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## 8 POPULATIONS POTENTIALLY AT INCREASED RISK FOR OZONE

- RELATED HEALTH EFFEC TS

Interindividual variation in human responses to air pollution exposure suggests that some 

### 1 groups are at increased risk for detrimental effects in response to ambient exposure to an 

### 2 air pollutant. The NAAQS are intended to provide an adequate margin of safety for both 

### 3 the population as a whole and those individuals potentially at increased risk for health 

### 4 effects in response to ambient air pollution (Preface to this ISA). To facili tate the 

### 5 identification of populations at greater risk for O 3 - related health effects, studies have 

### 6 evaluated factors that may contribute to the susceptibility and/or vulnerability of an 

### 7 individual to O 3 . The definitions of susceptibility and vulnerability have been found to 

### 8 vary across studies, but in most instances “ susceptibility ” refers to biological or intrinsic 

### 9 factors (e.g., lifestage, sex) while “ vulnerability ” refers to nonbiological or extrinsic 

### 10 factors (e.g., socioeconomic status [SES]) ( U.S. EPA, 2010c
, 2009d ) . Additionally, in 

### 11 some cases, the terms “ at

- risk ” and “ sensitive ” populations have been used to encompass 

### 12 these concepts more generally. Previous ISAs and reviews ( Sacks et al., 2011 ; U.S. EPA, 

### 13 2010c
, 2009d ) have used an all encompassing definition for “ susceptible population ” to 

### 14 focus on identifying the populations at greater risk for O 3 - induced heath effects and 

### 15 circumvent the need to distinguish between susceptible and vulnerable factors. I n this 

### 16 chapter, “ at

- risk ” groups are defined as those with characteristics that increase the risk of 

### 17 O 3 - related health effects in a population. These characteristics include various factors, 

### 18 such as genetic background, race, sex, lifestage, diet, preexisting disease, SES, and 

### 19 characteristics that may modify exposure to O 3 (e.g., time spent outdoors). 

### 20
Individuals, and ultimately populations, could experience increased risk for O 3 - induced 

### 21 health effects due to: 

### 22

 Intrinsically increased risk: This de scribes individuals at greater risk due to a 

### 23 biological mechanism; 

### 24

 Extrinsically increased risk: This describes individuals at greater risk due to an 

### 25 external, non

- biological factor; and 

### 26

 Increased dose: This describes individuals that have a greater dose a t a given 

### 27 concentration due to breathing patterns or other factors 

### 28
In addition, some individuals might be placed at risk of experiencing a greater exposure 

### 29 by being exposed at higher concentrations. For example, individuals in lower SES groups 

### 30 might be exp osed to higher O 3 concentrations due to less availability/use of home air 

### 31 conditioners (i.e., more open windows on high O 3 days). 

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- 2 September 2011 Examples of potential factors intrinsically related to increased risk through biological 

### 1 mechanisms are genetic background an d sex, while extrinsic factors, such as SES, may 

### 2 also increase the risk of O 3 - related health effects. However, some factors that may lead to 

### 3 increased risk of O 3 - related health effects have both intrinsic and extrinsic components. 

### 4 For example, SES may affe ct access to medical care, which could then affect the 

### 5 presence of preexisting diseases and conditions often considered to be intrinsic factors. 

### 6 Additionally, children tend to spend more time outdoors than adults, which increases 

### 7 their dose of O 3 , but they also have intrinsic differences compared to adults based on 

### 8 lung growth and development. 

### 9
The emphasis of this chapter is on identifying and understanding the characteristics that 

### 10 potentially increase the risk of O 3 - related health effects, regardless of w hether the 

### 11 increased risk at a given concentration is due to intrinsic factors, extrinsic factors, or 

### 12 increased dose. The following sections examine factors that may modify the association 

### 13 between O 3 and health effects, but does not categorize them as intr insic factors, extrinsic 

### 14 factors, or increased dose, due to the convoluted and often connected pathways between 

### 15 factors. However, the different role of intrinsic risk, extrinsic risk, and increased dose are 

### 16 discussed as appropriate throughout the chapter. 

### 17
Epidemiologic studies often conduct stratified analyses to identify the presence or 

### 18 absence of effect measure modification to indicate whether O 3 differentially affects 

### 19 certain populations. This allows researchers to examine the effects of O 3 exposure wit hin 

### 20 each group under study. A thorough evaluation of potential effect measure modifiers may 

### 21 help identify populations that are more at

- risk to health effects associated with O 3 

### 22 exposure. Toxicological and controlled human exposure studies can provide suppo rt and 

### 23 biological plausibility for factors that may lead to increased risk for O 3 - related health 

### 24 effects through the study of animal models of disease or individuals with underlying 

### 25 disease or genetic polymorphisms that allow for comparisons between subgro ups. The 

### 26 results from these studies, combined with those results obtained through stratified 

### 27 analyses in epidemiologic studies, comprise the overall weight of evidence for the 

### 28 increased risk of specific populations to O 3 - related health effects. 

### 29
This chapt er discusses the epidemiologic, controlled human exposure, and toxicological 

### 30 studies evaluated in Chapters 5, 6, and 7 that provide information on potential at

- risk 

### 31 populations. The epidemiologic studies included in this chapter consist of only those 

### 32 studi es that presented stratified results (e.g., males versus females or <65 years of age 

### 33 versus ≥ 65 years of age). This approach allowed for a comparison between populations 

### 34 exposed to similar O 3 concentrations and within the same study design. Numerous 

### 35 studi es that focus on only one potentially at

- risk population are described in previous 

### 36 chapters, but these studies are not discussed in detail in this chapter because of the lack of 

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- 3 September 2011 an adequate comparison group within the study. Controlled human exposure studi es that 

### 1 consisted of individuals with an underlying disease or genetic polymorphism, or studies 

### 2 that categorized the study population by age, race, etc., and toxicological studies that 

### 3 used animal models of disease were also evaluated for coherence and bio logical 

### 4 plausibility. 

### 5
Factors examined that may lead to increased risk of O 3 - related health effects based on the 

### 6 overall evidence integrated across disciplines are described in greater detail in the 

### 7 following sections. 

### 8



## 8.1 Preexisting Disease/Conditions

Indiv iduals with certain preexisting diseases are likely to constitute an at

- risk population. 

### 9 Previous O 3 AQCDs concluded that some people with preexisting pulmonary disease, 

### 10 especially asthma, are among those at increased risk from O 3 exposure. Extensive 

### 11 toxic ological evidence was available indicating that altered physiological, morphological 

### 12 and biochemical states typical of respiratory diseases, such as asthma, COPD, and 

### 13 chronic bronchitis, may render people sensitive to additional oxidative burden induced by 

### 14 O 3 exposure. In addition, a number of epidemiologic studies found that some individuals 

### 15 with respiratory diseases are at increased risk of O 3 - related effects. Little evidence, 

### 16 however, was available on the potential for increased risk for people with othe r 

### 17 preexisting conditions, such as cardiovascular diseases. 

### 18
Recent studies that examined whether preexisting diseases and conditions lead to 

### 19 increased risk of O 3 - induced health effects were identified and are summarized below. 

### 20 Table 8

- 1 displays the prevalence rates of some of these conditions categorized by age 

### 21 and region among adults in the U.S. population; data for children, when available, are 

### 22 present ed within sections. Substantial proportions of the U.S. population are affected by 

### 23 these conditions and therefore may represent a potentially large at

- risk population. While 

### 24 these diseases and conditions are intrinsic to individuals, the pathways to their 

### 25 development may have intrinsic or extrinsic origins. 

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### Table 8

- 1 Prevalence of respiratory diseases, cardiovascular diseases, and diabetes among adul ts by age and region in the U.S.

Adults N (in thousands) Age Region Chronic Disease/Condition 18

- 44 45

- 64 65

- 74 75+ Northeast Midwest South West Respiratory Diseases Asthma a 28,260 13.5 12.0 12.0 10.0 12.8 13.4 11.2 13.9 COPD Chronic Bronchitis 9,832 3.2 5.5 5.9 5.3 3.4 4.8 5.2 2.9 Emphysema 3,789 0.2 2.0 5.7 5.0 1.2 1.9 1.9 1.3 Cardiovascular Diseases All Heart Disease 26,628 4.6 12.3 26.7 39.2 11.3 12.7 12.2 9.9 Coronary Heart Disease 14,428 1.1 6.7 16.9 26.7 5.7 6.5 7.3 4.9 Hypertension 56,159 8.7 32.5 54.4 61.1 22.9 24.1 27.1 20.6 Diabetes 18,651 2.3 12.1 20.4 17.3 4.5 7.6 9.0 7.7

a Asthma prevalence is reported for “ ever had asthma ” Source: Statistics for adults: Pleis et al. ( 2009 )



### 8.1.1 Influenza/Infections

Recent studies have indicated that underlying infections may increase the risk of 

### 1 individuals to O 3 - related health effects, although there are only a limited number of 

### 2 studies. A study of hospitalizations in Hong Kong reported that increased levels of 

### 3 influenza intensity resulted in increased excess risk of respiratory disease hospitalizations 

### 4 related t o O 3 exposure ( Wong et al., 2009 ) . In addition, a study of lung function in 

### 5 asthmatic children reported decreases in lung function with increased short

- term O 3 

### 6 exposure for those with upper respiratory infections but not for those without infections 

### 7 ( Lewis et al., 2005 ) . Toxicological studies provide biological plausibility for the increase 

### 8 in O 3 - induced health effects observed in epidemiologic studies that examined infections. 

### 9 Toxicological studies demonstrated that 0.08 ppm O 3 increased streptococcus

- induced 

### 10 mortality, regardless of whether O 3 exposure precedes or follows infection ( Miller et al., 

### 11 1978 ; Coffin and Gardner, 1972 ; Coffin et al., 1967 ) . Ozone exposure likely impairs host 

### 12 defenses, which may increase mortality due to an infectious agent. However, there is little 

### 13 toxicological evidence that infection or influenza itself renders an individual at greater 

### 14 risk of an O 3 - induced health effect. 

### 15

8.1.2 Asthma

Previous O 3 AQCDs identified individuals with asthma as a population at risk for O 3 - 

### 16 relat ed health effects. Within the U.S., approximately 12% of adults have reported ever 

### 17Draft

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- 5 September 2011 having asthma ( Pleis et al., 2009 ) . The prevalence of asthma is approximately 7.2%. 

### 1 16.2%, and 16.6% among U.S. children aged 0

- 4, 5

- 11, and 12

- 17, respectively ( Bloom 

### 2 et al., 2008 )

. 

### 3
Multiple epidemiologic studies included within this ISA have evaluated the potential for 

### 4 increased risk of O 3 - related health effects among individuals with asthma. A study of 

### 5 lifeguards in Texas reported decreased lung function with short

- term O 3 exposure among 

### 6 both individuals with and without asthma, however, the decrease was greater among 

### 7 those with asthma ( Thaller et al., 2008 ) . A Mexican study of children ages 6

- 14 detected 

### 8 an association between short

- term O 3 and wheeze, cough, and bronchodilator use among 

### 9 asthmatics but not non

- asthmatics, although this may have been the re sult of a small 

### 10

non

- asthmatic population ( Escamilla

- Nuñez et al., 2008 ) . A study of the modification of 

### 11 the effect of greater O 3 associated decreases in short

- term O 3 exposure on lung function 

### 12 by airway hyperresponsiveness (AHR) (a condition common among asthmatics) reported 

### 13 greater O 3 - associated decreases in lung function in elderly individuals with AHR, 

### 14 especially among those wh o were obese ( Alexeeff et al., 2007 ) . However, no evidence 

### 15 for increased risk was found in a study performed amo ng children in Mexico City that 

### 16 examined the effect of short

- term O 3 exposure on respiratory health ( Barraza

- Villarreal et 

### 17 al., 2008 ) . In this study, a positive association was reported for airway inflammation 

### 18 among asthmatic children, but the observed association was similar in magnitude to that 

### 19 of non

- asthmatics. Similarly, a study of children in California reported an association 

### 20 between O 3 concentration and exhaled nitric oxide fraction (FeNO) that persisted both 

### 21 among children with and without asthma as well as those with and without respiratory 

### 22 allergy ( Berhane et al., 2011 ) . Finally, some studies have reported null results for both 

### 23 individuals with and without asthma. Khatri et al. ( 2009 ) found no association between 

### 24 short

- term O 3 exposure and altered lung function for either asthmatic or non

- asthmatic 

### 25 adults, but did not e a decrease in lung function among individuals with allergies. 

### 26
Additional evidence for difference in effects among asthmatics has been observed in 

### 27 studies that examined the association between O 3 exposure and altered lung function by 

### 28 asthma medication us e. A study of children with asthma living in Detroit reported a 

### 29 greater association between short

- term O 3 and lung function for corticosteroid users 

### 30 compared with noncorticosteroid users ( Lewis et al., 2005 ) . Conversely, another study 

### 31 found decreased lung function among noncorticosteroid users compared to users, 

### 32 although in this study, a large proportion of non

- users were considered to be persistent 

### 33 asthmatics ( Hernández

- Cadena et al., 2009 ) . Lung function was not related to short

- term 

### 34 O 3 exposure among corticosteroid users and non

- users in a study taking place during the 

### 35 winter months in Canada ( Liu et al., 2009a ) . Additionally, a study of airway 

### 36 inflammation reported a counterintuitive inverse association with O 3 of similar 

### 37 magnitude for all groups of corticoste roid users and non

- users ( Qian et al., 2009 )

. 

### 38Draft

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- 6 September 2011 Controlled human exposu re studies that have examined the effects of O 3 on both 

### 1 individuals with asthma and healthy controls are limited. Based on studies reviewed in 

### 2 the 1996 and 2006 O 3 AQCDs, subjects with asthma appeared to be more sensitive to 

### 3 acute effects of O 3 in terms of FEV 1 and inflammatory responses than healthy 

### 4

non

- asthmatic subjects. For instance, Horstman et al. ( 1995 ) observed that 

### 5 mild

- to

- moderate asthmatics, on av erage, experienced double the O 3 - induced FEV 1 

### 6 decrement of healthy subjects (19% versus 10%, respectively, p = 0.04). Moreover, a 

### 7 statistically significant positive correlation between FEV 1 responses to O 3 exposure and 

### 8 baseline lung function was observed i n individuals with asthma, i.e., responses increased 

### 9 with severity of disease. Minimal evidence exists suggesting that individuals with asthma 

### 10 have smaller O 3 - induced FEV 1 decrements than healthy subjects (3% versus 8%, 

### 11 respectively) ( Mudway et al., 2001 ) . However, the asthmatics in t hat study also tended to 

### 12 be older than the healthy subjects, which could partially explain their lesser response 

### 13 since FEV 1 responses to O 3 exposure diminish with age. Individuals with asthma also 

### 14 had significantly more neutrophils in the BALF (18 hours po stexposure) than similarly 

### 15 exposed healthy individuals ( Peden et al., 1997 ; Scannell et al., 1996 ; Basha et al., 1994 )

. 

### 16 Furthermore, one newer study examined the effects of O 3 on both individuals wi th atopic 

### 17 asthma and healthy controls ( Hernandez et al., 2010 ) . Greater numbers of neutrophils, 

### 18 higher levels of cytokines and hyaluronan, and greater expression of macrophage 

### 19 cell

- surface markers were observed in induced sputum of atopic asthmatics compared 

### 20 with hea lthy controls. Differences in O 3 - induced epithelial cytokine expression were 

### 21 noted in bronchial biopsy samples from asthmatics and healthy controls ( Bosson et al., 

### 22 2003 )

. Cell

- surface marker and cytokine expression results, and the presence of 

### 23 hyaluronan, are consistent with O 3 havin g greater effects on innate and adaptive 

### 24 immunity in these asthmatic individuals (see Section 5.4.2.2). In addition, older studies 

### 25 have demonstrated that O 3 exposure leads to increased bronchial reactivity to inhaled 

### 26 allergens in mild allergic asthmatics ( Kehrl et al., 1999 ; Jorres et al., 1996 ) and to the 

### 27 influx of eosinophils in individuals with pre

- existing allergic disease ( Vagaggini et al., 

### 28 2002 ; Peden et al., 1995 ) . Taken to gether, these results point to several mechanistic 

### 29 pathways which could account for the enhanced sensitivity to O 3 in subjects with asthma 

### 30 (see Section 5.4.2.2). 

### 31
Toxicological studies provide biological plausibility for greater effects of O 3 among 

### 32 those w ith asthma or AHR. In animal toxicological studies, an asthmatic phenotype is 

### 33 modeled by allergic sensitization of the respiratory tract. Many of the studies that provide 

### 34 evidence that O 3 exposure is an inducer of AHR and remodeling utilize these types of 

### 35 animal models. For example, a series of experiments in infant rhesus monkeys have 

### 36 shown these effects, but only in monkeys sensitized to house dust mite allergen ( Fanucchi 

### 37 et al., 2006 ; Joad et al., 2006 ; Schelegle et al., 2003 ) . Similarly, Funabashi et al. ( 2004 ) 

### 38 demonstrated adverse changes in pulmonary function in mice exposed to O 3 , and Wagner 

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- 7 September 2011 et al. ( 2007 ) demonstrated enhanced inflammatory responses in rats exposed to O 3 , but 

### 1 only in animals sensitized to allergen. In general, it is the combined effects of O 3 and 

### 2 allergic sensitization which result in measurable effects on pulmonary function. In a 

### 3 bleomycin induced pulmonary fibrosis model, exposure to 250 ppb O 3 for 5 days 

### 4 increased pulmonary inflammation and fibrosis, along w ith the frequency of 

### 5 bronchopneumonia in rats. Thus, short

- term exposure to O 3 may enhance damage in a 

### 6 previously injured lung ( Oyarzún et al., 2005 )

. 

### 7

In the 2006 O 3 AQCD, the potential for individuals with asthma to have greater risk of 

### 8 O 3 - related health effects was supported by a number of controlled human exposure 

### 9 studies, evidence from to xicological studies, and a limited number of epidemiologic 

### 10 studies. Overall, in the recent epidemiologic literature some, but not all, studies report 

### 11 greater risk of health effects among individuals with asthma. Studies examining effect 

### 12 measure modificatio n of the relationship between short

- term O 3 exposure and altered 

### 13 lung function by corticosteroid use provided limited evidence of O 3 - related health 

### 14 effects. Inconsistent findings observed in epidemiologic studies may be due to the 

### 15 differences in O 3 concent ration across the studies. Additionally, recent studies of 

### 16 behavioral responses have found that studies do not take into account individual 

### 17 behavioral adaptations to forecasted air pollution levels (such as avoidance and reduced 

### 18 time outdoors), which may u nderestimate the observed associations in studies that 

### 19 examined the effect of O 3 exposure on respiratory health ( Neidell and Kinney, 2010 )

. 

### 20 This could explain some inconsistency observed among recent epidemiologic studies. 

### 21 The evidence from controlled human exposure studies provides support for increased 

### 22 detriments in FEV 1 and greater inf lammatory responses to O 3 in individuals with asthma 

### 23 than in healthy individuals without a history of asthma. The collective evidence for 

### 24 increased risk of O 3 - related health effects among individuals with asthma from controlled 

### 25 human exposure studies is su pported by recent toxicological studies which provide 

### 26 biological plausibility for heightened risk of asthmatics to respiratory effects due to O 3 

### 27
exposure. 

### 28

8.1.3 Chronic Obstructive Pulmonary Disease (COPD)

Although not extensively examined in the literature, ini tial evidence suggests that 

### 29 preexisting COPD may modify the association between short

- term O 3 exposure and 

### 30 cardiovascular

- related health effects. In the U.S. over 4% of adults report having chronic 

### 31 bronchitis and almost 2% report having emphysema, both of which are classified as 

### 32 COPD ( Pleis et al., 2009 )

. 

