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8 POPULATIONS POTENTIALLY AT INCREASED RISK FOR 

OZONE-RELATED HEALTH EFFECTS

1 Interindividual variation in human responses to air pollution exposure can result in some 

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

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

4 both the population as a whole and those potentially at increased risk for health effects in 

5 response to ambient air pollution (Preface to this ISA). To facilitate the identification of 

6 populations and lifestages at greater risk for air pollutant related health effects, studies 

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

8 individual to air pollutants. The definitions of susceptibility and vulnerability have been 

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

10 intrinsic factors (e.g., lifestage, sex, preexisting disease/conditions) while “vulnerability” 

11 refers to non-biological or extrinsic factors (e.g., socioeconomic status [SES]) (U.S. EPA, 

12 2010c, 2009d). In some cases, the terms “at-risk” and “sensitive” populations have been 

13 used to encompass these concepts more generally. The main goal of this evaluation is to 

14 identify and understand those factors that result in a population or lifestage being at 

15 increased risk of an air pollutant-related health effect, not to categorize the factors. To 

16 this end, previous ISAs and reviews (Sacks et al., 2011; U.S. EPA, 2010c, 2009d) have 

17 used “susceptible populations” to encompass these various factors. In this chapter, 

18 “at-risk” is the all-encompassing term used for groups with specific factors that increase 

19 the risk of an air pollutant (e.g., O3)-related health effects in a population. 

20 Individuals, and ultimately populations, could experience increased risk for air pollutant 

21 induced health effects via multiple avenues. A group with intrinsically increased risk 

22 would have some factor(s) that increases risk for an effect through a biological 

23 mechanism. In general, people in this category would have a steeper concentration24 risk relationship, compared to those not in the category. Potential factors that are often 

25 considered intrinsic include genetic background and sex. A group of people could also 

26 have extrinsically increased risk, which would be through an external, non-biological 

27 factor. Examples of extrinsic factors include SES and diet. Some groups are at risk of 

28 increased internal dose at a given exposure concentration, which includes individuals 

29 that have a greater dose of delivered pollutant because of breathing pattern. This 

30 category would include persons who work outdoors or exercise outdoors. In addition, 

31 some outdoor workers could have greater exposure (concentration x time), regardless 

32 of the delivered dose. Finally, there are those who might be placed at increased risk 

33 for experiencing a greater exposure by being exposed at a higher concentration. For 
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1 example, groups of people exposed to higher air pollutant concentrations due to less 

2 availability/use of home air conditioners (i.e., more open windows on high O3 days).

3 Some factors described above are multifaceted and may influence the risk of an air 

4 pollutant related health effect through a combination of avenues. For example, SES may 

5 affect access to medical care, which itself may contribute to the presence of preexisting 

6 diseases and conditions considered as intrinsic factors. Additionally, children tend to 

7 spend more time outdoors at higher levels of activity than adults, which leads to 

8 increased intake dose and exposure, but they also have biological (i.e., intrinsic) 

9 differences when compared to adults. 

10 The emphasis of this chapter is to identify and understand the factors that potentially 

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

12 due to intrinsic factors, extrinsic factors, increased dose/exposure or a combination, due 

13 to the often connected pathways between factors. The following sections examine factors 

14 that potentially lead to increased risk of O3-related health effects and characterize the 

15 overall weight of evidence for each factor. Most of the factors are related to greater health 

16 effects given a specific dose but there is also discussion of increased internal dose and/or 

17 exposure at a given concentration integrated throughout the sections (i.e., lifestage, 

18 outdoor workers, and air conditioning use).

Approach to Classifying Potential At-Risk Factors

19 To identify factors that potentially lead to some populations being at greater risk to air 

20 pollutant related health effects, the evidence across relevant scientific disciplines 

21 (i.e., exposure sciences, dosimetry, controlled human exposure, toxicology, and 

22 epidemiology) was evaluated. In this systematic approach, the collective evidence is used 

23 to examine coherence of effects across disciplines and determine biological plausibility. 

24 By first focusing on studies (i.e., epidemiologic or controlled human exposure) that 

25 conduct stratified analyses it is possible to identify factors that may result in some 

26 populations being at greater risk of an air pollutant related health effect. These types of 

27 studies allow for an evaluation of populations exposed to similar air pollutant (e.g., O3) 

28 concentrations within the same study design. Experimental studies also provide important 

29 lines of evidence in the evaluation of factors that may lead to increased risk of an air 

30 pollutant related-health effect. Toxicological studies conducted using animal models of 

31 disease and controlled human exposure studies that examine individuals with underlying 

32 disease or genetic polymorphisms may provide evidence in the absence of stratified 

33 epidemiologic analyses. Additionally these studies can provide support for coherence 

34 with the health effects observed in epidemiologic studies as well as an understanding of 

35 biological plausibility. The collective results across the scientific disciplines comprise the 
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1 overall weight of evidence that is used to determine whether a specific factor results in a 

2 population being at increased risk of an air pollutant related health effect. 

3 Building on the causal framework discussed in detail in the Preamble and used 

4 throughout the ISA, conclusions are made regarding the strength of evidence for each 

5 factor that may contribute to increased risk of an O3-related health effect based on the 

6 evaluation and synthesis of evidence across scientific disciplines. The conclusions drawn 

7 considered the “Aspects to Aid in Judging Causality” discussed in Table 1 of the 

8 Preamble. The categories considered for evaluating the potential increased risk of an air 

9 pollutant-related health effect are “adequate evidence,” “suggestive evidence,” 

10 “inadequate evidence,” and “evidence of no effect.” They are described in more detail in 

11 Table 8-1.

Table 8-1 Classification of Evidence for Potential At-Risk Factors.

Health Effects

Adequate 

evidence

There is substantial, consistent evidence within a discipline to conclude that a factor results in a population or 

lifestage being at increased risk of air pollutant-related health effect(s) relative to some reference population or 

lifestage. Where applicable this includes coherence across disciplines. Evidence includes multiple high-quality 

studies.

Suggestive 

evidence

The collective evidence suggests that a factor results in a population or lifestage being at increased risk of an air 

pollutant-related health effect relative to some reference population or lifestage, but the evidence is limited due to 

some inconsistency within a discipline or, where applicable, a lack of coherence across disciplines. 

Inadequate 

evidence

The collective evidence is inadequate to determine if a factor results in a population or lifestage being at increased 

risk of an air pollutant-related health effect relative to some reference population or lifestage. The available studies 

are of insufficient quantity, quality, consistency and/or statistical power to permit a conclusion to be drawn. 

Evidence of no 

effect

There is substantial, consistent evidence within a discipline to conclude that a factor does not result in a population 

or lifestage being at increased risk of air pollutant-related health effect(s) relative to some reference population or 

lifestage. Where applicable this includes coherence across disciplines. Evidence includes multiple high-quality 

studies.

12 This chapter evaluates the various factors indicated in the literature that may result in a 

13 population being at increased risk of an O3-related health effect. For further detail on the 

14 epidemiologic, controlled human exposure, and toxicological studies included in this 

15 chapter, see Chapters 5, 6, and 7.

8.1 Genetic Factors

16 The potential effects of air pollution on individuals with specific genetic characteristics 

17 have been examined; studies often target polymorphisms in already identified candidate 

18 susceptibility genes or in genes whose protein products are thought to be involved in the 

19 biological mechanism underlying the health effect of an air pollutant (Sacks et al., 2011). 

20 As a result, multiple studies that examined the effect of short- and long-term O3 exposure 

21 on respiratory function have focused on whether various gene profiles lead to an 
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1 increased risk of O3-related health effects. For more details on the function and mode of 

2 action of the genetic factors discussed in this section, see Section 5.4.2.1. Additionally, a 

3 limited number of toxicological studies have examined the joint effects of nutrition and 

4 genetics. Details on these toxicological studies of nutrition and genetics can be found in 

5 Section 5.4.2.3.

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

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

8 role... in the innate susceptibility to O3” (U.S. EPA, 2006b). Epidemiologic, controlled 

9 human exposure, and toxicological studies performed since the 2006 O3 AQCD have 

10 continued to examine the roles of GSTM1 and TNF-α in modifying O3-related health 

11 effects and have examined other gene variants that may also increase risk. Due to small 

12 sample sizes, many controlled human exposure studies are limited in their ability to test 

13 genes with low frequency minor alleles and therefore, some genes important for 

14 O3-related health effects may not have been examined in these types of studies. A 

15 summary of effect measure modification findings from epidemiologic and controlled 

16 human exposure studies discussed in this section is included as Table 8-2.
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Table 8-2 Summaries of results from epidemiologic and controlled human 

exposures studies of modification by genetic variants.

Gene variant Comparison group Health outcome /population Effect modification of 

association for the gene 

variant

Reference

GSTM1 null GSTM1 positive Respiratory symptoms among 

asthmatic children

↑ Romieu et al. (2006)

GSTP1 Val/Val GSTP1 Ile/Ile or Ile/Val Respiratory symptoms among 

asthmatic children

↑

GSTP1 Ile/Ile 

or Ile/Val 

GSTP1 Val/Val Lung function among 

asthmatic children

↓

GSTP1 Ile/Val 

or Val/Val 

GSTP1 Ile/Ile Lung function among adults ↓ Alexeeff et al. (2008)

HMOX1 S/L or L/L HMOX1 S/S Lung function among adults ↓

NQO1 wildtype 

and GSTM1 null

Other combinations Lung function among healthy 

adults with exercise

↓ Bergamaschi et al. 

