# Chapter 8. Populations Susceptible to O zone - related Health Effects

1 Interindividua l variation in human responses to air pollut ion 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 popul ation 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 pop ulations at greater risk for O 3 - related health



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



### 7 individual to O 3 . 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 sensi tive 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 O 3 - induced heath effects. This definition identifies susceptible



### 18 populations as the following:

Individual- and population

- level characteristics that increase the risk of O 3 - related health effects in a population including, but not limite d 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 O 3 (e.g., time spent outdoors).



### 19 To examine whether O 3 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 O 3

. 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 O 3 - 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 popula tions to O 3 - 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 chapt er include only those epidemiologic studies that present ed



### 8 stratified results (e.g., males versus females or <65 y ea rs of age versus ≥ 65 y ea rs of age ). This



### 9 approach allowed for a comparison between populations exposed to similar O 3 concentrations and



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



### 11 population are described in previou s 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 F actors examined for possible susceptibility to O 3 - related health effects based on the over all



### 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 whet her pre

- existing diseases and conditions lead to increased susceptibility to



### 20 O 3 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 proport ions 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 1 8 y ea rs 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

Cor onary Heart D isease 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 infectio ns may increase susceptibility of



### 2 individuals to O 3 - 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 ris k of respiratory disease hospitalizations related to O 3 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 O 3 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 O 3 A QCDs (U.S. EPA, 1996, 080828 ; U.S. EPA, 2006, 088089 ) identified asthmatic



### 9 individual s as a population susceptible to O 3 - 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 O 3 - related health effects. No evidence for increased susceptibility was



### 13 found in a study that examined the effect of short

- term O 3 exposure on respiratory health (Barraza



### 14 Villarreal et al., 2008, 156254 ) . A positive association was reported for airway inflammation among



### 15 asthmatic children , but t he observed association was similar in magnitude to that of non

- asthmatics

. 

### 16 However, several studies have indicat ed some evidence for increased susceptibility of asthmatics



### 17 related to O 3 exposure . A study of lifeguards in Texas reported lung function decreases with short



### 18 term O 3 exposure among both asthmatics and non

- asthmatics, however, the decrease was greater



### 19 amon g asthmatics (Thaller et al., 2008, 195869 )

. A Mexi can study of children ages 6

- 14 detected an

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39 association between short

- term O 3 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 O 3
associated decreases in short- term O 3 exposure on lung function by airway hyperresponsiveness

(AHR) (a condition common among asthmatics) reported greater O 3 - 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 O 3 exposure and airway inflammation

(FE NO ) among elderly individuals stratified the study popu lation 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 O 3 exposure and lung function for either asthmatic or non

- asthmatic adult s, but did note a

decrease in lung function among individuals with aller gies 5) 594282 Khatri et al., 2009,

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

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

[IHD]) (Lagorio et al., 2006, 089800 ) . No association was observed between O 3 expos ure 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 O 3 exposure and lung function by asthma medication use. A

study of asthmatic children living in Detroit reported a greater association between short

- term O 3 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 O 3 exposure for corticosteroid users and non

- users in a study taking place during the

winter mon ths in Canada (Liu et al., 2009, 192003 )

. Add itionally, a study of airway inflammation

reported a counterintuitive inverse association with O 3 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 O 3 on both asthmatic

and healthy controls are limited. Based on studies reviewed in the 1996 and 2006 O 3 AQCD

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

to acute effects of O 3 i n terms of FEV 1 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 O 3 - induced FEV 1 decrement of healthy subjects (19% versus 10%,

respectively, p = 0.04). Moreover, a statistically significant positive correlation betwe en FEV 1
responses to O 3 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 O 3 ­
induced FEV 1 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 FEV 1 responses to O 3 diminish with age.