### 33Draft

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- 8 September 2011 In a recent study, Peel et al. ( 2007 ) found that individuals with COPD were at increased 

### 1 risk of cardiovascular ED visits in response to short

- term O 3 exposure compared to 

### 2 h ealthy individuals in Atlanta, GA. The authors reported that short

- term O 3 exposure was 

### 3 associated with higher odds of an ED visit for peripheral and cerebrovascular disease 

### 4 among individuals with COPD compared to individuals without COPD. However, 

### 5 preexis ting COPD did not increase the odds of hospitalization for all CVD outcomes (i.e. 

### 6 IHD, dysrhythmia, or congestive heart failure). In an additional study performed in 

### 7 Taiwan, both individuals with and without COPD had higher odds of congestive heart 

### 8 failure associated with O 3 exposure on warm days ( Lee e t al., 2008a ) . An additional 

### 9 study also found no association between O 3 exposure and lung function regardless of 

### 10 whether the study participant had COPD or other health issues (asthma or IHD) ( Lagorio 

### 11 et al., 2006 )

. 

### 12
Recent epidemiologic evidence indicates that persons with CO PD may have increased 

### 13 O 3 - related cardiovascular effects, but little information is available for other O 3 - related 

### 14 health effects among individuals with COPD. 

### 15

8.1.4 Cardiovascular Disease

Cardiovascular disease (CVD) has become increasingly prevalent in the U.S. , with about 

### 16 12% of adults reporting a diagnosis of heart disease ( Table 8

- 1 ). A high prevalence of 

### 17 other cardiovascular

- related conditions has also b een observed, such as hypertension 

### 18 which is prevalent among approximately 24% of adults. In the 2006 O 3 AQCD, little 

### 19 evidence was available regarding preexisting CVD as a susceptibility factor. Recent 

### 20 epidemiologic studies have examined cardiovascular

- rela ted diseases as modifiers of the 

### 21 O 3 - outcome associations; however, no recent evidence is available from controlled 

### 22 human exposure studies or toxicological studies. 

### 23

Peel et al. ( 2007 ) compared the associations between short

- term O 3 exposure and 

### 24 cardiovascular ED visits in Atlanta, GA among multiple comorbid conditions. The 

### 25 authors found no evidence of increased risk of cardiovascular ED visits in individuals 

### 26 previously diagnos ed with dysrhythmia, congestive heart failure, or hypertension 

### 27 compared to healthy individuals. Similarly, a study in France examined the association 

### 28 between O 3 concentrations and ischemic cerebrovascular events (ICVE) and myocardial 

### 29 infarction (MI) and th e influence of multiple vascular risk factors on any observed 

### 30 associations ( Henrotin et al., 2010 ) . The associa tion between O 3 exposure and ICVE was 

### 31 elevated for individuals with multiple risk factors, specifically individuals with diabetes 

### 32 or hypertension. For the association between O 3 and MI, increased odds were apparent 

### 33 only for those with hypercholesterolaemia. In a study conducted in Taiwan, a positive 

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- 9 September 2011 association was observed for O 3 on warm days and congestive heart failure hospital 

### 1 admissions (HAs), but the association did not dif fer between individuals with/without 

### 2 hypertension or with/without dysrhythmia ( Lee et al., 2008a ) . Another study in Taiwan 

### 3 reported that the association between O 3 levels and ED visits for arrhythmias were 

### 4 greater on warm days among those with congestive heart failure compared to those 

### 5 without congestive heart failure; however, the estimate and 95% CIs for those without 

### 6 congestive heart failure is completely contained within the 95% CI of those with 

### 7 congestive heart failure ( Chiu and Yang, 2009 )

. 

### 8
Although not studied extensively, a study has examined the increased risk of O 3 - related 

### 9 changes in blood markers for individuals with CVD. There was a greater association 

### 10 between O 3 exposure and some, but not all, blood inflammatory markers among 

### 11 ind ividuals with a history of CVD. Liao et al. ( 2005 ) found that fibrinogen was positively 

### 12 associated with short

- term O 3 exposure but this association was present only among 

### 13 individuals with a history of CVD. No association was observed among those without a 

### 14 history of C VD. However, for another biomarker (vWF), CVD status did not modify the 

### 15 positive association with short

- term O 3 exposure ( Liao et al., 2005 )

. 

### 16
Mortality studies provide some evidence for a potential increase in O 3 - induced mortality 

### 17 in individuals with preexisting atrial f ibrillation and atherosclerosis. In a study of 48 U.S. 

### 18 cities, increased risk of mortality with short

- term O 3 exposure was observed only among 

### 19 individuals with secondary atrial fibrillation ( Medina

- Ramón and Schwartz, 2008 ) . No 

### 20 association was observed for short

- term O 3 exposure and mortality in a study of 

### 21 individuals with diabetes with or without CVD prior to death; however, there w as some 

### 22 evidence of increased risk of mortality during the warm season if individuals had diabetes 

### 23 and atherosclerosis compared to only having diabetes ( Goldberg et al., 2006 )

. 

### 24
Finally, although not extensively examined, a study explored whether a preexisting CVD 

### 25 increased the risk of an O 3 - induced respiratory effect. Lagorio et al. ( 2006 ) examined the 

### 26 effect of O 3 exposure on lung function among participants with a variety of preexisting 

### 27 diseases, including IHD. No association was observed regardless o f whether the 

### 28 participant had IHD. 

### 29

Overall, most short

- term exposure studies did not report increased O 3 - related health 

### 30 effects for individuals with preexisting CVD, with the possible exception of O 3 exposure 

### 31 and mortality. Future research among those with CVD compared to those without will 

### 32 increase the understanding of potential increased risk of O 3 - related health effects among 

### 33 this group. 

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- 10 September 2011 

### 8.1.5 Diabetes

Recent literature has not extensively examined whether individuals with diabetes (about 

### 1 8% of U.S. adults) a re potentially at increased risk of O 3 - related health effects. In a study 

### 2 of short

- term O 3 exposure and cardiovascular ED visits in Atlanta, GA, no association 

### 3 was observed for individuals with or without diabetes ( Peel et al., 2007 ) . A similar study 

### 4 conducted in Taiwan reported a positive association between O 3 exposure on warm days 

### 5 and HAs for congestive heart failure; however, no modification of the association by 

### 6 diabetes was observed ( Lee et al., 2008a ) . Finally, in a study of O 3 exposure and ED 

### 7 visits for arrhythmia in Taiwan, there was no evidence of effect measure modification by 

### 8 diabetes on warm or cool days ( Chiu and Yang, 2009 )

. 

### 9

8.1.6 Hyperthyroidism

Hyperthyr oidism has been identified in toxicological studies as a potential factor that may 

### 10 lead to increased risk of O 3 - related health effects but has not yet been explored in 

### 11 epidemiologic or controlled human exposure studies. Lung damage and inflammation due 

### 12

to oxidative stress may be modulated by thyroid hormones. Compared to controls, 

### 13 hyperthyroid rats exhibited elevated levels of BAL neutrophils and albumin after a 4

- hour 

### 14 exposure to O 3 , indicating O 3 - induced inflammation and damage. Hyperthyroidism did 

### 15 not af fect production of reactive oxygen or nitrogen species, but BAL phospholipids were 

### 16 increased, indicating greater activation of Type II cells and surfactant protein production 

### 17 compared to normal rats ( Huffman et al., 2006 ) . Thus, this study provides some 

### 18 underlying evidence which suggests that individuals with hyperthyroidism may represent 

### 19

an at

- risk population. 

### 20



## 8.2 Life stage

The 1996 and 2006 O 3 AQCDs identified children, especially those with asthma, and 

### 21 older adults as at

- risk populations. These previous AQCDs reported clinical evidence that 

### 22 children have greater spirometric responses to O 3 than middle

- aged and older a dults 

### 23 ( U.S. EPA, 1996a ) . Similar results were observed for symptomatic responses and O 3 

### 24 exposure. Among older adults, most studies reported in the 2006 O 3 AQCD reported 

### 25 greater effects of short

- term O 3 exposure and mortality compared to other age groups. 

### 26 New evidence, summarized below, further supports these findings. 

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- 11 September 2011 

### 8.2.1 Children

The 2000 Census reported that 28.6% of the U.S. population was under 20 years of age, 

### 1 with 14.1 % under the age of 10 ( SSDAN CensusScope, 2010a ) . Children are considered 

### 2 to be more at risk for O 3 - related health effects compared to adults because they spend 

### 3 more time outside and are more highly active, especially during the summer when O 3 

### 4 concentrations are the highest ( U.S . EPA, 2006b ) . Moreover, children ’ s respiratory 

### 5 systems are undergoing lung growth until about 18

- 20 years of age and are therefore 

### 6 thought to be intrinsically more at risk for O 3 - induced damage ( U.S. EPA, 2006b )

. 

### 7

The 1996 O 3 AQCD, reported clinical evidence that children, adolescents, and young 

### 8 adults (<18 years of age) appear, on average, to have nearly equivalent spirometric 

### 9 responses to O 3 exposure, but have greater responses than middle

- aged and older adults 

### 10 ( U.S. EPA, 1996a ) . Sy cal mptomatic responses (e.g., cough, shortness of breath, pain on 

### 11 deep inspiration) to O 3 exposure, however, appear to increase with age until early 

### 12 adulthood and the n gradually decrease with increasing age ( U.S. EPA, 1996a ) . For 

### 13 subjects aged 18

- 36 years, McDonnell et al. ( 1999 ) reported that symptom responses 

### 14 from O 3 exposure also decrease with increasing age. Complete lung growth and 

### 15 development is not achieved until 18

- 20 years of age in women and the early 20s for 

### 16 men; pulmonary function is at its maximum during this time as well. Additionally, PBPK 

### 17 modeling reported regional extraction of O 3 to be higher in infants compared to adults. 

### 18 This is thought to be due to the smaller nasal and pulmonary regions ’ surface area in 

### 19 children under the age of 5 years compared to the total a irway surface area observed in 

### 20 adults ( Sarangapani et al., 2003 )

. 

### 21
Recent epidemiologic studies have been performed examining different age groups and 

### 22 their susceptibility to O 3 - rel ated respiratory HAs and emergency department (ED) visits. 

### 23 A study in Cyprus of short

- term O 3 concentrations and respiratory HA detected possible 

### 24 effect measure modification by age with a larger association among individuals < 

### 25 15 years of age compared with those > 15 years of age. However, this difference was 

### 26 only apparent with a 2

- day lag ( Middleton et al., 2008 ) . Similarly, a Canadian study of 

### 27 asthma

- ED visits reported the strongest O 3 - related associations among 5

- to 14

- year olds 

### 28 compared to the other age groups (ages examined 0

- 75+) ( Villeneuve et al., 2007 )

. 

### 29 Greater O 3 - associated change in asthma

- related ED visits were also reported among 

### 30 children (<15 years) as compared to adults (15 to 64 years) in a study from Finland 

### 31 ( Halonen et al., 2009 ) . A study of New York City HAs demonstrated an increase in the 

### 32 association between O 3 exposure and asthma

- related HAs for 6

- to 18

- year olds 

### 33 compared to those < 6 years old and those > 18 years old ( Silverman and Ito, 2010 )

. 

### 34 When examining long

- term O 3 exposure and ast hma HA among children, associations 

### 35 were determined to be larger among children 1 to 2 years old compared to children 2 to 6 

### 36Draft

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- 12 September 2011 years old ( Lin et al., 2008b ) . A few studies reported positive associations among both 

### 1 children and adults and no modification of the effect by age. A study performed in Hong 

### 2 Kong examined O 3 exposure and ast hma

- related HAs for ages 0 to14, 15 to 65, and >65 

### 3 ( Ko et al., 2007 ) . The researchers reported that the association was greater among the 0 to 

### 4 14 and 14 to 65 age groups compared to the >65 age group. Another study looking at 

### 5 asthma

- related ED v isits and O 3 exposure in Maine reported positive associations for all 

### 6 age groups (ages 2 to 65) ( Paulu and Smith, 2008 ) . Effe cts of O 3 exposure on asthma 

### 7 hospitalizations among both children and adults (<18 and ≥18 years old) were 

### 8 demonstrated in a study in Washington, but only children (<18 years of age) had 

### 9 statistically significant results at lag day 0, which the authors wrot e, “ suggests that 

### 10 children are more immediately responsive to adverse effects of O 3 exposure ” ( Mar and 

### 11 Koenig, 2009 )

. 

### 12
The evidence observed in epidemiologic studies is supported by recent toxic ological 

### 13 studies which observed O 3 - induced health effects in immature animals. Early life 

### 14 exposures of multiple species of laboratory animals, including infant monkeys, resulted 

### 15 in changes in conducting airways at the cellular, functional, ultra

- structural , and 

### 16 morphological levels. Carey et al. ( 2007 ) conducted a study of O 3 exposure in infant 

### 17 rhesus macaques, whose nasal airways closely resemble that of humans. Monkeys were 

### 18 exposed either acutely for 5 days to 0.5 ppm O 3 , or episodically for 5 biweekly cycles 

### 19 alternating 5 days of 0.5 ppm O 3 with 9 days of filtere d air, designed to mimic human 

### 20 exposure (70 days total). All monkeys acutely exposed to O 3 had moderate to marked 

### 21 necrotizing rhinitis, with focal regions of epithelial exfoliation, numerous infiltrating 

### 22 neutrophils, and some eosinophils. The distribution, character, and severity of lesions in 

### 23 episodically exposed monkeys were similar to that of acutely exposed animals. Neither 

### 24 group exhibited mucous cell metaplasia proximal to the lesions, a protective adaptation 

### 25 observed in adult monkeys exposed continuou sly to 0.3 ppm O 3 in another study 

### 26 ( Harkema et al., 1987a ) . Functional (increased airway resistance and responsiveness with 

### 27 antigen + O 3 co

- exposure) and cellular changes in cond ucting airways (increased 

### 28 numbers of inflammatory eosinophils) also manifested among the infant monkeys 

### 29 ( Plopper et al., 2007 ) . In addition, the lung structure of the conducting airways was 

### 30 signif icantly stunted or altered versus control animals and this aberrant development was 

### 31 persistent 6 months postexposure ( Fanucchi et al., 2006 )

. 

### 32
Similarly, rat fetuses exposed to O 3 in utero had significant ultrastructural changes in 

### 33 bronchiolar epithelium when examined near the end of gestation ( López et al., 2008 ) . In 

### 34 addition, exposure of mice to mixtures of air pollutants early in development affected pup 

### 35 lung cytokine levels (TNF, IL

- 1, KC, IL

- 6, and MCP

- 1) ( Auten et al., 2009 ) . In utero 

### 36 exposure of animals to PM augmented O 3 - induced airw ay hyper

- reactivity in these pups 

### 37 as juveniles. 

### 38Draft

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- 13 September 2011 Age may affect the inflammatory response to O 3 exposure. In comparing neonatal mice 

### 1 to adult mice, increased bronchoalveolar lavage (BAL) neutrophils were observed in four 

### 2 strains of neonates 24 hours after exposure to 0.8 ppm O 3 for 5 hours ( Vancza et al., 

### 3 2009 ) . Three of these strains also exhibit ed increased BAL protein, although the two 

### 4 endpoints were not necessarily consistently correlated in a given strain. In some strains, 

### 5 however, adults were more sensitive, indicating a strain

- age interaction. Toxicological 

### 6 studies reported that the differen ce in effects among younger lifestage may be due to 

### 7
age

- related changes in endogenous antioxidants and sensitivity to oxidative stress. A 

### 8 recent study demonstrated that 0.25 ppm O 3 exposure differentially alters expression of 

### 9 metalloproteinases in the skin of young (8 weeks old) and aged (18 months old) mice, 

### 10 indicating age

- related susceptibility to oxidative stress ( Fortino et al., 2007 ) . Valacchi et 

### 11 al. ( 2007 ) found that aged mice had more vitamin E in their plasma but less in their lun gs 

### 12 compared to young mice, which may affect their pulmonary antioxidant defenses. Servais 

### 13 et al. ( 2005 ) found higher levels of oxidative damage indicators in immature (3 weeks 

### 14 old) and aged (20 months old) rats compared to adult rats, which were relatively resistant 

### 15 to an intermittent 7

- day exposure to 0.5 ppm O 3 . Immature rats exh ibited a higher 

### 16 ventilation rate, which may have increased exposure. Additionally, a series of 

### 17 toxicological studies reported an association between O 3 exposure and bradycardia that 

### 18 was present among young mice but not among older mice ( Hamade et al., 2010 ; 

### 19 Tankersley et al., 2010 ; Hamade and Tankersley, 2009 ; Hamade et al., 2008 ) . Regression 

### 20 analysis revealed a significant interaction between age and strain on heart rate, which 

### 21 implies that aging may affect heart rate differently between mouse strains ( Tankersley et 

### 22 al., 2010 ) . The authors proposed that the genetic differences between the mice strains 

### 23 could be altering the formation of ROS, which tends to increase with age, thus 

### 24 modulating the changes in cardiopulmonary physiology after O 3 exposure. 

### 25
The previous and current human clinical and toxico logical studies reported evidence of 

### 26 increased risk from O 3 exposure for younger ages, which provides coherence and 

### 27 biological plausibility to the epidemiologic studies on children. Recent studies of 

### 28 respiratory HAs and ED visits observed inconsistent find ings for associations among 

### 29 children and young adults, although generally studies reported positive associations 

### 30 among both children and adults or just among children. For other outcomes, there were 

### 31 also inconsistent findings regarding increased risk of O 3 - related health effects. The 

### 32 interpretation of these studies is limited by the lack of consistency in comparison age 

### 33 groups and outcomes examined. 

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- 14 September 2011 

### 8.2.2 Older Adults

Older adults may be at greater risk of health effects associated with O 3 exposure through 

### 1

a va riety of intrinsic pathways. The gradual decline in physiological processes that occur 

### 2 with aging may lead to increased risk of O 3 - related health effects ( U.S. EPA, 2006a )

. 

### 3 Older adults may also differ in amounts of exposure because diminished symptomatic 

### 4 responses may allow the elderly to withstand increased continued O 3 exposure. In 

### 5 addition, older adults, in ge neral, have a higher prevalence of preexisting diseases 

### 6 compared to younger age groups and this may also lead to increased susceptibility to 

### 7 O 3 - related health effects (see Table 8

- 1 that gives preexisting rates by age).With the 

### 8 number of older Americans increasing in upcoming years (estimated to increase from 

### 9 12.4% of the U.S. population to 19.7% between 2000 to 2030, which is approximately 35 

### 10 million and 71.5 million individuals, respectively) this group represents a large 

### 11 population potentially at risk of O 3 - related health effects ( SSDAN CensusScope, 2010a ; 

### 12 U.S. Census Bureau, 2010 )

. 

