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8 POPULATIONS POTENTIALLY AT INCREASED 

RISK FOR OZONE-RELATED HEALTH EFFECTS 

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

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

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

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

5 effects in response to ambient air pollution (Preface to this ISA). To facilitate the 

6 identification of populations at greater risk for O3-related health effects, studies have 

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

8 individual to O3. The definitions of susceptibility and vulnerability have been found to 

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

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

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

12 some cases, the terms “at-risk” and “sensitive” populations have been used to encompass 

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

14 2010c, 2009d) have used an all encompassing definition for “susceptible population” to 

15 focus on identifying the populations at greater risk for O3-induced heath effects and 

16 circumvent the need to distinguish between susceptible and vulnerable factors. In this 

17 chapter, “at-risk” groups are defined as those with characteristics that increase the risk of 

18 O3-related health effects in a population. These characteristics include various factors, 

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

20 characteristics that may modify exposure to O3 (e.g., time spent outdoors). 

21 Individuals, and ultimately populations, could experience increased risk for O3-induced 

22 health effects due to: 

23  Intrinsically increased risk: This describes individuals at greater risk due to a 

24 biological mechanism;

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

26 external, non-biological factor; and

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

28 concentration due to breathing patterns or other factors

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

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

31 might be exposed to higher O3 concentrations due to less availability/use of home air 

32 conditioners (i.e., more open windows on high O3 days). 
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1 Examples of potential factors intrinsically related to increased risk through biological 

2 mechanisms are genetic background and sex, while extrinsic factors, such as SES, may 

3 also increase the risk of O3-related health effects. However, some factors that may lead to 

4 increased risk of O3-related health effects have both intrinsic and extrinsic components. 

5 For example, SES may affect access to medical care, which could then affect the 

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

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

8 their dose of O3, but they also have intrinsic differences compared to adults based on 

9 lung growth and development. 

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

11 potentially increase the risk of O3-related health effects, regardless of whether the 

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

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

14 between O3 and health effects, but does not categorize them as intrinsic factors, extrinsic 

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

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

17 discussed as appropriate throughout the chapter. 

18 Epidemiologic studies often conduct stratified analyses to identify the presence or 

19 absence of effect measure modification to indicate whether O3 differentially affects 

20 certain populations. This allows researchers to examine the effects of O3 exposure within 

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

22 help identify populations that are more at-risk to health effects associated with O3

23 exposure. Toxicological and controlled human exposure studies can provide support and 

24 biological plausibility for factors that may lead to increased risk for O3-related health 

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

26 disease or genetic polymorphisms that allow for comparisons between subgroups. The 

27 results from these studies, combined with those results obtained through stratified 

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

29 increased risk of specific populations to O3-related health effects. 

30 This chapter discusses the epidemiologic, controlled human exposure, and toxicological 

31 studies evaluated in Chapters 5, 6, and 7 that provide information on potential at-risk 

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

33 studies that presented stratified results (e.g., males versus females or <65 years of age 

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

35 exposed to similar O3 concentrations and within the same study design. Numerous 

36 studies that focus on only one potentially at-risk population are described in previous 

37 chapters, but these studies are not discussed in detail in this chapter because of the lack of 
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1 an adequate comparison group within the study. Controlled human exposure studies that 

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

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

4 used animal models of disease were also evaluated for coherence and biological 

5 plausibility. 

6 Factors examined that may lead to increased risk of O3-related health effects based on the 

7 overall evidence integrated across disciplines are described in greater detail in the 

8 following sections.

8.1 Preexisting Disease/Conditions

9 Individuals with certain preexisting diseases are likely to constitute an at-risk population. 

10 Previous O3 AQCDs concluded that some people with preexisting pulmonary disease, 

11 especially asthma, are among those at increased risk from O3 exposure. Extensive 

12 toxicological evidence was available indicating that altered physiological, morphological 

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

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

15 O3 exposure. In addition, a number of epidemiologic studies found that some individuals 

16 with respiratory diseases are at increased risk of O3-related effects. Little evidence, 

17 however, was available on the potential for increased risk for people with other 

18 preexisting conditions, such as cardiovascular diseases.

19 Recent studies that examined whether preexisting diseases and conditions lead to 

20 increased risk of O3-induced health effects were identified and are summarized below. 

21 Table 8-1 displays the prevalence rates of some of these conditions categorized by age 

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

23 presented within sections. Substantial proportions of the U.S. population are affected by 

24 these conditions and therefore may represent a potentially large at-risk population. While 

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

26 development may have intrinsic or extrinsic origins.
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Table 8-1 Prevalence of respiratory diseases, cardiovascular diseases, and 

diabetes among adults 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

Asthmaa 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

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

2 individuals to O3-related health effects, although there are only a limited number of 

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

4 influenza intensity resulted in increased excess risk of respiratory disease hospitalizations 

5 related to O3 exposure (Wong et al., 2009). In addition, a study of lung function in 

6 asthmatic children reported decreases in lung function with increased short-term O3

7 exposure for those with upper respiratory infections but not for those without infections 

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

9 in O3-induced health effects observed in epidemiologic studies that examined infections. 

10 Toxicological studies demonstrated that 0.08 ppm O3 increased streptococcus-induced 

11 mortality, regardless of whether O3 exposure precedes or follows infection (Miller et al., 

12 1978; Coffin and Gardner, 1972; Coffin et al., 1967). Ozone exposure likely impairs host 

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

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

15 risk of an O3-induced health effect.

8.1.2 Asthma

16 Previous O3 AQCDs identified individuals with asthma as a population at risk for O3-

17 related health effects. Within the U.S., approximately 12% of adults have reported ever 
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1 having asthma (Pleis et al., 2009). The prevalence of asthma is approximately 7.2%. 

2 16.2%, and 16.6% among U.S. children aged 0-4, 5-11, and 12-17, respectively (Bloom 

3 et al., 2008).

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

5 increased risk of O3-related health effects among individuals with asthma. A study of 

6 lifeguards in Texas reported decreased lung function with short-term O3 exposure among 

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

8 those with asthma (Thaller et al., 2008). A Mexican study of children ages 6-14 detected 

9 an association between short-term O3 and wheeze, cough, and bronchodilator use among 

10 asthmatics but not non-asthmatics, although this may have been the result of a small 

11 non-asthmatic population (Escamilla-Nuñez et al., 2008). A study of the modification of 

12 the effect of greater O3 associated decreases in short-term O3 exposure on lung function 

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

14 greater O3-associated decreases in lung function in elderly individuals with AHR, 

15 especially among those who were obese (Alexeeff et al., 2007). However, no evidence 

16 for increased risk was found in a study performed among children in Mexico City that 

17 examined the effect of short-term O3 exposure on respiratory health (Barraza-Villarreal et 

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

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

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

21 between O3 concentration and exhaled nitric oxide fraction (FeNO) that persisted both 

22 among children with and without asthma as well as those with and without respiratory

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

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

25 short-term O3 exposure and altered lung function for either asthmatic or non-asthmatic 

26 adults, but did note a decrease in lung function among individuals with allergies. 

27 Additional evidence for difference in effects among asthmatics has been observed in 

28 studies that examined the association between O3 exposure and altered lung function by 

29 asthma medication use. A study of children with asthma living in Detroit reported a 

30 greater association between short-term O3 and lung function for corticosteroid users 

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

32 found decreased lung function among noncorticosteroid users compared to users, 

33 although in this study, a large proportion of non-users were considered to be persistent 

34 asthmatics (Hernández-Cadena et al., 2009). Lung function was not related to short-term 

35 O3 exposure among corticosteroid users and non-users in a study taking place during the 

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

37 inflammation reported a counterintuitive inverse association with O3 of similar 

38 magnitude for all groups of corticosteroid users and non-users (Qian et al., 2009).
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1 Controlled human exposure studies that have examined the effects of O3 on both 

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

3 the 1996 and 2006 O3 AQCDs, subjects with asthma appeared to be more sensitive to 

4 acute effects of O3 in terms of FEV1 and inflammatory responses than healthy 

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

6 mild-to-moderate asthmatics, on average, experienced double the O3-induced FEV1

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

8 statistically significant positive correlation between FEV1 responses to O3 exposure and 

9 baseline lung function was observed in individuals with asthma, i.e., responses increased 

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

11 have smaller O3-induced FEV1 decrements than healthy subjects (3% versus 8%, 

12 respectively) (Mudway et al., 2001). However, the asthmatics in that study also tended to 

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

14 since FEV1 responses to O3 exposure diminish with age. Individuals with asthma also 

15 had significantly more neutrophils in the BALF (18 hours postexposure) than similarly 

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

17 Furthermore, one newer study examined the effects of O3 on both individuals with atopic 

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

19 higher levels of cytokines and hyaluronan, and greater expression of macrophage 

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

21 with healthy controls. Differences in O3-induced epithelial cytokine expression were 

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

23 2003). Cell-surface marker and cytokine expression results, and the presence of 

24 hyaluronan, are consistent with O3 having greater effects on innate and adaptive 

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

26 have demonstrated that O3 exposure leads to increased bronchial reactivity to inhaled 

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

28 influx of eosinophils in individuals with pre-existing allergic disease (Vagaggini et al., 

29 2002; Peden et al., 1995). Taken together, these results point to several mechanistic 

30 pathways which could account for the enhanced sensitivity to O3 in subjects with asthma 

31 (see Section 5.4.2.2).

