### Draft

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- 1 June 2012 

## 8 POPULATIONS POTE NTIALLY AT INCREASED RISK FOR
OZONE

- RELATED HEALTH EFFEC TS

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

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

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

### 3
both the population as a whole and those potentially at increased risk for health effects in 

### 4
response to ambient air pollution (Preface to this ISA). To facilitate the identification of 

### 5

po pulations and lifestages at greater risk for air pollutant related health effects, studies 

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

### 7
individual to air pollutants. The definitions of susceptibility and vulne rability have been 

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

### 9
intrinsic factors (e.g., lifestage, sex, preexisting disease/conditions) while “vulnerability” 

### 10

refers to non

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

### 11

2010c

, 2009d ) . In some cases, the terms “at

- risk” and “sensitive” populations have been 

### 12
used to encompass these concepts more generally. The main goal of this evaluation is to 

### 13

identif y and understand those factors that result in a population or lifestage being at 

### 14
increased risk of an air pollutant

- related health effect, not to categorize the factors. To 

### 15
this end, previous ISAs and reviews ( Sacks et al., 2011 ; U.S. EPA, 2010c

, 2009d ) have 

### 16
used “susceptible populations” to encompass these various factors. In this chapter, 

### 17

“at

- risk” is the all

- encompassing term used for groups wi th specific factors that increase 

### 18
the risk of an air pollutant (e.g., O 3 )

- related health effects in a population. 

### 19

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

### 20

induced health effects via multiple avenues. A gro up with i 

### ntrinsically increased risk 

### 21

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

### 22
mechanism. In general, people in this category would have a steeper concentration



### 23
risk relationship, compared to those not in the category

. Potential factors that are often 

### 24

considered intrinsic include genetic background and sex. 

### A group of people could also 

### 25
have extrinsically increased risk, which would be through an external, non

- biological 

### 26
factor. Examples of extrinsic factors include SES and diet. Some groups are at risk of 

### 27

i ncreased internal dose at a given exposure concentration, which includes individuals 

### 28
that have a greater dose of delivered pollutant because of breathing pattern. This 

### 29
category would include persons who work outdoors or exercise outdoors. In addition, 

### 30
some outdoor workers could have greater exposure (concentration x time), regardless 

### 31
of the delivered dose. Finally, there are those who might be placed at increased risk 

### 32
for experiencing a greater exposure by being expose d at a higher concentration . For 

### 33

### Draft

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- 2 June 2012 example, groups of people exposed to higher air pollutant concentrations due to less 

### 1
availability/use of home air conditioners (i.e., more open windows on high O 3 

### days). 

### 2

Some factors described above are multifaceted and ma y influence the risk of an air 

### 3
pollutant related health effect through a combination of avenues. For example, SES may 

### 4
affect access to medical care, which itself may contribute to the presence of preexisting 

### 5

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

### 6
spend more time outdoors at higher levels of activity than adults, which leads to 

### 7
increased intake dose and exposure, but they also have biological (i.e., intrinsic) 

### 8
differences when compared to adults. 

### 9

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

### 10

increase the risk of O 3 - related health effects, regardless of whether the increased risk is 

### 11
due to intrinsic factors, extrinsic factors, increased dose/exposure or a combination, d ue 

### 12
to the often connected pathways between factors. The following sections examine factors 

### 13
that potentially lead to increased risk of O 3 - related health effects and characterize the 

### 14
overall weight of evidence for each factor. Most of the factors are related to greater health 

### 15
effects given a specific dose but there is also discussion of in creased internal dose and/or 

### 16
exposure at a given concentration integrated throughout the sections (i.e., lifestage, 

### 17
outdoor workers, and air conditioning use). 

### 18

Approach to C lassifying Potential At

- Risk Factors

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

### 19
pollutant related health effects, the evidence across relevant scientific disciplines 

### 20

(i.e., exposure sciences, dosimetry, contr olled human exposure, toxicology, and 

### 21
epidemiology) was evaluated. In this systematic approach, the collective evidence is used 

### 22
to examine coherence of effects across disciplines and determine biological plausibility. 

### 23
By first focusing on studies (i.e., ep idemiologic or controlled human exposure) that 

### 24
conduct stratified analyses it is possible to identify factors that may result in some 

### 25
populations being at greater risk of an air pollutant related health effect. These types of 

### 26

studies allow for an evaluatio n of populations exposed to similar air pollutant (e.g., O 3 ) 

### 27
concentrations within the same study design. Experimental studies also provide important 

### 28
lines of evidence in the evaluation of factors that may lead to increased risk of an air 

### 29
pollutant related

- health effect. Toxicological studies conducted using animal models of 

### 30
disease and controlled human exposure studies that examine individuals with underlying 

### 31
disease or genetic polymorphisms may provide evidence in the absence of stratified 

### 32
epidemiologic a nalyses. Additionally these studies can provide support for coherence 

### 33
with the health effects observed in epidemiologic studies as well as an understanding of 

### 34
biological plausibility. The collective results across the scientific disciplines comprise the 

### 35

### Draft

– Do Not Cite or Quote 8

- 3 June 2012 ov erall weight of evidence that is used to determine whether a specific factor results in a 

### 1
population being at increased risk of an air pollutant related health effect. 

### 2

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

### 3
throughou t the ISA, conclusions are made regarding the strength of evidence for each 

### 4
factor that may contribute to increased risk of an O 3 - related health effect based on the 

### 5
evaluation and synthesis of evidence across scientific disciplines. The conclusions drawn 

### 6

c onsidered the “Aspects to Aid in Judging Causality” discussed in Table 1 of the 

### 7
Preamble. The categories considered for evaluating the potential increased risk of an air 

### 8
pollutant

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

### 9

“inade quate evidence,” and “evidence of no effect.” They are described in more detail in 

### 10

Table 8

- 1

. 

### 11

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 applicab le, 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 referen ce 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 concl ude 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 inclu des multiple high

- quality studies.

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

### 12
population being at increased risk of an O 3 - related health effect. For further detail on the 

### 13
epidemiologic, controlled human exposure, and toxicological studies included in this 

### 14
chapter, see Chapters 5, 6, and 7. 

### 15



## 8.1 Genetic Factors

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

### 16
have been examined; studies often target polymorphisms in al ready identified candidate 

### 17
susceptibility genes or in genes whose protein products are thought to be involved in the 

### 18
biological mechanism underlying the health effect of an air pollut ant ( Sacks et al., 2011 )

. 

### 19
As a result, multiple studies that examined the effect of short

- and long

- term O 3 exposure 

### 20
on respiratory function have focused on whether various gene profiles lead to an 

### 21

### Draft

– Do Not Cite or Quote 8

- 4 June 2012 increased risk of O 3 - related health effects. For more details on the function and mode of 

### 1
action of the genetic factor s discussed in this section, see Section 5.4.2.1 . Additionally, a 

### 2
limited number of toxicological studies have examined the joint effects of nutriti on and 

### 3
genetics. Details on these toxicological studies of nutrition and genetics can be found in 

### 4

Section 5.4.2.3

. 

### 5

Multiple genes, including glutathione S

- transferase Mu 1 (GSTM1) and tumor necrosis 

### 6

factor

- α (TNF

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

### 7
role... in the innate susceptibility to O 3 ” ( U.S. EPA, 2006b ) . Epidemiologic, controlled 

### 8
human exposure, and toxicological studies performed since the 2006 O 3 AQCD have 

### 9

continued to examine the roles of GSTM1 and TNF

- α in modifying O 3 - related health 

### 10
effects and have examined other gene variants that may also increase risk. Due to small 

### 11
sample sizes, many controlled human exposure studies are limited in their ability to test 

### 12

genes w ith low frequency minor alleles and therefore, some genes important for 

### 13

O 3 - related health effects may not have been examined in these types of studies. A 

### 14
summary of effect measure modification findings from epidemiologic and controlled 

### 15
human exposure studi es discussed in this section is included as Table 8

- 2

. 

### 16

### Draft

– Do Not Cite or Quote 8

- 5 June 2012 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

- to

moderate 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 ↑

Epidemiologic studies that examined the effects of short

- term exposure to O 3 on lung 

### 1
function included analyses of potential gene

- environment interactions. R omieu et al. 

### 2

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

### 3
among children with GSTM1 null or glutathione S

- transferase P 1 (GSTP1) Val/Val 

### 4
genotypes compared with children with GSTM1 positive or GSTP1 Ile/Ile or Ile /Val 

### 5
genotypes, respectively. However, results suggested that O 3 - associated decreases in lung 

### 6
function may be greater among children with GSTP1 Ile/Ile or Ile/Val compared to 

### 7

GSTP1 Val/Val. Alexeeff et al. (2008 ) reported greater O 3 - related decreases in lung 

### 8
function among GSTP1 Val/Val adults than those with GSTP1 Ile/Ile or GSTP1 Ile/Val 

### 9
genotypes. In addition, they detected greater O 3 - associ ated decreases in lung function for 

### 10
adults with long GT dinucleotide repeats in heme

- oxygenase

- 1 (HMOX1) promoters. 

### 11

### Draft

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- 6 June 2012 Several controlled human exposure studies have reported that genetic polymorphisms of 

### 1
antioxidant enzymes may modulate pulmonary function an d inflammatory responses to 

### 2

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

### 3
(wt) in combination with GSTM1 null genotype had greater decreases in lung function 

### 4
parameters with exposure to O 3 ( Bergamaschi et al., 2001 )

. Vagaggini et al. (2010 ) 

### 5
exposed mild

- to

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

### 6

NQO1 wt and GSTM1 null, there was no evidence of cha nges in lung function or 

### 7
inflammatory responses to O 3

. Kim et al. (2011 ) also recently conducted a study among 

### 8
young adults, about half of whom were GSTM1

- null and half of whom were 

### 9

GSTM1

- sufficient. They detect ed no difference in the FEV 1 responses to O 3 exposure by 

### 10
GSTM1 genotype and did not examine NQO1. In another study that examined GSTM1 

### 11
but not NQO1, asthmatic children with GSTM1 null genotype ( Romieu et al., 2004b ) 

### 12
were reported to have greater decreases in lung function in relation to O 3 exposure. 

### 13
Additionally, supplementation with antioxidants (Vitamins C and E) had a slightly more 

### 14
beneficial effect among GSTM1 null children (for more on modification by diet, see 

### 15

Section 8.4.1 ). 