### 13
Multiple epidemiologic studies of O 3 exposure and HAs were stratified by age groups. A 

### 14 positive association was rep orted between O 3 levels and respiratory HAs for adults ≥65 

### 15 years old but not for those adults aged 15 to 64 years ( Halonen et al., 2009 ) . In the same 

### 16 study, no association was observed between O 3 concentration and respiratory m ortality 

### 17 among those ≥65 years old or those 15 to 64 years old; however, an inverse association 

### 18 between O 3 concentration and cardiovascular mortality was present among individuals ≥ 

### 19 65 years old but not among individuals < 65 years old. This inverse associ ation among 

### 20 those ≥65 years old persisted when examining HAs for coronary heart disease. A study of 

### 21 CVD

- related hospital visits in Bangkok, Thailand reported an increase in percent change 

### 22 for hospital visits with previous day and cumulative 2

- day O 3 levels among those ≥ 

### 23 65 years old, whereas no association was present for individuals less than 65 years of age 

### 24 ( Buadong et al., 2009 ) . No association was observed for current day or cumulative 3

- day 

### 25 averages in any age group. A study examining O 3 and HAs for CVD

- related health 

### 26 effects reported no association for individuals aged 15 to 64 or individuals aged ≥ 65 

### 27 years, although one lag

- time did show an inverse effect for coronary heart disease among 

### 28 elderly that was not present among 15

- to 64

- year olds ( Halonen et al., 2009 ) . No 

### 29 modification by age (40 to 64 y ear olds versus >64 year olds) was observed in a study 

### 30 from Brazil examining O 3 levels and COPD ED visits ( Arbex et al., 2009 )

. 

### 31
The majority of recent studies reported greater effects of short

- term O 3 exposure and 

### 32 mortality among older adults, which is consistent with the findings of the 2006 O 3 

### 33 AQCD. A study conducted in 48 cities across the U.S. reported larger effects among 

### 34 adults ≥65 years old compared to those < 65 years ( Medina

- Ramón and Schwartz , 2008 )

. 

### 35 Further investigation of this study population revealed no association between O 3 

### 36Draft

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- 15 September 2011 exposure and mortality until age 50 and a reduced effect after age 80 ( Zanobetti and 

### 1 Schwartz, 2008a ) . A study of 7 urban centers in Chile reported similar results, with 

### 2 greater effects in adults ≥65 years old, however the effects were smaller among those 

### 3 ≥85 years old compared to those in the 75 to 84 years old age range ( Cakmak et al., 

### 4 2007 ) . More recently, a st udy conducted in the same area reported similar associations 

### 5 between O 3 exposure and mortality in adults aged < 64 years old and 65 to 74 years old, 

### 6 but the risk was increased among older age groups ( Cakmak et al., 2011 ) . A study 

### 7 performed in China reported greater effects in populations ≥45 years old (compared to 5 

### 8 to 44 year olds), with statistically si gnificant effects present only among those ≥65 years 

### 9 old ( Kan et al., 2008 ) . An Italian study reported higher risk of all

- cause mortality 

### 10 associated with increased O 3 concentrations among individuals ≥85 year old as compared 

### 11 to those 35 to 84 years old. Those 65 to 74 and 75 to 84 years old did not show a greater 

### 12 increase in risk compared to those aged 35 to 64 years ( Stafoggia et al., 2010 ) . The Air 

### 13 Pollution and Health: A European and North American Appr oach (APHENA) project 

### 14 examined the association between O 3 exposure and mortality for those <75 and ≥ 

### 15 75 years of age. In Canada, the associations for all

- cause and cardiovascular mortality 

### 16 were greater among those ≥75 years old in the summer

- only and all

- y ear analyses. Age 

### 17 groups were not compared in the analysis for respiratory mortality in Canada. In the U.S., 

### 18 the association for all

- cause mortality was slightly greater for those <75 years of age 

### 19 compared to those ≥75 years old in summer

- only analyses. No consistent pattern was 

### 20 observed for CVD mortality. In Europe, slightly larger associations for all

- cause 

### 21 mortality were observed in those <75 years old in all

- year and summer

- only analyses. 

### 22 Larger associations were reported among those <75years for CVD mo rtality in all

- year 

### 23 analyses, but the reverse was true for summer

- only analyses ( Katsouyanni et al., 2009 )

. 

### 24
Biological plausibility for increased risk among older adults is provided by clinical and 

### 25 toxicological studies. Respiratory symptom responses to O 3 exposure appears to increase 

### 26 with age until early adulthood and then gradually decrease with increasing age ( U.S. 

### 27 EPA, 1996a ) , which may put them at increased risk by withstanding continued O 3 

### 28 exposure. Regarding cardiac outcomes, biological plausibility is provided by a 

### 29 toxicological study. O 3 exposure resulted in an increase in left ventricular chamber 

### 30 dimensions at end diastole (LVEDD) i n young and old mice, whereas decreases in left 

### 31 ventricular posterior wall thickness at end systole (PWTES) were only observed among 

### 32 older mice ( Tankersley et al., 2010 ) . Other toxicological studies also indicate increased 

### 33 susceptibility in older animals for some endpoints. The hippocampus, one of the main 

### 34 regions affected by age

- related neurodegenerative diseases, may be more sensitive to 

### 35 oxidative damage in aged rats. In a study of young (47 days) and aged (900 days) rats 

### 36 exposed to 1 ppm O 3 for 4 hours, O 3 - induced lipid peroxidation occurred to a greater 

### 37 extent in the striatum of young rats, whereas it was highest in the hippocampus in aged 

### 38

rats ( Rivas

- Arancibia et al., 2000 ) . In young mice, healing of skin wounds is not 

### 39Draft

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- 16 September 2011 significantly affected by O 3 exposure ( Lim et al., 2006 ) . However, exposure to 0.5 ppm 

### 1 O 3 for 6 h/day significantly delays wound closure in aged mice. 

### 2
Although some outcomes reported mixed findi ngs regarding an increase in risk for older 

### 3 adults, recent studies of O 3 exposure and mortality reported associations present for older 

### 4 adults. This is consistent with the results reported in the 2006 O 3 AQCD. 

### 5



## 8.3 Sex

The distribution of males and females in t he U.S. is similar. In 2000, 49.1% of the U.S. 

### 6 population was male and 50.9% were female. The distribution did vary by age with a 

### 7 greater prevalence of females ≥65 years old compared to males ( SSDAN CensusScope, 

### 8 2010a ) . The 2006 O 3 AQCD did not report evidence of differences between the sexes i n 

### 9 health responses to O 3 exposure. Recent epidemiologic studies have evaluated the effects 

### 10 of short

- term and long

- term exposure to O 3 on multiple health endpoints stratified by sex 

### 11 and overall, the results are inconsistent. 

### 12
A study in Maine that examined short

- term O 3 concentrations and asthma ED visits 

### 13 detected greater effects among males ages 2 to14 years and among females ages 15 to 34 

### 14 years compared to males and females in the same age groups (no difference was detected 

### 15 for males and females aged 35 to 64) ( Paulu and Smith, 2008 ) . A Canadian study 

### 16 reported no associations between short

- term O 3 and respiratory infection HAs f or either 

### 17 boys or girls under the age of 15 ( Lin et al., 2005 ) , whereas another Canadian study 

### 18 reported a slightly higher but non

- statistically significant increase in respiratory HA for 

### 19 males (mean ages 47.6 to 69.0 years) ( Cakmak et al., 2006b ) . A recent study from Hong 

### 20 Kong examini ng individuals of all ages reported no effect measure modification by sex 

### 21 for overall respiratory disease HAs, but did detect a greater excess risk of HAs for COPD 

### 22 among females compared to males ( Wong et al., 2009 ) . Similarly a study in Brazil found 

### 23 higher effect estimates for COPD ED visits among females compared to males ( Arbex et 

### 24 al., 2009 ) . Higher levels of respiratory HA with greater O 3 concentrations was also 

### 25 observed for fem ales in a study of individuals living in Cyprus ( Middleton et al., 2008 )

. 

### 26 A study of lung function unr elated to HA and ED visits was conducted among lifeguards 

### 27 in Texas and reported decreased lung function with increased O 3 exposure among 

### 28 females but not males ( Thaller et al., 2008 ) . This study included individuals aged 16 to 27 

### 29 years, and the majority of participants were male. A New York study found no effect 

### 30 measure modification of the association between long

- term O 3 exposure and asthma HA 

### 31

am ong males and females between 1 and 6 years old ( Lin et al., 2008b )

. 

### 32

In addit ion to examining the potential modification of O 3 associations with respiratory 

### 33 outcomes by sex, studies also examined cardiovascular

- related outcomes specifically 

### 34Draft

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- 17 September 2011 HAs and ED visits. All of these studies reported no effect modification by sex with some 

### 1

stu dies reporting null associations for both males and females ( Wong et al., 2009 ; 

### 2 Middleton et al., 2008 ; Villeneuve et al., 2006a ) and one study reporting a positive 

### 3 associations for both sexes ( Cakmak et al., 2006a ) . A French study examining the 

### 4 associations between O 3 concentrations and risk of ischemic strokes (not limited to ED 

### 5 visits or HAs) reported no association for either males or females with lags of 0, 2, or 

### 6 3 days ( Henrotin et al., 2007 ) . A positive association was reported for males with a lag of 

### 7 1 day, but this association was null for females. The authors noted that men in the study 

### 8 had much higher rates of current and former smokin g than women (67.4% versus 9.3%). 

### 9
A biomarker study investigating the effects of O 3 concentrations on high

- sensitivity 

### 10 C

- reactive protein (hs

- CRP), fibrinogen, and white blood cell (WBC) count, reported 

### 11 observations for various lag times ranging from 0 to 7 days ( Steinvil et al., 2008 ) . Most 

### 12 of the associations were null for males and females although one association between O 3 

### 13 and fibrinogen was positive for males and null for females (lag day 4); however, this 

### 14 positive association was null or negative when other pollu tants were included in the 

### 15 model. Only one study examining correlations between O 3 levels and oxidative DNA 

### 16 damage examined results stratified by sex. In this study Palli et al. ( 2009 ) reported 

### 17 stronger correlations for males than females, both during short

- term exposure (less than 

### 18 30 days) and long

- term exposure (0

- 90 days). However, the authors commented that this 

### 19 difference could have been partially explained by different distribu tions of exposure to 

### 20 traffic pollution at work. 

### 21

A few studies have examined the association between short

- term O 3 concentrations and 

### 22 mortality stratified by sex and in contrast with studies of other endpoints, were more 

### 23 consistent in reporting elevated ris ks among females. These studies, conducted in the 

### 24 U.S. ( Medina

- Ramón and Schwartz, 2008 ) , Italy ( Stafoggia et al., 2010 ) , and Asia ( Kan 

### 25 et al., 2008 ) , reported larger effect estimates in females compared to males. In the U.S. 

### 26 study, the elevated risk of mortality among females was greater specifically among those 

### 27 ≥60 years old ( Medina

- Ramón and Schwartz, 2008 ) . However, a recent study in Chile 

### 28 reported similar associations between O 3 exposure and mortality amo ng both men and 

### 29

women ( Cakmak et al., 2011 ) . One long

- term O 3 exposure study of r espiratory mortality 

### 30 stratified their results by sex and reported relative risks of 1.01 (95 % CI: 0.99, 1.04) for 

### 31 males and 1.04 (95% CIs 1.03, 1.07) for females ( Jerrett et al., 2009 )

. 

### 32
Experimental research provided a further understanding of the under lying mechanisms 

### 33 that may explain a possible differential risk in O 3 - related health effects among males and 

### 34 females. Several studies have suggested that physiological differences between sexes 

### 35 may predispose females to a greater susceptibility to O 3 . In fe males, lower plasma and 

### 36 nasal lavage fluid (NLF) levels of uric acid (most prevalent antioxidant), the initial 

### 37Draft

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- 18 September 2011 defense mechanism of O 3 neutralization, may be a contributing factor ( Housley et al., 

### 1 1996 ) . Consequently, reduced absorption of O 3 in the upper airways of females may 

### 2 promote its deeper penetratio n. Dosimetric measurements have shown that the absorption 

### 3 distribution of O 3 is independent of sex when absorption is normalized to anatomical 

### 4 dead space ( Bush et al., 1996 ) . Thus, a differential removal of O 3 by ur ic acid seems to 

### 5 be minimal. In general, the physiologic response of young healthy females to O 3 

### 6 exposure appears comparable to the response of young males ( Hazucha et al., 2003 ) . A 

### 7 few studies have examined changes in O 3 responses during various menstrual cycle 

### 8 phases. Lung functi on response to O 3 was enhanced during the follicular phase of the 

### 9 menstrual cycle compared to the luteal phase in a small study of women ( Fox et al., 

### 10 1993 ) . However, Seal et al. ( 1996 ) later reported no effect of menstrual cycle phase in 

### 11 their analysis of responses from 150 women, but conceded that the methods used by Fox 

### 12 et al. ( 1993 ) more precisely defined the menstrual cycl e phase. Another study also 

### 13 reported no difference in responses among females during the follicular and luteal phases 

### 14 of their cycle ( Weinmann et al., 1995a ) . Additionally, in this study the responses in 

### 15 women were comparable to those reported for men in the study. In a toxicological study, 

### 16 small differences in effects by sex were seen in adult mice with respect to pulmonary 

### 17 inflammation and injury after a 5

- h exposure to 0.8 ppm O 3 , and although adult females 

### 18 were generally more susceptible, these differences were strain

- dependent, with some 

### 19 strains exhibiting greater s usceptibility in males ( Vancza et al., 2009 ) . The most obvious 

### 20 sex difference was apparent in lactating females, which incurred the greatest lung injury 

### 21 or inflammation among several of the strains. 

### 22

Overall, results have varied, with recent evidence for increased risk for O 3 - related health 

### 23 effects present for females in some studies and males in o ther studies. Most studies 

### 24 examining the associations O 3 and mortality report females to be at greater risk than 

### 25 males. Little evidence is available regarding a difference between the sexes for other 

### 26 outcomes. Inconsistent findings were reported on whether effect measure modification 

### 27 exists by sex for respiratory and cardiovascular HAs and ED visits. 

### 28



## 8.4 Genetics

Multiple studies that examined the effect of short

- and long

- term O 3 exposure on 

### 29 respiratory function have focused on whether various gene profiles m odify the effect of 

### 30 O 3 on various health effects. A study of wheeze in infants reported larger associations 

### 31 between short

- term O 3 exposure and wheeze and difficulty breathing in infants whose 

### 32 mothers have asthma compared to infants of mothers without asthm a, illustrating the 

### 33 potential for genetics to play a role in O 3 - related health effects ( Triche et al., 2006 )

. 

### 34Draft

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- 19 September 2011 Multiple genes, including glutathione S

- transferase Mu 1 (GSTM1) and tumor ne crosis 

### 1 factor

- α (TNF

- α) were evaluated in the 2006 O 3 AQCD and found to have a “ potential 

### 2 role... in the innate susceptibility to O 3 . ” Studies performed since the 2006 O 3 AQCD 

### 3 have continued to examine the roles of GSTM1 and TNF

- α on O 3 - related health effect s 

### 4 and have also examined other gene variants that may increase the risk of O 3 - related 

### 5 health effects. Due to small sample sizes, many controlled human exposure studies are 

### 6 limited in their ability to test genes with low frequency and therefore, some genes 

### 7 important for O 3 - related health effects may not have been examined. 

### 8
Epidemiologic studies that examined the effects of short

- term exposure to O 3 on lung 

### 9 function included analyses of potential gene

- environment interactions. Romieu et al. 

### 10 ( 2006 ) reported an association between O 3 and respiratory symptoms that were larger 

### 11 among children with GSTM1 null or glutathione S

- transferase P 1 (GSTP1) Val/Val 

### 12 genotypes. However, results suggeste d that O 3 - associated decreases in lung function may 

### 13 be greater among children with GSTP1 Ile/Ile or Ile/Val compared to GSTP1 Val/Val. 

### 14 Alexeef et al. ( 200 8 ) reported greater decreases in lung function among GSTP1 Val/Val 

### 15 adults than those with other genotypes. In addition, they detected greater decreases in 

### 16 lung function for adults with long GT dinucleotide repeats in heme

- oxygenase

- 1 

### 17 (HMOX1) promoters. 

### 18
Several controlled human exposure studies have reported that genetic polymorphism of 

### 19 antioxidant enzymes may modulate pulmonary function and inflammatory response to O 3 

### 20 challenge. It appears that healthy carriers of NAD(P)H quinone oxidoreductase 1 (NQO1) 

### 21 wild type (wt) in combination with GSTM1 null genotype had greater decreases in lung 

### 22 function parameters with exposure to O 3 ( Bergamaschi et al., 2001 )

. Adults with GSTM1 

### 23 null only genotype did not show the same response to O 3 . In contra st, asthmatic children 

### 24 with GSTM1 null genotype ( Romieu et al., 2004a ) were reported to have greater 

### 25 decreases in lung function in relation to O 3 exposure. In a similar study, Vagaggini et al. 

### 26 ( 2010 ) exposed mild

- to

- moderate asthmatics to O 3 during moderate exercise. In subjects 

### 27 with NQO1 wt and GSTM1 null, there was no evidence of changes in lung function or 

### 28 inflammatory responses to O 3 . Kim et al. ( 2011 ) also recently conducted a study among 

### 29 young adults, about half of whom were GSTM1

- null and half of whom were 

### 30 GSTM1

- sufficient. They detected no difference in the FE V 1 responses to O 3 exposure by 

### 31 GSTM1 genotype. 

### 32
In a study of healthy volunteers with GSTM1 sufficient (n=19; 24 ± 3) and GSTM1 null 

### 33 (n=16; 25 ± 5) genotypes exposed to 400 ppb O 3 for 2 hours with exercise, Alexis et al. 

### 34 ( 2009 ) found genotype effects on inflammatory responses bu t not lung function responses 

### 35 to O 3 . At 4 hours post O 3 exposure, individuals with either GSTM1 genotype had 

### 36 significant increases in sputum neutrophils with a tendency for a greater increase in 

### 37Draft

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- 20 September 2011 GSTM1 sufficient than GSTM1 nulls. At 24 hours postexposure, neutrophils had 

### 1 returned to baseline levels in the GSTM1 sufficient individuals. In the GSTM1 null 

### 2 subjects, neutrophil levels increased from 4 to 24 hours and were significantly greater 

### 3 than both baseline levels and levels at 24 hours in the GSTM1 suffici ent individuals. In 

### 4 addition, O 3 exposure increased the expression of the surface marker CD14 in airway 

### 5 neutrophils of GSTM1 null subjects compared with GSTM1 sufficient subjects. CD14 

### 6 and TLR4 are co

- receptors for endotoxin, and signaling through this inn ate immune 

### 7 pathway has been shown to be important for a number of biological responses to O 3 

### 8 exposure in toxicological studies ( Garantziotis et al., 2010 ; Hollingsworth et al., 2010 ; 

### 9 Hollingsworth et al., 2004 ; Kleeberger et al., 2000 ) . Alexis et al. ( 2009 ) also 

### 10 demonstrated decreased numbers of airway macrophages at 4 and 24 hours following O 3 

### 11 exposure in GSTM1 sufficient subjects. Airway macrophages in GSTM1 null subjects 

### 12 were greater in number and found to have greater oxidative burst an d phagocytic 

### 13 capability than those of GSTM1 sufficient subjects. Airway macrophages and dendritic 

### 14 cells from GSTM1 null subjects exposed to O 3 expressed higher levels of the surface 

### 15 marker HLA

- DR, again suggesting activation of the innate immune system. Si nce there 

### 16 was no FA control in the Alexis et al. ( 2009 ) study, effects of the exposure other than O 3 

### 17 cannot be ruled out. In general, the findings between these studies are inconsistent and 

### 18 additional, better

- controlled studies are needed to clarify the influence of genetic 

### 19 poly morphisms on O 3 responsiveness in humans. 

### 20
Several epidemiologic studies of long

- term O 3 exposure examined interactions with 

### 21 different gene variants, including GSTP1, HMOX1, and TNF

- α using data from the 

### 22 Children ’ s Health Study. A study among children repor ted a three

- way interaction effect 

### 23 between Ile105 homozygotes of GSTP1, O 3 exposure, and playing more than two team 

### 24 sports, and new onset of asthma ( Islam et al., 2009 ) . Additionally, Islam et al. found that 

### 25

non

- Hispanic white children with less than 23 repeats in the HMOX1 gene had decreased 

### 26 risk of new

- onset asthma ( Islam et al., 2008 ) . ARG1 and ARG2 (encoded by arginases) 

### 27 modification were examined for the association between genotypes and new

- onset 

### 28 asthma ( Salam et al., 2009 ) . Reduced asthma risk was observed among atopic chil dren 

### 29 living in high O 3 concentration areas and having the ARG1 haplotypes. There was no 

### 30 difference in risk for children with ARG2 haplotypes. A decreased risk of bronchitic 

### 31 symptoms was observed among asthmatic children in low O 3 concentration areas with 

### 32
T NF

- α variant G

- 308A (TNF

- 308GG genotype), a variant that may alter gene expression. 