32 Toxicological studies provide biological plausibility for greater effects of O3 among 

33 those with asthma or AHR. In animal toxicological studies, an asthmatic phenotype is 

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

35 evidence that O3 exposure is an inducer of AHR and remodeling utilize these types of 

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

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

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

39 demonstrated adverse changes in pulmonary function in mice exposed to O3, and Wagner 
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1 et al. (2007) demonstrated enhanced inflammatory responses in rats exposed to O3, but 

2 only in animals sensitized to allergen. In general, it is the combined effects of O3 and 

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

4 bleomycin induced pulmonary fibrosis model, exposure to 250 ppb O3 for 5 days 

5 increased pulmonary inflammation and fibrosis, along with the frequency of 

6 bronchopneumonia in rats. Thus, short-term exposure to O3 may enhance damage in a 

7 previously injured lung (Oyarzún et al., 2005). 

8 In the 2006 O3 AQCD, the potential for individuals with asthma to have greater risk of 

9 O3-related health effects was supported by a number of controlled human exposure 

10 studies, evidence from toxicological studies, and a limited number of epidemiologic 

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

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

13 measure modification of the relationship between short-term O3 exposure and altered 

14 lung function by corticosteroid use provided limited evidence of O3-related health 

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

16 differences in O3 concentration across the studies. Additionally, recent studies of 

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

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

19 time outdoors), which may underestimate the observed associations in studies that 

20 examined the effect of O3 exposure on respiratory health (Neidell and Kinney, 2010). 

21 This could explain some inconsistency observed among recent epidemiologic studies. 

22 The evidence from controlled human exposure studies provides support for increased 

23 detriments in FEV1 and greater inflammatory responses to O3 in individuals with asthma 

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

25 increased risk of O3-related health effects among individuals with asthma from controlled 

26 human exposure studies is supported by recent toxicological studies which provide 

27 biological plausibility for heightened risk of asthmatics to respiratory effects due to O3

28 exposure.

8.1.3 Chronic Obstructive Pulmonary Disease (COPD)

29 Although not extensively examined in the literature, initial evidence suggests that 

30 preexisting COPD may modify the association between short-term O3 exposure and 

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

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

33 COPD (Pleis et al., 2009).
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1 In a recent study, Peel et al. (2007) found that individuals with COPD were at increased 

2 risk of cardiovascular ED visits in response to short-term O3 exposure compared to 

3 healthy individuals in Atlanta, GA. The authors reported that short-term O3 exposure was 

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

5 among individuals with COPD compared to individuals without COPD. However, 

6 preexisting COPD did not increase the odds of hospitalization for all CVD outcomes (i.e. 

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

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

9 failure associated with O3 exposure on warm days (Lee et al., 2008a). An additional 

10 study also found no association between O3 exposure and lung function regardless of 

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

12 et al., 2006). 

13 Recent epidemiologic evidence indicates that persons with COPD may have increased 

14 O3-related cardiovascular effects, but little information is available for other O3-related 

15 health effects among individuals with COPD. 

8.1.4 Cardiovascular Disease

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

17 12% of adults reporting a diagnosis of heart disease (Table 8-1). A high prevalence of 

18 other cardiovascular-related conditions has also been observed, such as hypertension 

19 which is prevalent among approximately 24% of adults. In the 2006 O3 AQCD, little 

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

21 epidemiologic studies have examined cardiovascular-related diseases as modifiers of the 

22 O3-outcome associations; however, no recent evidence is available from controlled 

23 human exposure studies or toxicological studies. 

24 Peel et al. (2007) compared the associations between short-term O3 exposure and 

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

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

27 previously diagnosed with dysrhythmia, congestive heart failure, or hypertension 

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

29 between O3 concentrations and ischemic cerebrovascular events (ICVE) and myocardial 

30 infarction (MI) and the influence of multiple vascular risk factors on any observed 

31 associations (Henrotin et al., 2010). The association between O3 exposure and ICVE was 

32 elevated for individuals with multiple risk factors, specifically individuals with diabetes 

33 or hypertension. For the association between O3 and MI, increased odds were apparent 

34 only for those with hypercholesterolaemia. In a study conducted in Taiwan, a positive 
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1 association was observed for O3 on warm days and congestive heart failure hospital 

2 admissions (HAs), but the association did not differ between individuals with/without 

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

4 reported that the association between O3 levels and ED visits for arrhythmias were 

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

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

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

8 congestive heart failure (Chiu and Yang, 2009).

9 Although not studied extensively, a study has examined the increased risk of O3-related 

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

11 between O3 exposure and some, but not all, blood inflammatory markers among 

12 individuals with a history of CVD. Liao et al. (2005) found that fibrinogen was positively 

13 associated with short-term O3 exposure but this association was present only among 

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

15 history of CVD. However, for another biomarker (vWF), CVD status did not modify the 

16 positive association with short-term O3 exposure (Liao et al., 2005).

17 Mortality studies provide some evidence for a potential increase in O3-induced mortality 

18 in individuals with preexisting atrial fibrillation and atherosclerosis. In a study of 48 U.S. 

19 cities, increased risk of mortality with short-term O3 exposure was observed only among 

20 individuals with secondary atrial fibrillation (Medina-Ramón and Schwartz, 2008). No 

21 association was observed for short-term O3 exposure and mortality in a study of 

22 individuals with diabetes with or without CVD prior to death; however, there was some 

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

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

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

26 increased the risk of an O3-induced respiratory effect. Lagorio et al. (2006) examined the 

27 effect of O3 exposure on lung function among participants with a variety of preexisting 

28 diseases, including IHD. No association was observed regardless of whether the 

29 participant had IHD.

30 Overall, most short-term exposure studies did not report increased O3-related health 

31 effects for individuals with preexisting CVD, with the possible exception of O3 exposure 

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

33 increase the understanding of potential increased risk of O3-related health effects among 

34 this group.
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8.1.5 Diabetes 

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

2 8% of U.S. adults) are potentially at increased risk of O3-related health effects. In a study 

3 of short-term O3 exposure and cardiovascular ED visits in Atlanta, GA, no association 

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

5 conducted in Taiwan reported a positive association between O3 exposure on warm days 

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

7 diabetes was observed (Lee et al., 2008a). Finally, in a study of O3 exposure and ED 

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

9 diabetes on warm or cool days (Chiu and Yang, 2009).

8.1.6 Hyperthyroidism

10 Hyperthyroidism has been identified in toxicological studies as a potential factor that may 

11 lead to increased risk of O3-related health effects but has not yet been explored in 

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

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

14 hyperthyroid rats exhibited elevated levels of BAL neutrophils and albumin after a 4-hour 

15 exposure to O3, indicating O3-induced inflammation and damage. Hyperthyroidism did 

16 not affect production of reactive oxygen or nitrogen species, but BAL phospholipids were 

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

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

19 underlying evidence which suggests that individuals with hyperthyroidism may represent 

20 an at-risk population. 

8.2 Lifestage

21 The 1996 and 2006 O3 AQCDs identified children, especially those with asthma, and 

22 older adults as at-risk populations. These previous AQCDs reported clinical evidence that 

23 children have greater spirometric responses to O3 than middle-aged and older adults

24 (U.S. EPA, 1996a). Similar results were observed for symptomatic responses and O3

25 exposure. Among older adults, most studies reported in the 2006 O3 AQCD reported 

26 greater effects of short-term O3 exposure and mortality compared to other age groups. 