### 16

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

### 17

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

### 18

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

### 19

to O 3 . At 4 hours post

- O 3 exposure, individuals with either GSTM1 genotype had 

### 20
statistically significa nt increases in sputum neutrophils with a tendency for a greater 

### 21

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

### 22

had returned to baseline levels in the GSTM1 sufficient individuals. In the GS TM1 null 

### 23
subjects, neutrophil levels increased from 4 to 24 hours and were significa ntly greater 

### 24

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

### 25

addition, O 3 exposure increased the expression of the surface marker C D14 in airway 

### 26
neutrophils of GSTM1 null subjects compared with GSTM1 sufficient subjects. CD14 

### 27

and TLR4 are co

- receptors for endotoxin, and signaling through this innate immune 

### 28
pathway has been shown to be important for a number of biological responses to O 3 

### 29
exposure in toxicological studies ( Garantziotis et al., 2010 ; Hollingsworth et al., 2010 ; 

### 30
Hollingsworth et al., 2004 ; Kleeberger et al., 2000 )

. Alexis et al. ( 2009 ) also 

### 31
demonstrated decreased numbers of airway macrophages at 4 and 24 hours following O 3 

### 32
exposure in GSTM1 sufficient subjects. Airway macrophages in GSTM1 null subjects 

### 33
were greater in number and found to have greater oxidative burst and phagocyt ic 

### 34
capability following O 3 exposure than those of GSTM1 sufficient subjects. Airway 

### 35
macrophages and dendritic cells from GSTM1 null subjects exposed to O 3 expressed 

### 36
higher levels of the surface marker HLA

- DR, again suggesting activation of the innate 

### 37

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

### 38
of the exposure other than O 3 cannot be ruled out. In general, the findings between these 

### 39

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- 7 June 2012 studies are inconsistent. It is possible that different genes may be important for different 

### 1
phenotypes. Additional studies, which include appropriate controls, are needed to clarify 

### 2
the influence of genetic polymorphisms on O 3 responsiveness in humans. 

### 3

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

### 4

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

### 5
among individuals due to genetic variability ( Tankersley et al., 2010 ; Chuang et al., 2009 ; 

### 6
Hamade and Tankersley, 2009 ; Hamade et al., 2008 ) . Thus strains of mice which are 

### 7
prone to or resistant to O 3 - induced effects have been used to systematically identify 

### 8
candidate genes that may increase risk of O 3 - related health effects. Genome wide linkage 

### 9
analyses have identified quantitative trait loci for O 3 - induced lung inflammation and 

### 10
hyperpermeability on chromosome 17 ( Kleeberger et al., 1997 ) and chromosome 4 

### 11

( Kleeberger et al., 2000 ) , respectively, using recombinant inbred strains of mice. M ore 

### 12
specifically, these studies found that TNF (protein product is the inflammatory cytokine 

### 13

TNF

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

### 14
candidate susceptibility genes ( Kleeberger et al., 2000 ; Kleeberger et al., 1997 ) . The TNF 

### 15
receptors 1 and 2 have also been found to play a role in injury, inflammation, and airway 

### 16
hyperreactivity in studies of O 3 - exposed knockout mice ( Cho et al., 2001 ) . In addition to 

### 17
Tlr4, other innate immune pattern recognition signaling pathway genes, including Tlr2 

### 18
and Myd88, appear to be important in responses to O 3 , as demonstrated by Williams et al. 

### 19

(2007b ) . A role for the inflammatory cytokine IL

- 6 has been demonstrate d in 

### 20

gene

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

### 21

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

- 10, an anti

- inflammatory cytokine, 

### 22
demonstrated increased pulmonary inflammation in response to O 3 exposure ( Backus et 

### 23

al., 2010 ) . Thu s genes related to innate immune signaling and pro

- and anti

- inflammatory 

### 24
genes are important for O 3 - induced responses. 

### 25

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

### 26
factor erythroid 2

- related factor 2 (Nrf

- 2), s uggesting a role for genetic differences in 

### 27
altering the formation of ROS ( Hamade et al., 2010 ; Cho and Kleeberger, 2007 )

. 

### 28
Additionally, some studies have reported O 3 - related effects to vary by Inf

- 1 and Inf

- 2 

### 29
quantitative trait loci ( Tankersley and Kleeberger, 1994 ) and a gene coding for Clara cell 

### 30
secretory protein (CCSP) ( Broeckaert et al., 2003 ; Wattiez et al., 2003 )

. Other 

### 31
investigations in inbred mouse strains found that differences in expression of certain 

### 32
proteins, such a s CCSP ( Broeckaert et al., 2003 ) and MARCO ( Dahl et al., 2007 ) , are 

### 33
responsible for phenotypic characteristics, such as epithelial permeability and scavenging 

### 34
of oxidized lipids, respectively, which conf er sensitivity to O 3

. 

### 35

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

### 36
and is thought to participate in lung damage. Mice deficient in the gene for inducible 

### 37

### Draft

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- 8 June 2012 nitric oxide synthase (NOS2/NOSII/iNOS) are partially protec ted against lung injury 

### 1

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

### 2
TLR4 pathway described above. Similarly, iNOS deficient mice do not produce reactive 

### 3
nitrogen intermediates after O 3 exposure, in contrast to their wild

- type counterparts, and 

### 4
also produce less PGE2 comparatively ( Fakhrzadeh et al., 2002 ) . These gene

- deficient 

### 5
mice were protected from O 3 - induced lung injury and inflammation. In contrast, another 

### 6
study using a similar exposure concentration but longer duration of exposure foun d that 

### 7
iNOS deficient mice were more susceptible to O 3 - induced lung damage ( Kenyon et al., 

### 8

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

### 9
role or mediates damage. 

### 10

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

### 11
counterparts, are resistant to O 3 - induced AHR and inflammation. NQO1 catalyzes the 

### 12
reduction of quinones to hydroquinones, and is capable of both protective detoxification 

### 13
reactions and redox cycling reactions resulting in the generation of reactive oxygen 

### 14
species. Reduced production of inflammatory mediators and cells and blunted AHR were 

### 15
observed in NQO1 null mice after exposure to 1 ppm O 3 for 3 hours. These results 

### 16
correlated with those from in vitro experiments in which human bronchial epithelial cells 

### 17
treated with an NQO1 inhibitor exhibited reduced inflammatory responses to exposure to 

### 18

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

### 19
biomarkers of oxidative stress and increased pulmonary function decrements obse rved in 

### 20

O 3 - exposed individuals bearing both the wild

- type NQO1 gene and the null GSTM1 gene 

### 21

( Bergamaschi et al., 2001 )

. 

### 22

The role of TNF

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

### 23
through depletion experiments, b ut a more recent toxicological study investigated the 

### 24

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

### 25

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

### 26
identify in the midst of the sev ere pathological changes caused by constitutive TNF

- α 

### 27
overexpression. However, there was evidence that TNF transgenic mice were more 

### 28
susceptible to O 3 /PM

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

### 29
creatine kinase after pollutant expo sure, which may suggest potential systemic or cardiac 

### 30
related effects. Differential susceptibility to O 3 among inbred strains of animals does not 

### 31
seem to be dose dependent since absorption of 18 O in various strains of mice did not 

### 32

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

. 

### 33

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

### 34
effects. Cockayne syndrome, a rare autosomal recessive disorder in humans, is 

### 35
characterized by UV sensitivity abnormalities, neurological abnormalities, and premature 

### 36
aging. The same genetic defect in mice (Csb
- /

- ) makes them sensitive to oxidative 

### 37

### Draft

– Do Not Cite or Quote 8

- 9 June 2012 stressors, including O 3

. Kooter et al. (2007 ) demonstrated that Csb
- /

- mice produced 

### 1
significa ntly more TNF

- α after exposure to 0.8 ppm O 3 th an their wild

- type counterparts. 

### 2

However, there were no statistically significa nt differences in other markers of 

### 3
inflammation or lung injury between the two strains of mice. 

### 4

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

### 5
involvement in populations being potentially more at

- risk than others to the effects of O 3 

### 6
exposure on health. Controlled human exposure and epidemiologic studies have reported 

### 7

some evidence of O 3 - related increases in respiratory symptoms or decr eases in lung 

### 8
function with variants including GSTM1, GSTP1, HMOX1 and NQO1, although the 

### 9
results are not consistent across studies and gene variants. Future studies of these and 

### 10
other genes in human populations will be important for determining the role o f each 

### 11
genotype and its effect on risk as well as finding coherence across the disciplines. NQO1 

### 12

deficient mice were found to be resistant to O 3 - induced AHR and inflammation, 

### 13
providing biological plausibility for results of studies in humans. Additionally, studies of 

### 14
rodents have identified a number of other genes that may affect O 3 - related health 

### 15
outcomes, including genes related to innate immune signaling and pro

- and 

### 16

anti

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

### 17



## 8.2 Preexisting Disease/Conditions

Individuals with certain preexisting diseases are likely to constitute an at

- risk population. 

### 18
This may be the result of individuals with a preexisting disease/condition having less 

### 19
reserve than healthy individuals, so although the absol ute change may be the same, the 

### 20
health consequences are different. Previous O 3 AQCDs concluded that some people with 

### 21
preexisting pulmonary disease, especially asthma, are among those at increased risk of an 

### 22

O 3 - related health effect. Extensive toxicological evidence indicates that altered 

### 23
physiological, morphological and biochemical states typical of respiratory diseases may 

### 24
render people at risk of an additional oxidative burden induced by O 3 exposure. In 

### 25

addition, a number of epidemiologic studies found th at some individuals with respiratory 

### 26

diseases are at increased risk of O 3 - related effects. The majority of the studies identified 

### 27
in previous AQCDs focused on whether preexisting respiratory diseases result in 

### 28

increased risk of O 3 - related health effects, w ith a limited number of studies examining 

### 29
other preexisting diseases, such as cardiovascular. 

### 30

Studies identified since the completion of the 2006 O 3 AQCD that examined whether 

### 31
preexisting diseases and conditions lead to increased risk of O 3 - induced health effects 

### 32

were identified and are summarized below. Table 8

- 3 displays the prevalence rates of 

### 33
some of these conditions categorized by age and region among adults in the U.S. 

### 34

### Draft

– Do Not Cite or Quote 8

- 10 June 2012 population; data for children, when available, are presented within the following sections. 

### 1
Substantial proportions of the U.S. population are affected by these conditions and 

### 2
therefore may represent a potentially large at

- risk population. While these diseases and 

### 3
conditions represent biological or intrinsic factors that could lead to increased risk, the 

### 4
pathways to their development may have in trinsic or extrinsic origins. 

### 5

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

Asthma a 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

Recent studies have indicated that underlying infections may increase the risk of O 3 - 

### 6

related health e ffects because O 3 exposure likely impairs host defenses, which may 

### 7
increase the body’s response to an infectious agent. However, there is little epidemiologic 

### 8
or experimental evidence that infection or influenza itself renders an individual at greater 

### 9

risk of an O 3 - induced health effect. A study of hospitalizations in Hong Kong reported 

### 10
that increased levels of influenza intensity resulted in increased excess risk of respiratory 

### 11
disease hospitalizations related to O 3 exposure ( Wong et al., 2009 ) . In addition, a study of 

### 12
lung function in asthmatic children reported decreases in lung function with increased 

### 13

short

- term O 3 exposure for those with upper respiratory infections but not for those 

### 14

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

### 15
plausibility for the increase in O 3 - induced health effects observed in epidemiologic 

### 16

studies that examined inf ections by way of studies that demonstrated that exposure to 

### 17

### Draft

– Do Not Cite or Quote 8

- 11 June 2012 0.08 ppm O 3 increased streptococcus

- induced mortality, regardless of whether O 3 

### 1
exposure preceded or followed infection ( Miller et al., 1978 ; Coffin and Gardner, 1972 ; 

### 2

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

### 3
potential fo r increased risk to be conferred by an infection but the number of studies is 

### 4
limited. There have only been a few epidemiologic studies and these studies examine 

### 5
different outcomes (respiratory

- related hospital admissions or lung function) and 

### 6

different mo difiers (influenza or respiratory infection). In some of the toxicological 

### 7

studies, the O 3 exposure came before the infection. Therefore, evidence is inadequate to 

### 8

determine if influenza/infections increase the risk of O 3 - related health effects. 

### 9

8.2.2 Asthma

Pre vious O 3 AQCDs identified individuals with asthma as a population at increased risk 

### 10

of O 3 - related health effects. Within the U.S., approximately 7.3% of adults have reported 

### 11
currently having asthma ( Pleis et al., 2009 ) , and 9.5% of children have reported currently 

### 12
having asthma ( Bloom et al., 2008 ) . For more detailed prevalence by age, see Table 8

- 4

. 

### 13

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.

