's Health Study and the Swiss Study on Air Pollution and Lung Disease in Adults suggest that NO 2 at ambient levels may not have an independent effect on lung function level or growth; however, ambient NO 2 level may be associated with lung function growth in the context of the other pollutants that occur with ambient NO 2. In this regard, it is uncertain whether NO 2 itself is the active pollutant that interacts with other pollutants, such as ozone, or whether it serves as a surrogate for high levels of fresh emissions from combustion sources such as motor vehicles.

Particulates, acids and lung function development The acute effects of nitric acid vapor on lung function have not been extensively studied. In a clinical study, exposure to 50ppb resulted in modest acute reductions in FEV 1 among children with asthma. 36 In an epidemiologic study of Dutch children, reduced flow rates were associated with same-day exposure to ambient nitrous acid which is in equilibrium with nitric acid. 37 Although cross-sectional associations of PMlo and PM2. 5 mass concentration with lung function have been inconsistent, total suspended particulate level has been associated with decreased lung function growth in children in Poland and PMlo and PM2. 5 levels with lung function in children in Southern California. 1'14'15'17'34'38 The effect of PM may be due, in part, to particle acidity, as particle strong acidity, characterized by sulfur dioxide-derived acidic sulfate particles, has been associated cross-sectionally with lung function level. 26 In the Children's Health Study, we observed a strong association with vapor phase acids and deficits in lung function growth; however, this association was not due to particle acidity as Southern California had low concentrations of SO 2 and acidic sulfate particles during the study period. High ambient concentrations of NO 2 were the primary source of nitric acid vapor in southern California. These findings suggest that the effects of gaseous nitric acid and acid sulfate aerosols on lung function level and growth may be mediated, in part, by the H § produced in the lung; however, the findings in the Children's Health Study suggest that vapor acids may be a surrogate marker for other species that occur in a polluted atmosphere in which vehicle emissions have undergone significant photooxidation.

Other ambient pollutants and lung function development Although motor vehicle exhaust is the primary source of many of the ambient air pollutants associated with adverse effects on lung function, the role of high levels of exposure to freshly emitted motor vehicle exhaust in lung function growth or level is an important unanswered question. There is some evidence supporting an effect of fresh exhaust on lung function based on experimental studies, studies of children who live near highways with heavy traffic volumes, and studies of exposures in tunnels. In a cross-sectional study of 1191 Dutch children living near busy roadways, deficits in lung flow rates were observed in children living within 300 m of a busy roadway. 39 The deficits were larger for traffic counts of trucks, which were powered primarily by diesel, than for automobiles, which were powered primarily by gasoline, and stronger for girls than for boys. 39 In a study of 4320 fourth grade children in Munich, traffic density diminished forced expiratory flow. 4~ In preschool children in Leipzig, exposure to heavy traffic was cross-sectionally associated with lower FVC and FEV1.41 In contrast, a study using repeated cross-sectional surveys of 200 non-smoking women living in each of 3 areas in Tokyo within 20 m of major roads, 20-150 m from the same roads, and in a separate suburban low traffic neighborhood, traffic exposure was not associated with lung function. 42'43 The effects of living near heavily traveled roadways may be related to NO 2 exposure; however, a number of other pollutants that are emitted in exhaust are of interest, including diesel exhaust and ultrafine particles. Diesel exhaust is a traffic-related pollutant that contains high levels of NO 2, fine particles, and organic compounds. Diesel exhaust appears to have acute and chronic effects on lung function. 44 In the Children's Health Study, we have reported that elemental carbon levels, a marker for diesel exhaust, was associated with reduced lung function growth in children. 15 Further work is needed to investigate the components or characteristics of diesel exhaust that affect lung function development and decline. Urban particulate matter consists of three size modes: ultrafine particles of <0.1 ktm diameter, accumulation mode particles (which together form the fine particle mode, <2.5 ~tm diameter) and coarse mode particles between 2.5 and 10 ktm diameter. Ultrafine particles contribute very little to the overall mass of fine particles, but are very high in number especially within 100m of roadways. These particles are of interest because they have high deposition in the distal lung, have large surface areas coated in organic compounds and transition metals, and have the ability to induce oxidative stress and inflammation in the lung. 45 No investigations of the chronic effects of ultrafine particles on lung function growth or decline have been reported. Although ultrafine particles may be important, determining the particle size distribution of fine particles in general may be required. For example, the number of accumulation mode but not ultrafine particles was consistently inversely associated with PEFR and no associations were observed

with large particles or particle m a s s . 46'47 Given the biological effects of ultrafine particles on the lung, studies of the effects on lung function are a high priority.