27 New evidence, summarized below, further supports these findings.
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8.2.1 Children 

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

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

3 to be more at risk for O3-related health effects compared to adults because they spend 

4 more time outside and are more highly active, especially during the summer when O3

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

6 systems are undergoing lung growth until about 18-20 years of age and are therefore 

7 thought to be intrinsically more at risk for O3-induced damage (U.S. EPA, 2006b). 

8 The 1996 O3 AQCD, reported clinical evidence that children, adolescents, and young 

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

10 responses to O3 exposure, but have greater responses than middle-aged and older adults 

11 (U.S. EPA, 1996a). Sycalmptomatic responses (e.g., cough, shortness of breath, pain on 

12 deep inspiration) to O3 exposure, however, appear to increase with age until early 

13 adulthood and then gradually decrease with increasing age (U.S. EPA, 1996a). For 

14 subjects aged 18-36 years, McDonnell et al. (1999) reported that symptom responses 

15 from O3 exposure also decrease with increasing age. Complete lung growth and 

16 development is not achieved until 18-20 years of age in women and the early 20s for 

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

18 modeling reported regional extraction of O3 to be higher in infants compared to adults. 

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

20 children under the age of 5 years compared to the total airway surface area observed in 

21 adults (Sarangapani et al., 2003). 

22 Recent epidemiologic studies have been performed examining different age groups and 

23 their susceptibility to O3-related respiratory HAs and emergency department (ED) visits. 

24 A study in Cyprus of short-term O3 concentrations and respiratory HA detected possible 

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

26 15 years of age compared with those > 15 years of age. However, this difference was 

27 only apparent with a 2-day lag (Middleton et al., 2008). Similarly, a Canadian study of 

28 asthma-ED visits reported the strongest O3-related associations among 5- to 14-year olds 

29 compared to the other age groups (ages examined 0-75+) (Villeneuve et al., 2007). 

30 Greater O3-associated change in asthma-related ED visits were also reported among 

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

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

33 association between O3 exposure and asthma-related HAs for 6- to 18-year olds 

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

35 When examining long-term O3 exposure and asthma HA among children, associations 

36 were determined to be larger among children 1 to 2 years old compared to children 2 to 6 
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1 years old (Lin et al., 2008b). A few studies reported positive associations among both 

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

3 Kong examined O3 exposure and asthma-related HAs for ages 0 to14, 15 to 65, and >65 

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

5 14 and 14 to 65 age groups compared to the >65 age group. Another study looking at 

6 asthma-related ED visits and O3 exposure in Maine reported positive associations for all 

7 age groups (ages 2 to 65) (Paulu and Smith, 2008). Effects of O3 exposure on asthma 

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

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

10 statistically significant results at lag day 0, which the authors wrote, “suggests that 

11 children are more immediately responsive to adverse effects of O3 exposure” (Mar and 

12 Koenig, 2009). 

13 The evidence observed in epidemiologic studies is supported by recent toxicological 

14 studies which observed O3-induced health effects in immature animals. Early life 

15 exposures of multiple species of laboratory animals, including infant monkeys, resulted 

16 in changes in conducting airways at the cellular, functional, ultra-structural, and 

17 morphological levels. Carey et al. (2007) conducted a study of O3 exposure in infant 

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

19 exposed either acutely for 5 days to 0.5 ppm O3, or episodically for 5 biweekly cycles 

20 alternating 5 days of 0.5 ppm O3 with 9 days of filtered air, designed to mimic human 

21 exposure (70 days total). All monkeys acutely exposed to O3 had moderate to marked 

22 necrotizing rhinitis, with focal regions of epithelial exfoliation, numerous infiltrating 

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

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

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

26 observed in adult monkeys exposed continuously to 0.3 ppm O3 in another study 

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

28 antigen + O3 co-exposure) and cellular changes in conducting airways (increased 

29 numbers of inflammatory eosinophils) also manifested among the infant monkeys 

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

31 significantly stunted or altered versus control animals and this aberrant development was 

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

33 Similarly, rat fetuses exposed to O3 in utero had significant ultrastructural changes in 

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

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

36 lung cytokine levels (TNF, IL-1, KC, IL-6, and MCP-1) (Auten et al., 2009). In utero 

37 exposure of animals to PM augmented O3-induced airway hyper-reactivity in these pups 

38 as juveniles. 
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1 Age may affect the inflammatory response to O3 exposure. In comparing neonatal mice 

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

3 strains of neonates 24 hours after exposure to 0.8 ppm O3 for 5 hours (Vancza et al., 

4 2009). Three of these strains also exhibited increased BAL protein, although the two 

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

6 however, adults were more sensitive, indicating a strain-age interaction. Toxicological 

7 studies reported that the difference in effects among younger lifestage may be due to 

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

9 recent study demonstrated that 0.25 ppm O3 exposure differentially alters expression of 

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

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

12 al. (2007) found that aged mice had more vitamin E in their plasma but less in their lungs 

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

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

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

16 to an intermittent 7-day exposure to 0.5 ppm O3. Immature rats exhibited a higher 

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

18 toxicological studies reported an association between O3 exposure and bradycardia that 

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

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

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

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

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

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

25 modulating the changes in cardiopulmonary physiology after O3 exposure.

26 The previous and current human clinical and toxicological studies reported evidence of 

27 increased risk from O3 exposure for younger ages, which provides coherence and 

28 biological plausibility to the epidemiologic studies on children. Recent studies of 

29 respiratory HAs and ED visits observed inconsistent findings for associations among 

30 children and young adults, although generally studies reported positive associations 

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

32 also inconsistent findings regarding increased risk of O3-related health effects. The 

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

34 groups and outcomes examined. 
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8.2.2 Older Adults 

1 Older adults may be at greater risk of health effects associated with O3 exposure through 

2 a variety of intrinsic pathways. The gradual decline in physiological processes that occur 

3 with aging may lead to increased risk of O3-related health effects (U.S. EPA, 2006a). 

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

5 responses may allow the elderly to withstand increased continued O3 exposure. In 

6 addition, older adults, in general, have a higher prevalence of preexisting diseases 

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

8 O3-related health effects (see Table 8-1 that gives preexisting rates by age).With the 

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

10 12.4% of the U.S. population to 19.7% between 2000 to 2030, which is approximately 35 

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

12 population potentially at risk of O3-related health effects (SSDAN CensusScope, 2010a; 

13 U.S. Census Bureau, 2010). 

14 Multiple epidemiologic studies of O3 exposure and HAs were stratified by age groups. A 

15 positive association was reported between O3 levels and respiratory HAs for adults ≥65 

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

17 study, no association was observed between O3 concentration and respiratory mortality 

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

19 between O3 concentration and cardiovascular mortality was present among individuals ≥ 

20 65 years old but not among individuals < 65 years old. This inverse association among 

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

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

23 for hospital visits with previous day and cumulative 2-day O3 levels among those ≥ 

24 65 years old, whereas no association was present for individuals less than 65 years of age 

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

26 averages in any age group. A study examining O3 and HAs for CVD-related health 

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

28 years, although one lag-time did show an inverse effect for coronary heart disease among 

29 elderly that was not present among 15- to 64-year olds (Halonen et al., 2009). No 

30 modification by age (40 to 64 year olds versus >64 year olds) was observed in a study 

31 from Brazil examining O3 levels and COPD ED visits (Arbex et al., 2009).

32 The majority of recent studies reported greater effects of short-term O3 exposure and 

33 mortality among older adults, which is consistent with the findings of the 2006 O3

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

35 adults ≥65 years old compared to those < 65 years (Medina-Ramón and Schwartz, 2008). 

36 Further investigation of this study population revealed no association between O3
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1 exposure and mortality until age 50 and a reduced effect after age 80 (Zanobetti and 

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

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

4 ≥85 years old compared to those in the 75 to 84 years old age range (Cakmak et al., 

5 2007). More recently, a study conducted in the same area reported similar associations 

6 between O3 exposure and mortality in adults aged < 64 years old and 65 to 74 years old, 

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

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

9 to 44 year olds), with statistically significant effects present only among those ≥65 years 

10 old (Kan et al., 2008). An Italian study reported higher risk of all-cause mortality 

11 associated with increased O3 concentrations among individuals ≥85 year old as compared 

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

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

14 Pollution and Health: A European and North American Approach (APHENA) project 

15 examined the association between O3 exposure and mortality for those <75 and ≥ 

16 75 years of age. In Canada, the associations for all-cause and cardiovascular mortality 

17 were greater among those ≥75 years old in the summer-only and all-year analyses. Age 

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

19 the association for all-cause mortality was slightly greater for those <75 years of age 

20 compared to those ≥75 years old in summer-only analyses. No consistent pattern was 

21 observed for CVD mortality. In Europe, slightly larger associations for all-cause 

22 mortality were observed in those <75 years old in all-year and summer-only analyses. 