### 3 Asthmatics also sh ow significantly more neutrophils in the BALF (18 hour s 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 O 3 among those with asthma or



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



### 8 allergic sensitization of the respir atory tract. Many of the studies that provide evidence that O 3 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 mo nkeys



### 11 sensitized to house dust mite allergen (Fanucchi et al., 2006, 096491 ; Joad et al., 2006, 5 96390 ;



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



### 13 changes in pulmonary function in mice exposed to O 3 , and Wagner et al. (2007, 596420 )



### 14 demonstrated enhanced inflammatory responses in rats exposed to O 3 , but only in animals sensitized

to allerge n. In general, it is the combined effects of O 3 and allergic sensitization which result in



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



### 17 exposure to 250 ppb O 3 for 5 days increased pulmonary inflammation and fib rosis, along with the



### 18 frequency of bronchopneumonia in rats. Thus short

- term exposure to O 3 may enhance damage in a



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

. In the 2006 O 3 AQCD, the potential for asthmatics to have greater susceptibility to O 3 - 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 epi demiologic 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 O 3 and lung function by corticosteroid use had mixed results . Inconsistent findings of epidemiologic



### 26 studies may be due to the differences in O 3 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 FEV 1 and inflammatory responses to O 3 in



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



### 32 toxicologic al studies adds to the evidence for heightened susceptibility of asthmatics to effects of O 3 

### 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 O 3 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 O 3 exposure on cardiovascular ED visits compared to healthy



### 3 individuals in Atlanta, GA

. They reported that short- term O 3 exposure was associated with higher



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

compared to individ uals without COPD

. H owever, 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 hig her odds of



### 8 congestive heart failure associated with O 3 exposure on warm days (Lee et al., 2008, 192076 ).



### 9 In a study of elderly individuals, although O 3 was associated with greater increases in airway

inflammation (FE NO ) among elderly individuals with than without COPD, the number of individuals



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



### 12 (Delfino et al., 2010, 647222 ) . An additional study also found no association between O 3 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 i ndicate that COPD modifies the association between



### 16 O 3 exposure and respiratory effects, but COPD may affect O 3 - 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 pre



### 21 existing CVD as a susceptibility factor. Recent epidemiologic studies have examined cardiovascular



### 22 related diseases as modifiers of the O 3 - 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 O 3 ex posure and

cardiovascular ED visit s 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 O 3 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 as sociation between O 3 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 ).

A mong individuals with a history of CVD there was a greater association between O 3 

### 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 O 3 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 Howev er, for another biomarker (vWF), CVD status did not modify the positive association with



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

. 

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



### 5 mort ality studies

. A study of 48 U.S. cities reported increased risk of mortality with short

- term O 3


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



### 7 2008, 193829 )

. No association was observed for short

- term O 3 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 O 3 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 O 3 - related health effects for individuals with



### 15 CVD with the possible exception of O 3 exposure and mortality. Future research among those with



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



### 17 O 3 - 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 O 3 - related health effects. In a study of short

- term O 3 

### 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 O 3 exposure on warm days and HAs for co ngestive 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. populati on is u nder 20 y ea rs 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 O 3 - 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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39 summer when O 3 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 O 3 - induced damage (U.S. EPA, 2006, 088089 )

. Multiple s tudies have been performed examining different age groups and their susceptibility

to O 3 - related respiratory HA s and emergency department ( ED ) visits. A study in Cyprus of short

term O 3 co ncentrations and respiratory HA detected possible effect measure modification by age

with a larger association among individuals less than 15 y ea rs of age compared with those over

15 y ea rs 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 O 3 - associated change in asthma

- related

ED visits among children (<15 year ) as compared to adults (15

- 64 y ea rs ) (Halonen et al., 2009,

625764 ) . A study of New Yor k City HAs demonstrated an increase in the association between O 3 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 O 3 exposure and asthma HA among children reported larger associations among children 1 - to 2- year old

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

associations among both children and adults and no modification of the e ffect by age

. A study

performed in Hong Kong examined O 3 and asthma

- related HA s for ages 0

- 14, 15

- 65, and >65 (Ko et

al., 2007, 092844 )

. The researchers reported t hat 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 O 3 on asthma hospitalizations among

both children and adults (<18 and ≥18 y ea rs old) but reported that only children had stati sti cally