Susceptibility to ambient pollutants and lung function development Because airway defenses to inhaled oxidants are interacting systems, a number of host and genetic factors may contribute to fetal and children's lung function responses to air pollutants. Asthma and other respiratory conditions appear to be important determinants of lung function growth and decline following exposure to elevated levels of air pollutants. Time-activity patterns and sex may also modify the effects of air pollution on lung function growth and development. Dietary factors may affect lung growth as well as responses to air pollutants. 48-51A growing number of susceptibility genes have been identified as participants in the pathogenesis of persistent lung damage. 52'53Genotypes that result in a higher intensity oxidative stress, inflammatory responses or altered tissue response to damage appear to be associated with increased susceptibility to respiratory effects from acute and chronic exposure to air pollutants. 53-56

AIR P O L L U T I O N A N D A S T H M A OCCURRENCE Asthma is a large and growing threat to children's health and well-being. 57 In some communities, the prevalence of asthma in school-age children exceeds 25% and the prevalence has been rapidly rising in many regions of the developed world. 3~ Although asthma is the subject of intense research efforts, its etiology and the explanation for the increase in prevalence have yet to be firmly established. 57'62-65 The role of air pollutants as etiologic agents and their roles in the asthma epidemic are controversial; however, emerging evidence suggests that the effects of ambient air pollutants on asthma occurrence warrant renewed research attention. Ambient air pollutants are clearly related to wheezing and other asthma-related symptoms across the life course. A wide spectrum of pollutants including ozone, PM10 and PM2. 5, NO 2, and SO 2 has been associated with exacerbation of asthma in children and adults. 1 Although it is accepted that combustion-related air pollution exacerbates asthma, little evidence is available to support a role for ambient air pollutants on prevalence or incidence of new onset asthma and it is generally thought that air pollution does not cause new cases of asthma. The consensus that combustion related air pollution does not cause asthma is supported by a large number of crosssectional studies. 66 For example, a comparison of asthma prevalence between East and West Germany showed a lower rate in East Germany, where pollution from coalburning was much higher. 67 In analyses of asthma prevalence at the beginning of the Children's Health Study, we also found that exposure to air pollution was associated

with exacerbation of chronic symptoms of asthma, 68 but that there was no association between asthma prevalence and any ambient air pollutant measured including ozone, PMlo and PM2.5 o r NO2 .69 The effect of air pollution on exacerbation of asthma, but lack of association with asthma prevalence or incidence is somewhat paradoxical based on our understanding of asthma pathobiology. This apparent paradox may be resolved by consideration of issues of interpretation of findings made from cross-sectional studies about the relationships of air pollution and asthma. A case in point is the relationship between ozone and asthma. In clinical toxicology studies using ambient levels of exposure, acute effects of ozone have been observed on lung function, airway responsiveness and measures of inflammation. 1 Notably, the effects were largely observed in conditions involving moderate exercise. The lung function and inflammatory changes observed in experimental studies are thought to explain the associations of ozone exposure with exacerbations including increased symptoms, respiratory hospitalization and medication use in individuals with asthma. However, the acute effects of ozone at ambient levels are present in children with and without asthma, and the lack of association between ozone and prevalence seen in epidemiologic studies might be explained, in part, by the fact that levels of physical activity were not considered in these studies. The dose of outdoor air pollutants deposited in the lung depends not only on local pollutant concentrations, but also on time-activity patterns including the usual frequency, duration and intensity of physical activity. Timing and location of exercise is also important, as children often exercise outdoors in the afternoon when pollutants such as ozone are at their highest levels. It follows that children who engage in high levels of physical activity and experience the highest doses of air pollutants to the lung are at greatest risk for the adverse effects of ozone. Because the onset of asthma may result in lower levels of physical activity and subsequently lower doses of ozone given a fixed ambient level of ozone, crosssectional studies of asthma prevalence may not provide valid estimates of the relationship between air pollution and asthma occurrence. Prospective studies are needed to investigate the effects of air pollution on asthma occurrence and account for the effects of exercise in high and low pollution environments. Very few prospective studies of the relationship between air pollution and incident asthma have been reported. We investigated the relationship between air pollution, physical activity levels and newly diagnosed asthma among school-aged children residing in 12 Southern California communities. We used participation in team sports to classify usual levels of vigorous physical activity. We examined the association of team sport participation with the subsequent development of asthma during five years of follow-up of 3535 fourth, seventh, and tenth grade children who were asthma-free and participated in the Children's Health Study. Study communities were selected based on high and low ambient ozone exposure, in combination with