23 Larger associations were reported among those <75years for CVD mortality in all-year 

24 analyses, but the reverse was true for summer-only analyses (Katsouyanni et al., 2009). 

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

26 toxicological studies. Respiratory symptom responses to O3 exposure appears to increase 

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

28 EPA, 1996a), which may put them at increased risk by withstanding continued O3

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

30 toxicological study. O3 exposure resulted in an increase in left ventricular chamber 

31 dimensions at end diastole (LVEDD) in young and old mice, whereas decreases in left 

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

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

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

35 regions affected by age-related neurodegenerative diseases, may be more sensitive to 

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

37 exposed to 1 ppm O3 for 4 hours, O3-induced lipid peroxidation occurred to a greater 

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

39 rats (Rivas-Arancibia et al., 2000). In young mice, healing of skin wounds is not 
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1 significantly affected by O3 exposure (Lim et al., 2006). However, exposure to 0.5 ppm 

2 O3 for 6 h/day significantly delays wound closure in aged mice.

3 Although some outcomes reported mixed findings regarding an increase in risk for older 

4 adults, recent studies of O3 exposure and mortality reported associations present for older 

5 adults. This is consistent with the results reported in the 2006 O3 AQCD.

8.3 Sex

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

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

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

9 2010a). The 2006 O3 AQCD did not report evidence of differences between the sexes in 

10 health responses to O3 exposure. Recent epidemiologic studies have evaluated the effects 

11 of short-term and long-term exposure to O3 on multiple health endpoints stratified by sex 

12 and overall, the results are inconsistent. 

13 A study in Maine that examined short-term O3 concentrations and asthma ED visits 

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

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

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

17 reported no associations between short-term O3 and respiratory infection HAs for either 

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

19 reported a slightly higher but non-statistically significant increase in respiratory HA for 

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

21 Kong examining individuals of all ages reported no effect measure modification by sex 

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

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

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

25 al., 2009). Higher levels of respiratory HA with greater O3 concentrations was also 

26 observed for females in a study of individuals living in Cyprus (Middleton et al., 2008). 

27 A study of lung function unrelated to HA and ED visits was conducted among lifeguards 

28 in Texas and reported decreased lung function with increased O3 exposure among 

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

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

31 measure modification of the association between long-term O3 exposure and asthma HA 

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

33 In addition to examining the potential modification of O3 associations with respiratory 

34 outcomes by sex, studies also examined cardiovascular-related outcomes specifically 
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1 HAs and ED visits. All of these studies reported no effect modification by sex with some 

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

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

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

5 associations between O3 concentrations and risk of ischemic strokes (not limited to ED 

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

7 3 days (Henrotin et al., 2007). A positive association was reported for males with a lag of 

8 1 day, but this association was null for females. The authors noted that men in the study 

9 had much higher rates of current and former smoking than women (67.4% versus 9.3%). 

10 A biomarker study investigating the effects of O3 concentrations on high-sensitivity 

11 C-reactive protein (hs-CRP), fibrinogen, and white blood cell (WBC) count, reported 

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

13 of the associations were null for males and females although one association between O3

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

15 positive association was null or negative when other pollutants were included in the 

16 model. Only one study examining correlations between O3 levels and oxidative DNA 

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

18 stronger correlations for males than females, both during short-term exposure (less than 

19 30 days) and long-term exposure (0-90 days). However, the authors commented that this 

20 difference could have been partially explained by different distributions of exposure to 

21 traffic pollution at work.

22 A few studies have examined the association between short-term O3 concentrations and 

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

24 consistent in reporting elevated risks among females. These studies, conducted in the 

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

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

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

28 ≥60 years old (Medina-Ramón and Schwartz, 2008). However, a recent study in Chile 

29 reported similar associations between O3 exposure and mortality among both men and 

30 women (Cakmak et al., 2011). One long-term O3 exposure study of respiratory mortality 

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

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

33 Experimental research provided a further understanding of the underlying mechanisms 

34 that may explain a possible differential risk in O3-related health effects among males and 

35 females. Several studies have suggested that physiological differences between sexes 

36 may predispose females to a greater susceptibility to O3. In females, lower plasma and 

37 nasal lavage fluid (NLF) levels of uric acid (most prevalent antioxidant), the initial 
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1 defense mechanism of O3 neutralization, may be a contributing factor (Housley et al., 

2 1996). Consequently, reduced absorption of O3 in the upper airways of females may 

3 promote its deeper penetration. Dosimetric measurements have shown that the absorption 

4 distribution of O3 is independent of sex when absorption is normalized to anatomical 

5 dead space (Bush et al., 1996). Thus, a differential removal of O3 by uric acid seems to 

6 be minimal. In general, the physiologic response of young healthy females to O3

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

8 few studies have examined changes in O3 responses during various menstrual cycle 

9 phases. Lung function response to O3 was enhanced during the follicular phase of the 

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

11 1993). However, Seal et al. (1996) later reported no effect of menstrual cycle phase in 

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

13 et al. (1993) more precisely defined the menstrual cycle phase. Another study also 

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

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

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

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

18 inflammation and injury after a 5-h exposure to 0.8 ppm O3, and although adult females 

19 were generally more susceptible, these differences were strain-dependent, with some 

20 strains exhibiting greater susceptibility in males (Vancza et al., 2009). The most obvious 

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

22 or inflammation among several of the strains.

23 Overall, results have varied, with recent evidence for increased risk for O3-related health 

24 effects present for females in some studies and males in other studies. Most studies 

25 examining the associations O3 and mortality report females to be at greater risk than 

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

27 outcomes. Inconsistent findings were reported on whether effect measure modification 

28 exists by sex for respiratory and cardiovascular HAs and ED visits. 

8.4 Genetics

29 Multiple studies that examined the effect of short- and long-term O3 exposure on 

30 respiratory function have focused on whether various gene profiles modify the effect of 

31 O3 on various health effects. A study of wheeze in infants reported larger associations 

32 between short-term O3 exposure and wheeze and difficulty breathing in infants whose 

33 mothers have asthma compared to infants of mothers without asthma, illustrating the 

34 potential for genetics to play a role in O3-related health effects (Triche et al., 2006).
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1 Multiple genes, including glutathione S-transferase Mu 1 (GSTM1) and tumor necrosis 

2 factor-α (TNF-α) were evaluated in the 2006 O3 AQCD and found to have a “potential 

3 role... in the innate susceptibility to O3.” Studies performed since the 2006 O3 AQCD 

4 have continued to examine the roles of GSTM1 and TNF-α on O3-related health effects 

5 and have also examined other gene variants that may increase the risk of O3-related 

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

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

8 important for O3-related health effects may not have been examined.

9 Epidemiologic studies that examined the effects of short-term exposure to O3 on lung 

10 function included analyses of potential gene-environment interactions. Romieu et al. 

11 (2006) reported an association between O3 and respiratory symptoms that were larger 

12 among children with GSTM1 null or glutathione S-transferase P 1 (GSTP1) Val/Val 

13 genotypes. However, results suggested that O3-associated decreases in lung function may 

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

15 Alexeef et al. (2008) reported greater decreases in lung function among GSTP1 Val/Val 

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

17 lung function for adults with long GT dinucleotide repeats in heme-oxygenase-1 

18 (HMOX1) promoters.

19 Several controlled human exposure studies have reported that genetic polymorphism of 

20 antioxidant enzymes may modulate pulmonary function and inflammatory response to O3

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

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

23 function parameters with exposure to O3 (Bergamaschi et al., 2001). Adults with GSTM1 

24 null only genotype did not show the same response to O3. In contrast, asthmatic children 

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

26 decreases in lung function in relation to O3 exposure. In a similar study, Vagaggini et al. 

27 (2010) exposed mild-to-moderate asthmatics to O3 during moderate exercise. In subjects 

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

29 inflammatory responses to O3. Kim et al. (2011) also recently conducted a study among 

30 young adults, about half of whom were GSTM1-null and half of whom were 

31 GSTM1-sufficient. They detected no difference in the FEV1 responses to O3 exposure by 

32 GSTM1 genotype. 

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

34 (n=16; 25 ± 5) genotypes exposed to 400 ppb O3 for 2 hours with exercise, Alexis et al. 