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

responsive to advers e effects of O 3 exposure.” (Mar and Koenig, 2009, 594410 )

. Additional ly, 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 O 3 AQCD, reported clinical evidence that children, adolescents, and young adults

(<18 year s of age) appear, on average, to have nearly equivalent spirometric responses to O 3 , but

have greater responses than middle

- age d and older adults when exposed to comparable O 3 doses

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

inspiration) to O 3 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 y ea rs
, McDonnell et al. (1999, 0 10939 ) reported that symptom responses from O 3 exposure also decrease

with increasing age. Lung growth and development is not achieved until 18

- 20 y ea rs 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 O 3 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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39 under the age of 5 compared to the total airwa y 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 O 3 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 O 3 , or episodically for 5 biweekly cycles

alternating 5 days of 0.5 ppm O 3 with 9 days of filtered air, designed to mimic human exposure

(70 days total). All monkeys acutely exposed to O 3 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 O 3 in another

study (Harkema et al., 1987, 040816 )

. Functional (increased airway resistance and responsiveness

wit h antigen + O 3 co

- exposure) and cellular changes in conducting airways (increased numbers of

inflammatory eosinophils ) also manifested among the i nfant 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 expos ed to O 3 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

O 3 - induced airway hyper

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

. Age may affect the immune response to O 3 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 O 3 fo r 5 hour s (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 strain

age interaction . In young mice, healing of skin wounds is not significantly affected by O 3 exposure (Lim et al., 2006, 670834 ) . However, exposure t o 0.5 ppm O 3 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 O 3 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 antioxidan t 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 -d ay exposure to 0.5 ppm O 3 . Immature rats exhibited a higher ventilation rate, which



### 4 may have increased exposure. Senescent rats had simila r 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 O 3 exposure and



### 7 bradycardia that was present among youn g 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 re vealed 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 th e formation of ROS, which tends to increase with age, thus modulating the changes in



### 13 cardiopulmonary physiology after O 3 exposure.



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

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



### 16 a mong children and young adults, although generally s tudies reported positive associations among



### 17 both children and adults or just among children . For other outcomes, inconsistent findings reg arding



### 18 susceptibility to O 3 - 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 A dults

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



### 21 susceptibility to O 3 - related health effects (U.S. EPA, 2006, 192082 ) . Diminished symptomatic



### 22 responses may also put the eld erly at increased risk for continued O 3 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 O 3 - related health effects (see Table 8 -1 that gives pre

existing 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 individu als, respectively) this group represents a large



### 28 population potentially susceptible to O 3 - 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 O 3 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 betw een O 3 levels and respiratory mortality among those 65 y ea rs and



### 33 older or those 15

- 64 y ea rs ; however, an inverse association between O 3 levels and cardiovascular



### 34 mortality was present among those 65 y ea rs and older but not among those under 65 y ea rs 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 cum ulative 2-day O 3 levels among those

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39 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 O 3 and HAs for CVD

- related health effects

reported no association for in dividuals 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 O 3 levels and COPD ED visits (Arbex et al.,

2009, 18433 4 ).

The majority of studies reported greater effects of short

- term O 3 exposure and mortality

among older adults , which is consistent with the findings of the 2006 O 3 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 y ea rs (Medina- Ramón and Schwartz, 2008, 193829 )

. Further inv esti gation of this study population reve a led no association between O 3 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 y ea rs old

age range (Cakmak et al., 2007, 091170 )

. A study performed in China reported greater ef fects in

populations 45 y ea rs and older (compared to 5

- 44 year olds), with statistically significant effects

present only among those 65 y ea rs and older (Kan et al., 2008, 156621 )

. An Italian study reported

higher risk of all

- cause mortality associated with increased O 3 concentrations among individuals

85 year and older as compared to those 35

- 84 y ea rs old

. Those 65

- 74 and 75

- 84 y ea rs did not show a

greater increase in risk compared to those age 35

- 64 y ea rs (Stafoggia et al., 2010, 625034 )

. The Air

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

association between O 3 exposure and mortality for those <75 and ≥ 75 y ea rs of age

. In Canada, the

associations for all

- cause and cardiovascular mortality were greater am ong those 75 y ea rs and older

in the summer

- only and all

- year analyses. Age groups were not compared in the analysis for

respiratory mortality in Canada. I n the U.S.

