Chapter 8. Populations Susceptible to Ozone-related Health Effects
 

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

2 populations are at increased risk for detrimental effects of ambient exposure to an air pollutant. The 

3 NAAQS are intended to provide an adequate margin of safety for both the population as a whole and 

4 those individuals potentially at increased risk for health effects in response to ambient air pollution 

5 (Section 1.1). To facilitate the identification of populations at greater risk for O3-related health 

6 effects, studies have evaluated factors that contribute to the susceptibility and/or vulnerability of an 

7 individual to O3. The definition for both of these terms has been found to vary across studies, but in 

8 most instances susceptibility refers to biological or intrinsic factors (e.g., lifestage, sex) while 

9 vulnerability refers to non-biological or extrinsic factors (e.g., SES) (U.S. EPA, 2009, 179916; 

10 U.S. EPA, 2010, 626035). Additionally, in some cases, the terms “at-risk” and sensitive populations 

11 have been used to encompass these concepts more generally. However, in many cases, a factor 

12 identified that increases an individual's risk for morbidity or mortality effects from exposure to an air 

13 pollutant cannot be easily categorized as either a susceptibility or vulnerability factor. 

14 As developed in previous ISAs and reviews (Sacks et al., In Press, 664486; U.S. EPA, 2009, 

15 179916; U.S. EPA, 2010, 626035), an all encompassing definition for “susceptible population” is 

16 used to circumvent the need to distinguish between susceptible and vulnerable, and to identify the 

17 populations at greater risk for O3-induced heath effects. This definition identifies susceptible 

18 populations as the following: 

Individual- and population-level characteristics that increase the risk of O3-related health 

effects in a population including, but not limited to: genetic background, birth outcomes (e.g., 

low birth weight, birth defects), race, sex, lifestage, lifestyle (e.g., smoking status, nutrition), 

preexisting disease, SES (e.g., educational attainment, reduced access to health care), and 

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

19 To examine whether O3 differentially affects certain populations, epidemiologic studies 

20 conduct stratified analyses to identify the presence or absence of effect measure modification. A 

21 thorough evaluation of potential effect measure modifiers may help identify populations that are 

22 more susceptible to O3. Although the design of toxicological and controlled human exposure studies 

23 do not allow for the examination of effect measure modifiers, both can provide support and 

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

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

Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and 

Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of 

developing science assessments such as the Integrated Science Assessments (ISAs) and the Integrated Risk Information System (IRIS). 

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1 genetic polymorphisms that allow for comparisons between subgroups. Therefore, the results from 

2 these studies, combined with those results obtained through stratified analyses in epidemiologic 

3 studies, comprise the overall weight of evidence for the increased susceptibility of specific 

4 populations to O3-related health effects. 

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

6 studies evaluated in Chapters 5, 6, and 7 that provide information on potentially susceptible 

7 populations. The studies in this chapter include only those epidemiologic studies that presented 

8 stratified results (e.g., males versus females or <65 years of age versus ≥ 65 years of age). This 

9 approach allowed for a comparison between populations exposed to similar O3 concentrations and 

10 within the same study design. Thus, numerous studies that focus on only one potentially susceptible 

11 population are described in previous chapters, but these studies are not discussed in detail in this 

12 chapter because of the lack of an adequate comparison group within the study. Included controlled 

13 human exposure studies are those that consisted of individuals with an underlying disease or genetic 

14 polymorphism, or studies that categorized the study population by age, race, etc. Included 

15 toxicological studies were those with animal models of disease. 

16 Factors examined for possible susceptibility to O3-related health effects based on the overall 

17 evidence integrated across disciplines are described in greater detail in the following sections. 

8.1. Pre -exis ting Dis eas e/Conditions 

18 Individuals with pre-existing disease are likely to constitute a susceptible population. Recent 

19 studies that examined whether pre-existing diseases and conditions lead to increased susceptibility to 

20 O3 were identified and are summarized below. Table 8-1 displays the prevalence rates of these 

21 conditions by age and region among adults in the U.S. population. Substantial proportions of the 

22 U.S. population are affected by these conditions and therefore may represent a potentially large 

23 susceptible population. 

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Table 8-1. Prevalence of respiratory diseases, cardiovascular diseases, and diabetes by age and

region among individuals 18 years and older in the U.S. 

N (in thousands) Age Region 

Chronic Disease/Condition 18-44 45-64 65-74 75+ Northeast Midwest South West 

Respiratory Diseases 

Asthma 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 

Source: Pleis et al. (2009, 629608). 

8.1.1. Influe nza/In fec tion s 

1 Recent studies have indicated that underlying infections may increase susceptibility of 

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

3 of hospitalizations in Hong Kong reported that increased levels of influenza intensity resulted in 

4 increased excess risk of respiratory disease hospitalizations related to O3 exposure (Wong et al., 

5 2009, 196722). In addition, a study of lung function in asthmatic children reported decreases in lung 

6 function with increased short-term O3 exposure for those with upper respiratory infections but not 

7 those without infections (Lewis et al., 2005, 081079). 

8.1.2. As th ma/Cortico s te roid Us e 

8 Previous O3 AQCDs (U.S. EPA, 1996, 080828; U.S. EPA, 2006, 088089) identified asthmatic 

9 individuals as a population susceptible to O3-related health effects, and approximately 12% of adults 

10 have reported ever having asthma (Pleis et al., 2009, 629608). 

11 Multiple epidemiologic studies included in this ISA have evaluated the potential for the 

12 susceptibility of asthmatics to O3-related health effects. No evidence for increased susceptibility was 

13 found in a study that examined the effect of short-term O3 exposure on respiratory health (Barraza14 Villarreal et al., 2008, 156254). A positive association was reported for airway inflammation among 

15 asthmatic children, but the observed association was similar in magnitude to that of non-asthmatics. 

16 However, several studies have indicated some evidence for increased susceptibility of asthmatics 

17 related to O3 exposure. A study of lifeguards in Texas reported lung function decreases with short18 term O3 exposure among both asthmatics and non-asthmatics, however, the decrease was greater 

19 among asthmatics (Thaller et al., 2008, 195869). A Mexican study of children ages 6-14 detected an 

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association between short-term O3 and wheeze, cough, and bronchodilator use among asthmatics but 

not non-asthmatics although this may have been the result of a small non-asthmatic population 

(Escamilla-Nuñez et al., 2008, 594284). A study of the modification of the effect of greater O3 

associated decreases in short-term O3 exposure on lung function by airway hyperresponsiveness 

(AHR) (a condition common among asthmatics) reported greater O3-associated decreases in lung 

function in elderly individuals with airway hyperresponsiveness, especially among those who were 

obese (Alexeeff et al., 2007, 195862). Finally, a study of O3 exposure and airway inflammation 

(FENO) among elderly individuals stratified the study population by asthmatics and non-asthmatics 

(Delfino et al., 2010, 647222). The regression coefficient was higher among asthmatics but the 95% 

CIs were wide due to the small number of asthmatics in the study (n=4), resulting in the inability to 

clearly identify a difference between the populations. Finally, some studies have reported null results 

for both asthmatics and nonasthmatics. Khatri et al. (2009, 594282) found no association between 

short-term O3 exposure and lung function for either asthmatic or non-asthmatic adults, but did note a 

decrease in lung function among individuals with allergies5)594282Khatri et al., 2009, 

(5)594282Khatri et al., 2009, (. One study compared individuals with asthma to individuals with 

other diseases/conditions (chronic obstructive pulmonary disease [COPD] or ischemic heart disease 

[IHD]) (Lagorio et al., 2006, 089800). No association was observed between O3 exposure and 

decrease in lung function among the asthmatic group or the other groups. 

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

that examined the association between O3 exposure and lung function by asthma medication use. A 

study of asthmatic children living in Detroit reported a greater association between short-term O3 and 

lung function for corticosteroid users compared with non-corticosteroid users (Lewis et al., 2005, 

081079). Conversely, another study found decreased lung function among non-corticosteroid users 

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

persistent asthmatics (Hernández-Cadena et al., 2009, 594283). Lung function was not related to 

short-term O3 exposure for corticosteroid users and non-users in a study taking place during the 

winter months in Canada (Liu et al., 2009, 192003). Additionally, a study of airway inflammation 

reported a counterintuitive inverse association with O3 of similar magnitude for all groups of 

corticosteroid users and non-users (Qian et al., 2009, 548793). 