varied levels of other pollutants. 69 In the Children's Health Study, the risk of new onset asthma was associated with the highest doses of ozone (Table 24.2). Within communities with high ozone (mean 59.6 ppb), the relative risk (RR) for newly diagnosed asthma among children playing 3 or more sports was 3.3 (95% CI, 1.9-5.8), compared with children playing no sports. There was no effect of physical activity in low ozone communities (mean 40.0ppb) (RR, 0.8; 95% CI, 0.4-1.6). Children who spent more time outside also had a higher incidence of asthma in high ozone communities (RR, 1.4; 95% CI, 1.0-2.1) but not in low ozone communities. Exposure to pollutants other than ozone did not modify the relationship between team sports, ozone, and new onset asthma. The Children's Health Study demonstrates that high levels of physical activity in a high ozone environment are associated with an increased risk for subsequent new onset asthma. The fact that the effect of high energy expenditure sports was larger than that of low expenditure sports, and that the risk in children who spent more time outdoors was higher in high ozone communities, strengthens the inference that ambient levels of exposure to ozone increases the likelihood of development of asthma in children with the largest lung doses. Exercise-induced asthma by itself was unlikely to account for these results, because asthma onset was associated with exercise only in polluted communities. In a second, large prospective study of asthma and air pollution, an increased risk for new onset of asthma was observed among non-smoking adult Seventh Day Adventists in communities with high ozone concentrations. 70 For males, but not females, the risk of new doctor-diagnosed asthma was associated with 20-year mean 8 h average ozone levels ( R R - 2 . 0 9 for a 27 ppb increase in ozone concentration, 95% CI-1.03-4.16). Taken together with the clinical data showing that ozone exposure causes inflammation and airway hyper-responsiveness, the findings from these two large prospective studies indicate that ozone exposure is associated with new onset asthma in groups with higher exposure from being outdoors and engaging in recreational and occupational physical activity.

While ozone appears to be related to new onset asthma in school-aged children and adults, clinical and experimental studies suggest that asthma could be caused by exposure to elevated levels of other pollutants in addition to ozone. High levels of NO 2 and PMlo are candidates based on the enhanced response of asthmatics to bronchial allergen challenge with dust mite allergen after exposure. 71 We found limited evidence for an effect of physical activity on asthma in communities with high levels of NO 2 and PMso; however, it should be noted that the statistical power of the study to identify an independent association of NO 2 and PMxo with the development of newly diagnosed asthma, or to identify such a multi-pollutant interaction between sports, ozone and other pollutants w a s l o w . 72 The current research questions of greatest interest concern the role of diesel exhaust and ultrafine particles on the incidence and prevalence of asthma. In cross-sectional studies, residential or school proximity to heavy traffic has been identified as a risk factor for asthma and for wheezing and other respiratory symptoms in children. 39'73-79 In one of the few experimental studies examining fresh vehicular traffic exhaust exposure, asthmatic response to allergens was reported to be increased in the presence of short-term exposure to air pollution in a road tunnel. Studies with better exposure assessment have been conducted in Holland, where environmental traffic maps have been validated against experimental and field measurements of NO 2 in a model which is calibrated yearly. In one study, children living along busy streets were found to have a higher prevalence of chronic respiratory symptoms and to take more medication for respiratory conditions than children living along quieter streets, 73 and in another study children living within 100 m of freeways were found to have increased rates of self-reported doctor diagnosed asthma. 76 In a British study, children admitted to the hospital for asthma were more likely to live in an area with high traffic flow than children admitted for non-respiratory illness. 75 However, other cross-sectional and case-control studies have concluded that traffic activity in the school locality or near homes is not a major determinant of wheeze or asthma in children.