35 (2009) found genotype effects on inflammatory responses but not lung function responses 

36 to O3. At 4 hours post O3 exposure, individuals with either GSTM1 genotype had 

37 significant increases in sputum neutrophils with a tendency for a greater increase in 
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1 GSTM1 sufficient than GSTM1 nulls. At 24 hours postexposure, neutrophils had 

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

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

4 than both baseline levels and levels at 24 hours in the GSTM1 sufficient individuals. In 

5 addition, O3 exposure increased the expression of the surface marker CD14 in airway 

6 neutrophils of GSTM1 null subjects compared with GSTM1 sufficient subjects. CD14 

7 and TLR4 are co-receptors for endotoxin, and signaling through this innate immune 

8 pathway has been shown to be important for a number of biological responses to O3

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

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

11 demonstrated decreased numbers of airway macrophages at 4 and 24 hours following O3

12 exposure in GSTM1 sufficient subjects. Airway macrophages in GSTM1 null subjects 

13 were greater in number and found to have greater oxidative burst and phagocytic 

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

15 cells from GSTM1 null subjects exposed to O3 expressed higher levels of the surface 

16 marker HLA-DR, again suggesting activation of the innate immune system. Since there 

17 was no FA control in the Alexis et al. (2009) study, effects of the exposure other than O3

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

19 additional, better-controlled studies are needed to clarify the influence of genetic 

20 polymorphisms on O3 responsiveness in humans.

21 Several epidemiologic studies of long-term O3 exposure examined interactions with 

22 different gene variants, including GSTP1, HMOX1, and TNF-α using data from the 

23 Children’s Health Study. A study among children reported a three-way interaction effect 

24 between Ile105 homozygotes of GSTP1, O3 exposure, and playing more than two team 

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

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

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

28 modification were examined for the association between genotypes and new-onset 

29 asthma (Salam et al., 2009). Reduced asthma risk was observed among atopic children 

30 living in high O3 concentration areas and having the ARG1 haplotypes. There was no 

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

32 symptoms was observed among asthmatic children in low O3 concentration areas with 

33 TNF-α variant G-308A (TNF-308GG genotype), a variant that may alter gene expression. 

34 There was no decrease in risk for children with this TNF-α variant and living in areas 

35 with high O3 concentrations. Additionally, this modification for high and low levels of 

36 O3 was not present among non-asthmatic children (Lee et al., 2009b). Wenten et al. 

37 (2009) observed increased risk of respiratory-related school absences among children 

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

39 children were living in high O3 concentration areas.
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1 In general, toxicological studies have reported differences in cardiac and respiratory 

2 effects after O3 exposure among different mouse strains, which alludes to differential risk 

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

4 Hamade and Tankersley, 2009; Hamade et al., 2008). Thus strains of mice which are 

5 prone to or resistant to O3-induced effects have been used to systematically identify 

6 candidate genes that may increase risk of O3-related health effects. Genome wide linkage 

7 analyses have identified quantitative trait loci for O3-induced lung inflammation and 

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

9 (Kleeberger et al., 2000), respectively, using recombinant inbred strains of mice. More 

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

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

12 candidate susceptibility genes (Kleeberger et al., 2000; Kleeberger et al., 1997). The TNF 

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

14 hyperreactivity in studies of O3-exposed knockout mice (Cho et al., 2001). In addition to 

15 Tlr4, other innate immune pattern recognition signaling pathway genes, including Tlr2 

16 and Myd88, appear to be important in responses to O3, as demonstrated by Williams et 

17 al. (2007b). A role for the inflammatory cytokine IL-6 has been demonstrated in 

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

19 al., 2005b; Yu et al., 2002). Mice deficient in IL-10, an anti-inflammatory cytokine, 

20 demonstrated increased pulmonary inflammation in response to O3 exposure (Backus et 

21 al., 2010). Thus genes related to innate immune signaling and pro- and anti-inflammatory 

22 genes are important for O3-induced responses.

23 Altered O3 responses between mouse strains could be due to genetic variability in 

24 nuclear factor erythroid 2-related factor 2 (Nrf-2), suggesting a role for genetic 

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

26 2007). Additionally, some studies have reported O3-related effects to vary by Inf-1 and 

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

28 Clara cell secretory protein (CCSP) (Broeckaert et al., 2003; Wattiez et al., 2003). Other 

29 investigations in inbred mouse strains found that differences in expression of certain 

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

31 responsible for phenotypic characteristics, such as epithelial permeability and scavenging 

32 of oxidized lipids, respectively, which confer sensitivity to O3.

33 Nitric oxide (NO), derived from activated macrophages, is produced upon exposure to O3

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

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

36 (Kleeberger et al., 2001), and it appears that O3-induced iNOS expression is tied to the 

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

38 nitrogen intermediates after O3 exposure, in contrast to their wild-type counterparts, and 
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1 also produce less PGE2 comparatively (Fakhrzadeh et al., 2002). These gene-deficient 

2 mice were protected from O3-induced lung injury and inflammation. In contrast, another 

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

4 iNOS deficient mice were more susceptible to O3-induced lung damage (Kenyon et al., 

5 2002). Therefore it is unclear whether inducible nitric oxide synthase plays a protective 

6 role or mediates damage.

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

8 counterparts, are resistant to O3-induced AHR and inflammation. NQO1 catalyzes the 

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

10 reactions and redox cycling reactions resulting in the generation of reactive oxygen 

11 species. Reduced production of inflammatory mediators and cells and blunted AHR were 

12 observed in NQO1 null mice after exposure to 1 ppm O3 for 3 hours. These results 

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

14 treated with an NQO1 inhibitor exhibited reduced inflammatory responses to exposure to 

15 0.4 ppm O3 for 5 hours. This study may provide biological plausibility for the increased 

16 biomarkers of oxidative stress and increased pulmonary function decrements observed in 

17 O3-exposed individuals bearing both the wild-type NQO1 gene and the null GSTM1 gene 

18 (Corradi et al., 2002; Bergamaschi et al., 2001).

19 The role of TNF-α signaling in O3-induced responses has been previously established 

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

21 effects of combined O3 and PM exposure in transgenic TNF overexpressing mice. 

22 Kumarathasan et al. (2005) found that subtle effects of these pollutants were difficult to 

23 identify in the midst of the severe pathological changes caused by constitutive TNF-α 

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

25 susceptible to O3/PM-induced oxidative stress, and they exhibited elevation of a serum 

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

27 related effects. Differential susceptibility to O3 among inbred strains of animals does not 

seem to be dose dependent since absorption of 18 28 O in various strains of mice did not 

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

30 Defects in DNA repair mechanisms may also confer increased risk of O3-related health 

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

32 characterized by UV sensitivity abnormalities, neurological abnormalities, and premature

aging. The same genetic defect in mice (Csb-/- 33 ) makes them sensitive to oxidative 

stressors, including O3. Kooter et al. (2007) demonstrated that Csb-/- 34 mice produced 

35 significantly more TNF-α after exposure to 0.8 ppm O3 than their wild-type counterparts. 

36 However, there were no significant differences in other markers of inflammation or lung 
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1 injury between the two strains of mice. Further discussion of candidate genes in the 

2 context of their respective signaling pathways can be found in Chapter 5.

3 Overall, multiple genes, such as GSTM1, GSTP1, HMOX-1, NQO1, and TNF-α, appear 

4 to potentially be involved in populations being more at-risk than others to the effects of 

5 O3 exposure on health. Future studies of these and other genes in human populations will 

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

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

8 studies of rodents have identified a number of other genes that may affect O3-related 

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

10 power limitations.

8.5 Diet

11 Diet was not examined as a factor affecting risk in previous O3 AQCDs, but recent 

12 studies have examined modification of the association between O3 and health effects by 

13 dietary factors. Because O3 mediates some of its toxic effects through oxidative stress, 

14 the antioxidant status of an individual is an important factor that may contribute to 

15 increased risk of O3-related health effects. Supplementation with vitamin E has been 

16 investigated in a number of studies as a means of inhibiting O3-mediated damage. 