### 33 There was no decrease in risk for children with this TNF

- α variant and living in areas 

### 34 with high O 3 concentrations. Additionally, this modification for high and low levels of 

### 35 O 3 was not present among non

- asthmatic children ( Lee et al., 2009b ) . Wenten et al. 

### 36 ( 2009 ) observ ed increased risk of respiratory

- related school absences among children 

### 37 with variants of catalase (CAT) and myeloperoxidase (MPO) genes, especially when the 

### 38 children were living in high O 3 concentration areas. 

### 39Draft

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- 21 September 2011 In general, toxicological studies have reporte d differences in cardiac and respiratory 

### 1 effects after O 3 exposure among different mouse strains, which alludes to differential risk 

### 2 among individuals due to genetic variability ( Tankersley et al., 2010 ; Chuang et al., 2009 ; 

### 3 Hamade and Ta nkersley, 2009 ; Hamade et al., 2008 ) . Thus strains of mice which are 

### 4 prone to or resistant to O 3 - induced effects have been used to systematically identify 

### 5 candidate genes that may increase risk of O 3 - related health effects. Genome wide linkage 

### 6 analyses have identified quantitative trait loci for O 3 - induced lung inflammation and 

### 7 hyperpermeability on chromosome 17 ( Kleeberger et al., 1997 ) and chromosome 4 

### 8 ( Kleeberger et al., 2000 ) , respectively, us ing recombinant inbred strains of mice. More 

### 9 specifically, these studies found that Tnf (protein product is the inflammatory cytokine 

### 10 TNF

- α) and Tlr4 (protein product is TLR4, involved in endotoxin responses) were 

### 11 candidate susceptibility genes ( Kleeberger et al., 2000 ; Kleeber ger et al., 1997 ) . The TNF 

### 12 receptors 1 and 2 have also been found to play a role in injury, inflammation, and airway 

### 13 hyperreactivity in studies of O 3 - exposed knockout mice ( Cho et al., 2001 ) . In addition to 

### 14 Tlr4, other innate immune pattern recognit ion signaling pathway genes, including Tlr2 

### 15 and Myd88, appear to be important in responses to O 3 , as demonstrated by Williams et 

### 16 al. ( 2007b ) . A role for the inflammatory cytokine I L

- 6 has been demonstrated in 

### 17
gene

- deficient mice with respect to inflammation and injury, but not AHR ( Johnston et 

### 18 al., 2005b ; Yu et al., 2002 ) . Mice deficient in IL

- 10, an anti

- inflammatory cytokine, 

### 19 demonstrated increased pulmonary inflammation in response to O 3 exposure ( Backus et 

### 20 al., 2010 ) . Thus genes r elated to innate immune signaling and pro

- and anti

- inflammatory 

### 21 genes are important for O 3 - induced responses. 

### 22

Altered O 3 responses between mouse strains could be due to genetic variability in 

### 23 nuclear factor erythroid 2

- related factor 2 (Nrf

- 2), suggesting a role for genetic 

### 24 differences in altering the formation of ROS ( Hamade et al., 2010 ; Cho and Kleeberger, 

### 25 2007 ) . Additionally, some studies have reporte d O 3 - related effects to vary by Inf

- 1 and 

### 26 Inf

- 2 quantitative trait loci ( Tankersley and Kleeberger, 1994 ) and a gene coding for 

### 27 Clara cell secretory protein (CCSP) ( Broeckaert et al., 2003 ; Wattiez et al., 2003 )

. Other 

### 28 investigations in inbred mouse strains found that differences in expression of certain 

### 29 proteins, such as CCSP ( Broeckaert et al., 2003 ) and MARCO ( Dahl et al., 2007 ) , are 

### 30 responsible for phenotypic characteristics, such as epithelial permeability and scavenging 

### 31 of oxidized lipids, respectively, which confer sensitivity to O 3 . 

### 32
Nitric oxide (NO), derived from activated macrophages, is produced upon exposure to O 3 

### 33 and is thought to participate in lung damage. Mice deficient in the gene for inducible 

### 34 nitric oxide synthase (NOS2/NOSII/iNOS) are partially protected against lung injury 

### 35 ( Kleeberger et al., 2001 ) , and it appears that O 3 - induced iNOS expression is tied to the 

### 36 TLR4 pathway described above. Similarly, iNOS deficient mice do not produce reactive 

### 37 nitrogen intermediates after O 3 exposu re, in contrast to their wild

- type counterparts, and 

### 38Draft

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- 22 September 2011 also produce less PGE2 comparatively ( Fakhrzadeh et al., 2002 ) . These gene

- deficient 

### 1 mice were protected from O 3 - induced lung injury and inflammation. In contrast, another 

### 2 study using a similar exposure concentration but longer duration of exposure found that 

### 3 iNOS deficient mice were more susceptible to O 3 - i nduced lung damage ( Kenyon et al., 

### 4 2002 ) . Therefore it is unclear whether inducible nitric oxide synthase plays a protective 

### 5 role or mediates damage. 

### 6
Voynow et al. ( 2009 ) have shown that NQO1 deficient mice, like their human 

### 7 counterparts, are resistant to O 3 - induced AHR and inflammation. NQO1 ca talyzes the 

### 8 reduction of quinones to hydroquinones, and is capable of both protective detoxification 

### 9 reactions and redox cycling reactions resulting in the generation of reactive oxygen 

### 10 species. Reduced production of inflammatory mediators and cells and bl unted AHR were 

### 11 observed in NQO1 null mice after exposure to 1 ppm O 3 for 3 hours. These results 

### 12 correlated with those from in vitro experiments in which human bronchial epithelial cells 

### 13 treated with an NQO1 inhibitor exhibited reduced inflammatory response s to exposure to 

### 14 0.4 ppm O 3 for 5 hours. This study may provide biological plausibility for the increased 

### 15 biomarkers of oxidative stress and increased pulmonary function decrements observed in 

### 16 O 3 - exposed individuals bearing both the wild

- type NQO1 gene and the null GSTM1 gene 

### 17 ( Corradi et al., 2002 ; Bergamaschi et al., 2001 )

. 

### 18

The role of TNF

- α signaling in O 3 - induc ed responses has been previously established 

### 19 through depletion experiments, but a more recent toxicological study investigated the 

### 20 effects of combined O 3 and PM exposure in transgenic TNF overexpressing mice. 

### 21 Kumarathasan et al. ( 2005 ) found that subtle effects of these pol lutants were difficult to 

### 22 identify in the midst of the severe pathological changes caused by constitutive TNF

- α 

### 23 overexpression. However, there was evidence that TNF transgenic mice were more 

### 24 susceptible to O 3 /PM

- induced oxidative stress, and they exhibited elevation of a serum 

### 25 creatine kinase after pollutant exposure, which may suggest potential systemic or cardiac 

### 26 related effects. Differential susceptibility to O 3 among inbred strains of animals does not 

### 27 seem to be dose dependent since absorption of 18 O in various strains of mice did not 

### 28 correlate with resistance or sensitivity ( Vancza et al., 2009 )

. 

### 29
Defects in DNA repair mechanisms may also confer increased risk of O 3 - related health 

### 30 effects. Cockayne syndrome, a rare autosomal recessive disorder in humans, is 

### 31 characterized by UV sensitivity abnormalities, neurological abnormalities, and premature 

### 32 aging. The same genetic defect in mice (Csb - /

- ) makes them sensitive to oxidative 

### 33 stressors, including O 3 . Kooter et al. ( 2007 ) demonstrated that Csb - /

- mice produced 

### 34 significantl y more TNF

- α after exposure to 0.8 ppm O 3 than their wild

- type counterparts. 

### 35 However, there were no significant differences in other markers of inflammation or lung 

### 36Draft

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- 23 September 2011 injury between the two strains of mice. Further discussion of candidate genes in the 

### 1

contex t of their respective signaling pathways can be found in Chapter 5. 

### 2
Overall, multiple genes, such as GSTM1, GSTP1, HMOX

- 1, NQO1, and TNF

- α, appear 

### 3 to potentially be involved in populations being more at

- risk than others to the effects of 

### 4 O 3 exposure on hea lth. Future studies of these and other genes in human populations will 

### 5 be important for determining the role of each genotype and its effect on risk. For NQO1 

### 6 and TNF

- α, biological plausibility is provided by toxicological studies. Additionally, 

### 7 studies of rodents have identified a number of other genes that may affect O 3 - related 

### 8 health outcomes, but testing of these genes has not been performed in humans due to 

### 9 power limitations. 

### 10



## 8.5 Diet

Diet was not examined as a factor affecting risk in previous O 3 AQCDs, but recent 

### 11 studies have examined modification of the association between O 3 and health effects by 

### 12 dietary factors. Because O 3 mediates some of its toxic effects through oxidative stress, 

### 13 the antioxidant status of an individual is an important factor that m ay contribute to 

### 14 increased risk of O 3 - related health effects. Supplementation with vitamin E has been 

### 15 investigated in a number of studies as a means of inhibiting O 3 - mediated damage. 

### 16
Epidemiologic studies have examined effect measure modification by diet and found 

### 17 evidence that certain dietary components are related to the effect O 3 has on respiratory 

### 18 outcomes. The most recent study examined fruit/vegetable intake and Mediterranean diet 

### 19 ( Romieu et al., 2009 ) . Increases in these food patterns, which have been noted for their 

### 20 high vitamins C and E and omega

- 3 fatty acid content, protected against O 3 - related 

### 21 decreases in lung f unction among children living in Mexico City. Another study 

### 22 examined supplementation of the diets of asthmatic children in Mexico with vitamins C 

### 23 and E ( Sienra

- Monge et al., 2004 ) . Associations were detected between short

- term O 3 

### 24 exposure and nasal airway inflammation among children in the placebo group but not in 

### 25 those receiving the supplementation. The authors concluded that “ vitamin C and E 

### 26 supplementation above the minimum dietary requirement in asthmatic children with a 

### 27 low intake of vitamin E might provide some p rotection against the nasal acute 

### 28 inflammatory response to ozone. ” 

### 29
The epidemiologic evidence is supported by controlled human exposure studies, which 

### 30 have shown that the first line of defense against oxidative stress is antioxidants

- rich 

### 31 extracellular li ning fluid (ELF) which scavenge free radicals and limit lipid peroxidation. 

### 32 Exposure to O 3 depletes the antioxidant level in nasal ELF probably due to scrubbing of 

### 33 O 3 ( Mudway et al., 1999a ) ; however, the concentration and the activity of antioxidant 

### 34Draft

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- 24 September 2011 enzymes either in ELF or plasma do not appear to be related to O 3 responsiveness ( Samet 

### 1 et al., 2001 ; Avissar et al., 2000 ; Blomberg et al., 1999 ) . Carefully controlled studies of 

### 2 dietary antioxidant supplementation have demonstrated some protective effects of 

### 3

α

- tocopherol (a form of vitamin E) and ascorbate (vitamin C) on spirometric measures of 

### 4 lung function after O 3 exposure but not on the intensity of subjective symptoms and 

### 5 inflammatory response including cell recruitment, activation and a release of mediators 

### 6 ( Samet et al., 2001 ; Trenga et al., 2001 ) . Dietary antioxidants have also afforded partial 

### 7 protection to asthmatics by attenuating postexposure bronchial hyper responsiveness 

### 8 ( Trenga et al., 2001 )

. 

### 9
Toxicological studies provide evidence of biological plausibility to the epidemiologic and 

### 10 controlled human exposure studies. Wagner et al. ( 2009 ; 2007 ) have shown reductions in 

### 11 O 3 - exacerbated nasal allergy responses in rats with γ

- tocopherol treatment ( a form of 

### 12 vitamin E). O 3 - induced inflammation and mucus production were also inhibited by 

### 13
γ

- tocopherol. Inconsistent results were observed in toxicological studies of vitamin C 

### 14 deficiency and O 3 - induced responses. Guinea pigs deficient in vitamin C display ed only 

### 15 minimal injury and inflammation after exposure to O 3 ( Kodavanti et al., 1995 ) . A recent 

### 16 study in mice demonstrated a protective effect of β

- carotene in the skin, where it limited 

### 17 the production of proinflammatory markers and indicators of oxidative stress induced by 

### 18 O 3 exp osure ( Valacchi et al., 2009 ) . Defic iency of vitamin A, which has a role in 

### 19 regulating the maintenance and repair of the epithelial layer, particularly in the lung, 

### 20 appears to enhance the risk of O 3 - induced lung injury ( Paquette et al., 1996 )

. 

### 21 Differentially susceptible strains that were fed a vitamin A suffic ient diet were observed 

### 22 to have different tissue concentrations of the vitamin, potentially contributing to their 

### 23 respective differences in O 3 - related outcomes. In addition to the studies of antioxidants, 

### 24 one toxicological study examined protein deficiency . Protein deficiency alters the levels 

### 25 of enzymes and chemicals in the brain involved with redox status; exposure to 0.75 ppm 

### 26 O 3 has been shown to differentially affect Na + /K + ATPase, glutathione, and lipid 

### 27 peroxidation, depending on the nutritional status of the animal, but the significance of 

### 28 these changes is unclear ( Calderon Guzman et al., 2006 ) . There may be a protective 

### 29 effect of overall dietary restriction with respect to lung injury, possibly related to 

### 30 increased vitamin C in the lung surface fluid ( Kari et al., 1997 )

. 

### 31
Epidemiologic studies find that individuals with diets deficient in vitamins E and C are at 

### 32 risk for O 3 - related health effects. This is supported by controlled human exposure and 

### 33 toxicological studies. 

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- 25 September 2011 

## 8.6 Body Mass Index and Physical Conditioning

Obesity, defined as a BMI of 30 kg/m 2 or greater, is an issue of increasing importance in 

### 1 the U.S., with self

- reported rates of 26.7% in 2009, up from 19.8% in 2000 ( S herry et al., 

### 2 2010 ) . A few studies have been performed examining the association between BMI and 

### 3 O 3 - related changes in lung function. An epidemiologic study reported decreased lung 

### 4 function with increased short

- term O 3 exposure for both obese and non

- ob ese subjects; 

### 5 however, the magnitude of the reduction in lung function was greater for those subjects 

### 6 who were obese ( Alexeeff et al., 2007 ) . Further decrements in lung function were noted 

### 7 for obese individuals with AHR. Controlled human exposure studies have also detected 

### 8 differential effects of O 3 exposure on lung function for individuals with varying BMIs. In 

### 9

a r etrospective analysis of data from 541 healthy, nonsmoking, white males between the 

### 10 ages of 18

- 35 years from 15 studies conducted at the U.S. EPA Human Studies Facility in 

### 11 Chapel Hill, North Carolina, McDonnell et al. ( 2010 ) found that increased body mass 

### 12 index (BMI) was found to be associated with enhanced FEV 1 responses. The BMI effect 

### 13 was of the same order of magnitude but in the opposite direction of the age effec t 

### 14 whereby FEV 1 responses diminish with increasing age. In a similar analysis, Bennett et 

### 15 al. ( 2007 ) found enhanced FEV 1 decrements following O 3 exposure with increasing BMI 

### 16 in a group of healthy, nonsmoking, women (BMI range 15.7 to 33.4), but not among 

### 17 healthy, nonsmoking men (BMI range 19.1 to 32.9). In the women, greater O 3 - induced 

### 18 FEV 1 decrements were seen in individuals that were overweight/obese (BMI >25) 

### 19 compared normal weight (BMI from 18.5 to 25), and in normal weight compared to 

### 20 underweight (BMI <18.5). Even disregarding the five unde rweight women, a greater O 3 

### 21 response in the overweight/obese category (BMI >25) was observed compared with the 

### 22 normal weight group (BMI from 18.5 to 24.9). 

### 23
Studies in genetically and dietarily obese mice have shown enhanced pulmonary 

### 24 inflammation and inju ry with acute O 3 exposure, but responses to longer exposures at a 

### 25 lower concentration appear to differ. A recent study found that obese mice are actually 

### 26 resistant to O 3 - induced pulmonary injury and inflammation and reduced lung compliance 

### 27 following exposur e to 0.3 ppm O 3 for 72 hours, regardless of whether obesity was 

### 28 genetic

- or diet

- induced ( Shore et al., 2009 )

. 

### 29
In addition to studies of obesity, physical conditioning affe cts BMI and may also affect 

### 30 the risk of O 3 - related health effects. The 2008 Summary of Health Statistics for U.S. 

### 31 Adults from the C DC reported the prevalence of regular leisure

- time physical activity as 

### 32 slightly above 30% for adults ≥18 years of age in the U.S. ( Pleis et al., 2009 ) . Forty

- nine 

### 33 percent of individuals ≥65 years old reported no leisure

- time physical activity. A study of 

### 34 effect measure modification by exercise habits ten years prior to death observed excess 

### 35 risk of mortality with increasing O 3 concentrations among individuals that never 

### 36Draft

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- 26 September 2011 exercised compared to individuals that exercised at least once a month for both adults 

### 1 ≥30 years of age and adults ≥65 years of age ( Wong et al., 2007 ) . No recent studies 

### 2 examining modification of O 3 - related health effects by current physical activity were 

### 3 identified. 

### 4
Multiple epidemiologic and human clinical studies have reported increased O 3 - related 

### 5 respiratory health effects amon g obese individuals. Future research of the effect 

### 6 modification of the relationship between O 3 and other health

- related outcomes besides 

### 7 respiratory health effects by BMI and studies examining the role of physical conditioning 

### 8 will advance understanding of obesity as a factor potentially increasing an individual ’ s 

### 9 risk. 

### 10



## 8.7 Socioeconomic Status

SES is often represented by personal or neighborhood SES, educational attainment, 

### 11 health insurance status, and other such factors. SES is indicative of such things as access 

### 12 to healthcare, quality of housing, and pollution gradient. Based on the 2000 Census data, 

### 13 12.4% of Americans live in poverty (poverty threshold for family of four was $17,463) 

### 14 ( SSDAN CensusScope, 2010c )

. 