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

### 14

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

### 15
lifeguards in Texas reported decreased lung function with short

- term O 3 exposure among 

### 16
both individuals with and without asthma, however, the decrease was greater among 

### 17

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

- 14 detected 

### 18

an association between short

- term O 3 exposure and wheeze, cough, and bronchodilator 

### 19
use among asthmatics but not non

- asthmatics, although this may have been the result of a 

### 20

small n on

- asthmatic population ( Escamilla

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

### 21

### Draft

– Do Not Cite or Quote 8

- 12 June 2012 by airway hyperresponsiveness (AHR) (a conditio n common among asthmatics) reported 

### 1
greater short

- term O 3 - associated decreases in lung function in elderly individuals with 

### 2
AHR, especially among those who were obese ( Alexeeff et al., 2007 ) . However, no 

### 3
evidence for increased risk was found in a study performed among children in Mexico 

### 4
City that examined the effect of short

- term O 3 exposure on respiratory health ( Barraza



### 5

Villarreal et al., 2008 ) . In this study, a positive association was reported for airway 

### 6
inflammation among asthmatic children, but the observed association was similar in 

### 7
magnitude to that of non

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

### 8

an associa tion between O 3 concentration and exhaled nitric oxide fraction (FeNO) that 

### 9
persisted both among children with and without asthma as well as those with and without 

### 10
respiratory allergy ( Berhane et al., 2011 ) . Finally, Khatri et al. (2009 ) found no 

### 11

associ ation between short

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

### 12

or non

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

### 13
allergies. 

### 14

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

### 15

examined the association between O 3 exposure and altered lung function by asthma 

### 16
medication use. A study of children with asthma living in Detroit reported a greater 

### 17

association between short

- term O 3 and lung function for corticosteroid user s compared 

### 18

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

### 19
decreased lung function among noncorticosteroid users compared to corticosteroid users, 

### 20
although in this study, a large proportion of non

- users were considered to be pers istent 

### 21

asthmatics ( Hernández

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

- term 

### 22

O 3 exposure among corticosteroid users and non

- users in a study taking place during the 

### 23

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

### 24
inflammation reported a counterintuitive inverse association with O 3 of similar magnitude 

### 25

for all groups of corticosteroid users and non

- users ( Qian et al., 2009 )

. 

### 26

Controlled human exposure studies that have examined the effects of O 3 on individuals 

### 27
with asthma and healthy controls are limited. Based on studies reviewed in the 1996 and 

### 28

2006 O 3 AQCDs, subjects with asthma appeared to be at least as sensitive to acute effects 

### 29

of O 3 in terms of FEV 1 and inflammatory responses as healthy non

- asthmatic subjects. 

### 30

For instance, Horstman et al. (1995 ) observed that mild

- to

- moderate asthmatics, on 

### 31
average, experienced double the O 3 - induced FEV 1 decrement of healthy subjects (19% 

### 32
versus 10%, respectively, p = 0.04). Moreove r, a statistically significa nt positive 

### 33

correlation between FEV 1 responses to O 3 exposure and baseline lung function was 

### 34

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

### 35

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

### 36
considerable larger average O 3 - induced FEV 1 decrement than the healthy controls (25% 

### 37
vs. 16%, respectively) following exposure to O 3 with mode rate

- heavy exercise. Alexis et 

### 38

### Draft

– Do Not Cite or Quote 8

- 13 June 2012 al. (2000 ) and Jorres et al. (1996 ) also reported a tendency for slightly greater FEV 1 

### 1
decrements in asthmatics than healthy subjects. Minimal evidence exists suggesting that 

### 2

individuals with asthma have smaller O 3 - induced FEV 1 decrements than healthy subjects 

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

### 4
study also tended to be older than the healthy subjects, which could partially explain their 

### 5
lesser response sin ce FEV 1 responses to O 3 exposure diminish with age. Individuals with 

### 6
asthma also had more neutrophils in the BALF (18 hours postexposure) than similarly 

### 7
exposed healthy individuals ( Peden et al., 1997 ; Scannell et al., 1996 ; Basha et al., 1994 )

. 

### 8
Furthermore, a study examining the effects of O 3 on individuals with atopic asthma and 

### 9
healthy controls reported that greater numbers of neutrophils, higher levels of cytokines 

### 10

and h yaluronan, and greater expression of macrophage cell

- surface markers were 

### 11
observed in induced sputum of atopic asthmatics compared with healthy controls 

### 12

( Hernandez et al., 2010 ) . Differences in O 3 - induced epithelial cytokine expression were 

### 13
noted in bronchial biopsy samples from asthmatics and healthy controls ( Bosson et al., 

### 14

2003 ) . Cell

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

### 15
hyaluronan, are consistent with O 3 having greater effects on innate and adaptive 

### 16
immunity in these asthmatic individuals (see Section 5.4.2.2 ). In addition, studies have 

### 17

demonstrated that O 3 exposure leads to increased bronchial reactivity to inhaled allergens 

### 18
in mild allergic asthmatics ( Kehrl et al., 1999 ; Jorres et al., 1996 ) and to the influx of 

### 19
eosinophils in individuals with pre

- existing alle rgic disease ( Vagaggini et al., 2002 ; 

### 20

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

### 21

which could account for the increased risk of O 3 – related health effects in subjects with 

### 22

asthma (see Section 5.4.2.2 ). 

### 23

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

### 24
with asthma or AHR. In animal toxicological studies, an asthmatic phenotype is modeled 

### 25

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

### 26

that O 3 exposure is an inducer of AHR and remodeling utiliz e these types of animal 

### 27
models. For example, a series of experiments in infant rhesus monkeys have shown these 

### 28
effects, but only in monkeys sensitized to house dust mite allergen ( Fanucchi et al., 2006 ; 

### 29

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

### 30
changes in pulmonary function in mice exposed to O 3 , and Wagner et al. (2007 ) 

### 31

demonstrated enhanced inflamma tory responses in rats exposed to O 3 , but only in 

### 32
animals sensitized to allergen. In general, it is the combined effects of O 3 and allergic 

### 33
sensitization which result in measurable effects on pulmonary function. In a bleomycin 

### 34
induced pulmonary fibrosis mo del, exposure to 250 ppb O 3 for 5 days increased 

### 35
pulmonary inflammation and fibrosis, along with the frequency of bronchopneumonia in 

### 36

rats. Thus, short

- term exposure to O 3 may enhance damage in a previously injured lung 

### 37

( Oyarzún et al., 2005 )

. 

### 38

### Draft

– Do Not Cite or Quote 8

- 14 June 2012 In the 2006 O 3 AQCD, the potential for individuals with asthma to have greater risk of 

### 1

O 3 - rela ted health effects was supported by a number of controlled human exposure 

### 2
studies, evidence from toxicological studies, and a limited number of epidemiologic 

### 3
studies. Overall, in the recent epidemiologic literature some, but not all, studies report 

### 4

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

### 5
measure modification of the relationship between short

- term O 3 exposure and altered 

### 6
lung function by corticosteroid use provided limited and inconsistent evidence of 

### 7

O 3 - related health effects. Additionally, recent studies of behavioral responses have found 

### 8
that studies do not take into account individual behavioral adaptations to forecasted air 

### 9
pollution levels (such as avoidance and reduced time outdoors), which may underestima te 

### 10

the observed associations in studies that examined the effect of O 3 exposure on 

### 11
respiratory health ( Neidell and Kinney, 2010 ) . This could explain some inconsistency 

### 12
observed among recent epidemiologic studies. The evidence from controlled human 

### 13
exposure studies provides support for increased decrements in FEV 1 and greater 

### 14
inflammatory responses to O 3 in individuals with asthma than in healthy individuals 

### 15
without a history of asthma. The collective evidence for increased risk of O 3 - related 

### 16
health effects among individuals with asthma from controlled human exposu re studies is 

### 17
supported by recent toxicological studies which provide biological plausibility for 

### 18
heightened risk of asthmatics to respiratory effects due to O 3 exposure. Evidence 

### 19
indicating O 3 - induced respiratory effects among individuals with asthma is f urther 

### 20
supported by additional studies of O 3 - related respiratory effects (Section 6.2 ). Overall, 

### 21
there is adequate evidence for asthmatics to be a potentially at

- risk population based on 

### 22
the substantial, consistent evidence among controlled human exposure studies and 

### 23
coherence from epidemiologic and toxicological studies. 

### 24

8.2.3 Chronic Obstructive Pulmonary Disease (COPD)

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

### 25
having emphysema, both of which are classified as COPD ( Pleis et al., 2009 )

. 

### 26

A recent study reported no association between O 3 exposure and lung function regardless 

### 27
of whether the study participant had COPD or othe r preexisting diseases (asthma or IHD) 

### 28

( Lagorio et al., 2006 )

. 

### 29

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

### 30
cardiovascular ED visits in respons e to short

- term O 3 exposure compared to healthy 

### 31

individuals in Atlanta, GA. The authors reported that short

- term O 3 exposure was 

### 32
associated with higher odds of an emergency department (ED) visit for peripheral and 

### 33
cerebrovascular disease among individuals with COPD compared to individuals without 

### 34

### Draft

– Do Not Cite or Quote 8

- 15 June 2012 COPD. However, preexisting COPD did not increase the odds of hospitalization for all 

### 1

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

### 2
study performed in Taiwan, individuals with and without COPD had higher odds of 

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

### 4

discussed in Section 6.3 , most studies reported no overall association between O 3 

### 5
concentration and CVD morbidity. 

### 6

Recent epidemiologic evidence indicates that persons with COPD may have increased 

### 7

risk of O 3 - related cardiovascular effects, but little information is available on whether 

### 8

COPD leads to an increased risk of O 3 - induced respiratory effects. Overall, this small 

### 9
number of studies provides inadequate evidence to determine whether COPD results in 

### 10

increased risk of O 3 - related health effects. 

### 11

8.2.4 Cardiovascular Disease (CVD)

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

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

- 3 ). A high prevalence of other 

### 13

cardiovascular

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

### 14
prevalent among approximately 24% of adults. In the 2006 O 3 AQCD, little evidence wa s 

### 15
available regarding whether preexisting CVD contributed to increased risk of O 3 - related 

### 16
health effects. Recent epidemiologic studies have examined cardiovascular

- related 

### 17

diseases as modifiers of the O 3 - outcome associations; however, no recent evidence is 

### 18
available from controlled human exposure studies or toxicological studies. 

### 19

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

- term O 3 exposure and 

### 20

cardio vascular ED visits in Atlanta, GA among multiple comorbid conditions. The 

### 21

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

### 22
previously diagnosed with dysrhythmia, congestive heart failure, or hypertension 

### 23
compared to he althy individuals. Similarly, a study in France examined the association 

### 24

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

### 25
infarction (MI) and the influence of multiple vascular risk factors on any observed 

### 26

associations ( Henrotin et al., 2010 ) . The association between O 3 exposure and ICVE was 

### 27
elevated for individuals with multiple risk factors, specifically individuals with diabetes 

### 28
or hypertension. For the association between O 3 and MI, increased odds were apparent 

### 29
only for those with hypercholesterolemia. In a study conducted in Taiwan, a positive 

### 30

association was observed for O 3 o n warm days and congestive heart failure hospital 

### 31

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

### 32
hypertension or with/without dysrhythmia ( Lee et al., 2008a ) . Another study in Taiwan 

### 33
reported that the association between O 3 levels and ED visits for arrhythmias were greater 

### 34

### Draft

– Do Not Cite or Quote 8

- 16 June 2012 on warm days among those with congestive heart failure compared to those without 

### 1
congestive heart failure; however, the estimate and 95% CIs for those without congestive 

### 2
heart failure is completely contained within the 95% CI of those with congestive hear t 

### 3

failure ( Chiu and Yang, 2009 )

. 