Controlled human exposures studies that have examined the effects of O3 on both asthmatic 

and healthy controls are limited. Based on studies reviewed in the 1996 and 2006 O3 AQCD 

(U.S. EPA, 1996, 017831; U.S. EPA, 2006, 088089), asthmatic subjects appear to be more sensitive 

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

subjects. For instance, Horstman et al. (1995, 075834) observed mild-to-moderate asthmatics to, on 

average, experiences double the O3-induced FEV1 decrement of healthy subjects (19% versus 10%, 

respectively, p = 0.04). Moreover, a statistically significant positive correlation between FEV1 

responses to O3 and baseline lung function was observed in the asthmatic individuals, i.e., responses 

increased with severity of disease. Only study reported a tendency for asthmatics to have smaller O3­

induced FEV1 decrements than healthy subjects (3% versus 8%, respectively) (Mudway et al., 2001, 

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1 025327). However, the asthmatics in that study also tended to be older than the healthy subjects, 

2 which could partially explain their lesser response since FEV1 responses to O3 diminish with age. 

3 Asthmatics also show significantly more neutrophils in the BALF (18 hours postexposure) than 

4 similarly exposed healthy individuals (Basha et al., 1994, 075950; Peden et al., 1997, 085842; 

Scannell et al., 1996, 080755). 

6 Toxicological studies provide support for greater effects of O3 among those with asthma or 

7 airway hyperresponsiveness. In animal toxicological studies, an asthmatic phenotype is modeled by 

8 allergic sensitization of the respiratory tract. Many of the studies that provide evidence that O3 is an 

9 inducer of airway hyperresponsiveness and remodeling utilize these types of animal models. For 

example, a series of experiments in infant rhesus monkeys show these effects, but only in monkeys 

11 sensitized to house dust mite allergen (Fanucchi et al., 2006, 096491; Joad et al., 2006, 596390; 

12 Schelegle et al., 2003, 053778). Similarly, Funabashi et al. (2004, 596384) demonstrated adverse 

13 changes in pulmonary function in mice exposed to O3, and Wagner et al. (2007, 596420) 

14 demonstrated enhanced inflammatory responses in rats exposed to O3, but only in animals sensitized 

to allergen. In general, it is the combined effects of O3 and allergic sensitization which result in 

16 measurable effects on pulmonary function. In a bleomycin induced pulmonary fibrosis model, 

17 exposure to 250 ppb O3 for 5 days increased pulmonary inflammation and fibrosis, along with the 

18 frequency of bronchopneumonia in rats. Thus short-term exposure to O3 may enhance damage in a 

19 previously injured lung (Oyarzún et al., 2005, 596407). 

In the 2006 O3 AQCD, the potential for asthmatics to have greater susceptibility to O3-related 

21 effects was supported by a number of controlled human exposure studies, evidence from 

22 toxicological studies, and a limited number of epidemiologic studies. Overall, in the recent 

23 epidemiologic literature some, but not all, studies report greater effects among individuals with 

24 asthma. Studies examining effect measure modification of the relationship between short-term O3 

and lung function by corticosteroid use had mixed results. Inconsistent findings of epidemiologic 

26 studies may be due to the differences in O3 concentration across the studies. In addition, recent 

27 studies of behavioral responses have found studies that do not take into account individuals 

28 behavioral adaptation to forecasted air pollution levels (such as avoidance and reduced time 

29 outdoors) may be biased towards the null (Neidell and Kinney, 2010, 384492). Evidence from 

controlled human exposure studies support greater FEV1 and inflammatory responses to O3 in 

31 asthmatics than in healthy individuals without a history of asthma. Information from recent 

32 toxicological studies adds to the evidence for heightened susceptibility of asthmatics to effects of O3 

33 exposure. 

8.1.3. Chronic obs tructive pulmonary dis eas e (COPD) 

34 Although not extensively examined in the literature, initial evidence suggests that pre-existing 

COPD may modify of the association between short-term O3 exposure and cardiovascular-related 

36 health effects. In the U.S. over 4% of adults report having chronic bronchitis and almost 2% report 

37 having emphysema, both of which are classified as COPD. 

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1 In a recent study, Peel et al. (2007, 090442) found that individuals with COPD were more 

2 susceptible to effects of short-term O3 exposure on cardiovascular ED visits compared to healthy 

3 individuals in Atlanta, GA. They reported that short-term O3 exposure was associated with higher 

4 odds of an ED visit for peripheral and cerebrovascular disease among individuals with COPD 

compared to individuals without COPD. However, pre-existing COPD did not increase the odds of 

6 hospitalization for all CVD outcomes (i.e. IHD, dysrhythmia, or congestive heart failure). In an 

7 additional study performed in Taiwan, both individuals with and without COPD had higher odds of 

8 congestive heart failure associated with O3 exposure on warm days (Lee et al., 2008, 192076). 

9 In a study of elderly individuals, although O3 was associated with greater increases in airway 

inflammation (FENO) among elderly individuals with than without COPD, the number of individuals 

11 with COPD was small (n=5) and the 95% CI for the association in COPD subjects was wide 

12 (Delfino et al., 2010, 647222). An additional study also found no association between O3 exposure 

13 and lung function regardless of whether the study participant had COPD or other health issues 

14 (asthma or IHD) (Lagorio et al., 2006, 089800). 

Recent epidemiologic evidence does not indicate that COPD modifies the association between 

16 O3 exposure and respiratory effects, but COPD may affect O3-related cardiovascular effects. 

8.1.4. Ca rdio va s cular Dis ea s e 

17 Cardiovascular disease (CVD) has become increasingly prevalent in the U.S., with about 12% 

18 of adults reporting being diagnosed with heart disease. Additionally, a high prevalence of other 

19 cardiovascular-related conditions has also been observed, such as hypertension, which is prevalent 

among approximately 24% of adults. In the 2006 AQCD, little evidence was available regarding pre21 existing CVD as a susceptibility factor. Recent epidemiologic studies have examined cardiovascular22 related diseases as modifiers of the O3-outcome associations; however, no recent evidence is 

23 available from controlled human studies or toxicological studies. 

24 Peel et al. (2007, 090442) compared the associations between short-term O3 exposure and 

cardiovascular ED visits in Atlanta, GA among multiple comorbid conditions. The authors found no 

26 evidence of increased risk of cardiovascular ED visits in individuals previously diagnosed with 

27 dysrhythmia, congestive heart failure, or hypertension compared to healthy individuals. In Taiwan, a 

28 positive association was observed for O3 on warm days and congestive heart failure hospital 

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

or with/without dysrhythmia (Lee et al., 2008, 192076). Another study in Taiwan reported that the 

31 association between O3 levels and ED visits for arrhythmias were greater on warm days among those 

32 with congestive heart failure compared to those without congestive heart failure; however, the 

33 estimate and 95% CI for those without congestive heart failure is completely contained within the 

34 95% CI of those with congestive heart failure (Chiu and Yang, 2009, 603236). 

Among individuals with a history of CVD there was a greater association between O3 

36 exposure and certain, but not all, blood inflammatory markers. Liao et al. (2005, 088677) found that 

37 fibrinogen was positively associated with short-term O3 exposure but this association was present 

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1 only among individuals with a history of CVD. Those without CVD showed a null association. 

2 However, for another biomarker (vWF), CVD status did not modify the positive association with 

3 short-term O3 exposure0)088677Liao et al., 2005, (0)088677Liao et al., 2005, (. 

4 Some modification by pre-existing atrial fibrillation and atherosclerosis were noted in 

5 mortality studies. A study of 48 U.S. cities reported increased risk of mortality with short-term O3 

6 exposure among only individuals with secondary atrial fibrillation (Medina-Ramón and Schwartz, 

7 2008, 193829). No association was observed for short-term O3 exposure and mortality in a study of 

8 diabetics with or without CVD prior to death; however, there was some evidence of increased effects 

9 during the warm season if individuals had diabetes and atherosclerosis compared to having only 

10 diabetes (Goldberg et al., 2006, 088641). 

11 Finally, a study of O3 exposure and lung function was performed among participants with 

12 IHD, asthma, or COPD (Lagorio et al., 2006, 089800). No association was observed regardless of 

13 whether the participant had IHD. 