, the association for all

- cause mortality was slightly

greater for those younger than 75 y ea rs 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 summer

only analy ses. 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. R espiratory symptom responses to O 3 exposure appears to increase with

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

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

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

older adults may put them at increased risk for continued O 3 exposure. Regarding cardiac outcomes,

O 3 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 thic kness 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 grea ter
prevalence of females ≥ 65 y ea rs 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 O 3 on multiple health endpoints stratified by sex.



### 8 A study in Maine on short

- term O 3 concentrations and asthma ED visits detected greater



### 9 e ffects 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 O 3 exposure and asthma HA among males and females between 1 and 6 y ea rs old (Lin et



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

- term O 3 

### 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 in crease in



### 16 respiratory HA for males (mean ages 47.6 -69.0 y ea rs ) (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 (Won g 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, 18433 4 )

. 

### 21 Higher levels of respiratory HA with greater O 3 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 repo rted decreased lung



### 24 function with increased O 3 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 O 3 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 examini ng the associations between O 3 

### 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 n ote 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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39 A biomarker study investigating the effects of O 3 concentrations on high

- sensitivity C

- reactive

protein (hs

- CRP), fibrinogen, and white blood cel l 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 O 3 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 O 3 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 O 3 concentrations and

mortality stratified by sex and in contrast with studie s 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 y ea rs of age and older (Medina- Ramón and Schwartz, 2008,

193829 ) . One long

- term O 3 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 understand ing of the possible differential

susceptibility of male s and females to O 3 exposure. Several studies have suggested that physiological

differences between sexes may predispose females to a greater susceptibility to O 3 . Lower plasma

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

defense mechanism of O 3 neutralization, may be a contributing factor (Housley et al., 1996, 080811 )

. Consequently, reduced absorption of O 3 in the upper airways of females may promote its deeper

penetration. Dosimetric measurements have shown that the absorption distribution of O 3 is

independent of gender when absorption is normalized to anatomical dead space (Bush et al., 1 996,

080763 ) . Thus, a differential removal of O 3 by uric acid seems to be minimal. In general, the

physiologic response of young healthy females to O 3 exposu re 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 O 3 is en hanced (Fox et al., 1993, 043906 ) . Seal et al. (1996, 044251 ) later

r eported 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 pre cisely defined the menstrual

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

pulmonary inflammation and injury after a 5

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

were generally more susceptib le, 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, r esults have varied, with evidence for increased susceptibility for O 3 - related health



### 2 effects present for females in some studies and males in other studies. M ost studies examining O 3 

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



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

measure modification exi s ts 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 diffe rent 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 O 3 exposure on respiratory



### 9 function have focused on whether various genes modify the effect of O 3 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 O 3 - related susceptibility to health effects. A study of



### 12 wheeze in infants reported larger association s between short

- term O 3 exposure and wheeze and



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



### 14 asthma (Tr iche et al., 2006, 093274 ).

Multiple g enes, including glutathione S

- transferase Mu 1 ( GSTM1 ) and t umor necrosis



### 16 factor

- α ( TNF

- α ) were evaluated in the 2006 A QCD (U.S. EPA, 2006, 088089 ) and found to have a



### 17 “potential role... in the innate susceptibility to O 3 .” Studies performed since the last AQCD have



### 18 continued to examine the roles of GSTM1 and TNFα on O 3 - related health effects and have also



### 19 examined other gene variants that may increase susceptibility to O 3 - related health effects.

Epidemiologic studies that examined the effects of short

- term exposure to O 3 on lung function



### 21 included a nalyses of potential gene

- environment interactions

. Romieu et al. (2006, 090969 ) reported



### 22 an association between O 3 and respiratory symptoms that were larger among children with GSTM1



### 23 null or g lutathione S

- transferase P 1 ( GSTP1 ) Val/Val genot yp es . However, results suggested that O 3 ­ 

### 24 associa ted 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 gen otypes

. 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 O 3 challe nge.