### 4

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

### 5
changes in blood markers for individuals with CVD. There was a greater association 

### 6

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

### 7
individuals with a history of CVD ( Liao et al., 2005 )

. Liao et al. (2005 ) found that 

### 8
increased fibrinogen was positively associated with short

- term O 3 exposure but this 

### 9

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

### 10
was observed among those without a history of CVD. However, for another biomarker 

### 11
(vWF), CVD status did not modify the positive association with short

- term O 3 exposure 

### 12

( Liao et al., 2005 )

. 

### 13

Mor tality studies provide some evidence for a potential increase in O 3 - induced mortality 

### 14
in individuals with preexisting atrial fibrillation and atherosclerosis. In a study of 48 U.S. 

### 15
cities, increased risk of mortality with short

- term O 3 exposure was observe d only among 

### 16
individuals with secondary atrial fibrillation ( Medina

- Ramón and Schwartz, 2008 ) . No 

### 17

association was observed for short

- term O 3 exposure and mortality in a study of 

### 18
individuals with diabetes with or without CVD prior to death; however, there was some 

### 19
evidence of increased risk of mortality during the warm season if individuals had diabetes 

### 20
and atherosclerosis compared to only having diabetes ( Goldberg et al., 2006 )

. 

### 21

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

### 22

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

### 23

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

### 24
diseases, including IHD. No association was observed regardless of whether the 

### 25

participant had IHD. 

### 26

Overall, most short

- term exposure studies did not repo rt increased O 3 - related 

### 27
cardiovascular morbidity for individuals with preexisting CVD. However, as discussed in 

### 28

Section 6.3 , most studies reported no overall association between O 3 concentration and 

### 29
CV morbidity. Thus, it is likely the association would be null regardless of the 

### 30

stratification. A limited number of studies examined whether cardiovascular disease 

### 31

modifies the association between O 3 and respiratory effects. There was some evidence 

### 32

that cardiovascular disease increases the risk of O 3 - related mortality but again the number 

### 33
of studies was limited. Currently, evidence is inadequate to classify CVD as a potential 

### 34

at

- risk factor for O 3 - related health effects. Future research among those with CVD 

### 35
compared to those without will increase the understanding of potential increased risk of 

### 36

O 3 - related health effects among this group. 

### 37

### Draft

– Do Not Cite or Quote 8

- 17 June 2012 8.2.5 Diabetes

The literature has not extensively examined whether individ uals with diabetes (about 8% 

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

### 2

short

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

### 3

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

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

### 5
and hospital admissions for congestive heart failur e; however, no modification of the 

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

### 7
exposure and ED visits for arrhythmia in Taiwan, there was no evidence of effect 

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

. 

### 9
Currently, the limited number of epidemiologic studies as well as the lack of controlled 

### 10
human exposure or toxicological studies provides inadequate evidence to indicate 

### 11
whether diabetes results in a potentially increas ed risk of O 3 - related health effects. 

### 12

8.2.6 Hyperthyroidism

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

### 13

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

### 14
epidemiologic or control led human exposure studies. Lung damage and inflammation due 

### 15
to oxidative stress may be modulated by thyroid hormones. Compared to controls, 

### 16
hyperthyroid rats exhibited elevated levels of BAL neutrophils and albumin after a 4

- hour 

### 17

exposure to O 3 , indicatin g O 3 - induced inflammation and damage. Hyperthyroidism did 

### 18
not affect production of reactive oxygen or nitrogen species, but BAL phospholipids were 

### 19
increased, indicating greater activation of Type II cells and surfactant protein production 

### 20

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

### 21
underlying evidence, which suggests that individuals with hyperthyroidism may represent 

### 22

an at

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

### 23
evidence to determine whether hyperthyroidism results in potentially increased risk of 

### 24

O 3 - related health effects. 

### 25



## 8.3 Soc iodemographic Factors

8.3.1 Lifestage

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

### 26

older adults as at

- risk populations. These previous AQCDs reported clinical evidence that 

### 27

### Draft

– Do Not Cite or Quote 8

- 18 June 2012 children have greater spirometric responses to O 3 th an middle

- aged and older adults ( U.S. 

### 1

EPA, 1996a ) . Similar results were observed for symptomatic responses and O 3 exposure. 

### 2
Among older adults, most studies reported in the 2006 O 3 AQCD reported greater effects 

### 3

of short

- term O 3 exposure and mortality compared to other age groups ( U.S. EPA, 

### 4

2006b ) . Evidence published since the 2006 O 3 AQCD, summarized below, further 

### 5
supports these findings. 

### 6

8.3.1.1 Children

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

### 7
with 14.1% under the age of 10 ( SSDAN CensusScope, 2010a ) . Children’s respiratory 

### 8
systems are undergoing lung growth until about 18

- 20 years of age and are therefore 

### 9
thought to be intrinsically more at risk for O 3 - induced damage ( U.S. EPA, 2006b ) . It is 

### 10
generally recognized that children spend more time outdoors than adults, and therefore 

### 11

would be ex pected to have higher exposure to O 3 than adults. The ventilation rates also 

### 12
vary between children and adults, particularly during moderate/heavy activity. Children 

### 13
aged 11 years and older and adults have higher absolute ventilation rates than children 

### 14

age d 1

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

### 15
volumes, which tends to increase dose normalized to lung surface area. Exercise intensity 

### 16
has a substantial effect on ventilation rate, with high intensity activities res ulting in nearly 

### 17
double the ventilation rate during moderate activity among children and those adults less 

### 18
than 31 years of age. For more information on time spent outdoors and ventilation rate 

### 19
differences by age group, see Section 4.4.1

. 

### 20

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

### 21

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

### 22

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

- aged and older adults 

### 23

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

### 24
deep inspiration) to O 3 exposure, however, appear to increase with age until early 

### 25
adulthood and then gradually decrease with increasing age ( U.S. EPA, 1996a ) . For 

### 26
subjects aged 18

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

### 27

from O 3 exposure also decrease with increasing age. Complet e lung growth and 

### 28
development is not achieved until 18

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

### 29
men; pulmonary function is at its maximum during this time as well. Additionally, PBPK 

### 30
modeling reported lung regional extraction of O 3 to be higher in in fants compared to 

### 31
adults. This is thought to be due to the smaller nasal and pulmonary regions’ surface area 

### 32
in children under the age of 5 years compared to the total airway surface area observed in 

### 33

adults ( Sarangapani et al., 2003 )

. 

### 34

### Draft

– Do Not Cite or Quote 8

- 19 June 2012 Recent epidemiologic studies have examined different age groups and their risk to 

### 1

O 3 - related respiratory hospital admissions and ED visits. A study in Cyprus of short

- term 

### 2

O 3 concentrations and respiratory hospital admissions detected possible effect measure 

### 3
modification by age with a larger assoc iation among individuals <15 years of age 

### 4
compared with those >15 years of age. However, this difference was only apparent with a 

### 5

2

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

- eD visits 

### 6
reported the strongest O 3 - related associations among 5 to 14 year

- olds compared to the 

### 7
other age groups (ages examined 0

- 75+) ( Villeneuve et al., 2007 ) . Greater O 3 - associated 

### 8

risk in asthma

- related ED visits were also reported among children (<15 years) as 

### 9
compared to adults (15 to 64 years) in a study from Finland ( Halonen et al., 2009 ) . A 

### 10
study of New York City hospital admissions demonstrated an increase in the association 

### 11

between O 3 exposure and asthma

- related hospital admissions for 6 to 18 year

- olds 

### 12
compared to those <6 years old and those >18 years old ( Silverman and Ito, 2010 ) . When 

### 13
examining long

- term O 3 exposure and asthma hospital admissions among children, 

### 14
associations were determined to be larger among children 1 to 2 years old compared to 

### 15

chi ldren 2 to 6 years old ( Lin et al., 2008b ) . A few studies reported positive a ssociations 

### 16
among both children and adults and no modification of the effect by age. A study 

### 17
performed in Hong Kong examined O 3 exposure and asthma

- related hospital admissions 

### 18
for ages 0 to14, 15 to 65, and >65 ( Ko et al., 2007 ) . The researchers reported that the 

### 19
association was greater among the 0 to 14 and 14 to 65 age groups compared to the >65 

### 20
age group. Another study looking at asthma

- related ED visits and O 3 exposure in Maine 

### 21
reported positive associations for all age groups (ages 2 to 65) ( Paulu and Smith, 2008 )

. 

### 22

Effects of O 3 exposure on asthma hospitalizations among both children and adults (<18 

### 23

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

### 24
years of age) had statistically significa nt results at lag day 0, which the authors wrote, 

### 25

“suggests that children are more immediately responsive to adverse effects of O 3 

### 26

exposure” ( Mar and Koenig, 2009 )

. 

### 27

The evidence reported in epidemiologic studies is supported by recent toxicological 

### 28

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

### 29
exposures of multiple species of laboratory animals, including infa nt monkeys, resulted 

### 30
in changes in conducting airways at the cellular, functional, ultra

- structural, and 

### 31
morphological levels. Carey et al. (2007 ) conducted a study of O 3 exposure in infant 

### 32
rhesus macaques, whose respiratory tract closely resemble that of humans. Monkeys were 

### 33
exposed either acutely for 5 days to 0.5 ppm O 3 , or episodically for 5 biweekly cycles 

### 34
alternating 5 days of 0.5 ppm O 3 with 9 days of filtered air, designed to mimic human 

### 35

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

### 36
necrotizing rhinitis, with focal regions of epithelial exfoliation, numerous infiltrating 

### 37
neutrophils, and some eosinophils. The distribution, character, and severity of lesions in 

### 38
episodically exposed infant monkeys were similar to that of acutely exposed animals. 

### 39

### Draft

– Do Not Cite or Quote 8

- 20 June 2012 Neither exposure protocol for the infant monkeys produced mucous cell metaplasia 

### 1
proximal to the lesions, an adaptation observed in adult monkeys exposed continuously to 

### 2

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

### 3
resistance and responsiveness with antigen + O 3 co

- exposure) and cellular changes in 

### 4
conducting airways (increased numbers of inflammatory eosinophils) were common 

### 5
manifestations of exposure to O 3 among both the adult and infant monkeys ( Plopper et 

### 6

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

### 7

was stunted by O 3 and this aberrant development wa s persistent 6 months postexposure. 

### 8
This developmental endpoint was not, of course, studied in the adult monkey experiments 

### 9

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

### 10
between the infant and adult monkeys exposed to O 3 , but because the study de signs did 

### 11

not include concentration

- response experiments, it is not possible to determine whether 

### 12
the infant monkeys were more at risk for the effects of O 3

. 