17 Epidemiologic studies have examined effect measure modification by diet and found 

18 evidence that certain dietary components are related to the effect O3 has on respiratory 

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

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

21 high vitamins C and E and omega-3 fatty acid content, protected against O3-related 

22 decreases in lung function among children living in Mexico City. Another study 

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

24 and E (Sienra-Monge et al., 2004). Associations were detected between short-term O3

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

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

27 supplementation above the minimum dietary requirement in asthmatic children with a 

28 low intake of vitamin E might provide some protection against the nasal acute 

29 inflammatory response to ozone.”

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

31 have shown that the first line of defense against oxidative stress is antioxidants-rich 

32 extracellular lining fluid (ELF) which scavenge free radicals and limit lipid peroxidation. 

33 Exposure to O3 depletes the antioxidant level in nasal ELF probably due to scrubbing of 

34 O3 (Mudway et al., 1999a); however, the concentration and the activity of antioxidant 
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1 enzymes either in ELF or plasma do not appear to be related to O3 responsiveness (Samet 

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

3 dietary antioxidant supplementation have demonstrated some protective effects of 

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

5 lung function after O3 exposure but not on the intensity of subjective symptoms and 

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

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

8 protection to asthmatics by attenuating postexposure bronchial hyperresponsiveness 

9 (Trenga et al., 2001). 

10 Toxicological studies provide evidence of biological plausibility to the epidemiologic and 

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

12 O3-exacerbated nasal allergy responses in rats with γ-tocopherol treatment (a form of 

13 vitamin E). O3-induced inflammation and mucus production were also inhibited by 

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

15 deficiency and O3-induced responses. Guinea pigs deficient in vitamin C displayed only 

16 minimal injury and inflammation after exposure to O3 (Kodavanti et al., 1995). A recent 

17 study in mice demonstrated a protective effect of β-carotene in the skin, where it limited 

18 the production of proinflammatory markers and indicators of oxidative stress induced by 

19 O3 exposure (Valacchi et al., 2009). Deficiency of vitamin A, which has a role in 

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

21 appears to enhance the risk of O3-induced lung injury (Paquette et al., 1996). 

22 Differentially susceptible strains that were fed a vitamin A sufficient diet were observed 

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

24 respective differences in O3-related outcomes. In addition to the studies of antioxidants, 

25 one toxicological study examined protein deficiency. Protein deficiency alters the levels 

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

O3 has been shown to differentially affect Na+/K+ 27 ATPase, glutathione, and lipid 

28 peroxidation, depending on the nutritional status of the animal, but the significance of 

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

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

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

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

33 risk for O3 -related health effects. This is supported by controlled human exposure and 

34 toxicological studies.
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8.6 Body Mass Index and Physical Conditioning

Obesity, defined as a BMI of 30 kg/m2 1 or greater, is an issue of increasing importance in 

2 the U.S., with self-reported rates of 26.7% in 2009, up from 19.8% in 2000 (Sherry et al., 

3 2010). A few studies have been performed examining the association between BMI and 

4 O3-related changes in lung function. An epidemiologic study reported decreased lung 

5 function with increased short-term O3 exposure for both obese and non-obese subjects; 

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

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

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

9 differential effects of O3 exposure on lung function for individuals with varying BMIs. In 

10 a retrospective analysis of data from 541 healthy, nonsmoking, white males between the 

11 ages of 18-35 years from 15 studies conducted at the U.S. EPA Human Studies Facility in 

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

13 index (BMI) was found to be associated with enhanced FEV1 responses. The BMI effect 

14 was of the same order of magnitude but in the opposite direction of the age effect 

15 whereby FEV1 responses diminish with increasing age. In a similar analysis, Bennett et 

16 al. (2007) found enhanced FEV1 decrements following O3 exposure with increasing BMI 

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

18 healthy, nonsmoking men (BMI range 19.1 to 32.9). In the women, greater O3-induced 

19 FEV1 decrements were seen in individuals that were overweight/obese (BMI >25) 

20 compared normal weight (BMI from 18.5 to 25), and in normal weight compared to 

21 underweight (BMI <18.5). Even disregarding the five underweight women, a greater O3

22 response in the overweight/obese category (BMI >25) was observed compared with the 

23 normal weight group (BMI from 18.5 to 24.9). 

24 Studies in genetically and dietarily obese mice have shown enhanced pulmonary 

25 inflammation and injury with acute O3exposure, but responses to longer exposures at a 

26 lower concentration appear to differ. A recent study found that obese mice are actually 

27 resistant to O3-induced pulmonary injury and inflammation and reduced lung compliance 

28 following exposure to 0.3 ppm O3 for 72 hours, regardless of whether obesity was 

29 genetic- or diet-induced (Shore et al., 2009). 

30 In addition to studies of obesity, physical conditioning affects BMI and may also affect 

31 the risk of O3-related health effects. The 2008 Summary of Health Statistics for U.S. 

32 Adults from the CDC reported the prevalence of regular leisure-time physical activity as 

33 slightly above 30% for adults ≥18 years of age in the U.S. (Pleis et al., 2009). Forty-nine 

34 percent of individuals ≥65 years old reported no leisure-time physical activity. A study of 

35 effect measure modification by exercise habits ten years prior to death observed excess 

36 risk of mortality with increasing O3 concentrations among individuals that never 
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1 exercised compared to individuals that exercised at least once a month for both adults 

2 ≥30 years of age and adults ≥65 years of age (Wong et al., 2007). No recent studies 

3 examining modification of O3-related health effects by current physical activity were 

4 identified. 

5 Multiple epidemiologic and human clinical studies have reported increased O3-related 

6 respiratory health effects among obese individuals. Future research of the effect 

7 modification of the relationship between O3 and other health-related outcomes besides 

8 respiratory health effects by BMI and studies examining the role of physical conditioning 

9 will advance understanding of obesity as a factor potentially increasing an individual’s 

10 risk. 

8.7 Socioeconomic Status 

11 SES is often represented by personal or neighborhood SES, educational attainment, 

12 health insurance status, and other such factors. SES is indicative of such things as access 

13 to healthcare, quality of housing, and pollution gradient. Based on the 2000 Census data, 

14 12.4% of Americans live in poverty (poverty threshold for family of four was $17,463) 

15 (SSDAN CensusScope, 2010c).

16 Multiple epidemiologic studies have reported individuals of low SES to have increased 

17 risk for the effects of short-term O3 exposure on respiratory HAs and ED visits. A study 

18 performed in Korea examined the association between O3 concentrations and asthma HA 

19 and reported larger effect estimates in areas of moderate and low SES compared with 

20 areas of high SES (SES was based on average regional insurance rates) (Lee et al., 2006). 

21 A Canadian study reported inverse effects of O3 on respiratory HA and ED visits 

22 regardless of SES, measured by average census tract household income (Burra et al., 

23 2009). In addition, a study conducted across 10 cities in Canada found the largest 

24 association between O3 exposure and respiratory HA was among those with an 

25 educational level less than grade 9, but no consistent trend in the effect was seen across 

26 quartiles of income (Cakmak et al., 2006b). In New York State, larger associations 

27 between long-term O3 exposure and asthma HA were observed among children of 

28 mothers who did not graduate from high school, whose births were covered by 

29 Medicaid/self-paid, or who were living in poor neighborhoods compared to children 

30 whose mothers graduated from high school, whose births were covered by other 

31 insurance, or who were not living in poor neighborhoods, respectively (Lin et al., 2008b). 

32 The examination of the potential effects of SES on O3-related cardiovascular health 

33 effects is relatively limited. A study conducted in Canada reported the association 

34 between short-term O3 and ED visits for cardiac disease by quartiles of 
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1 neighborhood-level education and income. No effect measure modification was apparent 

2 for either measure of SES (Cakmak et al., 2006a). 