### 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 O 3 (Bergamaschi et al., 2001, 052670 ) . Adults with GSTM1 null only genotype did not



### 34 show the same response to O 3 . 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 O 3 

### 36 exposure. In a similar study, Vagaggini et al. (2010, 387127 ) exposed mild

- to

- moderate asthmatics to

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39 O 3 with moderate e xercise. In subjects with NQO1 wt and GSTM1 null , there was no evidence of

changes in lung function or inflammatory responses to O 3

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

25 ± 5) exposed to 400 ppb O 3 fo r 2 hour s with exercise, Alexis et al. (2009, 628542 ) found

genotype effects on inflammatory responses but not lung function responses to O 3 . At 4 h post O 3 exposure, individuals with both GSTM1 genotypes had significant increases in sp utum neutrophils

with a tendency for a greater increase in GSTM1 sufficient than nulls. At 24 hour s postexposure,
neutrophils had returned to baseline levels in the GSTM1 sufficient individuals. In the GSTM1 null

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

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

control in the Alexis et al. (2009, 628542 ) study, effects of the exposure other th an O 3 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 O 3 responsiveness in

humans.

Several epidemiologic studies of lo ng

- term O 3 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, O 3 , and playing more than two team
sports, and new onset of asthma (Is lam 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 )

. A RG1 and ARG2 (encoded by a rginases )

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 O 3 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

O 3 areas with TN F- α variant G

- 308A (TNF

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

expression. There was no decrease in risk for children with th is TNF

- α variant but living in areas

with high O 3 concentrations. Additionally, this modification for high and low levels o f O 3 was not

present among non

- asthmatic children (Lee et al., 2009, 199915 )

. Went e n et a l. (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

O 3 areas. Toxicological studies have reported differences in cardiac and respiratory effects after O 3 exposure among differe n t 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 O 3 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 O 3 - induced lung hyperpermeability (Kleeberger et al., 2000, 014895 ; Kleeberger et al., 2001, 016163 ) . Additionally, some studies have reported O 3 - 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 O 3 -induced airway hyperresponsi veness 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 O 3 for 3 hour s . 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 O 3 for 5 hour s

. 

### 9 The role of TNF

- α signaling in O 3 - induced responses has been previously established through

depletion exp eriments, but a more recent toxicological study investigated the effects of combined O 3 

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



### 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 O 3 /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 O 3 among inbred strains of animals does not



### 17 seem to be dose dependent since absorption of 18 O 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 O 3 - related health effects

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



### 21 sensitivity abnormalities, neurologic al abnormalities, and premature aging. The same genetic defect



### 22 in mice (Csb -/- ) makes them sensitive to oxidative stressors, including O 3 . Kooter et al. (2007,



### 23 596397 ) demonstrated that Csb -/- mice produced significantly more TNF

- α after exposure to 0.8 ppm



### 24 O 3 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 prev ious AQCDs, but recent studies have



### 27 examined modification of the association between O 3 and hea lth effect s by dietary factors. Because



### 28 O 3 mediates its toxic effects through oxidative stress, the antioxidant status of an individual is an



### 29 important factor th at may contribute to increased susceptibility to O 3 - related health effects.

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



### 31 inhibiting O 3 - mediated damage.



### 32 Epidemiologic studies have examin ed effect measure modific ation by diet and found evidence



### 33 that certain dietary components are related to the effect of O 3 has on respiratory outcomes

. The most



### 34 recent study examined fruit/vegetable intake and Medite rrane an 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 O 3 - 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 O 3 and nasal airway inflammation among children in the placebo group but not in those



### 4 receiving the supplementati on

. The authors conclude d 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 epidemiol ogic 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. E xposure to O 3 depletes

the antioxidant level in nasal ELF probably due to scrubbing of O 3 (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 O 3 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 prot ective effects of alpha

- tocopherol (a form of v itamin

E) and ascorbate ( v itamin C) on spirometric lung function from O 3 but not on the intensity of