### 13

Similarly, rat fetuses exposed to O 3 in utero had ultrastructural changes in bronchiolar 

### 14
epithelium when examined near the end of gestation ( López et al., 2008 ) . In addition, 

### 15
exposure of mice to mixtures of air pollutants early in development affected pup lung 

### 16
cytokine levels (TNF, IL

- 1, KC, IL

- 6, and MCP

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

### 17
of animals to PM augmented O 3 - induced airway hyper

- reactivity in these pups as 

### 18
juveniles. 

### 19

Age may affect the inflammatory response to O 3 exposure. In comparing neonatal mice to 

### 20
adult mice, increased bronchoalveolar lavage (BAL) neutrophils were observed in four 

### 21
strains of neonates 24 hours after exposure to 0.8 ppm O 3 for 5 hours ( Vancza et al., 

### 22

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

### 23
endpoints were not necessarily consistently correlated in a given strain. In some strains, 

### 24

however, adults were responsive , indicating a strain

- age interaction. Measurement of 18 O 

### 25

determined that the observed strain

- and age

- depen dent differences were not due to 

### 26

absorbed O 3 dose. Using electron microscopy, Bils (1970 ) studied the lungs of mice of 

### 27
different ages (4 days or 1 to 2 months) exposed to 0.6 to 1.3 ppm O 3 for 6 to 7 h/day for 

### 28
1 to 2 days and noted swelling of the alveolar epithelial lining cells without intra

- alveolar 

### 29
edema. Swelling of endothelial cells and o ccasional breaks in the basement membrane 

### 30
were observed. These effects were most evident in younger mice exposed for 2 days. 

### 31
Toxicological studies reported that the difference in effects among younger lifestage test 

### 32
animals may be due to age

- related change s in endogenous antioxidants and sensitivity to 

### 33
oxidative stress. A recent study demonstrated that 0.25 ppm O 3 exposure differentially 

### 34
altered expression of metalloproteinases in the skin of young (8 weeks old) and aged 

### 35

(18 months old) mice, indicating age

- related susceptibility to oxidative stress ( Fortino et 

### 36

al., 2007 )

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

### 37
plasma but less in their lungs compared to young mice, which may affect their pulm onary 

### 38

### Draft

– Do Not Cite or Quote 8

- 21 June 2012 antioxidant defenses. Servais et al. (2005 ) found high er levels of oxidative damage 

### 1
indicators in immature (3 weeks old) and aged (20 months old) rats compared to adult 

### 2
rats, the latter which were relatively resistant to an intermittent 7

- day exposure to 

### 3

0.5 ppm O 3 . Immature rats exhibited a higher ventilatio n rate, which may have increased 

### 4
exposure. Additionally, a series of toxicological studies reported an association between 

### 5

O 3 exposure and bradycardia that was present among young but not older mice ( Hamade 

### 6

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

. 

### 7
Regression analysis revealed an interaction between age and strain on heart rate, which 

### 8
implies that aging may affect heart rate differently among mouse strains ( Tankersley et 

### 9

al., 2010 ) . The authors pr oposed that the genetic differences between the mice strains 

### 10
could be altering the formation of ROS, which tends to increase with age, thus 

### 11
modulating the changes in cardiopulmonary physiology after O 3 exposure. 

### 12

The previous and recent human clinical and t oxicological studies reported evidence of 

### 13

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

### 14
biological plausibility for the findings from epidemiologic studies. Although there was 

### 15
some inconsistency, generally, the epidemiologi c studies reported larger associations for 

### 16
respiratory hospital admissions and ED visits for children than adults. The interpretation 

### 17
of these studies is limited by the lack of consistency in comparison age groups and 

### 18
outcomes examined. Toxicological studi es observed O 3 - induced health effects in 

### 19
immature animals, including infant monkeys, though the effects were not consistently 

### 20
greater in young animals than adults. However, overall, the epidemiologic, controlled 

### 21
human exposure, and toxicological studies pr ovide substantial and consistent evidence 

### 22
within and across disciplines. Therefore, there is adequate evidence to conclude that 

### 23
children are potentially at increased risk of O 3 - related health effects. 

### 24

8.3.1.2 Older Adults

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

### 25
a variety of intrinsic pathways. In addition, older adults may differ in their exposure and 

### 26
internal dose. Older adults were outdoors for a slightly longer proportion of the day than 

### 27
adults aged 18

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

### 28
adults aged 31

- less than 61 years. For more information on time spent outdoors and 

### 29
ventilation rate differences by age group, see Section 4.4.1 . The gradual decline in 

### 30
physiological processes that occur with aging may lead to increased risk of O 3 - related 

### 31

health effects ( U.S. EPA, 2006a ) . Respiratory symptom responses to O 3 exposure appears 

### 32
to increase with age until early adulthood and then gradually decrease wit h increasing age 

### 33

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

### 34

continued O 3 exposure and thus not seeking relief and avoiding exposure. In addition, 

### 35

### Draft

– Do Not Cite or Quote 8

- 22 June 2012 older adults, in general, have a higher prevalence of preexisting diseases, with the 

### 1
exception of asthma, compared to younger age groups and this may also lead to increased 

### 2

risk of O 3 - related health effects (see Table 8

- 3 that gives preexisting rates by age).With 

### 3
the number of older Americans increasing in upcoming years (estimated to increase from 

### 4
12.4% of the U.S. population to 19.7% between 2000 to 2030, which is approximately 

### 5

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

### 6
population potentially at risk of O 3 - related health effects ( SSDAN CensusScope, 2010a ; 

### 7

U.S. Census Bureau, 2010 )

. 

### 8

The majority of recent studies reported greater effects of short

- term O 3 exposure and 

### 9
mortality among older adults, which is consistent with the findings of the 2006 O 3 

### 10
AQCD. A study conducted in 48 cities across the U.S. reported larger effects among 

### 11

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

- Ramón and Schwartz, 2008 )

. 

### 12
Further investigation of this study population re vealed a trend of O 3 - related mortality risk 

### 13
that gets larger with increasing age starting at age 50 ( Zanobetti and Schwartz, 2008a ) . A 

### 14
study of 7 urban centers in Chile reported similar results, with greater effects in adults 

### 15

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

### 16

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

### 17
conducted in the same area reported similar associat ions between O 3 exposure and 

### 18
mortality in adults aged <64 years old and 65 to 74 years old, but the risk was increased 

### 19
among older age groups ( Cakmak et al., 2011 ) . A study performed in China reported 

### 20
greater effects in populations ≥ 45 years old (compared to 5 to 44 year

- olds), with 

### 21
statistically significa nt effe cts present only among those ≥ 65 years old ( Kan et al., 2008 )

. 

### 22
An Italian study reported higher risk of all

- cause mortality associ ated with increased O 3 

### 23
concentrations among individuals ≥ 85 years old as compared to those 35 to 84 years old. 

### 24

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

### 25

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

### 26
European and North American Approach (APHENA) project examined the association 

### 27

between O 3 exposure and mortality for those <75 and ≥ 75 years of age. In Canada, the 

### 28

associations for all

- cause and cardiovascular mortality were greater among those 

### 29

≥ 75 years old in the summer

- only and all

- year analyses. Age groups were not compared 

### 30
in the analysis for respiratory mortality in Canada. In the U.S., the association for 

### 31

all

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

### 32
years old in summer

- only analyses. No consistent pattern was observed for CVD 

### 33
mortality. In Europe, slightly larger associations for all

- c ause mortality were observed in 

### 34
those <75 years old in all

- year and summer

- only analyses. Larger associations were 

### 35
reported among those <75years for CVD mortality in all

- year analyses, but the reverse 

### 36

was true for summer

- only analyses ( Katsouyanni et al., 2009 )

. 

### 37

### Draft

– Do Not Cite or Quote 8

- 23 June 2012 Multiple epidemiologic studies of O 3 exposure and hospital admissions were stratified by 

### 1
age groups. A positive association was reported between short

- term O 3 exposure and 

### 2
respiratory hospital admissions for adult s ≥ 65 years old but not for those adults aged 15 

### 3

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

### 4

between O 3 concentration and respiratory mortality among those ≥ 65 years old or those 

### 5

15 to 64 years old; however, an inverse association between O 3 concentration and 

### 6
cardiovascular mortality was present among individuals ≥ 65 years old but not among 

### 7

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

### 8

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

- related 

### 9
hospital visits in Bangkok, Thailand reported an increase in percent change for hospital 

### 10
visits with previous day and cumulative 2

- day O 3 levels among those ≥ 65 years old, 

### 11

w hereas no association was present for individuals less than 65 years of age ( Bu adong et 

### 12

al., 2009 ) . No association was observed for current day or cumulative 3

- day averages in 

### 13
any age group. A study examining O 3 and hospital admissions for CVD

- related health 

### 14
effects reported no association for individuals aged 15 to 64 or individu als aged ≥ 65 

### 15
years, although one lag

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

### 16
elderly that was not present among 15 to 64 year

- olds ( Halonen et al., 2009 ) . However, as 

### 17

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

### 18
and often null so it is plausible that no association would be observed regardless of a ge. 

### 19
No modification by age (40 to 64 year

- olds versus >64 years old) was observed in a study 

### 20
from Brazil examining O 3 levels and COPD ED visits ( Arbex et al., 2009 )

. 

### 21

Biological plausibility for differences by age is provided by toxicological studies. O 3 

### 22
exposure resulted in an increase in left ventricular chamber dimen sions at end diastole 

### 23
(LVEDD) in young and old mice, whereas decreases in left ventricular posterior wall 

### 24
thickness at end systole (PWTES) were only observed among older mice ( Tankersley et 

### 25

al., 2010 ) . Other toxicological studies also indicate increased ris k in older animals for 

### 26
additional endpoints, including neurological and immune. The hippocampus, one of the 

### 27
main regions affected by age

- related neurodegenerative diseases, may be more sensitive 

### 28
to oxidative damage in aged rats. In a study of young (47 day s) and aged (900 days) rats 

### 29
exposed to 1 ppm O 3 for 4 hours, O 3 - induced lipid peroxidation occurred to a greater 

### 30
extent in the striatum of young rats, whereas it was highest in the hippocampus in aged 

### 31

rats ( Rivas

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

### 32
significa ntly affected by O 3 exposure ( Lim et al., 2006 ) . However, exposure to 0.5 ppm 

### 33

O 3 for 6 h/day significa ntly delays wound closure in aged mice. 

### 34

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

### 35
adults, recent epidemiologic studies report consistent positive associations between short



### 36

term O 3 exposure and mortality in older adults. The evidence fr om mortality studies is 

### 37
consistent with the results reported in the 2006 O 3 AQCD and is supported by 

### 38

### Draft

– Do Not Cite or Quote 8

- 24 June 2012 toxicological studies providing biological plausibility for increased risk of effects in older 

### 1
adults. Also, older adults may be experiencing increased exp osure compared to younger 

### 2
adults. Overall, adequate evidence is available indicating that older adults are potentially 

### 3

at increased risk of O 3 - related health effects based on the substantial and consistent 

### 4
evidence within epidemiologic studies on O 3 exposure and mortality and the coherence 

### 5
with toxicological studies. 

### 6

8.3.2 Sex

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

### 7
population was male and 50.9% were female. However, this distribution does vary by age 

### 8

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

### 9

CensusScope, 2010a ) . The 2006 O 3 AQCD did not report evidence of differences 

### 10
between the sexes in health responses to O 3 exposure ( U.S. EPA, 2006b ) . Recent 

### 11
epidemiologic studies have evaluated the effects of short

- term and long

- term exposure to 

### 12

O 3 on multiple health endpoints stratifi ed by sex. 

### 13

A study in Maine that examined short

- term O 3 concentrations and asthma ED visits 

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

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

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

### 17
reported no associations between sh ort

- term O 3 and respiratory infection hospital 

### 18
admissions for either boys or girls under the age of 15 ( Lin et al., 2005 ) , whereas another 

### 19
Canadian study reported a slightly higher but non

- statistically significa nt increase in 

### 20
respiratory hospital admissions for males (mean ages 47.6 to 69.0 years) ( Cakmak et al., 

### 21

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

### 22
effect measure modification by sex for overall respiratory disease hospital admissions, 

### 23
but did detect a greater excess risk of hospital admissions for COPD among females 

### 24
compared to males ( Wong et al., 2009 ) . Similarly a study in Brazil found higher effect 

### 25
estimates for COPD ED visits among females compared to males ( Arbex et al., 2009 )

. 