14 Overall, most studies do not report increased O3-related health effects for individuals with 

15 CVD with the possible exception of O3 exposure and mortality. Future research among those with 

16 CVD compared to those without will increase the understanding of potential susceptibility of 

17 O3-related health effects among this group. 

8.1.5. Dia be tes 

18 Recent literature has not extensively examined whether individuals with diabetes (about 8% of 

19 U.S. adults) are potentially susceptible to O3-related health effects. In a study of short-term O3 

20 exposure and cardiovascular ED visits in Atlanta, GA, no association was seen for individuals with 

21 or without diabetes (Peel et al., 2007, 090442). A similar study conducted in Taiwan reported a 

22 positive association between O3 exposure on warm days and HAs for congestive heart failure but 

23 again no modification by diabetes was observed (Lee et al., 2008, 192076). Finally, in a study of ED 

24 visits for arrhythmia in Taiwan, there was no effect measure modification by diabetes on warm or 

25 cool days (Chiu and Yang, 2009, 603236). 

8.2. Lifes tage 

26 The 2006 AQCD (U.S. EPA, 2006, 088089) identifies children, especially those with asthma, 

27 and older adults as susceptible populations. New evidence, summarized below, further supports these 

28 findings. 

8.2.1. Children 

29 The 2000 Census reports that 28.6% of the U.S. population is under 20 years of age, with 

30 14.1% under the age of 10 (Social Science Data Analysis Network; CensusScope and CensusScope, 

31 2010, 647298). Children are considered to be more susceptible to O3-related health effects compared 

32 to adults because they spend more time outside and are more highly active, especially during the 

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summer when O3 concentrations are the highest (U.S. EPA, 2006, 088089). Moreover, children’s 

respiratory systems are undergoing development until about age 18-20 and are therefore thought to 

be more sensitive to O3-induced damage (U.S. EPA, 2006, 088089). 

Multiple studies have been performed examining different age groups and their susceptibility 

to O3-related respiratory HAs and emergency department (ED) visits. A study in Cyprus of shortterm O3 concentrations and respiratory HA detected possible effect measure modification by age 

with a larger association among individuals less than 15 years of age compared with those over 

15 years of age. However, this difference was only apparent with a 2-day lag (Middleton et al., 2008, 

156760). Similarly, a Canadian study of asthma-ED visits reported a positive association among 5­

to 14-year olds but no association in any of the other age groups (ages examined 0-75+) (Villeneuve 

et al., 2007, 195859). A study in Finland reported a greater O3-associated change in asthma-related 

ED visits among children (<15 year) as compared to adults (15-64 years) (Halonen et al., 2009, 

625764). A study of New Yor k City HAs demonstrated an increase in the association between O3 

exposure and asthma-related hospitalizations for 6- to 18-year olds compared to those less than 6 and 

those older than 18 year of age (Silverman and Ito, 2010, 386252). A study of long-term O3 exposure 

and asthma HA among children reported larger associations among children 1- to 2-year old 

compared to children 2- to 6-year old (Lin et al., 2008, 196680). A few studies reported positive 

associations among both children and adults and no modification of the effect by age. A study 

performed in Hong Kong examined O3 and asthma-related HAs for ages 0-14, 15-65, and >65 (Ko et 

al., 2007, 092844). The researchers reported that the association was greater among the 0-14 and 

14-65 age groups compared to the >65 age group. Another study looking at asthma-related ED visits 

in Maine reported positive associations for all age groups (ages 2-65) (Paulu and Smith, 2008, 

180168). A study performed in Washington found effects of O3 on asthma hospitalizations among 

both children and adults (<18 and ≥18 years old) but reported that only children had statistically 

significant results at lag day 0, which the authors write, “suggests that children are more immediately 

responsive to adverse effects of O3 exposure.” (Mar and Koenig, 2009, 594410). Additionally, a 

study examining asthma physician visits reported consistently negative effects in all age groups 

(1-17 and 18-64) (Burra et al., 2009, 195868). 

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

(<18 years of age) appear, on average, to have nearly equivalent spirometric responses to O3, but 

have greater responses than middle-aged and older adults when exposed to comparable O3 doses 

(U.S. EPA, 1996, 017831). Symptomatic responses (e.g., cough, shortness of breath, pain on deep 

inspiration) to O3 exposure, however, appear to increase with age until early adulthood and then 

gradually decrease with increasing age (U.S. EPA, 1996, 017831). For subjects aged 18-36 years, 

McDonnell et al. (1999, 010939) reported that symptom responses from O3 exposure also decrease 

with increasing age. Lung growth and development is not achieved until 18-20 years of age in 

females and the early 20s for males; pulmonary function is at its maximum during this time as well. 

Additionally, PBPK modeling reported regional extraction of O3 to be higher in infants compared to 

adults. This is thought to be due to the smaller nasal and pulmonary regions surface area in children 

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under the age of 5 compared to the total airway surface area observed in adults (Sarangapani et al., 

2003, 054581). 

Recent toxicological studies support previous findings of greater susceptibility in immature 

animals. Early life exposures of multiple species of laboratory animals, including infant monkeys, 

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

morphological levels as is detailed below. Carey et al. (2007, 195752) conducted a study of O3 

exposure in infant rhesus macaques, whose nasal airways closely resemble that of humans. Monkeys 

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

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

(70 days total). All monkeys acutely exposed to O3 had moderate to marked necrotizing rhinitis, with 

focal regions of epitheliar exfoliation, numerous infiltrating neutrophils, and some eosinophils. The 

distribution, character, and severity of lesions in episodically exposed monkeys were similar to that 

of acutely exposed animals. Neither group exhibited mucous cell metaplasia proximal to the lesions, 

a protective adaptation observed in adult monkeys exposed continuously to 0.3 ppm O3 in another 

study (Harkema et al., 1987, 040816). Functional (increased airway resistance and responsiveness 

with antigen + O3 co-exposure) and cellular changes in conducting airways (increased numbers of 

inflammatory eosinophils) also manifested among the infant monkeys (Plopper et al., 2007, 596412). 

In addition, the lung structure of the conducting airways was significantly stunted or altered versus 

control animals and this aberrant development was persistent 6 months postexposure (Fanucchi et 

al., 2006, 096491). 

Similarly, rat fetuses exposed to O3 in utero had significant ultra-structural changes in 

bronchiolar epithelium when examined near the end of gestation ((López et al., 2008, 197786). In 

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

cytokine levels (TNF, IL-1, KC, IL-6, and MCP-1). In utero exposure of animals to PM augmented 

O3-induced airway hyper-reactivity in these pups as juveniles (Auten et al., 2009, 200760). 

Age may affect the immune response to O3 exposure. In comparing neonatal mice to adults, 

increased bronchoalveolar lavage (BAL) neutrophils were observed in four strains of neonates 24 h 

after exposure to 0.8 ppm O3 for 5 hours (Vancza et al., 2009, 596419). Three of these strains also 

exhibited increased BAL protein, although the two endpoints were not necessarily consistently 

correlated in a given strain. In some strains, however, adults were more sensitive, indicating a strainage interaction. In young mice, healing of skin wounds is not significantly affected by O3 exposure 

(Lim et al., 2006, 670834). However, exposure to 0.5 ppm O3 for 6 h/day significantly delays wound 

closure in aged mice. 

Increased susceptibility found in the younger lifestage may be due to age-related changes in 

endogenous antioxidants and sensitivity to oxidative stress. A recent study demonstrated that 

0.25 ppm O3 differentially alters expression of metalloproteinases in the skin of young (8 weeks) and 

aged (18 months) mice, indicating age-related susceptibility to oxidative stress (Fortino et al., 2007, 

596382). Valacchi et al. (2007, 596418) found that aged mice had more vitamin E in their plasma but 

less in their lungs compared to young mice, which may affect their pulmonary antioxidant defenses. 

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1 Servais et al. (2005, 195667) found higher levels of oxidative damage indicators in three week-old 

2 (immature) and 20 month-old (aged) rats compared to adult rats, which were relatively resistant to an 

3 intermittent 7-day exposure to 0.5 ppm O3. Immature rats exhibited a higher ventilation rate, which 

4 may have increased exposure. Senescent rats had similar ventilatory rates as adults, but their 

antioxidant enzyme responses had a different profile from those of adult rats. 