### 15
Multiple epidemiologic studies have reported individuals of low SES to have increased 

### 16 risk for the effects of short

- term O 3 exposure on respi ratory HAs and ED visits. A study 

### 17 performed in Korea examined the association between O 3 concentrations and asthma HA 

### 18 and reported larger effect estimates in areas of moderate and low SES compared with 

### 19 areas of high SES (SES was based on average regional i nsurance rates) ( Lee et al., 2006 )

. 

### 20 A Canadian study reported inverse effects of O 3 on respiratory HA and ED visits 

### 21 regardless of SES, measur ed by average census tract household income ( Burra et al., 

### 22 2009 ) . In addition, a study conducted across 10 cities in Canada found the largest 

### 23 association between O 3 exposure and respiratory HA was among those with an 

### 24 educational level less than grade 9, but no consistent trend in the effect was seen across 

### 25 quartiles of income ( Cakmak et al., 2006b ) . In New York State, larger associations 

### 26 between long

- term O 3 exposure and asthma HA were observed among children of 

### 27 mothers who did not graduate from high school, whose births were covered by 

### 28 Medicaid/self

- paid, or who were liv ing in poor neighborhoods compared to children 

### 29 whose mothers graduated from high school, whose births were covered by other 

### 30 insurance, or who were not living in poor neighborhoods, respectively ( Lin et al., 2008b )

. 

### 31
The examination of the potential effects of SES on O 3 - related cardiovascular health 

### 32 effects is relatively limited. A study conducted in Canada reported the association 

### 33 between short

- term O 3 and ED visits for cardiac disease by quartiles of 

### 34Draft

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- 27 September 2011 neighborhood

- level education and income. No effect measure modification was apparent 

### 1 for either measure of SES ( Cakmak et al., 2006a )

. 

### 2
Several studies were conducted that examined the modification of the relationship 

### 3 between short

- term O 3 concentrations and mortality by SES. A U.S. multicity study 

### 4 reported that communities with a higher proportion of the population unemployed had 

### 5 hi gher mortality effect estimates ( Bell and Dominici, 2008 ) . A study in seven urban 

### 6 centers in Chile repo rted on modification of the association between O 3 exposure and 

### 7 mortality using multiple SES markers ( Ca kmak et al., 2011 ) . Increased risk was observed 

### 8 among the categories of low SES for all measures (personal educational attainment, 

### 9 personal occupation, community income level). Additionally, the APHENA study, which 

### 10 examined the association between O 3 an d mortality by percentage unemployed, reported 

### 11 a higher percent change in mortality with increased percent unemployed but this varied 

### 12 across the regions included in the study (U.S., Canada, Europe) ( Katsouyanni et al., 

### 13 2009 ) . A Chinese study reported that the greatest effects between O 3 concentrations and 

### 14 mortality at lag day 0 were among individuals living in areas of high social deprivation 

### 15 (i.e. low SES), but this association was not consistent across lag days (at other lag times, 

### 16 the middle social deprivation index category had the greatest association) ( Wong et al., 

### 17 2008 ) . However, another study in Asia comparing low to high educational attainment 

### 18 populations reported no evidence of greater mortality effect s (total, CVD, or respiratory) 

### 19 ( Kan et al., 2008 ) . Additionally, a study in Italy reported no difference in risk of mortality 

### 20
among census

- block level derived income levels ( Stafoggia et al., 2010 ) . A stu dy of 

### 21 infant mortality in Mexico reported no association between O 3 concentrations and infant 

### 22 mortality among any of the three levels of SES determined using a socioeconomic index 

### 23 based on residential areas ( Romieu et al., 2004b ) . Another study in Mexico reported a 

### 24 positive association between O 3 levels at lag 0 and respiratory

- related infant mortality in 

### 25 only the low SES group (determined based on education, income, and household 

### 26 conditions across residential areas), but no association was observed in any of the SES 

### 27 groups with other lags ( Carbajal

- Arroyo et al., 2011 )

. 

### 28

Studies of O 3 concentrations and reproductive outcomes have also examined associations 

### 29 by SES levels. A study in California reported greater decreases in birth weight associated 

### 30 with full pregnancy O 3 concentration for those with neighborhood poverty levels of at 

### 31 least 7% compared with those in neighborhoods with less than 7% poverty ( Morello



### 32 Frosch et al., 2010 ) . However, no dose response was apparent and those with 

### 33 neighborhood poverty levels of 7

- 21% had greater decreases observed for the association 

### 34 than those living in areas with poverty rates of at least 22%. An Australian study reported 

### 35 an inverse association between O 3 exposure during days 31

- 60 of gestation and 

### 36 abdominal circumference during gestation ( Hansen et al., 2008 ) . The interaction with 

### 37 SES (area

- le vel measured socioeconomic disadvantage) was examined and although the 

### 38Draft

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- 28 September 2011 inverse association remained statistically significant in only the highest SES quartile, 

### 1 there were large confidence interval overlaps among estimates for each quartile so no 

### 2 difference in the association for the quartiles was apparent. 

### 3
Evidence from a controlled human exposure study that examined O 3 effects on lung 

### 4 function does not provide support for greater O 3 - related health effects in individuals of 

### 5 lower SES. In a follow

- up study ( Seal et al. , 1993 ) on modification by race, Seal et al. 

### 6 ( 1996 ) reported that, of three SES categories, individuals in the middle SES category 

### 7 showed greater concentration

- dependent decline in percent

- pr edicted FEV 1 (4

- 5% at 

### 8 400 ppb O 3 ) than in low and high SES groups. The authors did not have an “ immediately 

### 9 clear ” explanation for this finding and controlled human exposure studies are typically 

### 10 not designed to answer questions about SES. 

### 11

Overall, most studies of individuals have reported that individuals with low SES and 

### 12 those living in neighborhoods with low SES are more at risk for O 3 - related health effects

, 

### 13 resulting in higher odds of respiratory HAs and ED visits. Inconsistent results have been 

### 14 obse rved in the few studies examining effect modification of associations between O 3 

### 15 exposure and mortality and reproductive outcomes. 

### 16



## 8.8 Race/Ethnicity

Based on the 2000 Census, 69.1% of the U.S. population comprises non

- Hispanic whites. 

### 17 Approximately 12.1% of people reported their race/ethnicity as non

- Hispanic black and 

### 18 12.6% reported being Hispanic ( SSDA N CensusScope, 2010b )

. 

### 19

Two studies examined the associations between short

- term O 3 concentrations and 

### 20 mortality and reported higher effect estimates among blacks ( Medina

- Ramón and 

### 21 Schwartz, 2008 ) and among communities with larger proportions of blacks ( Bell and 

### 22 Dominici, 2008 ) . Another study examined long

- term exposure to O 3 concentrations and 

### 23 asthma HAs among children in New York State. These authors reported no statistically 

### 24 significant difference in the odds of asthma HA for bl acks compared to other races but 

### 25 did detect higher odds for Hispanics compared to non

- Hispanics ( Lin et al., 2008b )

. 

### 26
Additionally, recent epidemiologic studies have stratified by race when examining the 

### 27 association between O 3 concentration and birth outcomes. A study conducted in Atlanta, 

### 28 GA reported decreases in birth weight with increased third trimester O 3 concentrations 

### 29 among Hispanics but not among non

- Hispanic whites ( Darrow et al., 2011a ) . An inverse 

### 30 association was also present for n on

- Hispanic blacks but was not statistically significant. 

### 31 A California study reported that the greatest decrease in birth weight associated with full 

### 32 pregnancy O 3 concentration was among non

- Hispanic whites ( Morello

- Frosch et al., 

### 33Draft

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- 29 September 2011 2010 ) . The inverse association was also apparent, although not as strong, for 

### 1

non

- Hispanic blacks. Increased birth weight was associated with higher O 3 exposure 

### 2 among Hispanics and among non

- Hispanic Asians and Pacific Islanders but neither of 

### 3 these results were statistically significant. 

### 4
Similar to the epidemiologic studies, a controlled human exposure study suggested 

### 5 differences in lung function responses by race ( Seal et al., 1993 )

. The independent effects 

### 6 of sex

- race group and O 3 concentration on lung function were positive, but the 

### 7 interaction between sex

- race group and O 3 concentration was not statistically significant. 

### 8 The findings indicated some overall difference between the sex

- race groups that was 

### 9 independent of O 3 concentration (the concentration

- response curves for the four sex

- race 

### 10 groups are parallel). In a multiple comparison procedure on data collapsed across all O 3 

### 11 concentrations for each sex

- race group, both black men a nd black women had larger 

### 12 decrements in FEV 1 than did white men. The authors noted that the O 3 dose per unit of 

### 13 lung tissue would be greater in blacks and females than whites and males, respectively. 

### 14 That this difference in tissue dose might have affected responses to O 3 cannot be ruled 

### 15 out. The college students recruited for the Seal et al. ( 1993 ) study were probably from 

### 16 better educated and more SES advantaged families, thus reducing potential for these 

### 17 variables to be confounding factors. Que et al. also examined pulmonary responses to O 3 

### 18 exposure in blacks of African American ancestry and in whites. On average, the bl ack 

### 19 males experienced the greatest decrements in FEV 1 following O 3 exposure. This 

### 20 decrease was larger than the decrement observed among black females, white males, and 

### 21 white females. 

### 22
Overall, the results of recent studies suggest that there may be race

- re lated increase in 

### 23 risk of O 3 - related health effects for some outcomes, although the overall understanding of 

### 24 potential effect measure modification by race is limited by the small number of studies. 

### 25 Additionally, these results may be confounded by other fac tors, such as SES. 

### 26



## 8.9 Smoking

Previous O 3 AQCDs have concluded that smoking does not increase the risk of 

### 27 O 3 - related health effects; in fact, in controlled human exposure studies, smokers have 

### 28 been found to be at less risk of O 3 - related health effects than n on

- smokers. Data from 

### 29 recent interviews conducted as part of the 2008 National Health Interview Survey (NHIS) 

### 30 ( Pleis et al., 2009 ) have shown the rate of smoking among adults ≥18 years old to be 

### 31 approximately 20% in the U.S. Approximately 21% of individuals surveyed were 

### 32 identified as former smokers. 

### 33Draft

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- 30 September 2011 Bac carelli et al. ( 2007 ) performed a study of O 3 concentrations and plasma homocysteine 

### 1 levels (a risk facto r for vascular disease). They found no interaction of smoking (smokers 

### 2

versus non

- smokers) for the associations between O 3 concentrations and plasma 

### 3 homocysteine levels. Another study examined the association between O 3 and resting 

### 4 heart rate and also repo rted no interaction with smoking status (current smokers versus 

### 5

current non

- smokers) ( Ruidavets et al., 2005a )

. 

### 6
A study examining correlations between O 3 levels and oxidative DNA damage examined 

### 7 results stratified by current versus never and former smokers ( Palli et al., 2009 ) . Ozone 

### 8

was positively associated with DNA damage for short

- term and long

- term exposures 

### 9 among never/former smokers. For current smokers, short

- term O 3 concentrations were 

### 10 inversely associated with DNA damage; however, the number of current smokers in the 

### 11 study was sm all (n=12). 

### 12
The findings of Palli et al. ( 2009 ) were consistent with those from controlled human 

### 13 exposure studies that have confirmed that smokers are less responsive to O 3 exposur e 

### 14 than non

- smokers. Spirometric and plethysmographic pulmonary function decline, 

### 15 nonspecific AHR, and inflammatory responses of smokers to O 3 exposure were all 

### 16 weaker than those reported for non

- smokers. Similarly, the time course of development 

### 17 and recove ry from these effects, as well as their reproducibility, was not different from 

### 18

non

- smokers. Chronic airway inflammation with desensitization of bronchial nerve 

### 19 endings and an increased production of mucus may plausibly explain the 

### 20 pseudo

- protective effect of smoking ( Frampton et al., 1997b ; Torres et al., 1997 )

. 

### 21
These findings for smoking are consistent with previous AQCD conclusions. An 

### 22 epidemiologic study of O 3 - associated DNA damage reported smokers to be less at risk 

### 23 for O 3 - related health effects. However, both epidemiologic studies of short

- term 

### 24 exposure and CVD outcomes found no effect measure modification by smoking. 

### 25



## 8.10 Heightened Exposure

Studies included in the 2006 O 3 AQCD reported that individuals who partic ipate in 

### 26 outdoor activities or work to be a population at increased risk based on consistently 

### 27 reported associations between O 3 exposure and respiratory health outcomes in these 

### 28
groups ( U.S. EPA, 2006b ) . Outdoor workers are exposed to am bient O 3 concentrations 

### 29 outside for a greater period of time than individuals who spend their days indoors. 

### 30 Additionally, an increase in dose to the lower airways is possible during exercise due to 

### 31 both increases in the amount of air breathed (i.e., minute ventilation) and a shift from 

### 32 nasal to oronasal breathing ( Sawyer et al., 2007 ; Nodelman and Ultman, 1999 ; Hu et al., 

### 33 1994 ) . For further discussion of the association between FEV 1 responses to O 3 exposure 

### 34Draft

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- 31 September 2011 and minute ventilation, refer to Section 6.2.3.1 of the 2006 O 3 AQCD. A recent study has 

### 1 explored the potential effect measure modification of O 3 exposure and DNA damage by 

### 2 indoor/outdoor workplace ( Tovalin et al., 2006 ) . In a study of indoor and outdoor 

### 3 workers in Mexico, individuals who worked outdoors in Mexico City had a slight 

### 4 association between O 3 exposure and DNA damage (measured by comet tail length 

### 5 assay), whereas no association was observed for indoor workers in Mexico City. Workers 

### 6 in another Mexican city, Puebla, demonstrated no association between O 3 levels and 

### 7 DNA damage, regardless of whether they worked indoors or outdoors. 

### 8
Air conditioning use is an important component of O 3 exposure, as use of central air 

### 9 conditioning will limit exposure to O 3 by blocking the penetration of O 3 into the indoor 

### 10 environment (further information can be found in Secti on 4.4 of this ISA). Air 

### 11 conditioning use is a difficult effect measure modifier to examine in epidemiologic 

### 12 studies. Air conditioning use is often measured based on regional prevalence and may not 

### 13 reflect individual

- level use. More generally, air conditio ning prevalence is associated 

### 14 with temperature of a region; those areas with higher temperatures have a greater 

### 15 prevalence of households with air conditioning. Despite these limitations, a few studies 

### 16 have examined effect measure modification by prevalence of air conditioning use in an 

### 17 area. Studies examining multiple cities across the U.S. have assessed whether 

### 18 associations between O 3 concentrations and HA and mortality varied among areas with 

### 19 high and low prevalence of air conditioning. Medina

- Ramon et al

. ( 2006 ) conducted a 

### 20 study during the warm season and observed a greater ass ociation between O 3 levels and 

### 21 pneumonia HA among areas with a lower proportion of households having central air 

### 22 conditioning compared to areas with a larger proportion of households with air 

### 23 conditioning. The same trend of increased association for areas with a lower prevalence 

### 24 of central air conditioning was noted in a study of O 3 concentrations and mortality ( Bell 

### 25 and Dominici, 2008 ) . Conversely, Medina

- Ramón and Schwartz ( 2008 ) found that 

### 26 among individuals with atrial fibrillation, a lower r isk of mortality was observed for areas 

### 27 with a lower prevalence of central air conditioning. 

### 28

Previous work has shown that increased dose of O 3 concentrations from outdoor work 

### 29 leads to increased risk of O 3 - related health effects among individuals who participate in 

### 30 outdoor activities or work, although there is no evidence of modification by outdoor 

### 31 activity in this recent study. Lower prevalence of air conditioning also appears to affect 

### 32 risk of O 3 – related health effects, but this is not true of all st udies. Overall, increased 

### 33 exposure to outdoor air does appear to confer additional risk and individuals with greater 

### 34 exposure to outdoor air may experience more O 3 – related health effects. 

### 35Draft

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- 32 September 2011 

## 8.11 Healthy Responders

Within the general population, there is evidence for variability in responses to O 3 

### 1 exposure, with some healthy individuals demonstrating greater O 3 - related health effects 

### 2 compared to other healthy individuals in controlled human exposure studies. These 

### 3 individuals do not fit in any of the at

- risk popula tions discussed in this chapter; however, 

### 4 studies have found that they have greater responses to O 3 exposure than would be 

### 5 expected, indicating a unique population that needs to be considered. 

### 6
Controlled human exposure studies have demonstrated a large de gree of intersubject 

### 7 variability in lung function decrements, symptomatic responses, pulmonary 

### 8 inflammation, AHR, and altered epithelial permeability in healthy adults exposed to O 3 

### 9 ( Que et al. ; Holz et al., 2005 ; McDonnell, 1996 ) . The magnitude of increases in 

### 10 pulmonary inflammation, AHR, and epithelial permeability, in response to O 3 exposure, 

### 11 do not appear to be correlated, nor are these responses correlated with changes in lung 

### 12 function ( Que et al. ; Balmes et al., 1997 ; Balmes et al., 1996 ; Aris et al., 1995 ) . However, 

### 13 these responses to O 3 exposure in healthy individuals tend to be reproducible within a 

### 14 given individual over a period of several months indicating differences in the intrinsic 

### 15 responsiveness of individuals ( Holz et al., 2005 ; Hazucha et al., 2003 ; Holz et al., 1999 ; 

### 16 McDonnell et al., 1985a ) . It should be noted that even when group mean responses are 

### 17 small and seem physiologically insignificant, some intrinsically more responsive 

### 18 individuals experience distinctly larger effects under the same exposure conditions. For 

### 19 example, small group mean changes (e.g., <5%) in FEV 1 have been observed in healthy 

### 20 young adults at levels as low as 120 ppb O 3 for 1 to 3 hour exposure periods. However, 

### 21 some individuals within a study may experien ce FEV 1 decrements in excess of 15% 

### 22 under these conditions, even with group mean decrements of less than 5%. Therefore, 

### 23 within the general population, a proportion of otherwise healthy individuals, who do not 

### 24 have characteristics discussed above that incre ase risk, may be at increased risk of 

### 25 O 3 - induced health effects. 

### 26



## 8.12 Summary

In this section, epidemiologic, controlled human exposure, and toxicological studies have 

### 27 been evaluated that contribute information on potential at

- risk populations. Overall, this 

### 28

re view provides evidence that various factors may lead to increased risk of O 3 - related 

### 29 health effects. 

### 30
The populations identified in this section that are most at risk for O 3 - related health effects 

### 31 are individuals with influenza/infection, individuals with asthma, and younger and older 

### 32Draft

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- 33 September 2011 age groups. There were a small number of studies on influenza/infection but both 

### 1 reported influenza/infection to modify the association between O 3 exposure and 

### 2 respiratory effects, with individuals having influenza or an infec tion being at increased 

### 3 risk. Asthma as a factor affecting risk was supported by controlled human exposure and 

### 4 toxicological studies, as well as some evidence from epidemiologic studies. Most studies 

### 5 comparing age groups reported greater effects of short

- t erm O 3 exposure on mortality 

### 6 among older adults, although studies of other health outcomes had inconsistent findings 

### 7 regarding whether older adults were at increased risk. Generally, studies of age groups 

### 8 also reported positive associations for respiratory HAs and ED visits among children. 

### 9 Biological plausibility for this increased risk is supported by toxicological and clinical 

### 10 research. Diet and obesity are also both likely factors affecting risk. Multiple 

### 11 epidemiologic, controlled human exposure, and tox icological studies reported that diets 

### 12 deficient in vitamins E and C are associated with risk of O 3 - related health effects. 

### 13 Similarly, studies of effect measure modification by BMI observed greater O 3 - related 

### 14 respiratory decrements for individuals who were obese. 

### 15
Other potential factors [preexisting conditions (such as COPD and CVD), sex, and 

### 16 multiple genes (such as GSTM1, GSTP1, HMOX

- 1, NQO1, and TNF

- α) ] provided some 

### 17 evidence of increased risk, but further evidence is needed. In addition, examination of 

### 18 modification of the associations between O 3 exposure and health effects by SES and race 

### 19 were available in a limited number of studies, and demonstrated possible increased odds 

### 20 of health effects related to O 3 exposure among those with low SES and black race

. 