### 26
Higher levels of respiratory hospital admissions with greater O 3 concentrations was also 

### 27
observed for females in a study of individuals living in Cyprus ( Middle ton et al., 2008 )

. 

### 28
A study of lung function unrelated to hospital admissions and ED visits was conducted 

### 29
among lifeguards in Texas and reported decreased lung function with increased O 3 

### 30
exposure among females but not males ( Thaller et al., 2008 ) . This study included 

### 31
individuals aged 16 to 27 years, and the majority of participants were male. A New York 

### 32
study found no evidence of effect measure modification of the association between 

### 33
long

- term O 3 exposure and asthma hospital admissions among males and females 

### 34

between 1 and 6 years old ( Lin et al., 2008b )

. 

### 35

### Draft

– Do Not Cite or Quote 8

- 25 June 2012 In addition to examining the potential modification of O 3 associations with respiratory 

### 1
outcomes by sex, studies also examined cardiovascular

- related outcomes specifica lly 

### 2
hospital admissions and ED visits. All of these studies reported no effect modification by 

### 3
sex with some studies reporting null associations for both males and females ( Wong et 

### 4

al., 2009 ; Middleton et al., 2008 ; Villeneuve et al., 2006a ) and one study rep orting a 

### 5
positive associations for both sexes ( Cakmak et al., 2006a ) . A French study examining 

### 6

the associations between O 3 concentrations and risk of ischemic strokes (not limited to 

### 7
ED visits or hospital admissions) reported no association for either m ales or females with 

### 8
lags of 0, 2, or 3 days ( Henrotin et al., 2007 ) . A positive association was reported for 

### 9
males with a lag of 1 day, but this association was null for females. The authors noted 

### 10
that men in the study had much higher rates of current and former smoking than women 

### 11
(67.4% versus 9.3%). Additionally, cardiovascular hospital admissions and ED visits 

### 12

overall have demonst rated inconsistent and null results (Section 6.3.2.7 ). The lack of 

### 13
effect measure modification by sex may be indicative of the lack of association, not the 

### 14

lack of effect of sex. 

### 15

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

- sensitivity 

### 16

C

- reactive protein (hs

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

### 17
observations for various lag times ranging from 0 to 7 days ( Steinvil et al., 2008 ) . Most 

### 18

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

### 19
and fibrinogen was positive for males and null for females (lag day 4); however, this 

### 20
positive association was null or negative when other pollutants were included in the 

### 21
model. One study examining correlations between O 3 levels and oxidative DNA damage 

### 22
examined results stratified by sex. In this study Palli et al. (2009 ) reported stronger 

### 23
correlations for males than females, both during short

- term exposure (less than 30 days) 

### 24
and long

- ter m exposure (0

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

### 25

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

### 26
traffic pollution at work. 

### 27

A few studies have examined the association between short

- term O 3 concentra tions and 

### 28
mortality stratified by sex and, in contrast with studies of other endpoints, were more 

### 29
consistent in reporting elevated risks among females. These studies, conducted in the 

### 30

U.S. ( Medina

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

### 31

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

### 32
study, the elevated risk of mortality among females was greater specifically among those 

### 33

≥ 60 years old ( Medina

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

### 34
reported similar associations between O 3 exposure and mortality among both men and 

### 35

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

- term O 3 exposure study of respiratory mortality 

### 36
stratified their results by sex and reported relative risks of 1.01 (95% CI: 0.99, 1.04) for 

### 37

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

. 

### 38

### Draft

– Do Not Cite or Quote 8

- 26 June 2012 Experimental research provided a further understanding of the underlying mechanisms 

### 1
that may explain a possible differential risk in O 3 - related health effects among males and 

### 2
females. Several studies have suggested that physiological differences between sexes 

### 3
may predispose females to greater ef fects from O 3 . In females, lower plasma and nasal 

### 4
lavage fluid (NLF) levels of uric acid (most prevalent antioxidant), the initial defense 

### 5

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

. 

### 6
Consequently, reduced absorption of O 3 in the upper airways of females may promote i ts 

### 7
deeper penetration. Dosimetric measurements have shown that the absorption distribution 

### 8

of O 3 is independent of sex when absorption is normalized to anatomical dead space 

### 9

( Bush et al., 1996 ) . Thus, a differential re moval of O 3 by uric acid seems to be minimal. 

### 10
In general, the physiologic response of young healthy females to O 3 exposure appears 

### 11
comparable to the response of young males ( Hazucha et al., 2003 ) . A few studies have 

### 12
examined changes in O 3 responses during various menstrual cycle phase s. Lung function 

### 13

response to O 3 was enhanced during the follicular phase of the menstrual cycle compared 

### 14
to the luteal phase in a small study of women ( Fox et al., 1993 ) . However, Seal et al. 

### 15

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

### 16
from 150 women, but conceded that the methods used by Fox et al. (1993 ) more precisely 

### 17

de fined the menstrual cycle phase. Another study also reported no difference in responses 

### 18
among females during the follicular and luteal phases of their cycle ( Weinmann et al., 

### 19

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

### 20
reported for men in the study. In a toxicological study, small differences in effects by sex 

### 21
were seen in adult mice with respect to pulmonary inflammation and injury after a 5

- h 

### 22

exposure to 0.8 ppm O 3 , and although adult females were generally more at risk, these 

### 23

differences were strain

- dependent, with some strains exhibiting greater risk in males 

### 24

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

### 25

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

### 26

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

### 27
effects present for females in some studies and males in other studies. Most studies 

### 28
examining the associations O 3 and mortality report females to be at greater risk than 

### 29
males, but minimal evidence is available regarding a difference between the sexes for 

### 30
other outcomes. Inconsistent findings were repo rted on whether effect measure 

### 31
modification exists by sex for respiratory and cardiovascular hospital admissions and ED 

### 32
visits, although there is some indication that females are at increased risk of O 3 - related 

### 33
respiratory hospital admissions and ED visits . While O 3 - related effects may occur in both 

### 34
men and women, there is suggestive evidence exists indicating that females are at 

### 35
potentially increased risk of O 3 - related health effects as there are consistent findings 

### 36
among epidemiologic studies of mortality

. 

### 37

### Draft

– Do Not Cite or Quote 8

- 27 June 2012 8.3.3 Socioeconomic Status

SES is often represented by personal or neighborhood SES, which is comprised of a 

### 1
variety of components such as educational attainment, household income, health 

### 2

insurance status, and other such factors. SES is often indicative of s uch things as access 

### 3
to healthcare, quality of housing, and pollution gradient to which people are exposed. 

### 4
One or a combination of these components could modify the risk of O 3 - related health 

### 5

effects. Based on the 2000 Census data, 12.4% of Americans live in poverty (poverty 

### 6
threshold for family of four was $17,463) ( SSDAN CensusScope, 2010c ) . Althou gh 

### 7
included below, studies stratifying by SES that are conducted outside the U.S. may not be 

### 8
comparable to those studies from within the U.S. Having low SES in another country 

### 9
may be different than having low SES in the U.S. based on SES definitions, popul ation 

### 10
composition, and/or conditions in that country. 

### 11

Multiple epidemiologic studies have reported individuals of low SES to have increased 

### 12

risk for the effects of short

- term O 3 exposure on respiratory hospital admissions and ED 

### 13

visits. In New York State, larger associations between long

- term O 3 exposure and asthma 

### 14
hospital admissions were observed among children of mothers who did not graduate from 

### 15
high school, whose births were covered by Medicaid/self

- paid, or who were living in 

### 16
poor neighborhoods compa red to children whose mothers graduated from high school, 

### 17
whose births were covered by other insurance, or who were not living in poor 

### 18
neighborhoods, respectively ( Lin et al., 2008b ) . In addition, a study conducted across 10 

### 19
cities in Canada found the largest association between O 3 exposure and respiratory 

### 20
hospital admissions was a mong those with an educational level less than grade 9, but no 

### 21
consistent trend in the effect was seen across quartiles of income ( Cakmak et al., 2006b )

. 

### 22
A Canadian study reported inverse effects of O 3 on respiratory hospital admissions and 

### 23
ED visits for all levels of SES, measured by average census tract household income 

### 24

( Burra et al., 2009 ) . A study performed in Korea examined the association between O 3 

### 25
concentrations and asthma hospital admissions and reported larger effect estimates in 

### 26
areas of moderate and low SES compared with areas of high SES (SES was based on 

### 27
average regional insurance rates) ( Lee et al., 2006 )

. 

### 28

The examination of the potential effects of SES on O 3 - related cardiovascular health 

### 29

ef fects is relatively limited. A study conducted in Canada reported the association 

### 30

between short

- term O 3 and ED visits for cardiac disease by quartiles of 

### 31
neighborhood

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

### 32

for either measur e of SES ( Cakmak et al., 2006a ) . However, this may be due to the lack 

### 33
of association present between O 3 and ED visits for cardiac disease regardless of SES. 

### 34

Several studies were conducted that examined the modification of the relationship 

### 35

between short

- term O 3 concentrations and mortality by SES. A U.S. multicity study 

### 36

### Draft

– Do Not Cite or Quote 8

- 28 June 2012 reported that communities with a higher proportion of the population unemployed had 

### 1
higher O 3 - related mortality effect estimates ( Bell and Dominici, 2008 ) . A study in seven 

### 2
urban centers in Chile reported on modification of the association between O 3 exposure 

### 3
and mortality using multipl e SES markers ( Cakmak et al., 2011 ) . Increased risk was 

### 4
observed among the categories of low SES for all measures (personal educational 

### 5
attainment, personal occupation, community income level). Additionally, the APHENA 

### 6
study, which examined the association between O 3 and mortality by percentage 

### 7
unemployed, reported a higher percent change in mortality wit h increased percent 

### 8
unemployed but this varied across the regions included in the study (U.S., Canada, 

### 9

Europe) ( Katsouyanni et al., 2009 ) . A Chinese study reported that the greatest effects 

### 10

between O 3 concentrations and m ortality at lag day 0 were among individuals living in 

### 11
areas of high social deprivation (i.e., low SES), but this association was not consistent 

### 12
across lag days (at other lag times, the middle social deprivation index category had the 

### 13
greatest association) ( Wong et al., 2008 ) . However, another study in Asia comparing low 

### 14
to high educational attainment populations reported no evidence of greater mortality 

### 15
effects (total, CVD, or respiratory) ( Kan et al., 2008 ) . Additionally, a study in Italy 

### 16
reported no difference in risk of mortality among census

- block level derived income 

### 17

levels ( Stafoggia et al., 2010 ) . A study of infant mortality in Mexico reported no 

### 18

association between O 3 concentrations and infant mortality among any of the three levels 

### 19
of SES determined using a socioeconomic index based on residential areas ( Romieu et 

### 20

al. , 2004a ) . Another study in Mexico reported a positive association between O 3 levels at 

### 21
lag 0 and respiratory

- related infant mortality in only the low SES group (determined 

### 22

based on education, income, and household conditions across residential areas), b ut no 

### 23
association was observed in any of the SES groups with other lags ( Carbajal

- Arroyo et 

### 24

al., 2011 )

. 