6 Additionally, a series of toxicological studies reported an association between O3 exposure and 

7 bradycardia that was present among young mice but not among older mice (Hamade and Tankersley, 

8 2009, 596386; Hamade et al., 2008, 156515; Hamade et al., 2010, 666324; Tankersley et al., 2010, 

9 628062). Regression analysis revealed a significant interaction between age and strain on heart rate, 

which implies that aging may affect heart rate differently between mouse strains (Tankersley et al., 

11 2010, 628062). The authors propose that the genetic differences between the mice strains could be 

12 altering the formation of ROS, which tends to increase with age, thus modulating the changes in 

13 cardiopulmonary physiology after O3 exposure. 

14 The human clinical and toxicological studies reported evidence of increased susceptibility for 

younger ages. Studies of respiratory HA and ED visits observed mixed findings for associations 

16 among children and young adults, although generally studies reported positive associations among 

17 both children and adults or just among children. For other outcomes, inconsistent findings regarding 

18 susceptibility to O3-related health effects. The interpretation of these studies is limited by the lack of 

19 consistency in comparison age groups and outcomes examined. 

8.2.2. Older Adults 

The gradual decline in physiological processes that occur with aging may lead to increased 

21 susceptibility to O3-related health effects (U.S. EPA, 2006, 192082). Diminished symptomatic 

22 responses may also put the elderly at increased risk for continued O3 exposure. In addition, older 

23 adults have a higher prevalence of pre-existing diseases compared to younger age groups and this 

24 may also lead to increased susceptibility to O3-related health effects (see Table 8-1 that gives preexisting rates by age). Moreover, with the number of older Americans increasing in upcoming years 

26 (estimated to increase from 12.4% of the U.S. population to 19.7% between 2000 to 2030, which is 

27 approximately 35 million and 71.5 million individuals, respectively) this group represents a large 

28 population potentially susceptible to O3-related health effects (Social Science Data Analysis 

29 Network; CensusScope and CensusScope, 2010, 647298; U.S. Census Bureau, 2010, 647312). 

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

31 older but not for those adults aged 15-64 (Halonen et al., 2009, 625764). In the same study, no 

32 association was observed between O3 levels and respiratory mortality among those 65 years and 

33 older or those 15-64 years; however, an inverse association between O3 levels and cardiovascular 

34 mortality was present among those 65 years and older but not among those under 65 years of age. 

This inverse association among those 65 and older persisted when examining hospitalizations for 

36 coronary heart disease. A study of CVD-related hospital visits in Bangkok reported an increase in 

37 percent change for hospital visits with previous day and cumulative 2-day O3 levels among those 

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65 years and older, whereas no association was present for individuals less than 65 years of age. No 

association was observed for current day or cumulative three-day averages in any age group 

(Buadong et al., 2009, 602060). A study examining O3 and HAs for CVD-related health effects 

reported no association for individuals aged 15-64 or individuals aged 65 and older, although one 

lag-time did show an inverse effect for coronary heart disease among elderly that was not present 

among 15- to 64-year olds (Halonen et al., 2009, 625764). No modification by age (40-64 versus 

>64) was observed in a study from Brazil examining O3 levels and COPD ED visits (Arbex et al., 

2009, 184334). 

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

among older adults, which is consistent with the findings of the 2006 O3 AQCD (U.S. EPA, 2006, 

088089). A study conducted in 48 cities across the U.S. reported larger effects among adults 65 and 

older compared to those younger than 65 years (Medina-Ramón and Schwartz, 2008, 193829). 

Further investigation of this study population revealed no association between O3 and mortality until 

age 50 and a reduced effect after age 80 (Zanobetti and Schwartz, 2008, 195755). A study of 7 urban 

centers in Chile reported similar results, with greater effects in adults 65 and older, however the 

effects were smaller among those 85 year of age and older compared to those in the 75-84 years old 

age range (Cakmak et al., 2007, 091170). A study performed in China reported greater effects in 

populations 45 years and older (compared to 5-44 year olds), with statistically significant effects 

present only among those 65 years and older (Kan et al., 2008, 156621). An Italian study reported 

higher risk of all-cause mortality associated with increased O3 concentrations among individuals 

85 year and older as compared to those 35-84 years old. Those 65-74 and 75-84 years did not show a 

greater increase in risk compared to those age 35-64 years (Stafoggia et al., 2010, 625034). The Air 

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

association between O3 exposure and mortality for those <75 and ≥ 75 years of age. In Canada, the 

associations for all-cause and cardiovascular mortality were greater among those 75 years and older 

in the summer-only and all-year analyses. Age groups were not compared in the analysis for 

respiratory mortality in Canada. In the U.S., the association for all-cause mortality was slightly 

greater for those younger than 75 years of age compared to those 75 and older in summer-only 

analyses. No consistent pattern was observed for CVD mortality. In Europe, slightly larger 

associations for all-cause mortality were observed in those younger than 75 in all-year and summeronly analyses. Larger associations were reported among those <75 for CVD mortality in all-year 

analyses, but the reverse was true for summer-only analyses (Katsouyanni et al., 2009, 199899). 

Biological plausibility for increased susceptibility among older adults is provided by clinical 

and toxicological studies. Respiratory symptom responses to O3 exposure appears to increase with 

age until early adulthood and then gradually decrease with increasing age (U.S. EPA, 1996, 017831). 

The decrease in symptomatic responses with age was observed by McDonnell et al. (1999, 010939) 

in subjects aged 18 to 36 years. In contrast to young adults, the diminished symptomatic responses in 

older adults may put them at increased risk for continued O3 exposure. Regarding cardiac outcomes, 

O3 exposure resulted in an increase in left ventricular chamber dimensions at end diastole (LVEDD) 

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1 in young and old mice, whereas decreases in left ventricular posterior wall thickness at end systole
 

2 (PWTES) were only observed among older mice (Tankersley et al., 2010, 628062). 

8.3. Sex 

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

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

prevalence of females≥ 65 years old compared to males (Social Science Data Analysis Network; 

6 CensusScope and CensusScope, 2010, 647298). Recent epidemiologic studies have evaluated the 

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

8 A study in Maine on short-term O3 concentrations and asthma ED visits detected greater 

9 effects among males ages 2-14 and among females ages 15-34 compared to males and females in the 

same age groups (no difference was detected for males and females aged 35-64) (Paulu and Smith, 

11 2008, 180168). A New Yor k study found no effect measure modification of the association between 

12 long-term O3 exposure and asthma HA among males and females between 1 and 6 years old (Lin et 

13 al., 2008, 196680). Additionally, a Canadian study reported no associations between short-term O3 

14 and respiratory infection HAs for either boys or girls under the age of 15 (Lin et al., 2005, 087828), 

whereas another Canadian study reported a slightly higher but non-statistically significant increase in 

16 respiratory HA for males (mean ages 47.6-69.0 years) (Cakmak et al., 2006, 093272). A recent study 

17 from Hong Kong examining individuals of all ages reported no effect measure modification by sex 

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

19 females compared to males (Wong et al., 2009, 196722). Similarly a study in Brazil found higher 

effect estimates for COPD ED visits among females compared to males (Arbex et al., 2009, 184334). 

21 Higher levels of respiratory HA with greater O3 concentrations was also observed for females in a 

22 study of individuals living in Cyprus (Middleton et al., 2008, 156760). A study of lung function 

23 unrelated to HA and ED visits was conducted among lifeguards in Texas and reported decreased lung 

24 function with increased O3 exposure among females but not males (Thaller et al., 2008, 195869). 

This study included individuals aged 16-27, and the majority of participants were male. 

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

27 outcomes by sex, studies also examined cardiovascular-related outcomes specifically HAs and ED 

28 visits. All of these studies reported no effect modification by sex with some studies reporting null 

29 associations for both males and females (Middleton et al., 2008, 156760; Villeneuve et al., 2006, 

090191; Wong et al., 2009, 196722) and one study reporting a positive associations for both sexes 

31 (Cakmak et al., 2006, 099068). A French study examining the associations between O3 

32 concentrations and risk of ischemic strokes (not limited to ED visits or HAs) reported no association 

33 for either males or females with lags of 0, 2, or 3 days (Henrotin et al., 2007, 093270). A positive 

34 association was reported for males with a lag of 1 day, but this association was null for females. The 

authors note that men in the study had much higher rates of current and former smoking than women 

36 (67.4% versus 9.3%). 