(2001)

NQO1 wildtype 

and GSTM1 null

Other combinations Lung function among mild-tomoderate asthmatics with 

moderate exercise

= Vagaggini et al. (2010)

NQO1 wildtype 

and GSTM1 null

Other combinations Inflammatory responses 

among mild-to-moderate 

asthmatics with moderate 

exercise

=

GSTM1 null GSTM1 positive Lung function among healthy 

adults with intermittent 

moderate exercise

= Kim et al. (2011)

GSTM1 null GSTM1 positive Inflammatory responses 

among healthy adults with 

intermittent moderate exercise

=

GSTM1 null GSTM1 positive Lung function among 

asthmatic children

↓ Romieu et al. (2004b)

GSTM1 null GSTM1 positive Lung function among healthy 

adults with intermittent 

moderate exercise

= Alexis et al. (2009)

GSTM1 null GSTM1 positive Inflammatory changes among 

healthy adults with intermittent 

moderate exercise

↑

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

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

3 (2006) reported an association between O3 and respiratory symptoms that were larger 

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

5 genotypes compared with children with GSTM1 positive or GSTP1 Ile/Ile or Ile/Val 

6 genotypes, respectively. However, results suggested that O3-associated decreases in lung 

7 function may be greater among children with GSTP1 Ile/Ile or Ile/Val compared to 

8 GSTP1 Val/Val. Alexeeff et al. (2008) reported greater O3-related decreases in lung 

9 function among GSTP1 Val/Val adults than those with GSTP1 Ile/Ile or GSTP1 Ile/Val 

10 genotypes. In addition, they detected greater O3-associated decreases in lung function for 

11 adults with long GT dinucleotide repeats in heme-oxygenase-1 (HMOX1) promoters.
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1 Several controlled human exposure studies have reported that genetic polymorphisms of 

2 antioxidant enzymes may modulate pulmonary function and inflammatory responses to 

3 O3 challenge. Healthy carriers of NAD(P)H quinone oxidoreductase 1 (NQO1) wild type 

4 (wt) in combination with GSTM1 null genotype had greater decreases in lung function 

5 parameters with exposure to O3 (Bergamaschi et al., 2001). Vagaggini et al. (2010)

6 exposed mild-to-moderate asthmatics to O3 during moderate exercise. In subjects with 

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

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

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

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

11 GSTM1 genotype and did not examine NQO1. In another study that examined GSTM1 

12 but not NQO1, asthmatic children with GSTM1 null genotype (Romieu et al., 2004b)

13 were reported to have greater decreases in lung function in relation to O3 exposure. 

14 Additionally, supplementation with antioxidants (Vitamins C and E) had a slightly more 

15 beneficial effect among GSTM1 null children (for more on modification by diet, see 

16 Section 8.4.1).

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

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

19 (2009) found genotype effects on inflammatory responses but not lung function responses 

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

21 statistically significant increases in sputum neutrophils with a tendency for a greater 

22 increase in GSTM1 sufficient than GSTM1 nulls. At 24 hours postexposure, neutrophils 

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

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

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

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

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

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

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

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

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

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

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

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

35 capability following O3 exposure than those of GSTM1 sufficient subjects. Airway 

36 macrophages and dendritic cells from GSTM1 null subjects exposed to O3 expressed 

37 higher levels of the surface marker HLA-DR, again suggesting activation of the innate 

38 immune system. Since there was no FA control in the Alexis et al. (2009) study, effects 

39 of the exposure other than O3 cannot be ruled out. In general, the findings between these 
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1 studies are inconsistent. It is possible that different genes may be important for different 

2 phenotypes. Additional studies, which include appropriate controls, are needed to clarify 

3 the influence of genetic polymorphisms on O3 responsiveness in humans.

4 In general, toxicological studies have reported differences in cardiac and respiratory 

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

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

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

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

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

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

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

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

13 specifically, these studies found that TNF (protein product is the inflammatory cytokine 

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

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

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

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

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

19 and Myd88, appear to be important in responses to O3, as demonstrated by Williams et al. 

20 (2007b). A role for the inflammatory cytokine IL-6 has been demonstrated in 

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

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

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

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

25 genes are important for O3-induced responses.

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

27 factor erythroid 2-related factor 2 (Nrf-2), suggesting a role for genetic differences in 

28 altering the formation of ROS (Hamade et al., 2010; Cho and Kleeberger, 2007). 

29 Additionally, some studies have reported O3-related effects to vary by Inf-1 and Inf-2 

30 quantitative trait loci (Tankersley and Kleeberger, 1994) and a gene coding for Clara cell 

31 secretory protein (CCSP) (Broeckaert et al., 2003; Wattiez et al., 2003). Other 

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

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

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

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

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

37 and is thought to participate in lung damage. Mice deficient in the gene for inducible 
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1 nitric oxide synthase (NOS2/NOSII/iNOS) are partially protected against lung injury 

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

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

4 nitrogen intermediates after O3 exposure, in contrast to their wild-type counterparts, and 

5 also produce less PGE2 comparatively (Fakhrzadeh et al., 2002). These gene-deficient 

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

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

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

9 2002). Therefore it is unclear whether inducible nitric oxide synthase plays a protective 

10 role or mediates damage.

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

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

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

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

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

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

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

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

19 0.4 ppm O3 for 5 hours. This study may provide biological plausibility for the increased 

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

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

22 (Bergamaschi et al., 2001). 

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

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

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

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

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

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

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

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

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

seem to be dose dependent since absorption of 18 32 O in various strains of mice did not 

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

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

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

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

aging. The same genetic defect in mice (Csb-/- 37 ) makes them sensitive to oxidative 
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stressors, including O3. Kooter et al. (2007) demonstrated that Csb-/- 1 mice produced 

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

3 However, there were no statistically significant differences in other markers of 

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

5 Overall, for variants in multiple genes there is suggestive evidence for potential 

6 involvement in populations being potentially more at-risk than others to the effects of O3

7 exposure on health. Controlled human exposure and epidemiologic studies have reported 

8 some evidence of O3-related increases in respiratory symptoms or decreases in lung 

9 function with variants including GSTM1, GSTP1, HMOX1 and NQO1, although the 

10 results are not consistent across studies and gene variants. Future studies of these and 

11 other genes in human populations will be important for determining the role of each 

12 genotype and its effect on risk as well as finding coherence across the disciplines. NQO1 

13 deficient mice were found to be resistant to O3-induced AHR and inflammation, 

14 providing biological plausibility for results of studies in humans. Additionally, studies of 

15 rodents have identified a number of other genes that may affect O3-related health 

16 outcomes, including genes related to innate immune signaling and pro- and 

17 anti-inflammatory genes, which have not been investigated in human studies. 

8.2 Preexisting Disease/Conditions

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

19 This may be the result of individuals with a preexisting disease/condition having less 

20 reserve than healthy individuals, so although the absolute change may be the same, the 

21 health consequences are different. Previous O3 AQCDs concluded that some people with 

22 preexisting pulmonary disease, especially asthma, are among those at increased risk of an 

23 O3-related health effect. Extensive toxicological evidence indicates that altered 

24 physiological, morphological and biochemical states typical of respiratory diseases may 

25 render people at risk of an additional oxidative burden induced by O3 exposure. In 

26 addition, a number of epidemiologic studies found that some individuals with respiratory 

27 diseases are at increased risk of O3-related effects. The majority of the studies identified 

28 in previous AQCDs focused on whether preexisting respiratory diseases result in 

29 increased risk of O3-related health effects, with a limited number of studies examining 

30 other preexisting diseases, such as cardiovascular. 

31 Studies identified since the completion of the 2006 O3 AQCD that examined whether 

32 preexisting diseases and conditions lead to increased risk of O3-induced health effects 

33 were identified and are summarized below. Table 8-3 displays the prevalence rates of 

34 some of these conditions categorized by age and region among adults in the U.S. 
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1 population; data for children, when available, are presented within the following sections. 

2 Substantial proportions of the U.S. population are affected by these conditions and 

3 therefore may represent a potentially large at-risk population. While these diseases and 

4 conditions represent biological or intrinsic factors that could lead to increased risk, the 

5 pathways to their development may have intrinsic or extrinsic origins.

Table 8-3 Prevalence of respiratory diseases, cardiovascular diseases, and 

diabetes among adults by age and region in the U.S.

Adults

N (in thousands) Age Region

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

Respiratory Diseases

Asthmaa 16,380 7.2 7.5 7.8 6.4 7.7 8.0 5.9 8.4

COPD

Chronic Bronchitis 9,832 3.2 5.5 5.9 5.3 3.4 4.8 5.2 2.9

Emphysema 3,789 0.2 2.0 5.7 5.0 1.2 1.9 1.9 1.3

Cardiovascular Diseases

All Heart Disease 26,628 4.6 12.3 26.7 39.2 11.3 12.7 12.2 9.9

Coronary Heart Disease 14,428 1.1 6.7 16.9 26.7 5.7 6.5 7.3 4.9

Hypertension 56,159 8.7 32.5 54.4 61.1 22.9 24.1 27.1 20.6

Diabetes 18,651 2.3 12.1 20.4 17.3 4.5 7.6 9.0 7.7

a

Asthma prevalence is reported for “still has asthma.”

Source: Pleis et al. (2009); National Center for Health Statistics.