### 25

Studies of O 3 concentrations and reproductive outcomes have also examined associations 

### 26
by SES levels. A study in C alifornia reported greater decreases in birth weight associated 

### 27
with full pregnancy O 3 concentration for those with neighborhood poverty levels of at 

### 28
least 7% compared with those in neighborhoods with less than 7% poverty (the authors 

### 29
do not provide inform ation on how categories of the SES variable were determined) 

### 30

( Morello

- Frosch et al., 2010 ) . No dose response was apparent and those with 

### 31
neighb orhood poverty levels of 7

- 21% had greater decreases observed for the association 

### 32
than those living in areas with poverty rates of at least 22%. An Australian study reported 

### 33

an inverse association between O 3 exposure during days 31

- 60 of gestation and 

### 34

abdo minal circumference during gestation ( Hansen et al., 2008 ) . The interaction with 

### 35

SES (area

- level measured socioeconomic disadvantage) was examined and although the 

### 36
inverse association remained statistically significa nt in only the highest SES quartile, 

### 37
there were large confidence interval overlaps among estim ates for each quartile so no 

### 38
difference in the association for the quartiles was apparent. 

### 39

### Draft

– Do Not Cite or Quote 8

- 29 June 2012 Evidence from a controlled human exposure study that examined O 3 effects on lung 

### 1
function does not provide support for greater O 3 - related health effects in individuals of 

### 2

lower SES. In a follow

- up study ( Seal et al., 1993 ) on modification by race, Seal et al. 

### 3

(1996 ) reported that, of three SES categories, individuals in the middle SES category 

### 4

showe d greater concentration

- dependent decline in percent

- predicted FEV 1 (4

- 5% at 

### 5

400 ppb O 3 ) than in low and high SES groups. The authors did not have an “immediately 

### 6
clear” explanation for this finding and controlled human exposure studies are typically 

### 7

not d esigned to answer questions about SES. 

### 8

Overall, most studies of individuals have reported that individuals with low SES and 

### 9
those living in neighborhoods with low SES are more at risk for O 3 - related health effects

, 

### 10
resulting in increased risk of respirato ry hospital admissions and ED visits. Inconsistent 

### 11
results have been observed in the few studies examining effect modification of 

### 12

associations between O 3 exposure and mortality and reproductive outcomes. Also, a 

### 13
controlled human exposure study does not sup port evidence of increased risk of 

### 14
respiratory morbidity among individuals with lower SES. Overall, evidence is suggestive 

### 15
of SES as a factor affecting risk of O 3 - related health outcomes based on collective 

### 16
evidence from epidemiologic studies of respirator y hospital admissions but inconsistency 

### 17
among epidemiologic studies of mortality and reproductive outcomes. Further studies are 

### 18
needed to confirm this relationship, especially in populations within the U.S. 

### 19

8.3.4 Race/Ethnicity

Based on the 2000 Census, 69.1% of the U.S. population identified as non

- Hispanic 

### 20
whites. Approximately 12.1% of people reported their race/ethnicity as non

- Hispanic 

### 21
black and 12.6% reported being Hispanic ( SSDAN CensusScope, 2010b )

. 

### 22

Only a few studies examined the associations between short

- term O 3 concentrations and 

### 23
mortality and reported higher effect estimates among blacks ( Medina

- Ramón and 

### 24

Schwartz, 2008 ) and among communities with larger proportions of blacks ( Bell and 

### 25

Dominici, 2008 ) . Another study examined long

- term exposure to O 3 concentrations and 

### 26
asthma hospital admissions among children in Ne w York State. These authors reported 

### 27
no statistically significa nt difference in the odds of asthma hospital admissions for blacks 

### 28
compared to other races but did detect higher odds for Hispanics compared to 

### 29

non

- Hispanics ( Lin et al., 2008b )

. 

### 30

Additionally, recent epidemiologic studies have stratified by race when examining the 

### 31

asso ciation between O 3 concentration and birth outcomes. A study conducted in Atlanta, 

### 32
GA reported decreases in birth weight with increased third trimester O 3 concentrations 

### 33
among Hispanics but not among non

- Hispanic whites ( Darrow et al., 2011b ) . An inverse 

### 34

### Draft

– Do Not Cite or Quote 8

- 30 June 2012 association was also present for non

- Hispanic blacks but was not statistically significa nt. 

### 1
A California study reported that the greatest decrease in birth weight associated with full 

### 2

pregnancy O 3 concentration was among non

- Hispanic whites ( Morello

- Frosch et al., 

### 3

2010 ) . This inverse association was also apparent, although not as strong, for Hispanics 

### 4

and non

- Hispanic blacks. Increased birth weight was asso ciated with higher O 3 exposure 

### 5

among non

- Hispanic Asians and Pacific Islanders but these results were not statistically 

### 6
significa nt. 

### 7

Similar to the epidemiologic studies, a controlled human exposure study suggested 

### 8
differences in lung function responses by race ( Seal et al., 1993 ) . The independent effects 

### 9

of sex

- race group and O 3 concentration on lung function were positive, but the interaction 

### 10

between sex

- race group and O 3 concentration was not statistically significa nt. The 

### 11
findings indicated some overall differen ce between the sex

- race groups that was 

### 12
independent of O 3 concentration (the concentration

- response curves for the four sex

- race 

### 13
groups are parallel). In a multiple comparison procedure on data collapsed across all O 3 

### 14

concentrations for each sex

- race group , both black men and black women had larger 

### 15

decrements in FEV 1 than did white men. The authors noted that the O 3 dose per unit of 

### 16
lung tissue would be greater in blacks and females than whites and males, respectively. 

### 17

That this difference in tissue dose mi ght have affected responses to O 3 cannot be ruled 

### 18
out. The college students recruited for the Seal et al. (1993 ) study were probably from 

### 19
better educated and more SES advantaged families, thus reducing potential for these 

### 20
variables to be confounding f actors. Que et al. (2011 ) also examined pulmonary 

### 21

responses to O 3 exposure in blacks of African American ancestry and in whites. On 

### 22
average, the black males experienced the greatest decrements in FEV 1 following O 3 

### 23
exposure. This decrease was larger than the decrement observed among black females, 

### 24

white males, and white females. 

### 25

Overall, the results of recent studies indicate that there may be race

- related increase in 

### 26

risk of O 3 - related health effects for some outc omes, although the overall understanding of 

### 27
potential effect measure modification by race is limited by the small number of studies. 

### 28
Additionally, these results may be confounded by other factors, such as SES. Overall, 

### 29
evidence is inadequate to determine i f O 3 - related health effects vary by race because of 

### 30
the insufficient quantity of studies and lack of consistency within disciplines. 

### 31

### Draft

– Do Not Cite or Quote 8

- 31 June 2012 

## 8.4 Behavioral and Other Factors

8.4.1 Diet

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

### 1

re cent studies have examined modification of the association between O 3 and health 

### 2
effects by dietary factors. Because O 3 mediates some of its toxic effects through oxidative 

### 3
stress, the antioxidant status of an individual is an important factor that may con tribute to 

### 4

increased risk of O 3 - related health effects. Supplementation with Vitamins C and E has 

### 5
been investigated in a number of studies as a means of inhibiting O 3 - mediated damage. 

### 6

Epidemiologic studies have examined effect measure modification by diet and found 

### 7
evidence that certain dietary components are related to the effect O 3 has on respiratory 

### 8
outcomes. In a recent study the effects of fruit/vegetable intake and Mediterranean diet 

### 9

was examined ( Romieu et al., 2009 ) . Increases in these food patterns, which have been 

### 10
noted for their high Vitamins C and E and omega

- 3 fatty acid content, protected against 

### 11

O 3 - related dec reases in lung function among children living in Mexico City. Another 

### 12
study examined supplementation of the diets of asthmatic children in Mexico with 

### 13

Vitamins C and E ( Sienra

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

### 14

short

- term O 3 exposure and nasal air way inflammation among children in the placebo 

### 15
group but not in those receiving the supplementation. The authors concluded that 

### 16
“Vitamin C and E supplementation above the minimum dietary requirement in asthmatic 

### 17
children with a low intake of Vitamin E migh t provide some protection against the nasal 

### 18
acute inflammatory response to ozone.” 

### 19

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

### 20
have shown that the first line of defense against oxidative stress is antioxidants

- rich 

### 21

e xtracellular lining fluid (ELF) which scavenge free radicals and limit lipid peroxidation. 

### 22

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

### 23

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

### 24
enzymes either in ELF or plasma do not appear to be related to O 3 responsiveness 

### 25

(e.g., pulmonary function and inflammation) ( Samet et al., 2001 ; Avissar et al., 2000 ; 

### 26
Blomberg et al., 1999 ) . Carefully controlled studies of dietary antioxidant 

### 27
supplementation have demonstrated some protective effects of α

- tocopherol (a form of 

### 28
Vitamin E) and ascorbate (Vitamin C) on spirometric measures of lung function after O 3 

### 29
exposure but not on the intensity of subjective symptoms and inflammatory response 

### 30
including cell recruitment, activation and a release of mediators ( Samet et al., 2001 ; 

### 31
Trenga et al., 2001 ) . Dietary antioxidants have also afforded partial protection to 

### 32

### Draft

– Do Not Cite or Quote 8

- 32 June 2012 asthmatics by attenuating postexposure bronchial hyperresponsiveness ( Tre nga et al., 

### 1

2001 )

. 

### 2

Toxicological studies provide evidence of biological plausibility to the epidemiologic and 

### 3
controlled human exposure studies. Wagner et al. (2009 ); ( 2007 ) found reductions in 

### 4

O 3 - exacerbated nas al allergy responses in rats with γ

- tocopherol treatment (a form of 

### 5

Vitamin E). O 3 - induced inflammation and mucus production were also inhibited by 

### 6

γ

- tocopherol. Supplementation with Vitamins C and E partially ameliorated 

### 7

inflammation, oxidative stress, and airway hyperresponsiveness in guinea pigs exposed 

### 8
subchronically to 0.12 ppm O 3 ppm ( Chhabra et al., 2010 ) . Inconsistent results were 

### 9
observed in other toxicological studies of Vitamin C deficiency and O 3 - induced 

### 10
responses. Guinea pigs deficient in Vitamin C displayed only minimal injury and 

### 11
inflammation after exposure to O 3 ( Kodavanti et al., 1995 ) . A recent study in mice 

### 12
demonstrated a protective effect of β

- carotene in the skin, where it limited the production 

### 13
of proinflammatory markers a nd indicators of oxidative stress induced by O 3 exposure 

### 14

( Valacchi et al., 2009 ) . Deficiency of Vitamin A, which has a role in regulating the 

### 15
maintenance and repair of the epithelial layer, particularly in the lung, appears to enhance 

### 16

the risk of O 3 - induced lung injury ( Paquette et al., 199 6 ) . Differentially susceptible 

### 17

mouse strains that were fed a Vitamin A sufficient diet were observed to have different 

### 18
tissue concentrations of the vitamin, potentially contributing to their respective 

### 19

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

### 20
toxicological study examined protein deficiency. Protein deficiency alters the levels of 

### 21
enzymes and chemicals in the brain of rats involved with redox status; exposure to 

### 22

0.75 ppm O 3 has been shown to differentially affect Na + /K + ATPase, glutathione, and 

### 23
lipid peroxidation, depending on the nutritional status of the animal, but the significa nce 

### 24
of these changes is unclear ( Calderón Guzmán et al., 2006 ) . There may be a protective 

### 25

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

### 26

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

. 