3 Several studies were conducted that examined the modification of the relationship 

4 between short-term O3 concentrations and mortality by SES. A U.S. multicity study 

5 reported that communities with a higher proportion of the population unemployed had 

6 higher mortality effect estimates (Bell and Dominici, 2008). A study in seven urban 

7 centers in Chile reported on modification of the association between O3 exposure and 

8 mortality using multiple SES markers (Cakmak et al., 2011). Increased risk was observed 

9 among the categories of low SES for all measures (personal educational attainment, 

10 personal occupation, community income level). Additionally, the APHENA study, which 

11 examined the association between O3 and mortality by percentage unemployed, reported 

12 a higher percent change in mortality with increased percent unemployed but this varied 

13 across the regions included in the study (U.S., Canada, Europe) (Katsouyanni et al., 

14 2009). A Chinese study reported that the greatest effects between O3 concentrations and 

15 mortality at lag day 0 were among individuals living in areas of high social deprivation 

16 (i.e. low SES), but this association was not consistent across lag days (at other lag times, 

17 the middle social deprivation index category had the greatest association) (Wong et al., 

18 2008). However, another study in Asia comparing low to high educational attainment 

19 populations reported no evidence of greater mortality effects (total, CVD, or respiratory) 

20 (Kan et al., 2008). Additionally, a study in Italy reported no difference in risk of mortality 

21 among census-block level derived income levels (Stafoggia et al., 2010). A study of 

22 infant mortality in Mexico reported no association between O3 concentrations and infant 

23 mortality among any of the three levels of SES determined using a socioeconomic index 

24 based on residential areas (Romieu et al., 2004b). Another study in Mexico reported a 

25 positive association between O3 levels at lag 0 and respiratory-related infant mortality in 

26 only the low SES group (determined based on education, income, and household 

27 conditions across residential areas), but no association was observed in any of the SES 

28 groups with other lags (Carbajal-Arroyo et al., 2011).

29 Studies of O3 concentrations and reproductive outcomes have also examined associations 

30 by SES levels. A study in California reported greater decreases in birth weight associated 

31 with full pregnancy O3 concentration for those with neighborhood poverty levels of at 

32 least 7% compared with those in neighborhoods with less than 7% poverty (Morello33 Frosch et al., 2010). However, no dose response was apparent and those with 

34 neighborhood poverty levels of 7-21% had greater decreases observed for the association 

35 than those living in areas with poverty rates of at least 22%. An Australian study reported 

36 an inverse association between O3 exposure during days 31-60 of gestation and 

37 abdominal circumference during gestation (Hansen et al., 2008). The interaction with 

38 SES (area-level measured socioeconomic disadvantage) was examined and although the 
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1 inverse association remained statistically significant in only the highest SES quartile, 

2 there were large confidence interval overlaps among estimates for each quartile so no 

3 difference in the association for the quartiles was apparent.

4 Evidence from a controlled human exposure study that examined O3 effects on lung 

5 function does not provide support for greater O3-related health effects in individuals of 

6 lower SES. In a follow-up study (Seal et al., 1993) on modification by race, Seal et al. 

7 (1996) reported that, of three SES categories, individuals in the middle SES category 

8 showed greater concentration-dependent decline in percent-predicted FEV1 (4-5% at 

9 400 ppb O3) than in low and high SES groups. The authors did not have an “immediately 

10 clear” explanation for this finding and controlled human exposure studies are typically 

11 not designed to answer questions about SES. 

12 Overall, most studies of individuals have reported that individuals with low SES and 

13 those living in neighborhoods with low SES are more at risk for O3-related health effects,

14 resulting in higher odds of respiratory HAs and ED visits. Inconsistent results have been 

15 observed in the few studies examining effect modification of associations between O3

16 exposure and mortality and reproductive outcomes. 

8.8 Race/Ethnicity

17 Based on the 2000 Census, 69.1% of the U.S. population comprises non-Hispanic whites. 

18 Approximately 12.1% of people reported their race/ethnicity as non-Hispanic black and 

19 12.6% reported being Hispanic (SSDAN CensusScope, 2010b). 

20 Two studies examined the associations between short-term O3 concentrations and 

21 mortality and reported higher effect estimates among blacks (Medina-Ramón and 

22 Schwartz, 2008) and among communities with larger proportions of blacks (Bell and 

23 Dominici, 2008). Another study examined long-term exposure to O3 concentrations and 

24 asthma HAs among children in New York State. These authors reported no statistically 

25 significant difference in the odds of asthma HA for blacks compared to other races but 

26 did detect higher odds for Hispanics compared to non-Hispanics (Lin et al., 2008b). 

27 Additionally, recent epidemiologic studies have stratified by race when examining the 

28 association between O3 concentration and birth outcomes. A study conducted in Atlanta, 

29 GA reported decreases in birth weight with increased third trimester O3 concentrations 

30 among Hispanics but not among non-Hispanic whites (Darrow et al., 2011a). An inverse 

31 association was also present for non-Hispanic blacks but was not statistically significant. 

32 A California study reported that the greatest decrease in birth weight associated with full 

33 pregnancy O3 concentration was among non-Hispanic whites (Morello-Frosch et al., 
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1 2010). The inverse association was also apparent, although not as strong, for 

2 non-Hispanic blacks. Increased birth weight was associated with higher O3 exposure 

3 among Hispanics and among non-Hispanic Asians and Pacific Islanders but neither of 

4 these results were statistically significant.

5 Similar to the epidemiologic studies, a controlled human exposure study suggested 

6 differences in lung function responses by race (Seal et al., 1993). The independent effects 

7 of sex-race group and O3 concentration on lung function were positive, but the 

8 interaction between sex-race group and O3 concentration was not statistically significant. 

9 The findings indicated some overall difference between the sex-race groups that was 

10 independent of O3 concentration (the concentration-response curves for the four sex-race 

11 groups are parallel). In a multiple comparison procedure on data collapsed across all O3

12 concentrations for each sex-race group, both black men and black women had larger 

13 decrements in FEV1 than did white men. The authors noted that the O3 dose per unit of 

14 lung tissue would be greater in blacks and females than whites and males, respectively. 

15 That this difference in tissue dose might have affected responses to O3 cannot be ruled 

16 out. The college students recruited for the Seal et al. (1993) study were probably from 

17 better educated and more SES advantaged families, thus reducing potential for these 

18 variables to be confounding factors. Que et al. also examined pulmonary responses to O3

19 exposure in blacks of African American ancestry and in whites. On average, the black 

20 males experienced the greatest decrements in FEV1 following O3 exposure. This 

21 decrease was larger than the decrement observed among black females, white males, and 

22 white females. 

23 Overall, the results of recent studies suggest that there may be race-related increase in 

24 risk of O3-related health effects for some outcomes, although the overall understanding of 

25 potential effect measure modification by race is limited by the small number of studies. 

26 Additionally, these results may be confounded by other factors, such as SES. 

8.9 Smoking

27 Previous O3 AQCDs have concluded that smoking does not increase the risk of 

28 O3-related health effects; in fact, in controlled human exposure studies, smokers have 

29 been found to be at less risk of O3-related health effects than non-smokers. Data from 

30 recent interviews conducted as part of the 2008 National Health Interview Survey (NHIS) 

31 (Pleis et al., 2009) have shown the rate of smoking among adults ≥18 years old to be 

32 approximately 20% in the U.S. Approximately 21% of individuals surveyed were 

33 identified as former smokers. 
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1 Baccarelli et al. (2007) performed a study of O3 concentrations and plasma homocysteine 

2 levels (a risk factor for vascular disease). They found no interaction of smoking (smokers 

3 versus non-smokers) for the associations between O3 concentrations and plasma 

4 homocysteine levels. Another study examined the association between O3 and resting 

5 heart rate and also reported no interaction with smoking status (current smokers versus 

6 current non-smokers) (Ruidavets et al., 2005a). 

7 A study examining correlations between O3 levels and oxidative DNA damage examined 

8 results stratified by current versus never and former smokers (Palli et al., 2009). Ozone 

9 was positively associated with DNA damage for short-term and long-term exposures 

10 among never/former smokers. For current smokers, short-term O3 concentrations were 

11 inversely associated with DNA damage; however, the number of current smokers in the 

12 study was small (n=12). 

13 The findings of Palli et al. (2009) were consistent with those from controlled human 

14 exposure studies that have confirmed that smokers are less responsive to O3 exposure 

15 than non-smokers. Spirometric and plethysmographic pulmonary function decline, 

16 nonspecific AHR, and inflammatory responses of smokers to O3 exposure were all 

17 weaker than those reported for non-smokers. Similarly, the time course of development 

18 and recovery from these effects, as well as their reproducibility, was not different from 

19 non-smokers. Chronic airway inflammation with desensitization of bronchial nerve 

20 endings and an increased production of mucus may plausibly explain the 

21 pseudo-protective effect of smoking (Frampton et al., 1997b; Torres et al., 1997). 

22 These findings for smoking are consistent with previous AQCD conclusions. An 

23 epidemiologic study of O3-associated DNA damage reported smokers to be less at risk 

24 for O3-related health effects. However, both epidemiologic studies of short-term 

25 exposure and CVD outcomes found no effect measure modification by smoking.