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

protein (hs-CRP), fibrinogen, and white blood cell count (WBC), reported observations for various 

lag times ranging from 0 to 7 days (Steinvil et al., 2008, 188893). Most of the associations were null 

for males and females although one association between O3 and fibrinogen was positive for males 

and null for females (lag day 4); however, this positive association was null or negative when other 

pollutants were included in the model. Only one study examining correlations between O3 levels and 

oxidative DNA damage examined results stratified by sex. In this study Palli et al. (2009, 196688) 

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

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

could be partially explained by different distributions of exposure to traffic pollution at work. 

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

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

reporting elevated risks among females. These studies, conducted in the U.S. (Medina-Ramón and 

Schwartz, 2008, 193829), Italy (Stafoggia et al., 2010, 625034), and Asia (Kan et al., 2008, 156621), 

reported higher effects in females. In the U.S. study, the elevated risk of mortality among females 

was greater specifically among those 60 years of age and older (Medina-Ramón and Schwartz, 2008, 

193829). One long-term O3 exposure study of respiratory mortality stratified their results by sex and 

reported relative risks of 1.01 (95 % CI: 0.99, 1.04) for males and 1.04 (95% CIs 1.03, 1.07) for 

females (Jerrett et al., 2009, 194160). 

Experimental research provides a further understanding of the possible differential 

susceptibility of males and females to O3 exposure. Several studies have suggested that physiological 

differences between sexes may predispose females to a greater susceptibility to O3. Lower plasma 

and nasal lavage fluid (NLF) levels of uric acid (most prevalent antioxidant) in females, the initial 

defense mechanism of O3 neutralization, may be a contributing factor (Housley et al., 1996, 080811). 

Consequently, reduced absorption of O3 in the upper airways of females may promote its deeper 

penetration. Dosimetric measurements have shown that the absorption distribution of O3 is 

independent of gender when absorption is normalized to anatomical dead space (Bush et al., 1996, 

080763). Thus, a differential removal of O3 by uric acid seems to be minimal. In general, the 

physiologic response of young healthy females to O3 exposure appears comparable to the response 

of young males (Hazucha et al., 2003, 048168). During the follicular phase of the menstrual cycle, 

lung function response to O3 is enhanced (Fox et al., 1993, 043906). Seal et al. (1996, 044251) later 

reported no effect of menstrual cycle phase in their analysis of responses of 150 women, but 

conceded that the methods used by Fox et al. (1993, 043906) more precisely defined the menstrual 

cycle phase. In a toxicological study, small sex differences were seen in adult mice with respect to 

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

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

exhibiting greater susceptibility in males (Vancza et al., 2009, 596419). The most obvious sex 

difference was apparent in lactating females, which incurred the greatest lung injury or inflammation 

among several of the strains. 

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1 Overall, results have varied, with evidence for increased susceptibility for O3-related health 

2 effects present for females in some studies and males in other studies. Most studies examining O3 

3 and mortality report females to be more susceptible than males. Little evidence is available regarding 

4 a difference between the sexes for other outcomes. Mixed findings are reported on whether effect 

measure modification exists by sex for respiratory and cardiovascular HA and ED visits, although 

6 this inconsistency, at least in part, could be attributable to additional comparisons of different age 

7 groups and different respiratory health endpoints by the various studies. 

8.4. Genetics 

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

9 function have focused on whether various genes modify the effect of O3 on health. A study 

examining the relationship between a mother's asthma and her infant's respiratory health illustrated 

11 the potential for genetics to play a role in O3-related susceptibility to health effects. A study of 

12 wheeze in infants reported larger associations between short-term O3 exposure and wheeze and 

13 difficulty breathing in infants whose mothers have asthma compared to infants of mothers without 

14 asthma (Triche et al., 2006, 093274). 

Multiple genes, including glutathione S-transferase Mu 1 (GSTM1) and tumor necrosis 

16 factor-α (TNF-α) were evaluated in the 2006 AQCD (U.S. EPA, 2006, 088089) and found to have a 

17 “potential role... in the innate susceptibility to O3.” Studies performed since the last AQCD have 

18 continued to examine the roles of GSTM1 and TNFα on O3-related health effects and have also 

19 examined other gene variants that may increase susceptibility to O3-related health effects. 

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

21 included analyses of potential gene-environment interactions. Romieu et al. (2006, 090969) reported 

22 an association between O3 and respiratory symptoms that were larger among children with GSTM1 

23 null or glutathione S-transferase P 1 (GSTP1) Val/Val genot yp es. However, results suggested that O3­

24 associated decreases in lung function may be greater among children with GSTP1 Ile/Ile or Ile/Val 

compared to GSTP1 Val/Val. Alexeef et al. (2008, 195864) reported greater decreases in lung 

26 function among GSTP1 Val/Val adults than those with other genotypes. In addition, they detected 

27 greater decreases for adults with long GT dinucleotide repeats in heme-oxygenase-1 (HMOX1) 

28 promoters. 

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

antioxidant enzymes may modulate pulmonary function and inflammatory response to O3 challenge. 

31 It appears that healthy carriers of NAD(P)H quinone oxidoreductase 1 (NQO1) wild type (wt) in 

32 combination with GSTM1 null genotype had greater decreases in lung function parameters with 

33 exposure to O3 (Bergamaschi et al., 2001, 052670). Adults with GSTM1 null only genotype did not 

34 show the same response to O3. In contrast, asthmatic children with GSTM1 null genotype (Romieu 

et al., 2004, 056796) were reported to have greater decreases in lung function in relation to O3 

36 exposure. In a similar study, Vagaggini et al. (2010, 387127) exposed mild-to-moderate asthmatics to 

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O3 with moderate exercise. In subjects with NQO1 wt and GSTM1 null, there was no evidence of 

changes in lung function or inflammatory responses to O3. 

In a study of healthy volunteers with GSTM1 sufficient (n=19; 24±3) and GSTM1 null (n=16; 

25 ± 5) exposed to 400 ppb O3 for 2 hours with exercise, Alexis et al. (2009, 628542) found 

genotype effects on inflammatory responses but not lung function responses to O3. At 4 h post O3 

exposure, individuals with both GSTM1 genotypes had significant increases in sputum neutrophils 

with a tendency for a greater increase in GSTM1 sufficient than nulls. At 24 hours postexposure, 

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

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

baseline levels and levels at 24 hours in the GSTM1 sufficient individuals. Since there was no FA 

control in the Alexis et al. (2009, 628542) study, effects of the exposure other than O3 can not be 

ruled out. In general, the findings between studies are inconsistent and additional, better-controlled 

studies are needed to clarify the influence of genetic polymorphisms on O3 responsiveness in 

humans. 

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

gene variants, including GSTP1, HMOX1, and TNF-α. A study among children reported a three-way 

interaction effect between Ile105 homozygotes of GSTP1, O3, and playing more than two team 

sports, and new onset of asthma (Islam et al., 2009, 196715). Additionally, Islam et al. found that 

non-Hispanic white children with less than 23 repeats in the HMOX-1 gene had decreased risk of 

new-onset asthma (Islam et al., 2008, 097348). ARG1 and ARG2 (encoded by arginases) 

modification were examined for the association between genotypes and new-onset asthma (Salam et 

al., 2009, 596644). Reduced asthma risk was observed among atopic children living in high O3 areas 

and having the ARG1 haplotypes. There was no difference in risk for children with ARG2 

haplotypes. A decreased risk of bronchitic symptoms was observed among asthmatic children in low 

O3 areas with TNF-α variant G-308A (TNF-308GG genotype), a variant that may alter gene 

expression. There was no decrease in risk for children with this TNF-α variant but living in areas 

with high O3 concentrations. Additionally, this modification for high and low levels of O3 was not 

present among non-asthmatic children (Lee et al., 2009, 199915). Wenten et al. (2009, 597084) 

observed increased risk of respiratory-related school absences among children with variants of 

catalase (CAT) and myeloperoxidase (MPO) genes, especially when the children were living in high 

O3 areas. 