8.2.1 Influenza/Infections

6 Recent studies have indicated that underlying infections may increase the risk of O3-

7 related health effects because O3 exposure likely impairs host defenses, which may 

8 increase the body’s response to an infectious agent. However, there is little epidemiologic 

9 or experimental evidence that infection or influenza itself renders an individual at greater 

10 risk of an O3-induced health effect. A study of hospitalizations in Hong Kong reported 

11 that increased levels of influenza intensity resulted in increased excess risk of respiratory 

12 disease hospitalizations related to O3 exposure (Wong et al., 2009). In addition, a study of 

13 lung function in asthmatic children reported decreases in lung function with increased 

14 short-term O3 exposure for those with upper respiratory infections but not for those 

15 without infections (Lewis et al., 2005). Toxicological studies provide biological 

16 plausibility for the increase in O3-induced health effects observed in epidemiologic 

17 studies that examined infections by way of studies that demonstrated that exposure to 
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1 0.08 ppm O3 increased streptococcus-induced mortality, regardless of whether O3

2 exposure preceded or followed infection (Miller et al., 1978; Coffin and Gardner, 1972; 

3 Coffin et al., 1967). Overall, the epidemiologic and experimental evidence supports the 

4 potential for increased risk to be conferred by an infection but the number of studies is 

5 limited. There have only been a few epidemiologic studies and these studies examine 

6 different outcomes (respiratory-related hospital admissions or lung function) and 

7 different modifiers (influenza or respiratory infection). In some of the toxicological 

8 studies, the O3 exposure came before the infection. Therefore, evidence is inadequate to 

9 determine if influenza/infections increase the risk of O3-related health effects.

8.2.2 Asthma

10 Previous O3 AQCDs identified individuals with asthma as a population at increased risk 

11 of O3-related health effects. Within the U.S., approximately 7.3% of adults have reported 

12 currently having asthma (Pleis et al., 2009), and 9.5% of children have reported currently 

13 having asthma (Bloom et al., 2008). For more detailed prevalence by age, see Table 8-4.

Table 8-4 Prevalence of asthma by age in the U.S.

Age (years) N (in thousands) Percent

0-4 1,276 6.2

5-11 3,159 11.2

12-17 2,518 10.2

18-44 7,949 7.2

45-64 5,768 7.5

65-74 1,548 7.8

75+ 1,116 6.4

a

Asthma prevalence is reported for “still has asthma”

Source: Statistics for adults: Pleis et al. (2009); statistics for children: Bloom et al. (2008); National Center for Health Statistics.

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

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

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

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

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

19 an association between short-term O3 exposure and wheeze, cough, and bronchodilator 

20 use among asthmatics but not non-asthmatics, although this may have been the result of a 

21 small non-asthmatic population (Escamilla-Nuñez et al., 2008). A study of modification 
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1 by airway hyperresponsiveness (AHR) (a condition common among asthmatics) reported 

2 greater short-term O3-associated decreases in lung function in elderly individuals with 

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

4 evidence for increased risk was found in a study performed among children in Mexico 

5 City that examined the effect of short-term O3 exposure on respiratory health (Barraza6 Villarreal et al., 2008). In this study, a positive association was reported for airway 

7 inflammation among asthmatic children, but the observed association was similar in 

8 magnitude to that of non-asthmatics. Similarly, a study of children in California reported 

9 an association between O3 concentration and exhaled nitric oxide fraction (FeNO) that 

10 persisted both among children with and without asthma as well as those with and without 

11 respiratory allergy (Berhane et al., 2011). Finally, Khatri et al. (2009) found no 

12 association between short-term O3 exposure and altered lung function for either asthmatic 

13 or non-asthmatic adults, but did note a decrease in lung function among individuals with 

14 allergies. 

15 Evidence for difference in effects among asthmatics has been observed in studies that 

16 examined the association between O3 exposure and altered lung function by asthma 

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

18 association between short-term O3 and lung function for corticosteroid users compared 

19 with noncorticosteroid users (Lewis et al., 2005). Conversely, another study found 

20 decreased lung function among noncorticosteroid users compared to corticosteroid users, 

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

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

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

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

25 inflammation reported a counterintuitive inverse association with O3 of similar magnitude 

26 for all groups of corticosteroid users and non-users (Qian et al., 2009).

27 Controlled human exposure studies that have examined the effects of O3 on individuals 

28 with asthma and healthy controls are limited. Based on studies reviewed in the 1996 and 

29 2006 O3 AQCDs, subjects with asthma appeared to be at least as sensitive to acute effects 

30 of O3 in terms of FEV1 and inflammatory responses as healthy non-asthmatic subjects. 

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

32 average, experienced double the O3-induced FEV1 decrement of healthy subjects (19% 

33 versus 10%, respectively, p = 0.04). Moreover, a statistically significant positive 

34 correlation between FEV1 responses to O3 exposure and baseline lung function was 

35 observed in individuals with asthma, i.e., responses increased with severity of disease. 

36 Kreit et al. (1989) performed a short duration study in which asthmatics also showed a 

37 considerable larger average O3-induced FEV1 decrement than the healthy controls (25% 

38 vs. 16%, respectively) following exposure to O3 with moderate-heavy exercise. Alexis et 
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1 al. (2000) and Jorres et al. (1996) also reported a tendency for slightly greater FEV1

2 decrements in asthmatics than healthy subjects. Minimal evidence exists suggesting that 

3 individuals with asthma have smaller O3-induced FEV1 decrements than healthy subjects 

4 (3% versus 8%, respectively) (Mudway et al., 2001). However, the asthmatics in that 

5 study also tended to be older than the healthy subjects, which could partially explain their 

6 lesser response since FEV1 responses to O3 exposure diminish with age. Individuals with 

7 asthma also had more neutrophils in the BALF (18 hours postexposure) than similarly 

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

9 Furthermore, a study examining the effects of O3 on individuals with atopic asthma and 

10 healthy controls reported that greater numbers of neutrophils, higher levels of cytokines 

11 and hyaluronan, and greater expression of macrophage cell-surface markers were 

12 observed in induced sputum of atopic asthmatics compared with healthy controls 

13 (Hernandez et al., 2010). Differences in O3-induced epithelial cytokine expression were 

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

15 2003). Cell-surface marker and cytokine expression results, and the presence of 

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

17 immunity in these asthmatic individuals (see Section 5.4.2.2). In addition, studies have 

18 demonstrated that O3 exposure leads to increased bronchial reactivity to inhaled allergens 

19 in mild allergic asthmatics (Kehrl et al., 1999; Jorres et al., 1996) and to the influx of 

20 eosinophils in individuals with pre-existing allergic disease (Vagaggini et al., 2002; 

21 Peden et al., 1995). Taken together, these results point to several mechanistic pathways 

22 which could account for the increased risk of O3–related health effects in subjects with 

23 asthma (see Section 5.4.2.2). 

24 Toxicological studies provide biological plausibility for greater effects of O3 among those 

25 with asthma or AHR. In animal toxicological studies, an asthmatic phenotype is modeled 

26 by allergic sensitization of the respiratory tract. Many of the studies that provide evidence 

27 that O3 exposure is an inducer of AHR and remodeling utilize these types of animal 

28 models. For example, a series of experiments in infant rhesus monkeys have shown these 

29 effects, but only in monkeys sensitized to house dust mite allergen (Fanucchi et al., 2006; 

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

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

32 demonstrated enhanced inflammatory responses in rats exposed to O3, but only in 

33 animals sensitized to allergen. In general, it is the combined effects of O3 and allergic 

34 sensitization which result in measurable effects on pulmonary function. In a bleomycin 

35 induced pulmonary fibrosis model, exposure to 250 ppb O3 for 5 days increased 

36 pulmonary inflammation and fibrosis, along with the frequency of bronchopneumonia in 

37 rats. Thus, short-term exposure to O3 may enhance damage in a previously injured lung 

38 (Oyarzún et al., 2005). 
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1 In the 2006 O3 AQCD, the potential for individuals with asthma to have greater risk of 

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

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

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

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

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

7 lung function by corticosteroid use provided limited and inconsistent evidence of 

8 O3-related health effects. Additionally, recent studies of behavioral responses have found 

9 that studies do not take into account individual behavioral adaptations to forecasted air 

10 pollution levels (such as avoidance and reduced time outdoors), which may underestimate 

11 the observed associations in studies that examined the effect of O3 exposure on 

12 respiratory health (Neidell and Kinney, 2010). This could explain some inconsistency 

13 observed among recent epidemiologic studies. The evidence from controlled human 

14 exposure studies provides support for increased decrements in FEV1 and greater 

15 inflammatory responses to O3 in individuals with asthma than in healthy individuals 

16 without a history of asthma. The collective evidence for increased risk of O3-related 

17 health effects among individuals with asthma from controlled human exposure studies is 

18 supported by recent toxicological studies which provide biological plausibility for 

19 heightened risk of asthmatics to respiratory effects due to O3 exposure. Evidence 

20 indicating O3-induced respiratory effects among individuals with asthma is further 

21 supported by additional studies of O3-related respiratory effects (Section 6.2). Overall, 

22 there is adequate evidence for asthmatics to be a potentially at-risk population based on 

23 the substantial, consistent evidence among controlled human exposure studies and 

24 coherence from epidemiologic and toxicological studies. 

8.2.3 Chronic Obstructive Pulmonary Disease (COPD)

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

26 having emphysema, both of which are classified as COPD (Pleis et al., 2009).

27 A recent study reported no association between O3 exposure and lung function regardless 

28 of whether the study participant had COPD or other preexisting diseases (asthma or IHD) 

29 (Lagorio et al., 2006). 

30 Peel et al. (2007) found that individuals with COPD were at increased risk of 

31 cardiovascular ED visits in response to short-term O3 exposure compared to healthy 

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

33 associated with higher odds of an emergency department (ED) visit for peripheral and 

34 cerebrovascular disease among individuals with COPD compared to individuals without 
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1 COPD. However, preexisting COPD did not increase the odds of hospitalization for all 

2 CVD outcomes (i.e., IHD, dysrhythmia, or congestive heart failure). In an additional 

3 study performed in Taiwan, individuals with and without COPD had higher odds of 

4 congestive heart failure associated with O3 exposure on warm days (Lee et al., 2008a). As 

5 discussed in Section 6.3, most studies reported no overall association between O3

6 concentration and CVD morbidity.