There is increasing toxicologic and limited epidemiologic evidence supporting a role for ultrafine particles less than 0.1 ktm in diameter in the acute effects of particulates on asthma outcomes. There are few epidemiologic studies that have examined the association specifically between ultrafine particles and asthma outcomes, and the results are not consistent. One such study demonstrated an increase in cough and a decrease in peak expiratory flow among a panel of asthmatic patients as the number of ultrafine particles increased. 8~ The association was stronger than that observed for PM10 or for mass of particles of 0.1-0.5 ktm diameter. However, a study in Finland found that ultrafine particle number was not more strongly associated with variations in PEF than PM10 .81 There are no studies that specifically examine the chronic effect of ultrafine particles on children's health. Such research is needed to evaluate the implications of recent animal toxicological studies for potentially sensitive populations like children and subjects with asthma.

CONCLUSIONS Exposures to environmental toxicants are associated with a substantial burden of adverse respiratory health effects including abnormal lung function development, reduced lung function growth, and more rapid lung function decline over the life course. In the coming decades, as urban development continues and the number of motor vehicle burning fossil fuels increases, populations exposed to elevated levels of a wide variety of ambient air pollutants will grow and the burden of adverse effects on lung function growth and obstructive lung diseases will continue to increase. Because the cost of controlling environmental hazards such as ambient air pollution is often high, defining the full spectrum of adverse effects from ambient pollution and identification of the components or characteristics of air pollution that produce adverse effects is a high priority.

ACKNOWLEDGEMENT This work was supported in part by the National Institute of Environmental Health Science (Grants #SPO1ES11627, 1POLES11627 and #5P30ES07048), the Environmental Protection Agency (Contract #CR82670801), the National Heart, Lung and Blood Institute (Grant 1RO1HL61768) and the Hastings Foundation.

REFERENCES 1. Anonymous. Health effects of outdoor air pollution. Committee of the Environmental and Occupational Health Assembly of the American Thoracic Society. Am. J. Respir. Crit. Care Med. 1996; 153:3-50. 2. Peters J. Epidemiologic investigation to identify chronic health effects of ambient air pollutants in Southern California: Phase II final report. Report prepared for the California

Air Resources Board, Sacramento, CA by the University of Southern California School of Medicine, Department of Preventive Medicine, Los Angeles, CA. 1997. 3. Wiley J. Study of Children's Activity Patterns. Survey Research Center, University of California, Berkley, CA. 1991. 4. Lippmann M. Health effects of ozone: a critical review. J. Air Pollut. Control Assoc. 1989; 39:672-95. 5. Tager IB, Segal MR, Speizer F E e t al. The natural history of forced expiratory volumes. Effect of cigarette smoking and respiratory symptoms.Am. Rev. Respir. Dis. 1988; 138:837-49. 6. Gilliland FD, Berhane K, McConnell R et al. Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function. Thorax 2000; 55:271-6. 7. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during pregnancy. Effects on lung function during the first 18 months of life.Am. J. Respir. Crit. Care Med. 1995; 152:977-83. 8. U.S. Department of Health and Human Services. The Health Consequences of Involuntary Smoking. Report of the Surgeon General. Public Health Service, Washington, DC. 1986. 9. US Environmental Protection Agency. Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders. Washington, DC. 1992. 10. Samet JM, Lange P. Longitudinal studies of active and passive smoking.Am. J. Respir. Crit. Care Med. 1996; 154:$257-65. 11. Li YF, Gilliland FD, Berhane K et al. Effects of in utero and environmental tobacco smoke exposure on lung function in boys and girls with and without asthma. Am. J. Respir. Crit. Care Med. 2000; 162:2097-104. 12. Ritz B, Yu F. The effect of ambient carbon monoxide on low birth weight among children born in southern California between 1989 and 1993. Environ. Health Perspect. 1999; 107:17-25. 13. Ritz B, Yu F, Chapa G et al. Effect of air pollution on preterm birth among children born in Southern California between 1989 and 1993. Epidemiology 2000; 11:502-11. 14. Gauderman WJ, McConnell R, Gilliland F et al. Association between air pollution and lung function growth in southern California children. Am. J. Respir. Crit. Care Med. 2000; 162:1383-90. 15. Gauderman WJ, Gilliland GF, Vora H etal. Association between air pollution and lung function growth in southern California children: results from a second cohort. Am. J. Respir. Crit. Care Med. 2002; 166:76-84. 16. Frischer T, Studnicka M, Gartner C etal. Lung function growth and ambient ozone: a three-year population study in school children. Am. J. Respir. Crit. Care Med. 1999; 160: 390-96. 17. Jedrychowski W, Flak E, Mroz E. The adverse effect of low levels of ambient air pollutants on lung function growth in preadolescent children. Environ. Health Perspect. 1999; 107:669-74. 18. Ackermann-Liebrich U, Leuenberger P, Schwartz J et al. Lung function and long term exposure to air pollutants in Switzerland. Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) Team. Am. J. Respir. Crit. Care Med. 1997; 155:122-9. 19. Schindler C, Ackermann-Liebrich U, Leuenberger P etal. Associations between lung function and estimated average exposure to NO 2 in eight areas of Switzerland. The SAPALDIA Team. Swiss Study of Air Pollution and Lung Diseases in Adults. Epidemiology 1998; 9:405-11. 20. Abbey DE, Burchette RJ, Knutsen SF etal. Long-term particulate and other air pollutants and lung function in nonsmokers.Am.J. Respir. Crit. Care Med. 1998; 158:289-98. 21. Tashkin D, Detels R, Simmons Met al. The UCLA population studies of chronic obstructive respiratory disease: XI. Impact of air pollution and smoking on annual change in forced expiratory volume in one second. Am. J. Respir. Crit. Care Med. 1994; 149:1209-17.