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



### 17 of mediat ors (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 O 3 - exacerbated nasal allergy responses in rats with gamma

- tocopherol treatment (a



### 23 form of v itamin 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 O 3 responses . G uinea pigs deficient in a scorbate displayed only minimal injury and



### 26 inflammation after exposure to O 3 (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 O 3 exposure (Valacchi et al.,



### 29 2009, 20155 4 )

. 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 O 3 has been shown to differen tially 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/m 2 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 d ecreased lung function with increased short

- term O 3 

### 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 O 3 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 y ea rs 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 FEV 1 responses. The

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



### 11 whereby FEV 1 responses diminish with increasing age. In a similar analysis, Bennett et al. (2007,



### 12 418827 ) found enhanced FEV 1 decrements following O 3 exposure with increasing BMI in a group of



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



### 14 (BMI range 19.1 to 32.9). In the women, greater O 3 - induced FEV 1 decrements were seen in

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



### 16 t han in underweight (BMI <18.5) . Even disregarding th e five underweight women, a greater O 3 

### 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 show n enhanced pulmonary inflammation

and injur y with acute O 3 exposure, but responses to longer exposures at more relevant doses appear



### 21 to differ. A recent study found that obese mice are actually resistant to O 3 - induced pulmonary injury



### 22 and inflammation and reduced lung compliance following exposure to 0.3 ppm O 3 for 72 hour s
, 

### 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 O 3 - related

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



### 26 r elationship between O 3 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, e ducational 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 N etwork;



### 31 CensusScope and CensusScope, 2010, 647297 ).



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



### 33 the effect s of short

- term O 3 exposure on respiratory HAs and ED visits

. A study performed in Korea



### 34 examined the association between O 3 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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39 inverse eff ects of O 3 on respirato r y 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 O 3 and respiratory HA was among those with an

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

income ( Cakmak et al., 2006, 093272 )

. One study performed among children in New Yor k S tate
reported greater associations between long

- term O 3 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 in surance, and who were not living in poor

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

. One study reported the association betwe en short

- term O 3 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 O 3 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 O 3 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 O 3 concentrations and mortality a t 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

(a t 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 O 3 concentrations and infant mortality among any of the

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

al., 2004, 093074 ) . Another study in Mexic o reported a positive association between O 3 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 a ny of the SES groups with other lags (Carbajal

- Arroyo et al., In Press, 667773 )

. Evidence from a controlled human exposure study that examined O 3 effects on lung function

does not provide support for greater O 3 - 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

co ncentration

- dependent decline in percent

- predicted FEV 1 (4

- 5% at 400 ppb O 3 ) 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 neighborho ods with low SES have



### 2 reporte d that individuals with low SES are more susceptible to O 3 - 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 exami ne O 3 - 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 association s 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 O 3 by blocking the penetration of O 3 into the indoor environment (further



### 9 info rmation can be found in Section 4.4 ) . Air conditioning use is a difficult effect measure modi fier

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 O 3 concentrations and HA and mortality varied among areas with high and low prevalen ce of air



### 18 conditioning. Medina

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



### 19 observed a greater association between O 3 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 O 3 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 mortali ty 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 O 3 AQCD reported individuals who participate in outdoor



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



### 28 O 3 exposure and respiratory health outcomes in these groups (U.S. EPA, 2006, 088089 ) . Outdoor



### 29 workers are exposed to ambient O 3 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 th e association between FEV 1

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### 5

10

15

20

25

30

35

1 responses to O 3 and minute ventilation, refer to Section 6.2.3.1 of the 2006 O 3 AQCD (U.S. EPA,



### 2 2006, 088089 ).



### 3 A recent study has explored the potential effect measure modification of O 3 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 O 3 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 O 3 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 O 3 concentrations from outdoor work leads to increased



### 12 susceptibility to O 3 - related health effects among individuals wh o 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

- Hispa nic Whites.

Approximately 12.1 % of people reported their race/ethnicity as Non

- Hispanic Black and 12.6 %



### 16 reported being His panic (Social Science Data Analysis Network; CensusScope and CensusScope,



### 17 2010, 647301 )

. 