### 21
Individuals with increased outdoor exposure were examined in a recent study of outdoor 

### 22 workers, in which no effect modification was observed, and studies of air conditioning 

### 23 prevalence, which demonstrated inconsistent findings. However, previous evidence along 

### 24 with biological plausibility from toxicological and controlled human studies has shown 

### 25 individuals exposed to more outdoor air to be at increased risk of O 3 - related health 

### 26 effects. Studies of physical conditioning and smoking were conducted but little evidence 

### 27 was available to determine whether increased risk of O 3 - related health effects is present 

### 28 for these factors. The only studies examining effect measure modification by diabetes 

### 29 examined O 3 exposure and cardiovascular outcomes and none re ported increased risks for 

### 30 individuals with diabetes. Toxicological studies also identified hyperthyroidism to be a 

### 31 factor warranting further examination. Future research will provide additional insight into 

### 32 whether these factors affect risk of O 3 - related health effects. 

### 33Draft

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- 34 September 2011 

## 8.13 References

Alexeeff, SE; Litonjua, AA; Suh, H; Sparrow, D; Vokonas, PS; Schwartz, J. (2007). Ozone exposure and lung function: Effect modifi ed by obesity and airways hyperresponsiveness in the VA Normative Aging Study. Chest 132: 1890

- 1897. http://dx.doi.org/10.1378/chest.07

- 1126

. Alexeeff, SE; Litonjua, AA; Wright, RO; Baccarelli, A; Suh, H; Sparrow, D; Vokonas, PS; Schwartz, J. (2008). Ozone exposure, antioxidant genes, and lung function in an elderly cohort: VA Normative Aging Study. Occup E nviron Med 65: 736

- 742. http://dx.doi.org/10.1136/oem.2007.035253

. Alexis, NE; Zhou, H; Lay, JC; Harris, B; Hernandez, ML; Lu, TS; Bromberg, PA; Diaz

- Sanchez, D; Devlin, RB; Kleeberger, SR; Peden, DB. (2009). The glutathione

- S

- transferase Mu 1 null genotype modulates
ozone
- induced airway inflammation in human subjects. J Allergy Clin Immunol 124: 1222

- 122 8. http://dx.doi.org/10.1016/j.jaci.2009.07.036

. Arbex, AM; de Souza Conceicao, GM; Perez Cendon, S; Arbex, FF; Lopes, AC; Providello Moyses, E; Santiago, SL; Saldiva, PHN; Pereira, LAA; Ferreira Braga, AL. (2009). Urban air pollution and COPD

- related emergency room visits. J Epidemiol Community Health 966: 777

- 783. http://dx.doi.org/10.1136/jech.2008.078360

. Aris, RM; Tager, I; Christian, D; Kelly, T; Balmes, JR. (1995). Methacholine responsiveness is not associated with O3

- induced decreases in FEV1. Chest 107: 621

- 628. Auten, RL; Potts, EN; Mason, SN; Fischer, B; Huan g, Y; Foster, WM. (2009). Maternal exposure to particulate matter increases postnatal ozone

- induced airway hyperreactivity in juvenile mice. Am J Respir Crit Care Med 180: 1218

- 1226. http://dx.d oi.org/10.1164/rccm.200901

- 0116OC

. Avissar, NE; Reed, CK; Cox, C; Frampton, MW; Finkelstein, JN. (2000). Ozone, but not nitrogen dioxide, exposure decreases g lutathione peroxidases in epithelial lining fluid of human lung. Am J Respir Crit Care Med 162: 1342

- 1347. Baccarelli, A; Zanobetti, A; Martinelli, I; Grillo, P ; Hou, L; Lanzani, G; Mannucci, PM; Bertazzi, PA; Schwartz, J. (2007). Air pollution, smoking, and plasma homocysteine. Environ Health Perspect 115: 176

- 181. Backus, GS; Howden, R; Fostel, J; Bauer, AK; Cho, HY; Marzec, J; Peden, DB; Kleeberger, SR. (2010). Protective role of interleukin

- 10 in ozone

- induced pulmonary inflammation. Environ Health Perspect 118: 1721

- 1727. http://dx.doi.org/10.1289/ehp.1002182

. Balmes, JR; Chen, LL; Scannell, C; Tager, I; Christian, D; Hearne, PQ; Ke lly, T; Aris, RM. (1996). Ozone

induced decrements in FEV1 and FVC do not correlate with measures of inflammation. Am J Respir Crit Care Med 153: 904

- 909. Ba lmes, JR; Aris, RM; Chen, LL; Scannell, C; Tager, IB; Finkbeiner, W; Christian, D; Kelly, T; Hearne, PQ; Ferrando, R; Welch, B. (1997). Effects of ozone on normal and potentially sensitive human subjects. Part I: Airway inflammation and responsiveness t o ozone in normal and asthmatic subjects. Boston, MA: Health Effects Institute. Barraza

- Villarreal, A; Sunyer, J; Hernandez

- Cadena, L; Escamilla

- Nunez, MC; Sien ra
- Monge, JJ; Ramirez

Aguilar, M; Cortez

- Lugo, M; Holguin, F; Diaz

- Sanchez, D; Olin, AC; Romieu, I. (2008). Air pollution, airway inflammation, and lung function in a cohort study of Mexico City schoolchildren. Environ Health Perspect 116: 832

- 838. http://dx.doi.org/10.1289/ehp.10926

. Basha, MA; Gross, KB; Gwizdala, CJ; Haidar, AH; Popovich, J, Jr. (1994). Br onchoalveolar lavage neutrophilia in asthmatic and healthy volunteers after controlled exposure to ozone and filtered purified air. Chest 106: 1757

- 1765. Bell, ML; Dominici, F. (2008). Effect modification by community characteristics on the short

- term effects of ozone exposure and mortality in 98 US communities. Am J Epidemiol 167: 986

- 997. http://dx.doi.org/ 10.1093/aje/kwm396

. Bennett, WD; Hazucha, MJ; Folinsbee, LJ; Bromberg, PA; Kissling, GE; London, SJ. (2007). Acute pulmonary function response to ozone in yo ung adults as a function of body mass index. Inhal Toxicol 19: 1147

- 1154. http://dx.doi.org/10.1080/08958370701665475

. Bergamaschi, E; De Palma, G; Mozzoni, P; Vanni, S; Vettori, MV; Broeckaert, F; Bernard, A; Mutti, A. (2001). Polymorphism of quinone

- metabolizing enzymes and susceptibility to ozone

- induced acute effects. Am J Respir Crit Care Med 163: 1 426

- 1431.Draft

– Do Not Cite or Quote 8

- 35 September 2011 Berhane, K; Zhang, Y; Linn, WS; Rappaport, EB; Bastain, TM; Salam, MT; Islam, T; Lurmann, F; Gilliland, FD. (2011). The effect of ambient air poll ution on exhaled nitric oxide in the Children's Health Study. Eur Respir J 37: 1029

- 1036. http://dx.doi.org/10.1183/09031936.00081410

. Blomberg, A; Mudway, IS; Nordenhall, C; Hedenstrom, H; Kelly, FJ; Frew, AJ; Holgate, ST; Sandstrom, T. (1999). Ozone

- induced lung function decrements do not correlate with early airway inflammatory or antioxidant responses . Eur Respir J 13: 1418

- 1428. Bloom, B; Cohen, RA; Freeman, G. (2008). Summary health statistics for U.S. children: National Health Interview Survey, 2008. Washington, DC: National Center for Health Statistics. Bosson, J; Stenfors, N; Bucht, A; Helleday, R; Pourazar, J; Holgate, ST; Kelly, FJ; Sandstrom, T; Wilson, S; Frew, AJ; Blomberg, A. (2003). Ozone

- induced bronchial epithelial cytokine expression differs between healthy and asthmatic subjects. Clin Exp Allergy 33: 777

- 782. Broeckaert, F; Clippe, A; Wattiez, R; Falmagne, P; Bernard, A. (2003). Lung hyperpermeability, Clara

- cell secretory potein (CC16), and susceptibility to ozone of five inbred strains of mice. Inhal Toxicol 15: 1209

- 1230. Buadong, D; Jinsart, W; Funatagawa, I; Karita, K; Yano, E. (2009). Association between PM10 and O3 levels and hospital visits for cardiovascular diseases in Bangkok, Thailand. J E pidemiol 19: 182

- 188. http://dx.doi.org/10.2188/jea.JE20080047

. Burra, TA; Moineddin, R; Agha, MM; Glazie r, RH. (2009). Social disadvantage, air pollution, and asthma physician visits in Toronto, Canada. Environ Res 109: 567

- 574. http://dx.doi.org/10.1016/j.envres.2009.03.004

. Bush, ML; Asplund, PT; Miles, KA; Ben

- Jebria, A; Ultman, JS. (1996). Longitudinal distribution of O3 absorption in the lung: gender differences and intersubject variability. J A ppl Physiol 81: 1651

- 1657. Cakmak, S; Dales, RE; Judek, S. (2006a). Do gender, education, and income modify the effect of air pollution gases on cardiac dise ase? J Occup Environ Med 48: 89

- 94. http://dx.doi.org/10.1097/01.jom.0000184878.11956.4b

. Cakm ak, S; Dales, RE; Judek, S. (2006b). Respiratory health effects of air pollution gases: Modification by education and income. Arch Environ Occup Health 61: 5

- 10. Cakmak, S; Dales, RE; Vidal, CB. (2007). Air pollution and mortality in Chile: Susceptibility among the elderly. Environ Health Perspect 115: 524

- 527. Cakmak, S; Dales, RE; Angelica Rubio, M; Blanco Vidal, C. (2011). The risk of dying on days of higher air pollution among the socially disadvantaged elderly. Environ Res 111: 388

- 393. http://d x.doi.org/10.1016/j.envres.2011.01.003

. Calderon Guzman, D; Barragan Mejia, G; Hernandez Garcia, E; Juarez Olguin, H. (2006). Effect of nutritional status an d ozone exposure on some biomarkers of oxidative stress in rat brain regions. Nutr Cancer 55: 195

- 200. http://dx.doi.org/10.1207/s15327914nc5502_11

. Carbajal

- Arroyo, L; Miranda

- Soberanis, V; Medina

- Ramón, M; Rojas

- Bracho, L; Tzintzun, G; Solís

- Gutiérrez, P; Méndez

- Ramírez, I; Hurtado

- Díaz, M; Schwartz, J; Romieu, I. (2011). Effect of PM10 and O3 on inf ant mortality among residents in the Mexico City Metropolitan Area: A case

- crossover analysis, 1997

– 2005. J Epidemiol Community Health 65: 715

- 721. http://dx.doi.org/10.1136/jech.2009.101212

. Carey, SA; Minard, KR; Trease, LL; Wagner, JG; Garcia, GJ; Ballinger, CA; Kimbell, JS; Plopper, CG; Corley, RA; Postlethwait, EM; Harkema, JR; Einstein, DR. (2007). Three

- dimensional mapping of ozone

induced injury in the nasal airways of monkeys using magnetic resonance imaging and morphometric techniques. Toxicol Pathol 35: 27

- 40. http://dx.doi.org/10 .1080/01926230601072343

. Chiu, HF; Yang, CY. (2009). Air pollution and emergency room visits for arrhythmias: Are there potentially sensitive groups? J Toxicol Environ Health A 72: 817

- 823. http://dx.doi.org/10.1080/15287390902800405

. Cho, H,

- Y; Zhang, L,

- Y; Kleeberger, SR. (2001). Ozone

- induced lung inflammation and hyperreactivity are mediated via tumor necrosis factor

- "alpha" receptors. Am J Physiol 280: L537

- L546. Cho, HY; Kleeberger, SR. (2007). Genetic mechanisms of susceptibility to oxidative lung injury in mice. Free Radic Biol Med 42: 433

- 445. http://dx.doi.org/10.1016/j.freeradbiomed.2006.11.021

. Chuang, GC; Yang, Z; Westbrook, DG; Pompilius, M; Ballinger, CA; White, RC; Krzywanski, DM; Postlethwait, EM; Ballinger, SW. (2009). Pulmonary ozone exposure induces vascular dysfunction, mitochondrial damage, and atherogenesis. Am J Physiol Lung Cell Mol Physiol 297: L209

- L216. http://dx.doi.org/10.1152/ajplung.00102.2009

.Draft

– Do Not Cite or Quote 8

- 36 September 2011 Coffin, DL; Blommer, EJ; Gardner, DE; Holzman, R. (1967). Effect of air pollution on alteration of susceptibility to pulmonary infection. Cincinnati, OH: U.S. Department of Health, Education, and Welfare. Coffin, DL; Ga rdner, DE. (1972). Interaction of biological agents and chemical air pollutants. Ann Occup Hyg 15: 219

- 234. Corradi, M; Alinovi, R; Goldoni, M; Vettori, M; F olesani, G; Mozzoni, P; Cavazzini, S; Bergamaschi, E; Rossi, L; Mutti, A. (2002). Biomarkers of oxidative stress after controlled human exposure to ozone. Toxicol Lett 134: 219

- 225. Dahl, M; Bauer, AK; Arredouani, M; Soininen, R; Tryggvason, K; Kleeberger, SR; Kobzik, L. (2007). Protection against inhaled oxidants through scavenging of oxidized lipids by macrophage receptors MARCO and SR

- AI/II. J Clin Inve st 117: 757

- 764. http://dx.doi.org/10.1172/JCI29968

. Darrow, LA; Klein, M; Strickland, MJ; Mulholland, JA; Tolb ert, PE. (2011a). Ambient air pollution and birth weight in full

- term infants in Atlanta, 1994

- 2004. Environ Health Perspect 119: 731

- 737. http://dx.doi.org/10.1289/ehp.1002785

. Escamilla

- Nuñez, MC; Barraza

- Villarreal, A; Hernandez

- Cadena, L; Moreno

- Macias, H; Ramirez

- Aguilar, M; Sienra

- Monge, JJ; Cortez

- Lugo, M; Texcalac, JL; del Rio

- N avarro, B; Romieu, I. (2008). Traffic

- related air pollution and respiratory symptoms among asthmatic children, resident in Mexico City: The EVA cohort study. Respir Res 9: 74. http://dx.doi.org/10.1 186/1465

- 9921

- 9

- 74

. Fakhrzadeh, L; Laskin, JD; Laskin, DL. (2002). Deficiency in inducible nitric oxide synthase protects mice from
ozone
- induced lung inflamm ation and tissue injury. Am J Respir Cell Mol Biol 26: 413

- 419. Fanucchi, MV; Plopper, CG; Evans, MJ; Hyde, DM; Van Winkle, LS; Gershwin, LJ; Schelegle, ES. (2006). Cyclic exposure to ozone alters distal airway development in infant rhesus monkeys. Am J Physiol Lung Cell Mol Physiol 291: L644

- L650. http://dx.doi.org/10.1152/ajplung.00027.2006

. Fortino, V; Maioli, E; Torricelli, C; Davis, P; Valacchi, G. (2007). Cutaneous MMPs are differently modulated by environmental stressors in old and young mice. Toxic ol Lett 173: 73

- 79. http://dx.doi.org/10.1016/j.toxlet.2007.06.004

. Fox, SD; Adams, WC; Brookes, KA; Lasley, BL. (1993). Enhanced response to ozone exposure during the follicular phase of the menstrual cycle. Environ Health Perspect 101: 242

- 244. Frampton, MW; Morrow, PE; Torres, A; Cox, C; Voter, KZ; Utell, MJ; Gibb, FR; Speers, DM. (1997b). Ozone responsiveness in smokers and nonsmokers. Am J Respir Crit Care Med 155: 116

- 121. Funabashi, H; Shima, M; Kuwaki, T; Hiroshima, K; Kuriyama, T. (2004). Effects of repeated ozone exposure on pulmonary function and bronchial responsiveness in mice sensitized with ovalbumin. Toxicology 204: 75

- 83. http://dx.doi.org/10.1016/j.tox.2004.06.047

. Garantziotis, S; Li, Z; Potts, EN; Lindsey, JY; Stober, VP; Polosukhin, VV; Blackwell, TS; Schwartz, DA; Foster, WM; Hollingsworth, JW. (2010). TLR4 is necessary for hyaluronan

- mediated airway hyperresponsiveness after ozone inhalation. Am J Respir Crit Care Med 181: 666

- 675. http://dx.doi.org/10.1164/rccm.200903

- 0381OC

. Goldberg, MS; Burnett, RT; Yale, JF; Valois, MF; Brook, JR. (2006). Associations between ambient air poll ution and daily mortality among persons with diabetes and cardiovascular disease. Environ Res 100: 255

- 267. Halonen, JI; Lanki, T; Tiittanen, P; Niemi, JV; Loh , M; J, P. (2009). Ozone and cause

- specific cardiorespiratory morbidity and mortality. J Epidemiol Community Health 64: 814

- 820. http://dx.doi.org/10.1136/jech.2009.087106

. Hamade, AK; Rabold, R; Tankersley, CG. (2008). Adverse cardiovascular effects with acute particulate matter and ozone exposures: Interstrain variation in mic e. Environ Health Perspect 116: 1033

- 1039. http://dx.doi.org/10.1289/ehp.10689

. Hamade, AK; Tankersley, CG. (2009). Interstrain variation in cardiac and respiratory adaptation to repeated ozone and particulate matter exposures. Am J Physiol Regul Integr Comp Physiol 296: R1202

- R1215. http://dx.doi.org/1 0.1152/ajpregu.90808.2008

. Hamade, AK; Misra, V; Rabold, R; Tankersley, CG. (2010). Age

- related changes in cardiac and respiratory adaptation to acute ozone and carbon black exposures: Interstrain variation in mice. Inhal Toxicol 22: 84

- 94. http://dx.doi.org/10.3109/08958378.2010.503974

. Hansen, CA; Barnett, AG; Pritchard, G. (2008). The effect of ambient air pollution during early pregnancy on fetal ultrasonic measurements during mid

- pregnancy. Environ Health Perspect 116: 362

- 369.Draft

– Do Not Cite or Quote 8

- 37 September 2011 Harkema, JR; Plopper, CG; Hyde, DM; StGeorge, JA; Dungworth, DL. (1987a). Effects of an ambient level of ozone on primate nasal epithelial mucosubstances: quantitative histochemi stry. Am J Pathol 127: 90