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

8 risk of O3-related cardiovascular effects, but little information is available on whether 

9 COPD leads to an increased risk of O3-induced respiratory effects. Overall, this small 

10 number of studies provides inadequate evidence to determine whether COPD results in 

11 increased risk of O3-related health effects.

8.2.4 Cardiovascular Disease (CVD)

12 Cardiovascular disease has become increasingly prevalent in the U.S., with about 12% of 

13 adults reporting a diagnosis of heart disease (Table 8-3). A high prevalence of other 

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

15 prevalent among approximately 24% of adults. In the 2006 O3 AQCD, little evidence was 

16 available regarding whether preexisting CVD contributed to increased risk of O3-related 

17 health effects. Recent epidemiologic studies have examined cardiovascular-related 

18 diseases as modifiers of the O3-outcome associations; however, no recent evidence is

19 available from controlled human exposure studies or toxicological studies. 

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

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

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

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

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

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

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

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

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

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

30 only for those with hypercholesterolemia. In a study conducted in Taiwan, a positive 

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

32 admissions, but the association did not differ between individuals with/without 

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

34 reported that the association between O3 levels and ED visits for arrhythmias were greater
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1 on warm days among those with congestive heart failure compared to those without 

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

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

4 failure (Chiu and Yang, 2009).

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

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

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

8 individuals with a history of CVD (Liao et al., 2005). Liao et al. (2005) found that 

9 increased fibrinogen was positively associated with short-term O3 exposure but this 

10 association was present only among individuals with a history of CVD. No association 

11 was observed among those without a history of CVD. However, for another biomarker 

12 (vWF), CVD status did not modify the positive association with short-term O3 exposure 

13 (Liao et al., 2005).

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

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

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

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

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

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

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

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

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

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

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

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

26 participant had IHD.

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

28 cardiovascular morbidity for individuals with preexisting CVD. However, as discussed in 

29 Section 6.3, most studies reported no overall association between O3 concentration and 

30 CV morbidity. Thus, it is likely the association would be null regardless of the 

31 stratification. A limited number of studies examined whether cardiovascular disease 

32 modifies the association between O3 and respiratory effects. There was some evidence 

33 that cardiovascular disease increases the risk of O3-related mortality but again the number 

34 of studies was limited. Currently, evidence is inadequate to classify CVD as a potential 

35 at-risk factor for O3-related health effects. Future research among those with CVD 

36 compared to those without will increase the understanding of potential increased risk of 

37 O3-related health effects among this group.
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8.2.5 Diabetes 

1 The literature has not extensively examined whether individuals with diabetes (about 8% 

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

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

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

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

6 and hospital admissions for congestive heart failure; however, no modification of the 

7 association by diabetes was observed (Lee et al., 2008a). Finally, in a study of O3

8 exposure and ED visits for arrhythmia in Taiwan, there was no evidence of effect 

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

10 Currently, the limited number of epidemiologic studies as well as the lack of controlled 

11 human exposure or toxicological studies provides inadequate evidence to indicate 

12 whether diabetes results in a potentially increased risk of O3-related health effects. 

8.2.6 Hyperthyroidism

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

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

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

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

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

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

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

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

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

22 underlying evidence, which suggests that individuals with hyperthyroidism may represent 

23 an at-risk population; however, overall the lack of additional studies provides inadequate 

24 evidence to determine whether hyperthyroidism results in potentially increased risk of 

25 O3-related health effects. 

8.3 Sociodemographic Factors

8.3.1 Lifestage

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

27 older adults as at-risk populations. These previous AQCDs reported clinical evidence that 
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1 children have greater spirometric responses to O3 than middle-aged and older adults (U.S. 

2 EPA, 1996a). Similar results were observed for symptomatic responses and O3 exposure. 

3 Among older adults, most studies reported in the 2006 O3 AQCD reported greater effects 

4 of short-term O3 exposure and mortality compared to other age groups (U.S. EPA, 

5 2006b). Evidence published since the 2006 O3 AQCD, summarized below, further 

6 supports these findings.

8.3.1.1 Children 

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

8 with 14.1% under the age of 10 (SSDAN CensusScope, 2010a). Children’s respiratory 

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

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

11 generally recognized that children spend more time outdoors than adults, and therefore 

12 would be expected to have higher exposure to O3 than adults. The ventilation rates also 

13 vary between children and adults, particularly during moderate/heavy activity. Children 

14 aged 11 years and older and adults have higher absolute ventilation rates than children 

15 aged 1 -11 years. However, children have higher ventilation rates relative to their lung 

16 volumes, which tends to increase dose normalized to lung surface area. Exercise intensity 

17 has a substantial effect on ventilation rate, with high intensity activities resulting in nearly 

18 double the ventilation rate during moderate activity among children and those adults less 

19 than 31 years of age. For more information on time spent outdoors and ventilation rate 

20 differences by age group, see Section 4.4.1. 

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

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

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

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

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

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

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

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

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

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

31 modeling reported lung regional extraction of O3 to be higher in infants compared to 

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

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

34 adults (Sarangapani et al., 2003). 
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1 Recent epidemiologic studies have examined different age groups and their risk to 

2 O3-related respiratory hospital admissions and ED visits. A study in Cyprus of short-term 

3 O3 concentrations and respiratory hospital admissions detected possible effect measure 

4 modification by age with a larger association among individuals <15 years of age 

5 compared with those >15 years of age. However, this difference was only apparent with a 

6 2-day lag (Middleton et al., 2008). Similarly, a Canadian study of asthma-eD visits 

7 reported the strongest O3-related associations among 5 to 14 year-olds compared to the 

8 other age groups (ages examined 0-75+) (Villeneuve et al., 2007). Greater O3-associated 

9 risk in asthma-related ED visits were also reported among children (<15 years) as 

10 compared to adults (15 to 64 years) in a study from Finland (Halonen et al., 2009). A 

11 study of New York City hospital admissions demonstrated an increase in the association 

12 between O3 exposure and asthma-related hospital admissions for 6 to 18 year-olds 

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

14 examining long-term O3 exposure and asthma hospital admissions among children, 

15 associations were determined to be larger among children 1 to 2 years old compared to 

16 children 2 to 6 years old (Lin et al., 2008b). A few studies reported positive associations 

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

18 performed in Hong Kong examined O3 exposure and asthma-related hospital admissions 

19 for ages 0 to14, 15 to 65, and >65 (Ko et al., 2007). The researchers reported that the 

20 association was greater among the 0 to 14 and 14 to 65 age groups compared to the >65 

21 age group. Another study looking at asthma-related ED visits and O3 exposure in Maine 

22 reported positive associations for all age groups (ages 2 to 65) (Paulu and Smith, 2008). 

23 Effects of O3 exposure on asthma hospitalizations among both children and adults (<18 

24 and ≥ 18 years old) were demonstrated in a study in Washington, but only children (<18 

25 years of age) had statistically significant results at lag day 0, which the authors wrote, 

26 “suggests that children are more immediately responsive to adverse effects of O3

27 exposure” (Mar and Koenig, 2009). 

28 The evidence reported in epidemiologic studies is supported by recent toxicological 

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

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

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

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

33 rhesus macaques, whose respiratory tract closely resemble that of humans. Monkeys were 

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

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

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

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

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

39 episodically exposed infant monkeys were similar to that of acutely exposed animals. 
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1 Neither exposure protocol for the infant monkeys produced mucous cell metaplasia 

2 proximal to the lesions, an adaptation observed in adult monkeys exposed continuously to 

3 0.3 ppm O3 in another study (Harkema et al., 1987a). Functional (increased airway 

4 resistance and responsiveness with antigen + O3 co-exposure) and cellular changes in 

5 conducting airways (increased numbers of inflammatory eosinophils) were common 

6 manifestations of exposure to O3 among both the adult and infant monkeys (Plopper et 

7 al., 2007). In addition, the lung structure of the conducting airways in the infant monkeys 

8 was stunted by O3 and this aberrant development was persistent 6 months postexposure. 

9 This developmental endpoint was not, of course, studied in the adult monkey experiments 

10 (Fanucchi et al., 2006). Thus, some functional and biochemical effects were similar 

11 between the infant and adult monkeys exposed to O3, but because the study designs did 

12 not include concentration-response experiments, it is not possible to determine whether 

13 the infant monkeys were more at risk for the effects of O3.

14 Similarly, rat fetuses exposed to O3 in utero had ultrastructural changes in bronchiolar 

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

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

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

18 of animals to PM augmented O3-induced airway hyper-reactivity in these pups as 

19 juveniles. 

20 Age may affect the inflammatory response to O3 exposure. In comparing neonatal mice to 

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

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

23 2009). Three of these strains also exhibited increased BAL protein, although the two 

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

however, adults were responsive, indicating a strain-age interaction. Measurement of 18 25 O 

26 determined that the observed strain- and age-dependent differences were not due to 

27 absorbed O3 dose. Using electron microscopy, Bils (1970) studied the lungs of mice of 

28 different ages (4 days or 1 to 2 months) exposed to 0.6 to 1.3 ppm O3 for 6 to 7 h/day for 

29 1 to 2 days and noted swelling of the alveolar epithelial lining cells without intra-alveolar 

30 edema. Swelling of endothelial cells and occasional breaks in the basement membrane 

31 were observed. These effects were most evident in younger mice exposed for 2 days. 