Toxicological studies have reported differences in cardiac and respiratory effects after O3 

exposure among different mouse strains, which alludes to susceptibility among individuals due to 

genetic variability (Chuang et al., 2009, 197202; Hamade and Tankersley, 2009, 596386; Hamade et 

al., 2008, 156515; Tankersley et al., 2010, 628062). Altered O3 responses between two strains could 

be due to genetic variability in nuclear factor erythroid 2-related factor 2 (Nrf-2), suggesting a role 

for genetic differences in altering the formation of ROS. Another difference among strains is 

attributed to differences in O3-induced lung hyperpermeability (Kleeberger et al., 2000, 014895; 

Kleeberger et al., 2001, 016163). Additionally, some studies have reported O3-related effects to vary 

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1 by Inf-1 and Inf-2 genes (Tankersley and Kleeberger, 1994, 021420) and a gene coding for Clara cell 

2 secretory protein (CCSP) (Broeckaert et al., 2003, 055490; Wattiez et al., 2003, 043783). 

3 Voynow et al. (2009, 194311) have shown that NQO1 deficient mice, like their human 

4 counterparts, are resistant to O3-induced airway hyperresponsiveness and inflammation. Reduced 

production of inflammatory mediators and cells and blunted airway hyperresponsiveness were 

6 observed in NQO1-null mice after exposure to 1 ppm O3 for 3 hours. These results correlated with 

7 those from in vitro experiments in which human bronchial epithelial cells treated with an NQO1 

8 inhibitor exhibited reduced inflammatory responses to exposure to 0.4 ppm O3 for 5 hours. 

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

depletion experiments, but a more recent toxicological study investigated the effects of combined O3 

11 and PM exposure in transgenic TNF overexpressing mice. Kumarathasan et al. (2005, 596398) found 

12 that subtle effects of these pollutants were difficult to identify in the midst of the severe pathological 

13 changes caused by constitutive TNF-α overexpression. However, there was evidence that TNF 

14 transgenic mice were more susceptible to O3/PM-induced oxidative stress, and they exhibited 

elevation of a serum creatine kinase after pollutant exposure, which may suggest potential systemic 

16 or cardiac related effects. Differential susceptibility to O3 among inbred strains of animals does not 

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

18 resistance or sensitivity (Vancza et al., 2009, 596419). 

19 Defects in DNA repair mechanisms may also confer susceptibility to O3-related health effects. 

Cockayne syndrome, a rare autosomal recessive disorder in humans, is characterized by UV 

21 sensitivity abnormalities, neurological abnormalities, and premature aging. The same genetic defect 

22 in mice (Csb-/-) makes them sensitive to oxidative stressors, including O3. Kooter et al. (2007, 

23 596397) demonstrated that Csb-/- mice produced significantly more TNF-α after exposure to 0.8 ppm 

24 O3 than their wild-type counterparts. However, there were no significant differences in other markers 

of inflammation or lung injury between the two strains of mice. 

8.5. Diet 

26 Diet was not examined as a susceptibility factor in previous AQCDs, but recent studies have 

27 examined modification of the association between O3 and health effects by dietary factors. Because 

28 O3 mediates its toxic effects through oxidative stress, the antioxidant status of an individual is an 

29 important factor that may contribute to increased susceptibility to O3-related health effects. 

Supplementation with vitamin E has been investigated in a number of studies as a means of 

31 inhibiting O3-mediated damage. 

32 Epidemiologic studies have examined effect measure modification by diet and found evidence 

33 that certain dietary components are related to the effect of O3 has on respiratory outcomes. The most 

34 recent study examined fruit/vegetable intake and Mediterranean diet (Romieu et al., 2009, 548788). 

Increases in these food patterns, which have been noted for their high vitamins C and E and omega-3 

36 fatty acid content, protected against O3-related decreases in lung function among children living in 

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1 Mexico City. Another study examined supplementation of the diets of asthmatic children in Mexico 

2 with Vitamins C and E (Sienra-Monge et al., 2004, 196422). Associations were detected between 

3 short-term O3 and nasal airway inflammation among children in the placebo group but not in those 

4 receiving the supplementation. The authors concluded that “vitamin C and E supplementation above 

the minimum dietary requirement in asthmatic children with a low intake of vitamin E might provide 

6 some protection against the nasal acute inflammatory response to ozone.” 

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

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

9 lining fluid (ELF) which scavenge free radicals and limit lipid peroxidation. Exposure to O3 depletes 

the antioxidant level in nasal ELF probably due to scrubbing of O3 (Mudway et al., 1999, 001270); 

11 however, the concentration and the activity of antioxidant enzymes either in ELF or plasma do not 

12 appear to be related to O3 responsiveness (Avissar et al., 2000, 012528; Blomberg et al., 1999, 

13 001267; Samet et al., 2001, 019034). Carefully controlled studies of dietary antioxidant 

14 supplementation have demonstrated some protective effects of alpha-tocopherol (a form of vitamin 

E) and ascorbate (vitamin C) on spirometric lung function from O3 but not on the intensity of 

16 subjective symptoms and inflammatory response including cell recruitment, activation and a release 

17 of mediators (Samet et al., 2001, 019034; Trenga et al., 2001, 019845). Dietary antioxidants have 

18 also afforded partial protection to asthmatics by attenuating postexposure bronchial 

19 hyperresponsiveness (Trenga et al., 2001, 019845). 

Toxicological studies provide evidence of biological plausibility to the epidemiologic and 

21 controlled human exposure studies. Wagner et al. (2007, 596420; 2009, 201574) have shown 

22 reductions in O3-exacerbated nasal allergy responses in rats with gamma-tocopherol treatment (a 

23 form of vitamin E). Ozone-induced inflammation and mucus production were also inhibited by 

24 gamma-tocopherol. Inconsistent results are observed in toxicological studies of ascorbate deficiency 

and O3 responses. Guinea pigs deficient in ascorbate displayed only minimal injury and 

26 inflammation after exposure to O3 (Kodavanti et al., 1995, 077440). A recent study in mice 

27 demonstrated a protective effect of beta-carotene in the skin, where it limited the production of 

28 proinflammatory markers and indicators of oxidative stress induced by O3 exposure (Valacchi et al., 

29 2009, 201554). In addition to the studies of antioxidants, one toxicological study examined protein 

deficiency. Protein deficiency alters the levels of enzymes and chemicals in the brain involved with 

31 redox status; exposure to 0.75 ppm O3 has been shown to differentially affect Na+/K+ ATPase, 

32 glutathione, and lipid peroxidation, depending on the nutritional status of the animal, but the 

33 significance of these changes is unclear (Calderon Guzman et al., 2006, 596371). 

8.6. Bo d y Ma s s In d e x 

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

U.S., with self-reported rates of 26.7% in 2009, up from 19.8% in 2000 (Sherry et al., 2010, 

36 667866). A few studies have been performed examining the association between BMI and lung 

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1 function. An epidemiologic study reported decreased lung function with increased short-term O3 

2 exposure for both obese and non-obese subjects; however, the magnitude of the reduction in lung 

3 function was greater for those subjects who were obese (Alexeeff et al., 2007, 195862). Further 

4 decrements in lung function were noted for obese individuals with airway hyperresponsiveness. 

Controlled human exposure studies have also detected differential effects of O3 on lung function for 

6 individuals with varying BMIs. In a retrospective analysis of data from 541 healthy, nonsmoking, 

7 white males between the ages of 18-35 years from 15 studies conducted at the U.S. EPA Human 

8 Studies Facility in Chapel Hill, North Carolina, McDonnell et al. (2010, 383972) found that 

9 increased body mass index (BMI) was found to be associated with enhanced FEV1 responses. The 

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

11 whereby FEV1 responses diminish with increasing age. In a similar analysis, Bennett et al. (2007, 

12 418827) found enhanced FEV1 decrements following O3 exposure with increasing BMI in a group of 

13 healthy, nonsmoking, women (BMI range 15.7 to 33.4), but not among healthy, nonsmoking men 

14 (BMI range 19.1 to 32.9). In the women, greater O3-induced FEV1 decrements were seen in 

overweight/obese (BMI >25) than in normal weight (BMI from 18.5 to 25), and in normal weight 

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

17 response in the overweight/obese category (BMI >25), compared with the normal weight group 

18 (BMI from 18.5 to 24.9). 

19 Studies in genetically and dietarily obese mice have shown enhanced pulmonary inflammation 

and injury with acute O3exposure, but responses to longer exposures at more relevant doses appear 

21 to differ. A recent study found that obese mice are actually resistant to O3-induced pulmonary injury 

22 and inflammation and reduced lung compliance following exposure to 0.3 ppm O3 for 72 hours, 

23 regardless of whether obesity was genetic or diet-induced (Shore et al., 2009, 201551). 