8.10 Heightened Exposure 

26 Studies included in the 2006 O3 AQCD reported that individuals who participate in 

27 outdoor activities or work to be a population at increased risk based on consistently 

28 reported associations between O3 exposure and respiratory health outcomes in these 

29 groups (U.S. EPA, 2006b). Outdoor workers are exposed to ambient O3 concentrations 

30 outside for a greater period of time than individuals who spend their days indoors. 

31 Additionally, an increase in dose to the lower airways is possible during exercise due to 

32 both increases in the amount of air breathed (i.e., minute ventilation) and a shift from 

33 nasal to oronasal breathing (Sawyer et al., 2007; Nodelman and Ultman, 1999; Hu et al., 

34 1994). For further discussion of the association between FEV1 responses to O3 exposure 
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1 and minute ventilation, refer to Section 6.2.3.1 of the 2006 O3 AQCD. A recent study has 

2 explored the potential effect measure modification of O3 exposure and DNA damage by 

3 indoor/outdoor workplace (Tovalin et al., 2006). In a study of indoor and outdoor 

4 workers in Mexico, individuals who worked outdoors in Mexico City had a slight 

5 association between O3 exposure and DNA damage (measured by comet tail length 

6 assay), whereas no association was observed for indoor workers in Mexico City. Workers 

7 in another Mexican city, Puebla, demonstrated no association between O3 levels and 

8 DNA damage, regardless of whether they worked indoors or outdoors.

9 Air conditioning use is an important component of O3 exposure, as use of central air 

10 conditioning will limit exposure to O3 by blocking the penetration of O3 into the indoor 

11 environment (further information can be found in Section 4.4 of this ISA). Air 

12 conditioning use is a difficult effect measure modifier to examine in epidemiologic 

13 studies. Air conditioning use is often measured based on regional prevalence and may not 

14 reflect individual-level use. More generally, air conditioning prevalence is associated 

15 with temperature of a region; those areas with higher temperatures have a greater 

16 prevalence of households with air conditioning. Despite these limitations, a few studies 

17 have examined effect measure modification by prevalence of air conditioning use in an 

18 area. Studies examining multiple cities across the U.S. have assessed whether 

19 associations between O3 concentrations and HA and mortality varied among areas with 

20 high and low prevalence of air conditioning. Medina-Ramon et al. (2006) conducted a 

21 study during the warm season and observed a greater association between O3 levels and 

22 pneumonia HA among areas with a lower proportion of households having central air 

23 conditioning compared to areas with a larger proportion of households with air 

24 conditioning. The same trend of increased association for areas with a lower prevalence 

25 of central air conditioning was noted in a study of O3 concentrations and mortality (Bell 

26 and Dominici, 2008). Conversely, Medina-Ramón and Schwartz (2008) found that 

27 among individuals with atrial fibrillation, a lower risk of mortality was observed for areas 

28 with a lower prevalence of central air conditioning.

29 Previous work has shown that increased dose of O3 concentrations from outdoor work 

30 leads to increased risk of O3-related health effects among individuals who participate in 

31 outdoor activities or work, although there is no evidence of modification by outdoor 

32 activity in this recent study. Lower prevalence of air conditioning also appears to affect 

33 risk of O3–related health effects, but this is not true of all studies. Overall, increased 

34 exposure to outdoor air does appear to confer additional risk and individuals with greater 

35 exposure to outdoor air may experience more O3–related health effects.
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8.11 Healthy Responders

1 Within the general population, there is evidence for variability in responses to O3

2 exposure, with some healthy individuals demonstrating greater O3-related health effects 

3 compared to other healthy individuals in controlled human exposure studies. These 

4 individuals do not fit in any of the at-risk populations discussed in this chapter; however, 

5 studies have found that they have greater responses to O3 exposure than would be 

6 expected, indicating a unique population that needs to be considered.

7 Controlled human exposure studies have demonstrated a large degree of intersubject 

8 variability in lung function decrements, symptomatic responses, pulmonary 

9 inflammation, AHR, and altered epithelial permeability in healthy adults exposed to O3 

10 (Que et al.; Holz et al., 2005; McDonnell, 1996). The magnitude of increases in 

11 pulmonary inflammation, AHR, and epithelial permeability, in response to O3 exposure, 

12 do not appear to be correlated, nor are these responses correlated with changes in lung 

13 function (Que et al.; Balmes et al., 1997; Balmes et al., 1996; Aris et al., 1995). However, 

14 these responses to O3 exposure in healthy individuals tend to be reproducible within a 

15 given individual over a period of several months indicating differences in the intrinsic 

16 responsiveness of individuals (Holz et al., 2005; Hazucha et al., 2003; Holz et al., 1999; 

17 McDonnell et al., 1985a). It should be noted that even when group mean responses are 

18 small and seem physiologically insignificant, some intrinsically more responsive 

19 individuals experience distinctly larger effects under the same exposure conditions. For 

20 example, small group mean changes (e.g., <5%) in FEV1 have been observed in healthy 

21 young adults at levels as low as 120 ppb O3 for 1 to 3 hour exposure periods. However, 

22 some individuals within a study may experience FEV1 decrements in excess of 15% 

23 under these conditions, even with group mean decrements of less than 5%. Therefore, 

24 within the general population, a proportion of otherwise healthy individuals, who do not 

25 have characteristics discussed above that increase risk, may be at increased risk of 

26 O3-induced health effects.

8.12 Summary

27 In this section, epidemiologic, controlled human exposure, and toxicological studies have 

28 been evaluated that contribute information on potential at-risk populations. Overall, this 

29 review provides evidence that various factors may lead to increased risk of O3-related 

30 health effects. 

31 The populations identified in this section that are most at risk for O3-related health effects 

32 are individuals with influenza/infection, individuals with asthma, and younger and older 
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1 age groups. There were a small number of studies on influenza/infection but both 

2 reported influenza/infection to modify the association between O3 exposure and 

3 respiratory effects, with individuals having influenza or an infection being at increased 

4 risk. Asthma as a factor affecting risk was supported by controlled human exposure and 

5 toxicological studies, as well as some evidence from epidemiologic studies. Most studies 

6 comparing age groups reported greater effects of short-term O3 exposure on mortality 

7 among older adults, although studies of other health outcomes had inconsistent findings 

8 regarding whether older adults were at increased risk. Generally, studies of age groups 

9 also reported positive associations for respiratory HAs and ED visits among children.

10 Biological plausibility for this increased risk is supported by toxicological and clinical 

11 research. Diet and obesity are also both likely factors affecting risk. Multiple 

12 epidemiologic, controlled human exposure, and toxicological studies reported that diets 

13 deficient in vitamins E and C are associated with risk of O3-related health effects. 

14 Similarly, studies of effect measure modification by BMI observed greater O3-related 

15 respiratory decrements for individuals who were obese. 

16 Other potential factors [preexisting conditions (such as COPD and CVD), sex, and 

17 multiple genes (such as GSTM1, GSTP1, HMOX-1, NQO1, and TNF-α)] provided some 

18 evidence of increased risk, but further evidence is needed. In addition, examination of 

19 modification of the associations between O3 exposure and health effects by SES and race 

20 were available in a limited number of studies, and demonstrated possible increased odds 

21 of health effects related to O3 exposure among those with low SES and black race. 

22 Individuals with increased outdoor exposure were examined in a recent study of outdoor 

23 workers, in which no effect modification was observed, and studies of air conditioning 

24 prevalence, which demonstrated inconsistent findings. However, previous evidence along 

25 with biological plausibility from toxicological and controlled human studies has shown 

26 individuals exposed to more outdoor air to be at increased risk of O3-related health 

27 effects. Studies of physical conditioning and smoking were conducted but little evidence 

28 was available to determine whether increased risk of O3-related health effects is present 

29 for these factors. The only studies examining effect measure modification by diabetes 

30 examined O3 exposure and cardiovascular outcomes and none reported increased risks for 

31 individuals with diabetes. Toxicological studies also identified hyperthyroidism to be a 

32 factor warranting further examination. Future research will provide additional insight into 

33 whether these factors affect risk of O3-related health effects. 
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(2007). Air pollution, smoking, and plasma homocysteine. Environ Health Perspect 115: 176-181. 

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Balmes, JR; Aris, RM; Chen, LL; Scannell, C; Tager, IB; Finkbeiner, W; Christian, D; Kelly, T; Hearne, PQ; 

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