### 18 A couple of studies examined the associations between short

- term O 3 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 O 3 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 (L in 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 O 3 concentrations. The independe nt effects of gender

- race group and O 3 concentration on



### 28 lung function were positive, but the interaction between gender

- race group and O 3 concentration was



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

- race groups that is independent of O 3 concentration (the concentration

- response curves for the four



### 31 gender

- race groups are parallel). In a multiple comparison procedure on data collapsed across all O 3 

### 32 concentrations for each sex

- race group, both Black men and Black women had larger decrements in



### 33 FEV 1 than did White men. The authors noted that the O 3 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 res ponses to O 3 cannot be ruled out. The college students recruited for the Seal

March 20 11 8

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20

25

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1 et al. (1993, 039357 ) study a re 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, altho ugh 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 y ea rs of age and older in



### 9 the U.S . Forty

- nine percent of individuals 65 and older reported no leisure

- ti me physical activity

(Pleis et al., 2009, 629608 ) . Physical activit y 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 year s prior to death observed excess risk of mortality with

increasing O 3 concentrations among individuals that never exercised compar ed to individuals that



### 16 exercised at least once a month for both adults 30 y ea rs of age and older and adults 65 y ea rs of age



### 17 and older (Wong et al., 2007, 093278 ) . No recent studies examining modification of O 3 - related



### 18 health effects by current physical activity were identified.



# 8.12. Smoking

19 Previous O 3 AQCDs have concluded that smoking does not increase susceptibility to

O 3 - related heal th effects; in fact, in controlled human exposure studies, smokers have been found to



### 21 be less susceptible to O 3 - 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 O 3 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 O 3 conc entrations and plasma



### 28 homocysteine levels. Another study examined the association between O 3 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 O 3 levels and oxidative DNA damage examined



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



### 33 positi vely 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 O 3 concentrations were inversely associated with DNA



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



### 3 The fi ndings of Palli et al. (2009, 196688 ) are consistent w ith those from controlled human



### 4 exposure studies that have confirmed that smokers are less responsive to O 3 than non

- smokers.

Spirometric and plethysmographic pulmonary function decline, nonspecific airway hyperreactivity,



### 6 and inflammatory response of smok ers to O 3 were all weaker than the ones reported for non



### 7 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 O 3 - associated DNA damage reported smokers to be less susceptible to O 3 ­ 

### 14 related health effects. However, b oth epidemiologic studies of short

- term exposure and CVD

outcomes found no effect measure modification by smoking

. 

# 8.13. Hyperthyro idis 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 hormo nes. Compared to controls,



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

- h exposure to

O 3 , 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 hav e 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. Overal l, this review provides



### 28 evidence that various factors may lead to increased susceptibility to O 3 - related health effects.



### 29 The populations identified in this section that are most susceptible to O 3 - related health effects

are individuals with influenza/infec tion, 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 O 3 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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23 studies. Most studies comparing age groups reported great er effects of short

- term O 3 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 O 3 - related health effects. Similarly, studies of

effect measure modification by BMI observed greater O 3 - 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 O 3 exposure and health effects by SES and race were available in a limited

number of studies, and demonstrat ed possible increased odds of health effects related to O 3 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 w ith biological plausibility from

toxicological and controlled human studies has shown this population to be susceptible to O 3 - related

health effects. The only studies examining effect measure modification by diabetes examined O 3 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 O 3 - 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 fact ors affect susceptibility to O 3 - related health effects.

March 20 11 8

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Alexeeff, S. E.; Litonjua, A. A.; Wri ght, R. O.; Baccarelli, A.; Suh, H.; Sparrow, D.; Vokonas, P. S.; Schwartz, J. (2008). Ozone exposure, antioxidant genes, and lung function in an elderly cohort: VA normative aging study. Occup Environ Med, 65: 736

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Méndez

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induced injury in the nasal airways of monkeys using magnetic resonance imaging and morphometric techniques. Toxicol Pathol, 35: 27

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