32 Toxicological studies reported that the difference in effects among younger lifestage test 

33 animals may be due to age-related changes in endogenous antioxidants and sensitivity to 

34 oxidative stress. A recent study demonstrated that 0.25 ppm O3 exposure differentially 

35 altered expression of metalloproteinases in the skin of young (8 weeks old) and aged 

36 (18 months old) mice, indicating age-related susceptibility to oxidative stress (Fortino et 

37 al., 2007). Valacchi et al. (2007) found that aged mice had more Vitamin E in their 

38 plasma but less in their lungs compared to young mice, which may affect their pulmonary 
Draft – Do Not Cite or Quote 8-21 June 2012

1 antioxidant defenses. Servais et al. (2005) found higher levels of oxidative damage 

2 indicators in immature (3 weeks old) and aged (20 months old) rats compared to adult 

3 rats, the latter which were relatively resistant to an intermittent 7-day exposure to 

4 0.5 ppm O3. Immature rats exhibited a higher ventilation rate, which may have increased 

5 exposure. Additionally, a series of toxicological studies reported an association between 

6 O3 exposure and bradycardia that was present among young but not older mice (Hamade 

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

8 Regression analysis revealed an interaction between age and strain on heart rate, which 

9 implies that aging may affect heart rate differently among mouse strains (Tankersley et 

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

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

12 modulating the changes in cardiopulmonary physiology after O3 exposure.

13 The previous and recent human clinical and toxicological studies reported evidence of 

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

15 biological plausibility for the findings from epidemiologic studies. Although there was 

16 some inconsistency, generally, the epidemiologic studies reported larger associations for 

17 respiratory hospital admissions and ED visits for children than adults. The interpretation 

18 of these studies is limited by the lack of consistency in comparison age groups and 

19 outcomes examined. Toxicological studies observed O3-induced health effects in 

20 immature animals, including infant monkeys, though the effects were not consistently 

21 greater in young animals than adults. However, overall, the epidemiologic, controlled 

22 human exposure, and toxicological studies provide substantial and consistent evidence 

23 within and across disciplines. Therefore, there is adequate evidence to conclude that 

24 children are potentially at increased risk of O3-related health effects. 

8.3.1.2 Older Adults 

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

26 a variety of intrinsic pathways. In addition, older adults may differ in their exposure and 

27 internal dose. Older adults were outdoors for a slightly longer proportion of the day than 

28 adults aged 18-64 years. Older adults also have somewhat lower ventilation rates than 

29 adults aged 31 - less than 61 years. For more information on time spent outdoors and 

30 ventilation rate differences by age group, see Section 4.4.1. The gradual decline in 

31 physiological processes that occur with aging may lead to increased risk of O3-related 

32 health effects (U.S. EPA, 2006a). Respiratory symptom responses to O3 exposure appears 

33 to increase with age until early adulthood and then gradually decrease with increasing age 

34 (U.S. EPA, 1996a), which may put older adults at increased risk by withstanding 

35 continued O3 exposure and thus not seeking relief and avoiding exposure. In addition, 
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1 older adults, in general, have a higher prevalence of preexisting diseases, with the 

2 exception of asthma, compared to younger age groups and this may also lead to increased 

3 risk of O3-related health effects (see Table 8-3 that gives preexisting rates by age).With 

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

5 12.4% of the U.S. population to 19.7% between 2000 to 2030, which is approximately 

6 35 million and 71.5 million individuals, respectively) this group represents a large 

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

8 U.S. Census Bureau, 2010). 

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

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

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

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

13 Further investigation of this study population revealed a trend of O3-related mortality risk 

14 that gets larger with increasing age starting at age 50 (Zanobetti and Schwartz, 2008a). A 

15 study of 7 urban centers in Chile reported similar results, with greater effects in adults 

16 ≥ 65 years old, however the effects were smaller among those ≥ 85 years old compared to 

17 those in the 75 to 84 years old age range (Cakmak et al., 2007). More recently, a study 

18 conducted in the same area reported similar associations between O3 exposure and 

19 mortality in adults aged <64 years old and 65 to 74 years old, but the risk was increased 

20 among older age groups (Cakmak et al., 2011). A study performed in China reported 

21 greater effects in populations ≥ 45 years old (compared to 5 to 44 year-olds), with 

22 statistically significant effects present only among those ≥ 65 years old (Kan et al., 2008). 

23 An Italian study reported higher risk of all-cause mortality associated with increased O3

24 concentrations among individuals ≥ 85 years old as compared to those 35 to 84 years old. 

25 Those 65 to 74 and 75 to 84 years old did not show a greater increase in risk compared to 

26 those aged 35 to 64 years (Stafoggia et al., 2010). The Air Pollution and Health: A 

27 European and North American Approach (APHENA) project examined the association 

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

29 associations for all-cause and cardiovascular mortality were greater among those 

30 ≥ 75 years old in the summer-only and all-year analyses. Age groups were not compared 

31 in the analysis for respiratory mortality in Canada. In the U.S., the association for 

32 all-cause mortality was slightly greater for those <75 years of age compared to those ≥ 75 

33 years old in summer-only analyses. No consistent pattern was observed for CVD 

34 mortality. In Europe, slightly larger associations for all-cause mortality were observed in 

35 those <75 years old in all-year and summer-only analyses. Larger associations were 

36 reported among those <75years for CVD mortality in all-year analyses, but the reverse 

37 was true for summer-only analyses (Katsouyanni et al., 2009). 
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1 Multiple epidemiologic studies of O3 exposure and hospital admissions were stratified by 

2 age groups. A positive association was reported between short-term O3 exposure and 

3 respiratory hospital admissions for adults ≥ 65 years old but not for those adults aged 15 

4 to 64 years (Halonen et al., 2009). In the same study, no association was observed 

5 between O3 concentration and respiratory mortality among those ≥ 65 years old or those 

6 15 to 64 years old; however, an inverse association between O3 concentration and 

7 cardiovascular mortality was present among individuals ≥ 65 years old but not among 

8 individuals <65 years old. This inverse association among those ≥ 65 years old persisted 

9 when examining hospital admissions for coronary heart disease. A study of CVD-related 

10 hospital visits in Bangkok, Thailand reported an increase in percent change for hospital 

11 visits with previous day and cumulative 2-day O3 levels among those ≥ 65 years old, 

12 whereas no association was present for individuals less than 65 years of age (Buadong et 

13 al., 2009). No association was observed for current day or cumulative 3-day averages in 

14 any age group. A study examining O3 and hospital admissions for CVD-related health 

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

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

17 elderly that was not present among 15 to 64 year-olds (Halonen et al., 2009). However, as 

18 discussed in the Section on CVD hospital admissions (6.3.2.7), results were inconsistent 

19 and often null so it is plausible that no association would be observed regardless of age. 

20 No modification by age (40 to 64 year-olds versus >64 years old) was observed in a study 

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

22 Biological plausibility for differences by age is provided by toxicological studies. O3

23 exposure resulted in an increase in left ventricular chamber dimensions at end diastole 

24 (LVEDD) in young and old mice, whereas decreases in left ventricular posterior wall 

25 thickness at end systole (PWTES) were only observed among older mice (Tankersley et 

26 al., 2010). Other toxicological studies also indicate increased risk in older animals for 

27 additional endpoints, including neurological and immune. The hippocampus, one of the 

28 main regions affected by age-related neurodegenerative diseases, may be more sensitive 

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

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

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

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

33 significantly affected by O3 exposure (Lim et al., 2006). However, exposure to 0.5 ppm 

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

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

36 adults, recent epidemiologic studies report consistent positive associations between short37 term O3 exposure and mortality in older adults. The evidence from mortality studies is 

38 consistent with the results reported in the 2006 O3 AQCD and is supported by 
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1 toxicological studies providing biological plausibility for increased risk of effects in older 

2 adults. Also, older adults may be experiencing increased exposure compared to younger 

3 adults. Overall, adequate evidence is available indicating that older adults are potentially 

4 at increased risk of O3-related health effects based on the substantial and consistent 

5 evidence within epidemiologic studies on O3 exposure and mortality and the coherence 

6 with toxicological studies. 

8.3.2 Sex

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

8 population was male and 50.9% were female. However, this distribution does vary by age 

9 with a greater prevalence of females ≥ 65 years old compared to males (SSDAN 

10 CensusScope, 2010a). The 2006 O3 AQCD did not report evidence of differences 

11 between the sexes in health responses to O3 exposure (U.S. EPA, 2006b). Recent 

12 epidemiologic studies have evaluated the effects of short-term and long-term exposure to 

13 O3 on multiple health endpoints stratified by sex. 

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

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

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

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

18 reported no associations between short-term O3 and respiratory infection hospital 

19 admissions for either boys or girls under the age of 15 (Lin et al., 2005), whereas another 

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

21 respiratory hospital admissions for males (mean ages 47.6 to 69.0 years) (Cakmak et al., 

22 2006b). A recent study from Hong Kong examining individuals of all ages reported no 

23 effect measure modification by sex for overall respiratory disease hospital admissions, 

24 but did detect a greater excess risk of hospital admissions for COPD among females 

25 compared to males (Wong et al., 2009). Similarly a study in Brazil found higher effect 

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

27 Higher levels of respiratory hospital admissions with greater O3 concentrations was also 

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

29 A study of lung function unrelated to hospital admissions and ED visits was conducted 

30 among lifeguards in Texas and reported decreased lung function with increased O3

31 exposure among females but not males (Thaller et al., 2008). This study included 

32 individuals aged 16 to 27 years, and the majority of participants were male. A New York 

33 study found no evidence of effect measure modification of the association between 

34 long-term O3 exposure and asthma hospital admissions among males and females 

35 between 1 and 6 years old (Lin et al., 2008b).
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1 In addition to examining the potential modification of O3 associations with respiratory 

2 outcomes by sex, studies also examined cardiovascular-related outcomes specifically 

3 hospital admissions and ED visits. All of these studies reported no effect modification by 

4 sex with some studies reporting null associations for both males and females (Wong et 

5 al., 2009; Middleton et al., 2008; Villeneuve et al., 2006a) and one study reporting a 

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

7 the associations between O3 concentrations and risk of ischemic strokes (not limited to 

8 ED visits or hospital admissions) reported no association for either males or females with 

9 lags of 0, 2, or 3 days (Henrotin et al., 2007). A positive association was reported for 

10 males with a lag of 1 day, but this association was null for females. The authors noted 

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

12 (67.4% versus 9.3%). Additionally, cardiovascular hospital admissions and ED visits 

13 overall have demonstrated inconsistent and null results (Section 6.3.2.7). The lack of 

14 effect measure modification by sex may be indicative of the lack of association, not the 

15 lack of effect of sex. 