- 96. Hazucha, MJ; Folinsbee, LJ; Bromberg, PA. (2003). Distribution and reproducibility of spirometric response to ozone by gender a nd age. J Appl Physiol 95: 1917

- 1925. Henrotin, JB; Besancenot, JP; Bejot, Y; Giroud, M. (2007). Short

- term effects of ozone air pollution on ischaemic strok e occurrence: A case

- crossover analysis from a 10

- year population

- based study in Dijon, France. Occup Environ Med 64: 439

- 445. Henrotin, JB; Zeller, M; Lorgis, L; Cottin, Y; Giroud, M; Béjot, Y. (2010). Evidence of the role of short

- term exposure to ozone on ischaemic cerebral and cardiac events: The Dijon Vascular Project (DIVA). Heart 96: 1990

- 1996. ht tp://dx.doi.org/10.1136/hrt.2010.200337

. Hernández

- Cadena, L; Holguin, F; Barraza

- Villarreal, A; Del Río

- Navarro, BE; Sienra

- Monge, JJ; Romieu, I. (2009). Increased levels of outdoor air pollutants are associated with reduced bronchodilation in children with asthma. Chest 136: 1529

- 1536. http://dx.doi.org/10.1378/chest.08

- 1463

. Hernandez, ML; Lay, JC; Harris, B; Esther, CR; Brickey, WJ; Bromberg, PA; Diaz

- Sanchez, D; Devlin, RB; Kleeberger, SR; Alexis, NE; Peden, DB. (2010). Atopic asthmatic subjects but not atopic subjects without asthma have enhanced inflammatory response to ozone. J Allergy Clin Immunol 126: 537

- 544. http://dx.doi.org/10.1016/j.jaci.2010.06.043

. Hollingsworth, JW; Free, ME; Li, Z; Andrews, LN; Nakano, H; Cook, DN. (2010). Ozone activates pulmonary dendritic cells and promotes allergic sensitization through a Toll

- like receptor 4

- dependent mechanism. J Allergy Clin Immunol 125: 1167

- 1170. Hollingsworth, JW, II; Cook, DN; Brass, DM; Walker, JKL; Morgan, DL; Foster, WM; Schwartz, DA. (2004). The role of Toll

- like receptor 4 in environmental airway injury in mice. Am J Respir Crit Care Med 170: 126

- 132. Holz, O; Jorres, RA; Timm, P; Mucke, M ; Richter, K; Koschyk, S; Magnussen, H. (1999). Ozone

- induced airway inflammatory changes differ between individuals and are reproducible. Am J Respir Crit Care Med 159: 776

- 784. Holz, O; Tal

- Singer, R; Kanniess, F; Simpson, KJ; Gibson, A; Vessey, RSJ; Janicki, S; Magnussen, H; Jorres, RA; Richter, K. (2005). Validation of the human ozone challenge model as a tool for assessing anti

inflammatory drugs in ea rly development. J Clin Pharmacol 45: 498

- 503. Horstman, DH; Ball, BA; Brown, J; Gerrity, T; Folinsbee, LJ. (1995). Comparison of pulmonary responses of asth matic and nonasthmatic subjects performing light exercise while exposed to a low level of ozone. Toxicol Ind Health 11: 369

- 385. Housley, DG; Eccles, R; Richard s, RJ. (1996). Gender difference in the concentration of the antioxidant uric acid in human nasal lavage. Acta Otolaryngol 116: 751

- 754. Hu, S,

- C; Ben

- Jebri a, A; Ultman, JS. (1994). Longitudinal distribution of ozone absorption in the lung: Effects of respiratory flow. J Appl Physiol 77: 574

- 583. Huffman, LJ; B eighley, CM; Frazer, DG; McKinney, WG; Porter, DW. (2006). Increased susceptibility of the lungs of hyperthyroid rats to oxidant injury: Specificity of effects. Toxicology 225: 119

- 127. http://dx .doi.org/10.1016/j.tox.2006.05.008

. Islam, T; McConnell, R; Gauderman, WJ; Avol, E; Peters, JM; Gilliland, FD. (2008). Ozone, oxidant defense genes and risk o f asthma during adolescence. Am J Respir Crit Care Med 177: 388

- 395. http://dx.doi.org/10.1164/rccm.200706

- 863OC

. Islam, T; Berhane, K; McConnell, R; Gauderman, WJ; Avol, E; Peters, JM; Gilliland, FD. (2009). Glutathione

- S

transferase (GST) P1, GSTM1, exercise, ozone and asthma incidence in school children. Thorax 64: 197

- 202. http://dx.doi.org/10.1136/thx.2008.099366

. Jerrett, M; Burnett, RT; Pope, CA, III; Ito, K; Thurston, G; Krewski, D; Shi, Y; Calle, E; Thun, M. (2009). Long

term ozone exposure and mortality. N Engl J Med 360: 1085

- 1095. http://dx.doi.org/10.1056/NEJMoa0803894

. Joad, JP; Kott, KS; Bric, JM; Peake, JL; Plopper, CG; Schelegle, ES; Gershwin, LJ; Pinkerton, KE. (2006). Structural and functional localization of airway effects from episodic exposure of infant monkeys to allergen and/or oz one. Toxicol Appl Pharmacol 214: 237

- 243. http://dx.doi.org/10.1016/j.taap.2005.12.012

.Draft

– Do Not Cite or Quote 8

- 38 September 2011 Johnston, RA; Schwartzman, IN; Flynt, L; Shore, SA. (2005b). Role of interleukin

- 6 in murine airway responses to ozone. Am J Physiol Lung Cell Mol Physiol 288: L390

- L397. http://dx.doi.org/10.1152/ajplung.00007.2004

. Jorres, R; Nowak, D; Magnussen, H; Speckin, P; Koschyk, S. (1996). The effect of ozone exposure on allergen resp onsiveness in subjects with asthma or rhinitis. Am J Respir Crit Care Med 153: 56

- 64. Kan, H; London, SJ; Chen, G; Zhang, Y; Song, G; Zhao, N; Jiang, L; Chen, B. (2008). Season, sex, age, and education as modifiers of the effects of outdoor air pollution on daily mortality in Shanghai, China: The Public Health and Air Pollution in Asia (PAPA) Study. Environ Health Perspect 116: 1183

- 1188. Kari, F; Hatch, G; Slade, R; Crissman, K; Simeonova, PP; Luster, M. (1997). Dietary restriction mitigates ozone

induced lung inflammation in rats: A role for endogenous antioxid ants. Am J Respir Cell Mol Biol 17: 740

- 747. Katsouyanni, K; Samet, JM; Anderson, HR; Atkinson, R; Le Tertre, A; Medina, S; Samoli, E; Touloumi, G; Burnett, RT ; Krewski, D; Ramsay, T; Dominici, F; Peng, RD; Schwartz, J; Zanobetti, A. (2009). Air pollution and health: A European and North American approach (APHENA). (Research Report 142). Boston, MA: Health Effects Institute. http://pubs.healtheffects.org/view.php?id=327

. Kehrl, HR; Peden, DB; Ball, BA; Folinsbee, LJ; Horstman, DH. (1999). Increased specif ic airway reactivity of persons with mild allergic asthma after 7.6 hours of exposure to 0.16 ppm ozone. J Allergy Clin Immunol 104: 1198

- 1204. Kenyon, NJ; Van Der Vliet, A; Schock, BC; Okamoto, T; McGrew, GM; Last, JA. (2002). Susceptibility to ozone

induced acute lung injury in iNOS

- deficient mice. Am J Physiol 282: L540

- L545. Khatri, SB; Holguin, FC; Ryan, PB; Mannino, D; Erzurum, SC; Teague, WG. (2009). Association of ambient ozone exposure with airway inflammation and allergy in adults with asthma. J Asthma 46: 777

- 785. http://dx.doi.org/10.1080/02770900902779284

. Kim, CS; Alexis, NE; Rappold, AG; Kehrl, H; Hazucha, MJ; Lay, JC; Schmitt, MT; Case, M; Devlin, RB; Peden, DB; Diaz

- Sanchez, D. (2011). Lung function and inflammatory responses in healthy young adults exposed to 0.06 ppm ozone for 6.6 hours. Am J Respir Crit Care Med 183: 1215

- 1221. http: //dx.doi.org/10.1164/rccm.201011

- 1813OC

. Kleeberger, SR; Levitt, RC; Zhang, L,

- Y; Longphre, M; Harkema, J; Jedlicka, A; Eleff, SM; DiSilvestre, D; Holroyd, KJ. (1997). Linkage analysis of susceptibility to ozone

- induced lung inflammation in inbred mice. Nat Genet 17: 475

- 478. Kleeberger, SR; Reddy, S; Zhang, L,

- Y; Jedlicka, AE. (2000). Genetic susceptibility to ozone

- induced lung hyperpermeability: Role of toll

- like receptor 4. Am J Respir Cell Mol Biol 22: 620

- 627. Kl eeberger, SR; Reddy, SP; Zhang, L,

- Y; Cho, H,

- Y; Jedlicka, AE. (2001). Toll

- like receptor 4 mediates ozone

induced murine lung hyperpermeability via inducible nitric oxide synthase. Am J Physiol 280: L326

- L333. Ko, FWS; Tam, W; Wong, TW; Lai, CKW. (2007). Effects of air pollution on asthma hospitalization rates in different age groups in Hong Kong. Clin Exp Allergy 37: 1312

- 1319. Kodavanti, UP; Costa, DL; Dreher, KL; Crissman, K; Hatch, GE. (1995). Ozone

- induced tissue injury and changes in antioxidant homeostasis in normal and ascorbate

- deficient guinea pigs. Biochem Pharmacol 50: 243

- 251. http://dx.doi.org/10.1016/0006

- 2952(95)00 122

- G

. Kooter, IM; Pennings, JL; Fokkens, PH; Leseman, DL; Boere, AJ; Gerlofs

- Nijland, ME; Cassee, FR; Schalk, JA; Orzechowski, TJ; Schaap, MM; Breit, TM; Dorma ns, JA; van Oostrom, CT; de Vries, A; van Steeg, H. (2007). Ozone induces clear cellular and molecular responses in the mouse lung independently of the transcription

- coupled repair status. J Appl Physiol 102: 1185

- 1192. http://dx.doi.org/10.1152/japplphysiol.00796.2006

. Kumarathasan, P; Blais, E; Goegan, P; Yagminas, A; Guenette, J; Adamson, IY; C rapo, JD; Mason, RJ; Vincent, R. (2005). 90

- day repeated inhalation exposure of surfactant Protein

- C/tumor necrosis factor

alpha, (SP

- C/TNF

- alpha) transgenic mice to air pollutants. Int J Toxicol 24: 59

- 67. Lagorio, S; Forastiere, F; Pistelli, R; Iavarone, I; Michelozzi, P; Fano, V; Marconi, A; Ziemacki, G; Ostro, BD. (2006). Air pollution and lung function among susceptible adult subjects: A panel study. E nviron Health 5: 11. http://dx.doi.org/10.1186/1476

- 069X

- 5

- 11

. Lee, IM; Tsai, SS; Ho, CK; Chiu, HF; Wu, T N; Yang, CY. (2008a). Air pollution and hospital admissions for congestive heart failure: Are there potentially sensitive groups? Environ Res 108: 348

- 353. http://dx.doi.org/10.1016/j.envres.2 008.07.024

.Draft

– Do Not Cite or Quote 8

- 39 September 2011 Lee, JT; Son, JY; Kim, H; Kim, SY. (2006). Effect of air pollution on asthma

- related hospital admissions for children by socioeconomic status asso ciated with area of residence. Arch Environ Occup Health 61: 123

- 130. Lee, YL; McConnell, R; Berhane, K; Gilliland, FD. (2009b). Ambient ozone modifies the effect of tumor necrosis factor G

- 308A on bronchitic symptoms among children with asthma. Allergy 64: 1342

- 1348. http://dx.doi.org/10.1111/j.1398

- 9995.2009.02014.x

. Lewis, TC; Robins, TG; Dvonch, JT; Keeler, GJ; Yip, FY; Mentz, GB; Lin, X; Parker, EA; Israel, BA; Gonzalez, L; Hill, Y. (2005). Air pollution

- associated changes in lung function among asthmatic children in Detroit. Environ Health Perspect 113: 1068

- 1075. Liao, D; Heiss, G; Chinchilli, VM; Duan, Y; Folsom, AR; Lin, HM; Salomaa, V. (2005). Association of criteria pollutants with plasma hemostatic/inflammatory markers: A population

- based study. J Expo Sci Environ Epidemiol 15: 319

- 328. Lim, Y; Phu ng, AD; Corbacho, AM; Aung, HH; Maioli, E; Reznick, AZ; Cross, CE; Davis, PA; Valacchi, G. (2006). Modulation of cutaneous wound healing by ozone: Differences between young and aged mice. Toxicol Lett 160: 127

- 134. http://dx.doi.org/10.1016/j.toxlet.2005.06.013

. Lin, M; Stieb, DM; Chen, Y. (2005). Coarse particulate matter and hospitalization for r espiratory infections in children younger than 15 years in Toronto: A case

- crossover analysis. Pediatrics 116: 235

- 240. Lin, S; Liu, X; Le, LH; Hwang, SA. (2008b). Chronic exposure to ambient ozone and asthma hospital admissions among children. Environ Health Perspect 116: 1725

- 1730. http://dx.doi.org/10.1289/ehp.11184

. Liu, L; Poon, R; Chen, L; Frescura, AM; Montuschi, P; Ciabattoni, G; Wheeler, A; Dales, R. (2009a). Acute effects of air pollution on pulmonary function, airway inflammation, and oxidative stress in asthmatic children. Environ Health Perspect 117: 668

- 674. http://dx.doi.org/10.1289/ehp11813

. López, I; Sán chez, I; Bizarro, P; Acevedo, S; Ustarroz, M; Fortoul, T. (2008). Ultrastructural alterations during embryonic rats' lung development caused by ozone. J Electron Microsc (Tokyo) 57: 19

- 23. http://dx. doi.org/10.1093/jmicro/dfm033

. Mar, TF; Koenig, JQ. (2009). Relationship between visits to emergency departments for asthma and ozone exposure in greater Sea ttle, Washington. Ann Allergy Asthma Immunol 103: 474

- 479. McDonnell, WF. (1996). Individual variability in human lung function responses to ozone exposure. Environ Toxicol Pharmacol 2: 171

- 175. McDonnell, WF; Stewart, PW; Smith, MV; Pan, WK; Pan, J. (1999). Ozone

- induced respiratory symptoms: Exposure

- response m odels and association with lung function. Eur Respir J 14: 845

- 853. McDonnell, WF; Stewart, PW; Smith, MV. (2010). Prediction of ozone

- induced lung function responses in humans. Inhal Toxicol 22: 160

- 168. http://dx.doi.org/10.3109/08958370903089557

. McDonnell , WF, III; Horstman, DH; Abdul

- Salaam, S; House, DE. (1985a). Reproducibility of individual responses to ozone exposure. Am Rev Respir Dis 131: 36

- 40. Medina

- Ramon, M; Zanobetti, A; Schwartz, J. (2006). The effect of ozone and PM10 on hospital admissions for pneumonia and chronic obstructive pulmonary disease: A national multicity study. Am J Epidemiol 163: 579

- 588. http://dx.doi.org/10.1093/aje/kwj078

. Medina

- Ramón, M; Schwartz, J. (2008). Who is more vulnerable to die from ozone air pollution? Epidemiology 19 : 672

- 679. Middleton, N; Yiallouros, P; Kleanthous, S; Kolokotroni, O; Schwartz, J; Dockery, DW; Demokritou, P; Koutrakis, P. (2008). A 10

- year time

- series analysis of respiratory and cardiovascular morbidity in Nicosia, Cyprus: The effect of short

- term changes in air pollution and dust storms. Environ Health 7: 39. Miller, FJ; Illing, JW; Gardner, DE. (1978). Effect of urban ozone levels on laboratory

- induced respiratory infections. Toxicol Lett 2: 163

- 169. Morello

- Frosch, R; Jesdale, BM; Sadd, JL; Pastor, M. (2010). Ambient air pollution exposure and full

- term birth weight in California. Environ Health 9: 44. http://dx.doi.org/10.1186/1476

- 069X

- 9

- 44

. Mudway, IS; Blomberg, A; Frew, AJ; Holgate, ST; Sandstrom, T; Kelly, FJ. (1999a). Antioxidant consumption and repletion kinetics in nasal lavage fluid followin g exposure of healthy human volunteers to ozone. Eur Respir J 13: 1429

- 1438.Draft

– Do Not Cite or Quote 8

- 40 September 2011 Mudway, IS; Stenfors, N; Blomberg, A; Helleday, R; Dunster, C; Marklund, SL; Frew, AJ; Sandstrom, T; Kelly, FJ. (2001). Differences in basal airway antioxidant concentrations are not predictive of individual responsiveness to ozone: A comparison of healthy and mild asthmatic subjects. Free Radic Biol Med 31: 962

- 974. Neidell, M; Kinney, PL. (2010). Estimates of the association between ozone and asthma hospitalizations that account for behavioral responses to air quality information. Envi ron Sci Pol 13: 97

- 103. http://dx.doi.org/10.1016/j.envsci.2009.12.006

. Nodelman, V; Ultman, JS. (1999). Longitudinal distribution of chlorine absorption in human airways: A comparison to ozone absorption. J Appl Physiol 87: 2073

- 2080. Oyarzún, M; Dussaub at, N; González, S. (2005). Effect of 0.25 ppm ozone exposure on pulmonary damage induced by bleomycin. Biol Res 38: 353

- 358. Palli, D; Sera, F; Giovannelli , L; Masala, G; Grechi, D; Bendinelli, B; Caini, S; Dolara, P; Saieva, C. (2009). Environmental ozone exposure and oxidative DNA damage in adult residents of Florence, Italy. Environ Pollut 157: 1521

- 1525. http://dx.doi.org/S0269

- 7491(08)00472

- 7 [pii]10.1016/j.envpol.2008.09.011. Paquette, NC; Zhang, L,

- Y; Ellis, WA; Scott, AL; Kleeberger, SR. (1996). Vi tamin A deficiency enhances ozone

induced lung injury. Am J Physiol 270: L475

- L482. Paulu, C; Smith, AE. (2008). Tracking associations between ambient ozone and asthma

- related emergency department visits using case

- crossover analysis. J Public Health Manag Pract 14: 581

- 591. Peden, DB; Setzer, RW, Jr; Devlin, RB. (1995). Ozone exposure has both a priming effect on allergen

- induced responses and an intrinsic inflammatory action in the nasal airways of perennially allergic asthmatics. Am J Respir Crit Care Med 151: 1336

- 1345. Peden, DB; Boehlecke, B; Horstman, D; Devlin, R. (1997). Prolonged acute exposure to 0.16 ppm ozone induces eosinophilic airway inflammation in asthmatic subjects with allergies. J Allergy Clin Im munol 100: 802

- 808. Peel, JL; Metzger, KB; Klein, M; Flanders, WD; Mulholland, JA; Tolbert, PE. (2007). Ambient air pollution and cardiovascular emergency de partment visits in potentially sensitive groups. Am J Epidemiol 165: 625