22. Gong H Jr, Simmons MS, Linn WS eta1. Relationship between acute ozone responsiveness and chronic loss of lung function in residents of a high-ozone community. Arch. Environ. Health 1998; 53:313-19. 23. Lippmann M. Health effects of ozone. A critical review. Japca. 1989; 39:672-95. 24. Ackermann-Liebrich U, Leuenberger P, Schwartz J e t al. Lung function and long term exposure to air pollutants in Switzerland. Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) Team. Am. J. Respir. Crit. Care Med. 1997; 155:122-9. 25. Schwartz J. Lung function and chronic exposure to air pollution: a cross-sectional analysis of NHANES II. Environ. Res. 1989; 50:309-21. 26. Raizenne M, Neas LM, Damokosh AI et al. Health effects of acid aerosols on North American children: pulmonary function. Environ. Health Perspect. 1996; 104:506-14. 27. Kunzli N, Lurmann F, Segal M. Association between lifetime ambient ozone exposure and pulmonary function in college freshmen - results of a pilot study. Environ. Res. 1997; 72:8-23. 28. Galizia A, Kinney PL. Long-term residence in areas of high ozone: associations with respiratory health in a nationwide sample of nonsmoking young adults (see comments). Environ. Health Perspect. 1999; 107:675-9. 29. Kinney PL, Chae E. Diminished lung function in young adults is associated with long-term PM10 exposures. Proc. 14th Con. Int. Soc. Environ. Epidem. 2002:43. 30. Peters JM, Avol E, Gauderman WJ etal. A study of twelve southern California communities with differing levels and types of air pollution. II. Effects on pulmonary function. Am.J. Respir. Crit. Care Med. 1999; 159:768-75. 31. Dijkstra L, Houthuijs D, Brunekreef B etal. Respiratory health effects of the indoor environment in a population of Dutch children. Am. Rev. Respir. Dis. 1990; 142:1172-78. 32. Speizer FE, Ferris B Jr, Bishop YM et al. Respiratory disease rates and pulmonary function in children associated with NO z exposure.Am. Rev. Respir. Dis. 1980; 121:3-10. 33. Ware JH, Dockery DW, Spiro A III et al. Passive smoking, gas cooking, and respiratory health of children living in six cities. Am. Rev. Respir. DIS. 1984; 129:366-74. 34. Berkey CS, Ware JH, Dockery DW et al. Indoor air pollution and pulmonary function growth in preadolescent children. Am.J. Epidemiol. 1986; 123:250-60. 35. Neas LM, Dockery DW, Ware JH et al. Association of indoor nitrogen dioxide with respiratory symptoms and pulmonary function in children.Am. J. Epidemiol. 1991; 134:204-19. 36. Koenig JQ, Covert DS, Pierson WE. Effects of inhalation of acidic compounds on pulmonary function in allergic adolescent subjects. Environ. Health Perspect. 1989; 79:173-8. 37. Hoek G, Brunekreef B, Hofschreuder P et al. Effects of air pollution episodes on pulmonary function and respiratory symptoms. Toxicol. Ind. Health 1990; 6:189-97. 38. Pope CA III. Particulate pollution and health: a review of the Utah valley experience. J. Expo. Anal. Environ. Epidemiol. 1996; 6:23-34. 39. Brunekreef B, Janssen NA, de Hartog J etal. Air pollution from truck traffic and lung function in children living near motorways. Epidemiology 1997; 8:298-303. 40. Wjst M, Reitmeir P, Dold S etal. Road traffic and adverse effects on respiratory health in children. BMJ. 1993; 307:596-600. 41. Fritz GJ, Herbarth O. Pulmonary function and urban air pollution in preschool children. Int. J. Hyg. Environ. Health 2001; 203:235-44. 42. Maeda K, Nitta H, Nakai S. Exposure to nitrogen oxides and other air pollutants from automobiles. Public Health Rev. 1991; 19:61-72.