24 Multiple epidemiologic and human clinical studies have reported increased O3-related 

respiratory health effects among obese individuals. Future research of the effect modification of the 

26 relationship between O3 and other health-related outcomes besides respiratory health effects by BMI 

27 will advance understanding of obesity as a potential susceptibility factor. 

8.7. Socioeconomic Status 

28 SES is often represented by personal or neighborhood SES, educational attainment, health 

29 insurance status, and other such factors. Based on the 2000 Census data, 12.4% of Americans live in 

poverty (poverty threshold for family of four was $17,463) (Social Science Data Analysis Network; 

31 CensusScope and CensusScope, 2010, 647297). 

32 Multiple epidemiologic studies have reported individuals of low SES to be more susceptible to 

33 the effects of short-term O3 exposure on respiratory HAs and ED visits. A study performed in Korea 

34 examined the association between O3 concentrations and asthma HA and reported larger effect 

estimates in areas of moderate and low SES compared with areas of high SES (SES was based on 

36 average regional insurance rates) (Lee et al., 2006, 098248). Another Canadian study reported 

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inverse effects of O3 on respiratory HA and ED visits regardless of SES, measured by average census 

tract household income (Burra et al., 2009, 195868). In addition, a study conducted across 10 cities 

in Canada found the largest association between O3 and respiratory HA was among those with an 

educational level less than grade 9, but no consistent trend in the effect was seen across quartiles of 

income (Cakmak et al., 2006, 093272). One study performed among children in New Yor k State 

reported greater associations between long-term O3 exposure and asthma HA among children of 

mothers who did not graduate from high school, whose births were covered by Medicaid/self-paid, 

and who were living in poor neighborhoods compared to children whose mothers graduated from 

high school, whose births were covered by other insurance, and who were not living in poor 

neighborhoods, respectively (Lin et al., 2008, 196680). 

One study reported the association between short-term O3 and ED visits for cardiac disease by 

quartiles of neighborhood-level education and income. No effect measure modification was apparent 

for either measure of SES (Cakmak et al., 2006, 099068). 

Several studies were conducted examining the modification by SES of the relationship 

between short-term O3 concentrations and mortality. A U.S. multicity study reported that 

communities with a higher proportion of the population unemployed had higher mortality effect 

estimates (Bell and Dominici, 2008, 193828). A study examining effect measure modification of the 

association between O3 and mortality by percentage unemployed reported a higher percent change in 

mortality with increased percent unemployed but this varied across the regions included in the study 

(U.S., Canada, Europe) (Katsouyanni et al., 2009, 199899). A Chinese study reported that the 

greatest effects between O3 concentrations and mortality at lag day 0 were among those living in 

areas of high social deprivation (i.e. low SES), but this association was not consistent across lag days 

(at other lag times, the middle social deprivation index category had the greatest association) (Wong 

et al., 2008, 157151). However, another study in Asia comparing low to high educational attainment 

populations reported no evidence of greater mortality effects (total, CVD, or respiratory) (Kan et al., 

2008, 156621). Additionally, a study in Italy reported no difference in risk of mortality among 

census-block level derived income levels (Stafoggia et al., 2010, 625034). A study of infant mortality 

in Mexico reported no association between O3 concentrations and infant mortality among any of the 

three levels of SES determined using a socioeconomic index based on residential areas (Romieu et 

al., 2004, 093074). Another study in Mexico reported a positive association between O3 levels at lag 

0 and respiratory-related infant mortality in only the low SES group (determined based on education, 

income, and household conditions across residential areas), but no association was observed in any 

of the SES groups with other lags (Carbajal-Arroyo et al., In Press, 667773). 

Evidence from a controlled human exposure study that examined O3 effects on lung function 

does not provide support for greater O3-related health effects in individuals of lower SES. In a 

follow-up study (Seal et al., 1993, 039357) on modification by race, Seal et al. (1996, 044251) 

reported that, of three SES categories, individuals in the middle SES category showed greater 

concentration-dependent decline in percent-predicted FEV1 (4-5% at 400 ppb O3) than in low and 

high SES groups. The authors did not have an “immediately clear” explanation for this finding. 

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1 Overall, most studies of individuals and those living in neighborhoods with low SES have 

2 reported that individuals with low SES are more susceptible to O3-related health effects, resulting in 

3 higher odds of respiratory HAs and ED visits. This was not supported by a single controlled human 

4 exposure study conducted to examine O3-related effects on lung function for individuals from 

varying SES groups. Inconsistent results have been observed in the few studies examining effect 

6 modification of associations with mortality. 

8.8. Air Conditioning Us e 

7 Air conditioning use is an important component of exposure, as use of central air conditioning 

8 will limit exposure to O3 by blocking the penetration of O3 into the indoor environment (further 

9 information can be found in Section 4.4). Air conditioning use is a difficult effect measure modifier 

to examine, as it represents multiple components. More generally, air conditioning prevalence is 

11 associated with temperature of a region; those areas with higher temperatures have a greater 

12 prevalence of households with air conditioning. Second, it is a marker of SES, with individuals of 

13 low SES less likely to have an air conditioner. Finally, air conditioning use is often measured based 

14 on area prevalence and may not reflect individual-level use. Despite these limitations, a few studies 

have examined effect measure modification by prevalence of air conditioning use in an area. 

16 Studies examining multiple cities across the U.S. have assessed whether associations between 

17 O3 concentrations and HA and mortality varied among areas with high and low prevalence of air 

18 conditioning. Medina-Ramon et al. (2006, 087721) conducted a study during the warm season and 

19 observed a greater association between O3 levels and pneumonia HAs among areas with a lower 

proportion of households having central air conditioning compared to areas with a larger proportion 

21 of households without air conditioning. The same trend of increased association for areas with a 

22 lower prevalence of central air conditioning was noted in a study of O3 concentrations and mortality 

23 (Bell and Dominici, 2008, 193828). Conversely, Medina-Ramón and Schwartz (2008, 193829) found 

24 that among individuals with atrial fibrillation, a lower risk of mortality was observed for areas with a 

lower prevalence of central air conditioning. 

8.9. In vo lve m e n t in Outdoor Activities 

26 Studies included in the 2006 O3 AQCD reported individuals who participate in outdoor 

27 activities or work to be a susceptible population based on consistently reported associations between 

28 O3 exposure and respiratory health outcomes in these groups (U.S. EPA, 2006, 088089). Outdoor 

29 workers are exposed to ambient O3 concentrations outside for a greater period of time than 

individuals who spend their days indoors. Additionally, an increase in dose to the lower airways is 

31 possible with exercise due to both increases in amount of air breathed (i.e., minute ventilation) and a 

32 shift from nasal to oronasal breathing (Hu et al., 1994, 041323; Nodelman and Ultman, 1999, 

33 015112; Sawyer et al., 2007, 195142). For further discussion of the association between FEV1 

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1 responses to O3 and minute ventilation, refer to Section 6.2.3.1 of the 2006 O3 AQCD (U.S. EPA, 

2 2006, 088089). 

3 A recent study has explored the potential effect measure modification of O3 exposure and 

4 DNA damage by indoor/outdoor workplace (Tovalin et al., 2006, 091322). In a study of indoor and 

outdoor workers in Mexico, individuals who worked outdoors in Mexico City had a slight 

6 association between O3 exposure and DNA damage (measured by comet tail length assay), whereas 

7 no association was observed for indoor workers in Mexico City. Workers in another Mexican city, 

8 Puebla, demonstrated no association between O3 levels and DNA damage, regardless of whether they 

9 worked indoors or outdoors. 

Although there is no evidence of modification by outdoor activity in this recent study, previous 

11 work has shown that increased dose of O3 concentrations from outdoor work leads to increased 

12 susceptibility to O3-related health effects among individuals who participate in outdoor activities or 

13 work. 

8.10. Race/Ethnicity 

14 Based on the 2000 Census, 69.1% of the U.S. population comprises Non-Hispanic Whites. 

Approximately 12.1% of people reported their race/ethnicity as Non-Hispanic Black and 12.6% 

16 reported being Hispanic (Social Science Data Analysis Network; CensusScope and CensusScope, 

17 2010, 647301). 