- 633. Pleis, JR; Lucas, JW; Ward, BW. (2009). Summary health statistics for U.S. adu lts: National Health Interview Survey, 2008. In Vital and Health Statistics, 10 (Vol. 242). (DHHS 2010

- 1570). Hyattsville, MD: National Center for Health Statistics. Plopper, CG; Smiley

- Jewell, SM; Miller, LA; Fanucchi, MV; Evans, MJ; Buckpitt, AR; Avdalovic, M; Gershwin, LJ; Joad, JP; Kajekar, R; Larson, S; Pinkerton, KE; Van Winkle, LS; Schelegle, ES; Pieczarka, EM; Wu, R; Hyde, DM. (2007). Asthma/allergic a irways disease: Does postnatal exposure to environmental toxicants promote airway pathobiology? Toxicol Pathol 35: 97

- 110. http://dx.doi.org/10.1080/01926230601132030

. Qian, Z; Lin, H,

- M; Chinchilli, VM; Lehman, EB; Duan, Y; Craig, TJ; Wilson, WE; Liao, D; Lazarus, SC; Bascom, R. (2009). Interaction of ambient air pollutio n with asthma medication on exhaled nitric oxide among asthmatics. Arch Environ Occup Health 64: 168

- 176. http://dx.doi.org/10.1080/19338240903240616

. Que, LG; Stiles, JV; Sundy, JS; Foster, WM. (2011). Pulmonary function, bronchial reactivity, and epithelial permeability are response phenotypes to ozone and develop differentially in healthy humans. J A ppl Physiol 111: 679

- 687. http://dx.doi.org/10.1152/japplphysiol.00337.2011

. Rivas

- Arancibia, S; Dorado

- Martinez, C; Borgonio

- Perez, G; Hiriart

- Urdanivia, M; Verdugo

- Diaz, L; Duran

Vazquez, A; Colin

- Baranque, L; Avila

- Costa, MR. (2000). Effects of taurine on ozone

- induced memory deficits and lipid peroxidation levels in brains of young, mature, and old rats. Environ Res 82: 7

- 17. http://dx.doi.org/10.1006/enrs.1999.3996

. Romieu, I; Sienra

- Monge, JJ; Ra mirez

- Aguilar, M; Moreno

- Macias, H; Reyes

- Ruiz, NI; Estela del Rio

- Navarro, B; Hernandez

- Avila, M; London, SJ. (2004a). Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic chil dren in Mexico City. Thorax 59: 8

- 10. Romieu, I; Ramirez

- Aguilar, M; Moreno

- Macias, H; Barraza

- Villarreal, A; Miller, P; Hernandez

- Cadena, L; Carbajal

- Arroyo, L A; Hernandez

- Avila, M. (2004b). Infant mortality and air pollution: Modifying effect by social class. J Occup Environ Hyg 46: 1210

- 1216.Draft

– Do Not Cite or Quote 8

- 41 September 2011 Romieu, I; Ramirez

- A guilar, M; Sienra

- Monge, JJ; Moreno

- Macias, H; Del Rio

- Navarro, BE; David, G; Marzec, J; Hernandez

- Avila, M; London, S. (2006). GSTM1 and GSTP1 and respiratory health in asthmatic children exposed to ozone. Eur Respir J 28: 953

- 959. http://dx.doi.org/10.1183/09031936.06.00114905

. Romieu, I; Barraza

- Villarreal, A; Escamilla

- Núñez, C; Texcalac

- Sangrado r, JL; Hernandez

- Cadena, L; Díaz

Sánchez, D; De Batlle, J; Del Rio

- Navarro, BE. (2009). Dietary intake, lung function and airway inflammation in Mexico City school children exposed to air pollutants. Respir Res 10: 122. Ruidavets, J,

- B; Cassadou, S; Cournot, M; Bataille, V; Meybeck, M; Ferrieres, J. (2005a). Increased resting heart rate with pollutants in a population based study. J Epidemiol Community Hea lth 59: 685

- 693. Sacks, JD; Stanek, LW; Luben, TJ; Johns, DO; Buckley, BJ; Brown, JS; Ross, M. (2011). Particulate matter induced health effects: Who's susc eptible? Environ Health Perspect 119: 446

- 454. http://dx.doi.org/10.1289/ehp.1002255

. Salam, MT; Islam, T; G auderman, WJ; Gilliland, FD. (2009). Roles of arginase variants, atopy, and ozone in childhood asthma. J Allergy Clin Immunol 123: 596

- 602. http://dx.doi.org/10.1016/j.jaci.2008.12.020

. Samet, JM; Hatch, GE; Horstman, D; Steck

- Scott, S; Arab, L; Bromberg, PA; Levine, M; McDonnell, WF; Devlin, RB. (2001). Effect of antioxidant supplementation on ozone
- induced lung injury in human subjects. Am J Respir Crit Care Med 164: 819

- 825. Sarangapani, R; Gentry, PR; Covington, TR; Teeguarden, JG; Clewell HJ, I II. (2003). Evaluation of the potential impact of age

- and gender

- specific lung morphology and ventilation rate on the dosimetry of vapors. Inhal Toxicol 15: 987

- 1016. Sawyer, K; Brown, J; HazuchaM; Bennett, WD. (2007). The effect of exercise on nasal uptake of ozone in healthy human adults. J Appl Physiol 102: 1380

- 1386. http://dx.doi.org/10. 1152/japplphysiol.00269.2006

. Scannell, C; Chen, L; Aris, RM; Tager, I; Christian, D; Ferrando, R; Welch, B; Kelly, T; Balmes, JR. (1996). Greater ozone

- induc ed inflammatory responses in subjects with asthma. Am J Respir Crit Care Med 154: 24

- 29. Schelegle, ES; Miller, LA; Gershwin, LJ; Fanucchi, MV; Van Winkle, LS; Gerriets, JE; Walby, WF; Mitchell, V; Tarkington, BK; Wong, VJ; Baker, GL; Pantle, LM; Joad, JP; Pinkerton, KE; Wu, R; Evans, MJ; Hyde, DM; Plopper, CG. (2003). Repeated episodes of ozone inhalation amplifies the effects of allergen sensitization and in halation on airway immune and structural development in Rhesus monkeys. Toxicol Appl Pharmacol 191: 74

- 85. Seal, E, Jr; McDonnell, WF; House, DE; Salaam, SA; De witt, PJ; Butler, SO; Green, J; Raggio, L. (1993). The pulmonary response of white and black adults to six concentrations of ozone. Am J Respir Crit Care Med 147: 804

- 810. Seal, E, Jr; McDonnell, WF; House, DE. (1996). Effects of age, socioeconomic status, and menstrual cycle on pulmonary response to ozone. Arch Environ Occup Health 51: 132

- 137. Servais, S; Boussouar, A; Molnar, A; Douki, T; Pequignot, JM; Favier, R. (2005). Age

- related sensitivity to lung oxidative stress during ozone exposure. Free Radic Res 39: 305

- 316. http://dx.doi.org/10.1080/10715760400011098

. Sherry, B; Blanck, HM; Galuska, DA; Pan, L; Dietz, WH; Balluz, L. (2010). Vital signs: Stat e
- specific obesity prevalence among adults

- United States, 2009. MMWR Recomm Rep 59: 951

- 955. Shore, SA; Lang, JE; Kasahara, DI; Lu, FL; Verbout, NG; Si, H; W illiams, ES; Terry, RD; Lee, A; Johnston, RA. (2009). Pulmonary responses to subacute ozone exposure in obese vs. lean mice. J Appl Physiol 107: 1445

- 1452. http://dx.doi.org/10.1152/japplph ysiol.00456.2009

. Sienra

- Monge, JJ; Ramirez

- Aguilar, M; Moreno

- Macias, H; Reyes

- Ruiz, NI; Del Rio

- Navarro, BE; Ruiz

- Navarro, MX; Hatch, G; Crissman, K; Slade, R ; Devlin, RB; Romieu, I. (2004). Antioxidant supplementation and nasal inflammatory responses among young asthmatics exposed to high levels of ozone. Clin Exp Immunol 138: 317

- 322. http:// dx.doi.org/10.1111/j.1365

- 2249.2004.02606.x

. Silverman, RA; Ito, K. (2010). Age

- related association of fine particles and ozone with severe acute asthma in N ew York City. J Allergy Clin Immunol 125: 367

- 373.e365. http://dx.doi.org/10.1016/j.jaci.2009.10.061

. SSDAN CensusScope. (Social Science Data Analysis Network, CensusScope). (2010a). United States: Age distribution [Data Set]. Ann Arbor, Michigan: Social Science Data Analysis Network. Retrieved from http://www.censusscope.org/us/chart_age.htmlDraft

– Do Not Cite or Quote 8

- 42 September 2011 SSDAN CensusScope. (Social Science Data Analysis Network, CensusScope). (2010b). United States: Population by race [Data Set]. Ann Arbor, Michigan. Retrieved from http://www.censusscope.org/us/chart_race.html SSDAN CensusScope. (Social Science Data Analysis Network, CensusScope). (2010c). United States: Poverty by age [Data Set]. Ann Arbor, Michigan. Retrieved from http://www.censusscope.org/us/chart_poverty.html Stafoggia, M; Forastiere, F; Faustini, A; Biggeri, A; Bisanti, L; Cadum, E; Cernigliaro, A; Mallone, S; P andolfi, P; Serinelli, M; Tessari, R; Vigotti, MA; Perucci, CA. (2010). Susceptibility factors to ozone

- related mortality: A population

- based case

- crossover analysis. Am J Respir Crit Care Med 182: 376

- 384. http://dx.doi.org/10.1164/rccm.200908

- 1269OC

. Steinvil, A; Kordova

- Biezuner, L; Shapira, I; Berliner, S; Rogowski, O. (2008). Short

- term exposur e to air pollution and inflammation

- sensitive biomarkers. Environ Res 106: 51

- 61. Tankersley, CG; Kleeberger, SR. (1994). Ozone

- induced inflammation and alte red ventilation in genetically susceptible mice: A comparison of acute and subacute exposures. Toxicol Lett 72: 279

- 289. Tankersley, CG; Peng, RD; Bedga, D; Ga brielson, K; Champion, HC. (2010). Variation in echocardiographic and cardiac hemodynamic effects of PM and ozone inhalation exposure in strains related to Nppa and Npr1 gene knock

- out mice. Inhal Toxicol 22: 695

- 707. http://dx.doi.org/10.3109/08958378.2010.487549

. Thaller, EI; Petronella, SA; Hochman, D; Howard, S; Chhikara, RS; Brooks, EG. (2008 ). Moderate increases in ambient PM2.5 and ozone are associated with lung function decreases in beach lifeguards. J Occup Environ Med 50: 202

- 211. http://dx.doi.org/10.1097/JOM.0b013e31816386b4

. Torres, A; Utell, MJ; Morow, PE; Voter, KZ; Whitin, JC; Cox, C; Looney, RJ; Speers, DM; Tsai, Y; Frampton, MW. (1997). Airway inflammation in smokers and nons mokers with varying responsiveness to ozone. Am J Respir Crit Care Med 156: 728

- 736. Tovalin, H; Valverde, M; Morandi, MT; Blanco, S; Whitehead, L; Rojas, E. (2006). DNA damage in outdoor workers occupationally exposed to environmental air pollutants. Occup Environ Med 63: 230

- 236. Trenga, CA; Koenig, JQ; Williams, PV. (2001). Dietary antioxidants and ozone

- induced bronchial hyperresponsiveness in adults with asthma. Arch Environ Occup Health 56: 242

- 249. Triche, EW; Gent, JF; Holford, TR; Belanger, K; Bracken, MB; Beckett, WS; Naeher, L; McSharry, J,

- E; Leaderer, BP. (2006). Low

- level ozone exposure and respiratory symptoms in infants. Environ Health Perspect 114: 911

- 916. http://dx.doi.org/10.1289/ehp.8559

. U.S. Census Bureau. (2010). U.S. population projections [Data Set]. Retrieved from http://www.census.gov/population/www/projections/projectionsagesex.html U.S. EPA. (U.S. Environmental Protection Agency). (1996a). Air quality criteria for ozone and related photochemical oxidants. (EPA/600/P

- 93/004AF). Research Triangle Park, NC. U.S. EPA. ( U.S. Environmental Protection Agency). (2006a). Aging and toxic response: Issues relevant to risk assessment. (EPA/600/P

- 03/004A). Washington, DC. http://cfpub.epa.gov/ncea/cfm/record isplay.cfm?deid=156648

. U.S. EPA. (U.S. Environmental Protection Agency). (2006b). Air quality criteria for ozone and related photochemical oxidants. (EPA/600 /R

- 05/004AF). Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Research and Development. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=149923

. U.S. EPA. (U.S. Environmental Protection Agency). (2009d). Integrated science assessment for particulate matter. (EPA/600/R

- 08/139F). Research Triangle Park, NC. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=216546

. U.S. EPA. (U.S. Environmen tal Protection Agency). (2010c). Integrated science assessment for carbon monoxide. (EPA/600/R

- 09/019F). Research Triangle Park, NC. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?dei d=218686

. Vagaggini, B; Taccola, M; Clanchetti, S; Carnevali, S; Bartoli, ML; Bacci, E; Dente, FL; Di Franco, A; Giannini, D; Paggiaro, PL. (2002). Ozone expo sure increases eosinophilic airway response induced by previous allergen challenge. Am J Respir Crit Care Med 166: 1073

- 1077. Vagaggini, B; Bartoli, MLE; Cianc hetti, S; Costa, F; Bacci, E; Dente, FL; Di Franco, A; Malagrino, L; Paggiaro, P. (2010). Increase in markers of airway inflammation after ozone exposure can be observed also in stable treated asthmatics with minimal functional response to ozone. Respir Res 11: 5. http://dx.doi.org/10.1186/1465

- 9921

- 11

- 5

.Draft

– Do Not Cite or Quote 8

- 43 September 2011 Valacchi, G; Vasu, VT; Yokohama, W; Corbacho, AM; P hung, A; Lim, Y; Aung, HH; Cross, CE; Davis, PA. (2007). Lung vitamin E transport processes are affected by both age and environmental oxidants in mice. Toxicol Appl Pharmacol 222: 227

- 234. http://dx.doi.org/10.1016/j.taap.2007.04.010

. Valacchi, G; Pecorelli, A; Mencarelli, M; Maioli, E; Davis, PA. (2009). Beta

- carotene prevents ozone

- induced pr oinflammatory markers in murine skin. Toxicol Ind Health 25: 241

- 247. http://dx.doi.org/10.1177/0748233709103030

. Vancza, EM; Galdanes, K; Gunnison, A; Hatch, G; Gordon, T. (2009). Age, strain, and gender as factors for increased sensitivity of the mouse lung to inhaled ozone. Toxicol Sci 107: 535

- 543. http://dx.doi.org/10.1093/toxsci/kfn253

. Villeneuve, PJ; Chen, L; Stieb, D; Rowe, BH. (2006a). Associations between outdoor air poll ution and emergency department visits for stroke in Edmonton, Canada. Eur J Epidemiol 21: 689

- 700. Villeneuve, PJ; Chen, L; Rowe, BH; Coates, F. (2007). Out door air pollution and emergency department visits for asthma among children and adults: A case

- crossover study in northern Alberta, Canada. Environ Health Global Access Sci Source 6: 40. http://dx.doi .org/10.1186/1476

- 069X

- 6

- 40

. Voynow, JA; Fischer, BM; Zheng, S; Potts, EN; Grover, AR; Jaiswal, AK; Ghio, AJ; Foster, WM. (2009). NAD(P)H quinone oxidoreduct ase 1 is essential for ozone

- induced oxidative stress in mice and humans. Am J Respir Cell Mol Biol 41: 107

- 113. http://dx.doi.org/10.1165/rcmb.2008

- 0381OC

. Wagner, JG; Jiang, Q; Harkema, JR; Illek, B; Patel, DD; Ames, BN; Peden, DB. (2007). Ozone enhancement of lower airway allergic inflammation is prevented by gamma

- tocopherol. Free Radic Biol Med 43: 1176

- 1188. http://dx.doi.org/10.1016/j.freeradbiomed.2007.07.013

. Wagner, JG; Harkema, JR; J iang, Q; Illek, B; Ames, BN; Peden, DB. (2009). Gamma

- tocopherol attenuates
ozone
- induced exacerbation of allergic rhinosinusitis in rats. Toxicol Pathol 37: 481

- 491. http://dx.doi.org/10.1177/019 2623309335630

. Wattiez, R; Noel

- Georis, I; Cruyt, C; Broeckaert, F; Bernard, A; Falmagne, P. (2003). Susceptibility to oxidative stress: proteomic analysis of bronchoalveolar lavage from ozone

- sensitive and ozone

- resistant strains of mice. Proteomics 3: 658

- 665. http://dx.doi.org/10.1002/pmic.200300417

. Weinmann, GG; Weidenbach

- Gerbase, M; Foster, WM; Zacur, H; Frank, R. (1995a). Evidence for ozone

induced small

- airway dysfunction: Lack of menstrual

- cycle and gender effects. Am J Respir Crit Care Med 152: 988

- 996. Wenten, M; G auderman, WJ; Berhane, K; Lin, PC; Peters, J; Gilliland, FD. (2009). Functional variants in the catalase and myeloperoxidase genes, ambient air pollution, and respiratory

- related school absences: An example of epistasis in gene

- environment interactions. Am J Epidemiol 170: 1494

- 1501. http://dx.doi.org/10.1093/aje/kwp310

. Williams, AS; Leung, SY; Nath, P; Khora sani, NM; Bhavsar, P; Issa, R; Mitchell, JA; Adcock, IM; Chung, KF. (2007b). Role of TLR2, TLR4, and MyD88 in murine ozone

- induced airway hyperresponsiveness and neutrophilia. J Appl Physiol 103: 1189

- 1195. http://dx.doi.org/10.1152/japplphysiol.00172.2007

. Wong, C,

- M; Ou, C,

- Q; Thach, T,

- Q; Chau, Y,

- K; Chan, K,

- P; Ho, S,

- Y; Chung, RY; Lam, T
, - H; Hedley, AJ. (2007). Does regular exercise protect against air pollution

- associated mortality? Prev Med 44: 386

- 392. Wong, CM; Ou, CQ; Chan, KP; Chau, YK; Thach, TQ; Yang, L; Chung, RY; Thomas, GN; Peiris, JS; Wong, TW; Hedley, AJ; Lam, TH. (2008). The effects of air pollution on mortality in socially deprived urban areas in Hong Kong, China. Environ Health Perspect 116: 1189

- 1194. Wong, CM; Yang, L; Thach, TQ; Chau, PY; Chan, KP; Thomas, GN; Lam, TH; Wong, TW; Hedley, AJ; Peiris, JS. (2009). Modification by influenza on health effects of air pollution i n Hong Kong. Environ Health Perspect 117: 248

- 253. http://dx.doi.org/10.1289/ehp.11605

. Yu, M; Zheng, X; Witsch i, H; Pinkerton, KE. (2002). The role of interleukin

- 6 in pulmonary inflammation and injury induced by exposure to environmental air pollutants. Toxicol Sci 68: 488

- 497. Zanobetti, A; Schwartz, J. (2008a). Is there adaptation in the ozone mortality relationship: A multi

- city case

crossover analysis. Environ Health 7: 22. http://dx.doi.org/10.1186/1476

- 069X

- 7

- 22

.