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

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

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

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

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

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

22 model. One study examining correlations between O3 levels and oxidative DNA damage 

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

24 correlations for males than females, both during short-term exposure (less than 30 days) 

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

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

27 traffic pollution at work.

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

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

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

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

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

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

34 ≥ 60 years old (Medina-Ramón and Schwartz, 2008). However, a recent study in Chile 

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

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

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

38 males and 1.04 (95% CIs 1.03, 1.07) for females (Jerrett et al., 2009). 
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1 Experimental research provided a further understanding of the underlying mechanisms 

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

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

4 may predispose females to greater effects from O3. In females, lower plasma and nasal 

5 lavage fluid (NLF) levels of uric acid (most prevalent antioxidant), the initial defense 

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

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

8 deeper penetration. Dosimetric measurements have shown that the absorption distribution 

9 of O3 is independent of sex when absorption is normalized to anatomical dead space 

10 (Bush et al., 1996). Thus, a differential removal of O3 by uric acid seems to be minimal. 

11 In general, the physiologic response of young healthy females to O3 exposure appears 

12 comparable to the response of young males (Hazucha et al., 2003). A few studies have 

13 examined changes in O3 responses during various menstrual cycle phases. Lung function 

14 response to O3 was enhanced during the follicular phase of the menstrual cycle compared 

15 to the luteal phase in a small study of women (Fox et al., 1993). However, Seal et al. 

16 (1996) later reported no effect of menstrual cycle phase in their analysis of responses 

17 from 150 women, but conceded that the methods used by Fox et al. (1993) more precisely 

18 defined the menstrual cycle phase. Another study also reported no difference in responses 

19 among females during the follicular and luteal phases of their cycle (Weinmann et al., 

20 1995c). Additionally, in this study the responses in women were comparable to those 

21 reported for men in the study. In a toxicological study, small differences in effects by sex 

22 were seen in adult mice with respect to pulmonary inflammation and injury after a 5-h 

23 exposure to 0.8 ppm O3, and although adult females were generally more at risk, these 

24 differences were strain-dependent, with some strains exhibiting greater risk in males 

25 (Vancza et al., 2009). The most obvious sex difference was apparent in lactating females, 

26 which incurred the greatest lung injury or inflammation among several of the strains.

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

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

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

30 males, but minimal evidence is available regarding a difference between the sexes for 

31 other outcomes. Inconsistent findings were reported on whether effect measure 

32 modification exists by sex for respiratory and cardiovascular hospital admissions and ED 

33 visits, although there is some indication that females are at increased risk of O3-related 

34 respiratory hospital admissions and ED visits. While O3-related effects may occur in both 

35 men and women, there is suggestive evidence exists indicating that females are at 

36 potentially increased risk of O3-related health effects as there are consistent findings 

37 among epidemiologic studies of mortality. 
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8.3.3 Socioeconomic Status 

1 SES is often represented by personal or neighborhood SES, which is comprised of a 

2 variety of components such as educational attainment, household income, health 

3 insurance status, and other such factors. SES is often indicative of such things as access 

4 to healthcare, quality of housing, and pollution gradient to which people are exposed. 

5 One or a combination of these components could modify the risk of O3-related health 

6 effects. Based on the 2000 Census data, 12.4% of Americans live in poverty (poverty 

7 threshold for family of four was $17,463) (SSDAN CensusScope, 2010c). Although 

8 included below, studies stratifying by SES that are conducted outside the U.S. may not be 

9 comparable to those studies from within the U.S. Having low SES in another country 

10 may be different than having low SES in the U.S. based on SES definitions, population 

11 composition, and/or conditions in that country. 

12 Multiple epidemiologic studies have reported individuals of low SES to have increased 

13 risk for the effects of short-term O3 exposure on respiratory hospital admissions and ED 

14 visits. In New York State, larger associations between long-term O3 exposure and asthma 

15 hospital admissions were observed among children of mothers who did not graduate from 

16 high school, whose births were covered by Medicaid/self-paid, or who were living in 

17 poor neighborhoods compared to children whose mothers graduated from high school, 

18 whose births were covered by other insurance, or who were not living in poor 

19 neighborhoods, respectively (Lin et al., 2008b). In addition, a study conducted across 10 

20 cities in Canada found the largest association between O3 exposure and respiratory 

21 hospital admissions was among those with an educational level less than grade 9, but no 

22 consistent trend in the effect was seen across quartiles of income (Cakmak et al., 2006b). 

23 A Canadian study reported inverse effects of O3 on respiratory hospital admissions and 

24 ED visits for all levels of SES, measured by average census tract household income 

25 (Burra et al., 2009). A study performed in Korea examined the association between O3

26 concentrations and asthma hospital admissions and reported larger effect estimates in 

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

28 average regional insurance rates) (Lee et al., 2006).

29 The examination of the potential effects of SES on O3-related cardiovascular health 

30 effects is relatively limited. A study conducted in Canada reported the association 

31 between short-term O3 and ED visits for cardiac disease by quartiles of 

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

33 for either measure of SES (Cakmak et al., 2006a). However, this may be due to the lack 

34 of association present between O3 and ED visits for cardiac disease regardless of SES. 

35 Several studies were conducted that examined the modification of the relationship 

36 between short-term O3 concentrations and mortality by SES. A U.S. multicity study 
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1 reported that communities with a higher proportion of the population unemployed had 

2 higher O3-related mortality effect estimates (Bell and Dominici, 2008). A study in seven 

3 urban centers in Chile reported on modification of the association between O3 exposure 

4 and mortality using multiple SES markers (Cakmak et al., 2011). Increased risk was 

5 observed among the categories of low SES for all measures (personal educational 

6 attainment, personal occupation, community income level). Additionally, the APHENA 

7 study, which examined the association between O3 and mortality by percentage 

8 unemployed, reported a higher percent change in mortality with increased percent 

9 unemployed but this varied across the regions included in the study (U.S., Canada, 

10 Europe) (Katsouyanni et al., 2009). A Chinese study reported that the greatest effects 

11 between O3 concentrations and mortality at lag day 0 were among individuals living in 

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

13 across lag days (at other lag times, the middle social deprivation index category had the 

14 greatest association) (Wong et al., 2008). However, another study in Asia comparing low 

15 to high educational attainment populations reported no evidence of greater mortality 

16 effects (total, CVD, or respiratory) (Kan et al., 2008). Additionally, a study in Italy 

17 reported no difference in risk of mortality among census-block level derived income 

18 levels (Stafoggia et al., 2010). A study of infant mortality in Mexico reported no 

19 association between O3 concentrations and infant mortality among any of the three levels 

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

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

22 lag 0 and respiratory-related infant mortality in only the low SES group (determined 

23 based on education, income, and household conditions across residential areas), but no 

24 association was observed in any of the SES groups with other lags (Carbajal-Arroyo et 

25 al., 2011). 

26 Studies of O3 concentrations and reproductive outcomes have also examined associations 

27 by SES levels. A study in California reported greater decreases in birth weight associated 

28 with full pregnancy O3 concentration for those with neighborhood poverty levels of at 

29 least 7% compared with those in neighborhoods with less than 7% poverty (the authors 

30 do not provide information on how categories of the SES variable were determined) 

31 (Morello-Frosch et al., 2010). No dose response was apparent and those with 

32 neighborhood poverty levels of 7-21% had greater decreases observed for the association 

33 than those living in areas with poverty rates of at least 22%. An Australian study reported 

34 an inverse association between O3 exposure during days 31-60 of gestation and 

35 abdominal circumference during gestation (Hansen et al., 2008). The interaction with 

36 SES (area-level measured socioeconomic disadvantage) was examined and although the 

37 inverse association remained statistically significant in only the highest SES quartile, 

38 there were large confidence interval overlaps among estimates for each quartile so no 

39 difference in the association for the quartiles was apparent. 
Draft – Do Not Cite or Quote 8-29 June 2012

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

2 function does not provide support for greater O3-related health effects in individuals of 

3 lower SES. In a follow-up study (Seal et al., 1993) on modification by race, Seal et al. 

4 (1996) reported that, of three SES categories, individuals in the middle SES category 

5 showed greater concentration-dependent decline in percent-predicted FEV1 (4-5% at 

6 400 ppb O3) than in low and high SES groups. The authors did not have an “immediately 

7 clear” explanation for this finding and controlled human exposure studies are typically 

8 not designed to answer questions about SES. 

9 Overall, most studies of individuals have reported that individuals with low SES and 

10 those living in neighborhoods with low SES are more at risk for O3-related health effects,

11 resulting in increased risk of respiratory hospital admissions and ED visits. Inconsistent 

12 results have been observed in the few studies examining effect modification of 

13 associations between O3 exposure and mortality and reproductive outcomes. Also, a 

14 controlled human exposure study does not support evidence of increased risk of 

15 respiratory morbidity among individuals with lower SES. Overall, evidence is suggestive 

16 of SES as a factor affecting risk of O3-related health outcomes based on collective 

17 evidence from epidemiologic studies of respiratory hospital admissions but inconsistency 

18 among epidemiologic studies of mortality and reproductive outcomes. Further studies are 

19 needed to confirm this relationship, especially in populations within the U.S.