43. Nakai S, Nitta H, Maeda K. Respiratory health associated with exposure to automobile exhaust. III. Results of a cross-sectional study in 1987, and repeated pulmonary function tests from 1987 to 1990. Arch. Environ. Health 1999; 54:26-33. 44. Sydbom A, Blomberg A, Parnia S et al. Health effects of diesel exhaust emissions. Eur. Respir. J. 2001; 17:733-46. 45. Oberdorster G. Pulmonary effects of inhaled ultrafine particles. Int. Arch. Occup. Environ. Health 2001; 74:1-8. 46. Penttinen P, Timonen KL, Tiittanen P e t al. Number concentration and size of particles in urban air: effects on spirometric lung function in adult asthmatic subjects. Environ. Health Perspect. 2001; 109:319-23. 47. Penttinen P, Timonen KL, Tiittanen P etal. Ultrafine particles in urban air and respiratory health among adult asthmatics. Euro. Respir. J. 2001; 17:428-35. 48. Schunemann HJ, Grant BJ, Freudenheim JL etal. The relation of serum levels of antioxidant vitamins C and E, retinol and carotenoids with pulmonary function in the general population. Am. J. Respir. Crit. Care Med. 2001; 163:1246-55. 49. Schunemann HJ, McCann S, Grant BJ et al. Lung function in relation to intake of carotenoids and other antioxidant vitamins in a population-based study. Am. J. Epidemiol. 2002; 155:463-71. 50. Romieu I, Trenga C. Diet and obstructive lung diseases. Epidemiol. Rev. 2001; 23:268-87. 51. Romieu I, Sienra-Monge JJ, Ramirez-Aguilar M e t a l . Antioxidant Supplementation and Lung Functions among Children with Asthma Exposed to High Levels of Air Pollutants.Am. J. Respir. Crit. Care Med. 2002; 166:703-9. 52. Sandford AJ, Joos L, Pare PD. Genetic risk factors for chronic obstructive pulmonary disease. Curr. Opin. Pulmon. Med. 2002; 8:87-94. 53. He JQ, Ruan J, Connett JE etal. Antioxidant gene polymorphisms and susceptibility to a rapid decline in lung function in smokers. Am. J. Respir. Crit. Care Med. 2002; 166:323-8. 54. Gilliland FD, McConnell R, Peters J e t al. A theoretical basis for investigating ambient air pollution and children's respiratory health. Environ. Health Perspect. 1999; 107 (Suppl. 3):403-7. 55. Arbour NC, Lorenz E, Schutte BC et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet. 2000; 25:187-91. 56. Bergamaschi E, De Palma G, Mozzoni P e t al. Polymorphism of quinone-metabolizing enzymes and susceptibility to ozone-induced acute effects. Am. J. Respir. Crit. Care Med. 2001; 163:1426-31. 57. Redd SC. Asthma in the United States: burden and current theories. Environ. Health Perspect. 2002;ll0(Suppl. 4): 557-60. 58. Asher MI, Barry D, Clayton T et al. The burden of symptoms of asthma, allergic rhinoconjunctivities and atopic eczema in children and adolescents in six New Zealand centres: ISAAC Phase One. N. Z. Med. J. 2001; 114:114-20. 59. ISAAC Steering Committee. Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC) [see comments]. Eur. Respir. J. 1998; 12:315-35. 60. Mannino DM, Homa DM, Redd SC. Involuntary smoking and asthma severity in children: data from the third national health and nutrition examination survey. Chest 2002; 122:409-15. 61. Pekkanen J, Xu B, Jarvelin MR. Gestational age and occurrence of atopy at age 31 - a prospective birth cohort study in Finland. Clin. Exp. Allergy 2001; 31:95-102. 62. Pearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax 1999; 54:268-72.