18 A couple of studies examined the associations between short-term O3 concentrations and 

19 mortality and reported higher effect estimates among Blacks (Medina-Ramón and Schwartz, 2008, 

193829) and among communities with larger proportions of Blacks (Bell and Dominici, 2008, 

21 193828). Another study examined short-term exposure to O3 concentrations and asthma HAs among 

22 children in New Yor k State. These authors reported no statistically significant difference in the odds 

23 of asthma HA for Blacks compared to other races but did detect higher odds for Hispanics compared 

24 to non-Hispanics (Lin et al., 2008, 196680). 

Support for the epidemiologic studies is provided by a controlled human exposure study (Seal 

26 et al., 1993, 039357), which has compared lung function responses of Whites and Blacks exposed to 

27 a range of O3 concentrations. The independent effects of gender-race group and O3 concentration on 

28 lung function were positive, but the interaction between gender-race group and O3 concentration was 

29 not statistically significant. The findings indicate some overall difference between the gender-race 

groups that is independent of O3 concentration (the concentration-response curves for the four 

31 gender-race groups are parallel). In a multiple comparison procedure on data collapsed across all O3 

32 concentrations for each sex-race group, both Black men and Black women had larger decrements in 

33 FEV1 than did White men. The authors noted that the O3 dose per unit of lung tissue would be 

34 greater in blacks and females than whites and males, respectively. That this difference in tissue dose 

might have affected responses to O3 cannot be ruled out. The college students recruited for the Seal 

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1 et al. (1993, 039357) study are probably from better educated and more SES advantaged families, 

2 thus reducing potential for these variables to be confounding factors. 

3 Overall, the results of recent studies suggest that there may be race-related susceptibility for 

4 some outcomes, although the overall understanding of potential effect measure modification by race 

is limited by the small number of studies. Additionally, these results may be confounded by other 

6 factors, such as socioeconomic status. 

8.11. P hys ical Conditioning 

7 The 2008 Summary of Health Statistics for U.S. Adults from the CDC reported the prevalence 

8 of regular leisure-time physical activity as slightly above 30% for adults 18 years of age and older in 

9 the U.S. Forty-nine percent of individuals 65 and older reported no leisure-time physical activity 

(Pleis et al., 2009, 629608). Physical activity is of interest as a susceptibility factor because studies 

11 have demonstrated that exercise affects both the amount of air breathed (flow rate and breathing 

12 frequency increase) and type of breathing (switch from nasal to oronasal) (Hu et al., 1994, 041323; 

13 Nodelman and Ultman, 1999, 015112; Sawyer et al., 2007, 195142). A study of effect measure 

14 modification by exercise habits ten years prior to death observed excess risk of mortality with 

increasing O3 concentrations among individuals that never exercised compared to individuals that 

16 exercised at least once a month for both adults 30 years of age and older and adults 65 years of age 

17 and older (Wong et al., 2007, 093278). No recent studies examining modification of O3-related 

18 health effects by current physical activity were identified. 

8.12. Smoking 

19 Previous O3 AQCDs have concluded that smoking does not increase susceptibility to 

O3-related health effects; in fact, in controlled human exposure studies, smokers have been found to 

21 be less susceptible to O3-related health effects than non-smokers. Data from recent interviews 

22 conducted as part of the 2008 National Health Interview Survey (NHIS) (Pleis et al., 2009, 629608) 

23 have shown the rate of smoking among adults 18 year and older to be approximately 20% in the U.S. 

24 Approximately 21% of individuals surveyed were identified as former smokers. 

Baccarelli et al. (2007, 091310) performed a study of O3 concentrations and plasma 

26 homocysteine levels (a risk factor for vascular disease). They found no interaction of smoking 

27 (smokers versus non-smokers) for the associations between O3 concentrations and plasma 

28 homocysteine levels. Another study examined the association between O3 and resting heart rate and 

29 also reported no interaction with smoking status (current smokers versus current non-smokers) 

(Ruidavets et al., 2005, 089443). 

31 A study examining correlations between O3 levels and oxidative DNA damage examined 

32 results stratified by current versus never and former smokers (Palli et al., 2009, 196688). Ozone was 

33 positively associated with DNA damage for short-term and long-term exposures among never/former 

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1 smokers. For current smokers, short-term O3 concentrations were inversely associated with DNA 

2 damage; however, the number of current smokers was small (n=12). 

3 The findings of Palli et al. (2009, 196688) are consistent with those from controlled human 

4 exposure studies that have confirmed that smokers are less responsive to O3 than non-smokers. 

Spirometric and plethysmographic pulmonary function decline, nonspecific airway hyperreactivity, 

6 and inflammatory response of smokers to O3 were all weaker than the ones reported for non7 smokers. Similarly, the time course of development and recovery of these effects as well their 

8 reproducibility was not different from non-smokers. Chronic airway inflammation with 

9 desensitization of bronchial nerve endings and an increased production of mucus may plausibly 

explain the pseudo-protective effect of smoking (Frampton et al., 1997, 082692; Torres et al., 1997, 

11 084265). 

12 These findings for smoking are consistent with previous AQCD conclusions. An 

13 epidemiologic study of O3-associated DNA damage reported smokers to be less susceptible to O3­

14 related health effects. However, both epidemiologic studies of short-term exposure and CVD 

outcomes found no effect measure modification by smoking. 

8.13. Hyperthyroidis m 

16 A potential susceptibility factor has been identified in toxicological studies but has not yet 

17 been explored in epidemiologic or controlled human exposure studies. Lung damage and 

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

19 hyperthyroid rats exhibited elevated levels of BAL neutrophils and albumin after a 4-h exposure to 

O3, indicating inflammation and damage. Hyperthyroidism did not affect production of reactive 

21 oxygen or nitrogen species, but BAL phospholipids were increased, indicating greater activation of 

22 Type II cells and surfactant protein production compared to normal rats (Huffman et al., 2006, 

23 596388). Thus, this study provides some underlying evidence which suggests that individuals with 

24 hyperthyroidism may represent a susceptible population. Future studies in humans have the potential 

to identify this as additional susceptibility factors. 

8.14. Summary 

26 In this section, epidemiologic, controlled human exposure, and toxicological studies have been 

27 evaluated that contribute information on potential susceptibility factors. Overall, this review provides 

28 evidence that various factors may lead to increased susceptibility to O3-related health effects. 

29 The populations identified in this section that are most susceptible to O3-related health effects 

are individuals with influenza/infection, individuals with asthma, and older age groups. There were a 

31 small number of studies on influenza/infection but both reported influenza/infection to modify the 

32 association between O3 exposure and respiratory effects, with individuals having influenza or an 

33 infection being at increased susceptibility. Asthma as a susceptibility factor was supported by 

34 controlled human exposure and toxicological studies, as well as some evidence from epidemiologic 

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studies. Most studies comparing age groups reported greater effects of short-term O3 exposure on 

mortality among older adults. Diet and obesity are also both likely susceptibility factors. Multiple 

epidemiologic, controlled human exposure, and toxicological studies reported that diets deficient in 

Vitamins E and C are associated with susceptibility to O3-related health effects. Similarly, studies of 

effect measure modification by BMI observed greater O3-related respiratory decrements for 

individuals who were obese. 

Other potential factors [pre-existing conditions (such as COPD and CVD) young age, sex, and 

multiple genes (such as GSTM1, GSTP1, HMOX-1, NQO1, and TNF-α)] provided some evidence 

of susceptibility, but further evidence is needed. In addition, examination of modification of the 

associations between O3 exposure and health effects by SES and race were available in a limited 

number of studies, and demonstrated possible increased odds of health effects related to O3 exposure 

among those with low SES and Blacks. 

Individuals involved in outdoor activities were examined in a recent study but no effect 

modification was observed. However, previous evidence along with biological plausibility from 

toxicological and controlled human studies has shown this population to be susceptible to O3-related 

health effects. The only studies examining effect measure modification by diabetes examined O3 

exposure and cardiovascular outcomes, but none of the studies reported any change in the 

association by diabetes. 

Studies of air conditioning use, physical conditioning, and smoking were conducted but not 

much evidence was available to determine whether susceptibility to O3-related health effects is 

present for these factors. Toxicological studies also identified hyperthyroidism and the lifestage of 

gestation to be factors warranting further examination. Future research on these will provide 

additional insight into whether these factors affect susceptibility to O3-related health effects. 

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