8.3.4 Race/Ethnicity

20 Based on the 2000 Census, 69.1% of the U.S. population identified as non-Hispanic 

21 whites. Approximately 12.1% of people reported their race/ethnicity as non-Hispanic 

22 black and 12.6% reported being Hispanic (SSDAN CensusScope, 2010b). 

23 Only a few studies examined the associations between short-term O3 concentrations and 

24 mortality and reported higher effect estimates among blacks (Medina-Ramón and 

25 Schwartz, 2008) and among communities with larger proportions of blacks (Bell and 

26 Dominici, 2008). Another study examined long-term exposure to O3 concentrations and 

27 asthma hospital admissions among children in New York State. These authors reported 

28 no statistically significant difference in the odds of asthma hospital admissions for blacks 

29 compared to other races but did detect higher odds for Hispanics compared to 

30 non-Hispanics (Lin et al., 2008b). 

31 Additionally, recent epidemiologic studies have stratified by race when examining the 

32 association between O3 concentration and birth outcomes. A study conducted in Atlanta, 

33 GA reported decreases in birth weight with increased third trimester O3 concentrations 

34 among Hispanics but not among non-Hispanic whites (Darrow et al., 2011b). An inverse 
Draft – Do Not Cite or Quote 8-30 June 2012

1 association was also present for non-Hispanic blacks but was not statistically significant. 

2 A California study reported that the greatest decrease in birth weight associated with full 

3 pregnancy O3 concentration was among non-Hispanic whites (Morello-Frosch et al., 

4 2010). This inverse association was also apparent, although not as strong, for Hispanics 

5 and non-Hispanic blacks. Increased birth weight was associated with higher O3 exposure 

6 among non-Hispanic Asians and Pacific Islanders but these results were not statistically 

7 significant.

8 Similar to the epidemiologic studies, a controlled human exposure study suggested 

9 differences in lung function responses by race (Seal et al., 1993). The independent effects 

10 of sex-race group and O3 concentration on lung function were positive, but the interaction 

11 between sex-race group and O3 concentration was not statistically significant. The 

12 findings indicated some overall difference between the sex-race groups that was 

13 independent of O3 concentration (the concentration-response curves for the four sex-race 

14 groups are parallel). In a multiple comparison procedure on data collapsed across all O3

15 concentrations for each sex-race group, both black men and black women had larger 

16 decrements in FEV1 than did white men. The authors noted that the O3 dose per unit of 

17 lung tissue would be greater in blacks and females than whites and males, respectively. 

18 That this difference in tissue dose might have affected responses to O3 cannot be ruled 

19 out. The college students recruited for the Seal et al. (1993) study were probably from 

20 better educated and more SES advantaged families, thus reducing potential for these 

21 variables to be confounding factors. Que et al. (2011) also examined pulmonary 

22 responses to O3 exposure in blacks of African American ancestry and in whites. On 

23 average, the black males experienced the greatest decrements in FEV1 following O3

24 exposure. This decrease was larger than the decrement observed among black females, 

25 white males, and white females. 

26 Overall, the results of recent studies indicate that there may be race-related increase in 

27 risk of O3-related health effects for some outcomes, although the overall understanding of 

28 potential effect measure modification by race is limited by the small number of studies. 

29 Additionally, these results may be confounded by other factors, such as SES. Overall, 

30 evidence is inadequate to determine if O3-related health effects vary by race because of 

31 the insufficient quantity of studies and lack of consistency within disciplines.
Draft – Do Not Cite or Quote 8-31 June 2012

8.4 Behavioral and Other Factors

8.4.1 Diet

1 Diet was not examined as a factor potentially affecting risk in previous O3 AQCDs, but 

2 recent studies have examined modification of the association between O3 and health 

3 effects by dietary factors. Because O3 mediates some of its toxic effects through oxidative 

4 stress, the antioxidant status of an individual is an important factor that may contribute to 

5 increased risk of O3-related health effects. Supplementation with Vitamins C and E has 

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

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

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

9 outcomes. In a recent study the effects of fruit/vegetable intake and Mediterranean diet 

10 was examined (Romieu et al., 2009). Increases in these food patterns, which have been 

11 noted for their high Vitamins C and E and omega-3 fatty acid content, protected against 

12 O3-related decreases in lung function among children living in Mexico City. Another 

13 study examined supplementation of the diets of asthmatic children in Mexico with 

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

15 short-term O3 exposure and nasal airway inflammation among children in the placebo 

16 group but not in those receiving the supplementation. The authors concluded that 

17 “Vitamin C and E supplementation above the minimum dietary requirement in asthmatic 

18 children with a low intake of Vitamin E might provide some protection against the nasal 

19 acute inflammatory response to ozone.”

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

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

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

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

24 O3 (Mudway et al., 1999a); however, the concentration and the activity of antioxidant 

25 enzymes either in ELF or plasma do not appear to be related to O3 responsiveness 

26 (e.g., pulmonary function and inflammation) (Samet et al., 2001; Avissar et al., 2000; 

27 Blomberg et al., 1999). Carefully controlled studies of dietary antioxidant 

28 supplementation have demonstrated some protective effects of α-tocopherol (a form of 

29 Vitamin E) and ascorbate (Vitamin C) on spirometric measures of lung function after O3

30 exposure but not on the intensity of subjective symptoms and inflammatory response 

31 including cell recruitment, activation and a release of mediators (Samet et al., 2001; 

32 Trenga et al., 2001). Dietary antioxidants have also afforded partial protection to 
Draft – Do Not Cite or Quote 8-32 June 2012

1 asthmatics by attenuating postexposure bronchial hyperresponsiveness (Trenga et al., 

2 2001). 

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

4 controlled human exposure studies. Wagner et al. (2009); (2007) found reductions in 

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

6 Vitamin E). O3-induced inflammation and mucus production were also inhibited by 

7 γ-tocopherol. Supplementation with Vitamins C and E partially ameliorated 

8 inflammation, oxidative stress, and airway hyperresponsiveness in guinea pigs exposed 

9 subchronically to 0.12 ppm O3 ppm (Chhabra et al., 2010). Inconsistent results were 

10 observed in other toxicological studies of Vitamin C deficiency and O3-induced

11 responses. Guinea pigs deficient in Vitamin C displayed only minimal injury and 

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

13 demonstrated a protective effect of β-carotene in the skin, where it limited the production 

14 of proinflammatory markers and indicators of oxidative stress induced by O3 exposure 

15 (Valacchi et al., 2009). Deficiency of Vitamin A, which has a role in regulating the 

16 maintenance and repair of the epithelial layer, particularly in the lung, appears to enhance 

17 the risk of O3-induced lung injury (Paquette et al., 1996). Differentially susceptible 

18 mouse strains that were fed a Vitamin A sufficient diet were observed to have different 

19 tissue concentrations of the vitamin, potentially contributing to their respective 

20 differences in O3-related outcomes. In addition to the studies of antioxidants, one 

21 toxicological study examined protein deficiency. Protein deficiency alters the levels of 

22 enzymes and chemicals in the brain of rats involved with redox status; exposure to 

0.75 ppm O3 has been shown to differentially affect Na+/K+ 23 ATPase, glutathione, and 

24 lipid peroxidation, depending on the nutritional status of the animal, but the significance 

25 of these changes is unclear (Calderón Guzmán et al., 2006). There may be a protective 

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

27 increased Vitamin C in the lung surface fluid (Kari et al., 1997).

28 There is adequate evidence that individuals with reduced intake of Vitamins E and C are 

29 potentially at risk for O3-related health effects based on substantial, consistent evidence 

30 both within and among disciplines. The evidence from epidemiologic studies is supported 

31 by controlled human exposure and toxicological studies.

8.4.2 Obesity 

Obesity, defined as a BMI of 30 kg/m2 32 or greater, is an issue of increasing importance in 

33 the U.S., with self-reported rates of obesity of 26.7% in 2009, up from 19.8% in 2000 
Draft – Do Not Cite or Quote 8-33 June 2012

1 (Sherry et al., 2010). BMI may affect O3-related health effects through multiple avenues, 

2 such as, inflammation in the body, increased preexisting disease, and poor diet.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

25 inflammation and injury with acute O3 exposure, but responses to longer exposures at a 

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

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

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

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

30 Multiple epidemiologic, human clinical, and toxicological studies have reported 

31 suggestive evidence for increased O3-related respiratory health effects among obese 

32 individuals. Future research of the effect modification of the relationship between O3 and 

33 other health-related outcomes besides respiratory health effects by BMI and studies 

34 examining the role of physical conditioning will advance understanding of obesity as a 

35 factor potentially increasing an individual’s risk. 
Draft – Do Not Cite or Quote 8-34 June 2012

8.4.3 Smoking

1 Previous O3 AQCDs have concluded that smoking does not increase the risk of O3-related 

2 health effects; in fact, in controlled human exposure studies, smokers have been found to 

3 be less responsive to O3 than non-smokers. Data from recent interviews conducted as part 

4 of the 2008 National Health Interview Survey (NHIS) (Pleis et al., 2009) have shown the 

5 rate of smoking among adults ≥ 18 years old to be approximately 20% in the U.S. 

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

7 Baccarelli et al. (2007) performed a study of O3 concentrations and plasma homocysteine 

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

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

10 homocysteine levels. Another study examined the association between O3 and resting 

11 heart rate and also reported no interaction with smoking status (current smokers versus 

12 current non-smokers) (Ruidavets et al., 2005a). 

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

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

15 was positively associated with DNA damage for short-term and long-term exposures 

16 among never/former smokers. For current smokers, short-term O3 concentrations were 

17 inversely associated with DNA damage; however, the number of current smokers in the 

18 study was small (n = 12). 