63. Pearce N, Douwes J, Beasley R. The rise and rise of asthma: a new paradigm for the new millennium? J. Epidemiol. Biostat. 2000; 5:5-16. 64. Committee on the Assessment of Asthma and Indoor Air. Clearing the Air: Asthma and Indoor Exposures. Washington, DC: National Academy of Sciences, 2000. 65. Carter S, Platts-Mills T. Searching for the cause of the increase in asthma. Curt. Opin. Pediatr. 1998; 10:594-9. 66. Clark NM, Brown RW, Parker E etal. Childhood Asthma. Environ. Health Perspect. 1999; 107(Suppl. 3):421-9. 67. Wichmann HE, Heinrich J. Health effects of high level exposure to traditional pollutants in East G e r m a n y - review and ongoing research. Environ. Health Perspect. 1995; 103 (Suppl. 2):29-35. 68. McConnell R, Berhane K, Gilliland F et al. Air pollution and bronchitic symptoms in southern California children with asthma. Environ. Health Perspect. 1999; 107:757-60. 69. Peters JM, Avol E, Navidi W e t al. A study of twelve Southern California communities with differing levels and types of air pollution. I. Prevalence of respiratory morbidity. Am. J. Respir. Crit. Care Med. 1999; 159:760-7. 70. McDonnell WF, Abbey DE, Nishino N etal. Long-term ambient ozone concentration and the incidence of asthma in nonsmoking adults: the AHSMOG Study. Environ. Res. 1999; 80:110-21. 71. Jenkins HS, Devalia JL, Mister RL et al. The effect of exposure to ozone and nitrogen dioxide on the airway response of atopic asthmatics to inhaled allergen: dose- and time-dependent effects.Am. J. Respir. Crit. Care Med. 1999; 160:33-9. 72. McConnell R, Berhane K, Gilliland F et al. Asthma in exercising children exposed to ozone: a cohort study. Lancet 2002; 359:386-91.

73. Ciccone G, Forastiere F, Agabiti N etal. Road traffic and adverse respiratory effects in children. Occup. Environ. Med. 1998; 55:771-8. 74. Duhme H, Weiland S, Keil U et al. The association between self-reported symptoms of asthma and allergic rhinitis and self-reported traffic density on street residence in adolescents. Epidemiology 1996; 7:578-82. 75. Edwards J, Waiters S, Griffiths RK. Hospital admissions for asthma in preschool children: relationship to major roads in Birmingham, United Kingdom. Arch. Environ. Health 1994; 49:223-7. 76. van Vliet P, Knape M, de Hartog J et al. Motor vehicle exhaust and chronic respiratory symptoms in children living near freeways. Environ. Res. 1997; 74:122-32. 77. Venn A, Lewis S, Cooper M etal. Local road traffic activity and the prevalence, severity, and persistence of wheeze in school children: combined cross sectional and longitudinal study. Occup. Environ. Med. 2000; 57:152-8. 78. Waldron G, Pottle B, Dod J. Asthma and the motorways - one District's experience.J. Public Health Med. 1995; 17:85-9. 79. Weiland S, Mundt K, Ruckmann A et al. Self-reported wheezing and allergic rhinitis in children and traffic density on street residence.Ann. Epidemiol. 1994; 4:243-7. 80. Peters JM. Epidemiologic investigation to identify chronic health effects of ambient air pollutants in Southern California: Phase II final report. California Air Resources Board Contract #A033-186. University of Southern California, Los Angeles. 1997. 81. Pekkanen J, Timonen KL, Ruuskanen J etal. Effects of ultrafine and fine particles in urban air on peak expiratory flow among children with asthmatic symptoms. Environ. Res. 1997; 74:24-33.