19 The findings of Palli et al. (2009) were consistent with those from controlled human 

20 exposure studies that have confirmed that smokers are less responsive to O3 exposure 

21 than non-smokers. Spirometric and plethysmographic pulmonary function decline, 

22 nonspecific AHR, and inflammatory responses of smokers to O3 exposure were all 

23 weaker than those reported for non-smokers. Similarly, the time course of development 

24 and recovery from these effects, as well as their reproducibility, was not different from 

25 non-smokers. Chronic airway inflammation with desensitization of bronchial nerve 

26 endings and an increased production of mucus may plausibly explain the 

27 pseudo-protective effect of smoking (Frampton et al., 1997a; Torres et al., 1997). 

28 These findings for smoking are consistent with the conclusions from previous AQCDs. 

29 An epidemiologic study of O3-associated DNA damage reported smokers to be less at 

30 risk for O3-related health effects. In addition, both epidemiologic studies of short-term 

31 exposure and CVD outcomes found no evidence of effect measure modification by 

32 smoking. No toxicological studies provide biological support for O3-related effects. 

33 Overall, evidence of potential differences in O3-related health effects by smoking status is 

34 inadequate due to insufficient coherence and a limited number of studies.
Draft – Do Not Cite or Quote 8-35 June 2012

8.4.4 Outdoor Workers

1 Studies included in the 2006 O3 AQCD reported that individuals who participate in 

2 outdoor activities or work outside to be a population at increased risk based on 

3 consistently reported associations between O3 exposure and respiratory health outcomes 

4 in these groups (U.S. EPA, 2006b). Outdoor workers are exposed to ambient O3 

5 concentrations for a greater period of time than individuals who spend their days indoors. 

6 As discussed in Section 4.3.3 of this ISA, outdoor workers sampled during the work shift 

7 had a higher ratio of personal exposure to fixed-site monitor concentrations than health 

8 clinic workers who spent most of their time indoors. Additionally, an increase in dose to 

9 the lower airways is possible during outdoor exercise due to both increases in the amount 

10 of air breathed (i.e., minute ventilation) and a shift from nasal to oronasal breathing

11 (Sawyer et al., 2007; Nodelman and Ultman, 1999; Hu et al., 1994). For further 

12 discussion of the association between FEV1 responses to O3 exposure and minute 

13 ventilation, refer to Section 6.2.3.1 of the 2006 O3 AQCD. A recent study has explored 

14 the potential effect measure modification of O3 exposure and DNA damage by 

15 indoor/outdoor workplace (Tovalin et al., 2006). In a study of indoor and outdoor 

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

17 association between O3 exposure and DNA damage (measured by comet tail length 

18 assay), whereas no association was observed for indoor workers. However, workers in 

19 another Mexican city, Puebla, demonstrated no association between O3 levels and DNA 

20 damage, regardless of whether they worked indoors or outdoors. 

21 Previous studies have shown that increased exposure to O3 due to outdoor work leads to 

22 increased risk of O3-related health effects, specifically decrements in lung function (U.S. 

23 EPA, 2006b). Recent evidence from a stratified analysis does not indicate that increased 

24 O3 exposure due to outdoor work leads to DNA damage. However, the strong evidence 

25 from the 2006 O3 AQCD which demonstrated increased exposure, dose, and ultimately 

26 risk of O3-related health effects in this population supports that there is adequate evidence 

27 available to indicate that increased exposure to O3 through outdoor work potentially 

28 increases the risk of O3-related health effects.

8.4.5 Air Conditioning Use

29 Air conditioning use is an important component of O3 exposure, as use of central air 

30 conditioning will limit exposure to O3 by blocking the penetration of O3 into the indoor 

31 environment (see Section 4.3.2). Air conditioning use is a difficult effect measure 

32 modifier to examine in epidemiologic studies because it is often estimated using regional 

33 prevalence data and may not reflect individual-level use. More generally, air conditioning 
Draft – Do Not Cite or Quote 8-36 June 2012

1 prevalence is associated with temperature of a region; those areas with higher 

2 temperatures have a greater prevalence of households with air conditioning. Despite these 

3 limitations, a few studies have examined effect measure modification by prevalence of air 

4 conditioning use in an area. Studies examining multiple cities across the U.S. have 

5 assessed whether associations between O3 concentrations and hospital admissions and 

6 mortality varied among areas with high and low prevalence of air conditioning. Medina7 Ramon et al. (2006) conducted a study during the warm season and observed a greater 

8 association between O3 levels and pneumonia-hospital admissions among areas with a 

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

10 larger proportion of households with air conditioning. However, a similar observation 

11 was not observed when examining COPD hospital admissions complicating the 

12 interpretation of the results cfrom this study. Bell and Dominici (2008) found evidence of 

13 increased risk of O3-related mortality in areas with a lower prevalence of central air 

14 conditioning in a study of 98 U.S. communities. Conversely, Medina-Ramón and 

15 Schwartz (2008) found that among individuals with atrial fibrillation, a lower risk of 

16 mortality was observed for areas with a lower prevalence of central air conditioning.

17 The limited number of studies that examined whether air conditioning use modifies the 

18 association between O3 exposure and health has not provided consistent evidence across 

19 health endpoints. Therefore, the limited and inconsistent results across epidemiologic 

20 studies has provided inadequate evidence to determine whether a lower prevalence of air 

21 conditioning use leads to a potential increased risk of O3-related health effects. 

8.5 Summary

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

23 been evaluated and indicate that various factors may lead to increased risk of O3-related 

24 health effects (Table 8-5). 

25 The populations and lifestages identified in this section that have “adequate” evidence for 

26 potentially increased O3-related health effects are individuals with asthma, younger and 

27 older age groups, individuals with reduced intake of certain nutrients, and outdoor 

28 workers, based on consistency in findings across studies and evidence of coherence in 

29 results from different scientific disciplines. Asthma as a factor potentially affecting risk 

30 was supported by controlled human exposure and toxicological studies, as well as some 

31 evidence from epidemiologic studies. Generally, studies of age groups reported positive 

32 associations for respiratory hospital admissions and ED visits among children. Biological 

33 plausibility for this increased risk is supported by toxicological and clinical research. 

34 Also, children have higher exposure and dose due to increased time spent outdoors and 
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1 ventilation rate. Most studies comparing age groups reported greater effects of short-term 

2 O3 exposure on mortality among older adults, although studies of other health outcomes 

3 had inconsistent findings regarding whether older adults were at increased risk. Older 

4 adults may also withstand greater O3 exposure and not seek relief as quickly as younger 

5 adults. Multiple epidemiologic, controlled human exposure, and toxicological studies 

6 reported that reduced Vitamins E and C intake are associated with risk of O3-related 

7 health effects. Previous studies have shown that increased exposure to O3 due to outdoor 

8 work leads to a potentially increased risk of O3-related health effects and it is clear that 

9 outdoor workers have higher exposures, and possibly greater internal doses, of O3, which 

10 may lead to increased risk of O3-related health effects. 

Table 8-5 Summary of evidence for potential increased risk of ozone-related 

health effects.

Evidence Classification Potential At Risk Factor

Adequate evidence Asthma (Section 8.2.2)

Children (Section 8.3.1.1)

Older adults (Section 8.3.1.2)

Diet (Section 8.4.1)

Outdoor workers (Section 8.4.4)

Suggestive evidence Genetic factors (Section 8.1) 

Sex (Section 8.3.2)

SES (Section 8.3.3) 

Obesity (Section 8.4.2)

Inadequate evidence Influenza/Infection (Section 8.2.1)

COPD (Section 8.2.3)

CVD (Section 8.2.4)

Diabetes (Section 8.2.5)

Hyperthyroidism (Section 8.2.6)

Race/ethnicity (Section 8.3.4)

Smoking (Section 8.4.3)

Air conditioning use (Section 8.4.5)

Evidence of no effect --

11 In some cases, it is difficult to determine a factor that results in potentially increased risk 

12 of effects. For example, previous assessments have included controlled human exposure 

13 studies in which some healthy individuals demonstrate greater O3-related health effects 

14 compared to other healthy individuals. Intersubject variability has been observed for lung 

15 function decrements, symptomatic responses, pulmonary inflammation, AHR, and altered 

16 epithelial permeability in healthy adults exposed to O3 (Que et al., 2011; Holz et al., 

17 2005; McDonnell, 1996). These responses to O3 exposure in healthy individuals tend to 

18 be reproducible within a given individual over a period of several months indicating 

19 differences in the intrinsic responsiveness (Holz et al., 2005; Hazucha et al., 2003; Holz 

20 et al., 1999; McDonnell et al., 1985b). 
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1 Limitations include the challenge of evaluating effect measure modification in 

2 epidemiologic studies with widespread populations with variation in numerous factors. 

3 For a number of the factors described below, there are few available studies. Many 

4 toxicological and controlled human exposure studies are the only ones that have 

5 examined certain factors and therefore have not been replicated. In considering 

6 epidemiologic studies conducted in other countries, it is possible that those populations 

7 may differ in SES or other demographic indicators, thus limiting generalizability to a 

8 U.S. population. Additionally, many epidemiologic studies that stratify by factors of 

9 interest have small sample sizes, which can decrease precision of effect estimates. 

10 These challenges and limitations in evaluating the factors that can increase risk for 

11 experiencing O3-related health effects may contribute to conclusions that evidence for 

12 some factors, such as genetic factors, sex, SES, and obesity provided “suggestive” 

13 evidence of potentially increased risk. In addition, for a number of factors listed in 

14 Table 8-5 the evidence was inadequate to draw conclusions about potential increase in 

15 risk of effects. Overall, the factors most strongly supported as contributing to potentially 

16 increased risk of O3-related effects among various populations and lifestages were related 

17 to asthma, age group (children and older adults), dietary factors, and working outdoors.
Draft – Do Not Cite or Quote 8-39 June 2012

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