### 27

There is adequate evidence that individuals with reduced intake of Vitamins E and C are 

### 28
potentially at risk for O 3 - related health effects based on substantial, consistent evidence 

### 29
both within and among disciplines. The evidence from epidemiologic studies i s supported 

### 30
by controlled human exposure and toxicological studies. 

### 31

8.4.2 Obesity

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

### 32

the U.S., with self

- reported rates of obesity of 26.7% in 2009, up from 19.8% in 2000 

### 33

### Draft

– Do Not Cite or Quote 8

- 33 June 2012 ( Sherry et al., 2010 ) . BMI may affect O 3 - related health effects through multiple avenues, 

### 1
such as, inflammation in the body, incre ased preexisting disease, and poor diet. 

### 2

A few studies have been performed examining the association between BMI and 

### 3

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

### 4

function with increased short

- term O 3 exposure for both obese and non

- obese subjects; 

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

### 6

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

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

### 8

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

### 9
a retrospective analysis of data from 541 healthy, nonsmoking, white males between the 

### 10
ages of 18

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

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

### 12

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

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

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

### 15

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

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

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

### 18

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

### 19
compared to normal weight (BMI from 18.5 to 25), and in normal weight compared to 

### 20
underweight (BMI <18.5). Even disregarding the five underweight women, a greater O 3 

### 21
response in the overweight/obese category (BMI >25) was observed compared with the 

### 22
normal weight group (BMI from 18.5 to 24.9). 

### 23

Studies in genetically and dietarily obe se mice have shown enhanced pulmonary 

### 24
inflammation and injury with acute O 3 exposure, but responses to longer exposures at a 

### 25

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

### 26

resistant to O 3 - induced pulmonary injury an d inflammation and reduced lung compliance 

### 27
following exposure to 0.3 ppm O 3 for 72 hours, regardless of whether obesity was 

### 28
genetic

- or diet

- induced ( Shore et al., 2009 )

. 

### 29

Multiple epidemiologic, human clinical, and toxicological studies have reported 

### 30
suggestive evidence for increased O 3 - related respiratory health effects among obese 

### 31
individuals. Future research of the effect modification of the relationship between O 3 and 

### 32

o ther health

- related outcomes besides respiratory health effects by BMI and studies 

### 33
examining the role of physical conditioning will advance understanding of obesity as a 

### 34
factor potentially increasing an individual’s risk. 

### 35

### Draft

– Do Not Cite or Quote 8

- 34 June 2012 8.4.3 Smoking

Previous O 3 AQCDs have co ncluded that smoking does not increase the risk of O 3 - related 

### 1
health effects; in fact, in controlled human exposure studies, smokers have been found to 

### 2
be less responsive to O 3 than non

- smokers. Data from recent interviews conducted as part 

### 3

of the 2008 Nat ional Health Interview Survey (NHIS) ( Pleis e t al., 2009 ) have shown the 

### 4
rate of smoking among adults ≥ 18 years old to be approximately 20% in the U.S. 

### 5
Approximately 21% of individuals surveyed were identified as former smokers. 

### 6

Baccarelli et al. (2007 ) performed a study of O 3 concentrations and plasma homocysteine 

### 7
levels (a risk factor for vascular disease). They found no interaction of smoking (smokers 

### 8

versus non

- smokers) for the associations between O 3 concentrations and plasma 

### 9
homocysteine levels. Another study examined the association between O 3 and resting 

### 10
heart rate and also reported no interaction with smoking status (current s mokers versus 

### 11

current non

- smokers) ( Ruidavets et al., 2005a )

. 

### 12

A study examining correlations between O 3 le vels and oxidative DNA damage examined 

### 13
results stratified by current versus never and former smokers ( Palli et al., 2009 ) . Ozone 

### 14
was positively associated with DNA damage for short

- term and long

- term exposures 

### 15
among never/former smokers. For current smokers, short

- term O 3 concentrations were 

### 16
inversely associated with DNA damage; however, the number of current smokers in the 

### 17
study was small (n = 12). 

### 18

The findings of Palli et al. (2009 ) were consistent with those from controlled human 

### 19
exposure studies that have confirmed that smokers are less responsive to O 3 exposure 

### 20

than non

- smokers. Spirometric and plethysmographic pulmonary function decline, 

### 21
nonspecific AHR, and inflammatory responses of smokers to O 3 ex posure were all 

### 22
weaker than those reported for non

- smokers. Similarly, the time course of development 

### 23
and recovery from these effects, as well as their reproducibility, was not different from 

### 24

non

- smokers. Chronic airway inflammation with desensitization of bronchial nerve 

### 25
endings and an increased production of mucus may plausibly explain the 

### 26
pseudo

- protective effect of smoking ( Frampton et al., 1997a ; Torres et al., 1997 )

. 

### 27

These findings for smoking are consistent with the conclusions from previous AQCDs. 

### 28
An epidemiologic study of O 3 - associated DNA damage reported smokers to be less at 

### 29

risk for O 3 - related health effects. In addition, both epidemiolog ic studies of short

- term 

### 30
exposure and CVD outcomes found no evidence of effect measure modification by 

### 31
smoking. No toxicological studies provide biological support for O 3 - related effects. 

### 32
Overall, evidence of potential differences in O 3 - related health effe cts by smoking status is 

### 33
inadequate due to insufficient coherence and a limited number of studies. 

### 34

### Draft

– Do Not Cite or Quote 8

- 35 June 2012 8.4.4 Outdoor Workers

Studies included in the 2006 O 3 AQCD reported that individuals who participate in 

### 1
outdoor activities or work outside to be a population at in creased risk based on 

### 2
consistently reported associations between O 3 exposure and respiratory health outcomes 

### 3
in these groups ( U.S. EPA, 2006b ) . Outdoor workers are exposed to ambient O 3 

### 4
concentrations for a greater period of time than individuals who spend their days indoors. 

### 5

As discussed in Section 4.3.3 of this ISA, outdoor workers sampled during the work shift 

### 6
had a higher ratio of personal exposure to fixed

- site monitor concentrations than health 

### 7

clinic work ers who spent most of their time indoors. Additionally, an increase in dose to 

### 8
the lower airways is possible during outdoor exercise due to both increases in the amount 

### 9

of air breathed (i.e., minute ventilation) and a shift from nasal to oronasal breathing 

### 10

( Sawyer et al., 2007 ; Nodelman and Ultman , 1999 ; Hu et al., 1994 ) . For further 

### 11

discussion of the association between FEV 1 responses to O 3 exposure and minute 

### 12

ventilation, refer to Section 6.2.3.1 of th e 2006 O 3 AQCD. A recent study has explored 

### 13
the potential effect measure modification of O 3 exposure and DNA damage by 

### 14

indoor/outdoor workplace ( Tovalin et al., 2 006 ) . In a study of indoor and outdoor 

### 15

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

### 16

association between O 3 exposure and DNA damage (measured by comet tail length 

### 17
assay), whereas no association was observed for indoor wo rkers. However, workers in 

### 18
another Mexican city, Puebla, demonstrated no association between O 3 levels and DNA 

### 19
damage, regardless of whether they worked indoors or outdoors. 

### 20

Previous studies have shown that increased exposure to O 3 due to outdoor work leads to 

### 21

increased risk of O 3 - related health effects, specifically decrements in lung function ( U.S. 

### 22

EPA, 2006b ) . Recent evidence from a stratified analysis does not indicate that increased 

### 23

O 3 exposure due to outdoor work leads to DNA damage. However, the strong evidence 

### 24

from the 2006 O 3 AQCD whi ch demonstrated increased exposure, dose, and ultimately 

### 25

risk of O 3 - related health effects in this population supports that there is adequate evidence 

### 26
available to indicate that increased exposure to O 3 through outdoor work potentially 

### 27

increases the risk o f O 3 - related health effects. 

### 28

8.4.5 Air Conditioning Use

Air conditioning use is an important component of O 3 exposure, as use of central air 

### 29
conditioning will limit exposure to O 3 by blocking the penetration of O 3 into the indoor 

### 30

environment (see Section 4.3.2 ). Air conditioning use is a difficult effect measure 

### 31
modifier to examine in epidemiologic studies because it is often estimated using regional 

### 32
prevalence data and may not reflect individual

- l evel use. More generally, air conditioning 

### 33

### Draft

– Do Not Cite or Quote 8

- 36 June 2012 prevalence is associated with temperature of a region; those areas with higher 

### 1
temperatures have a greater prevalence of households with air conditioning. Despite these 

### 2

limitations, a few studies have examined eff ect measure modification by prevalence of air 

### 3
conditioning use in an area. Studies examining multiple cities across the U.S. have 

### 4

assessed whether associations between O 3 concentrations and hospital admissions and 

### 5
mortality varied among areas with high and low prevalence of air conditioning. Medina



### 6

Ramon et al. (20 06 ) conducted a study during the warm season and observed a greater 

### 7

association between O 3 levels and pneumonia

- hospital admissions among areas with a 

### 8
lower proportion of households having central air conditioning compared to areas with a 

### 9
larger proport ion of households with air conditioning. However, a similar observation 

### 10
was not observed when examining COPD hospital admissions complicating the 

### 11
interpretation of the results cfrom this study. Bell and Dominici (2008 ) found evidence of 

### 12

increased risk of O 3 - related mortality in areas with a lower prevalence of central air 

### 13
conditioning in a study of 98 U.S. communities. Conversely, Medina

- Ramón and 

### 14

Schwartz (2008 ) found that among individuals with atri al fibrillation, a lower risk of 

### 15
mortality was observed for areas with a lower prevalence of central air conditioning. 

### 16

The limited number of studies that examined whether air conditioning use modifies the 

### 17

association between O 3 exposure and health has not provided consistent evidence across 

### 18
health endpoints. Therefore, the limited and inconsistent results across epidemiologic 

### 19
studies has provided inadequate evidence to determine whether a lower prevalence of air 

### 20
conditioning use leads to a potential increas ed risk of O 3 - related health effects. 

### 21



## 8.5 Summary

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

### 22
been evaluated and indicate that various factors may lead to increased risk of O 3 - related 

### 23

health effects ( Table 8

- 5 ). 

### 24

The populations and lifestages identified in this section that have “adequate” evidence for 

### 25

potentially increased O 3 - related health effects are indivi duals with asthma, younger and 

### 26
older age groups, individuals with reduced intake of certain nutrients, and outdoor 

### 27
workers, based on consistency in findings across studies and evidence of coherence in 

### 28
results from different scientific disciplines. Asthma a s a factor potentially affecting risk 

### 29
was supported by controlled human exposure and toxicological studies, as well as some 

### 30
evidence from epidemiologic studies. Generally, studies of age groups reported positive 

### 31
associations for respiratory hospital admiss ions and ED visits among children. Biological 

### 32
plausibility for this increased risk is supported by toxicological and clinical research. 

### 33
Also, children have higher exposure and dose due to increased time spent outdoors and 

### 34

### Draft

– Do Not Cite or Quote 8

- 37 June 2012 ventilation rate. Most studies com paring age groups reported greater effects of short

- term 

### 1

O 3 exposure on mortality among older adults, although studies of other health outcomes 

### 2
had inconsistent findings regarding whether older adults were at increased risk. Older 

### 3
adults may also withstand greater O 3 exposure and not seek relief as quickly as younger 

### 4
adults. Multiple epidemiologic, controlled human exposure, and toxicological studies 

### 5
reported that reduced Vitamins E and C intake are associated with risk of O 3 - related 

### 6

health effects. Previou s studies have shown that increased exposure to O 3 due to outdoor 

### 7
work leads to a potentially increased risk of O 3 - related health effects and it is clear that 

### 8
outdoor workers have higher exposures, and possibly greater internal doses, of O 3 , which 

### 9
may lead to increased risk of O 3 - related health effects. 

### 10

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 (Sect ion 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

--

In some cases, it is difficult to determine a factor that results in potentially increased risk 

### 11
of effects. For example, previous assessments have included controlled human exposure 

### 12
studies in which some healthy individuals demonstrate greater O 3 - related health effects 

### 13
compared to other healthy individuals. Intersubject variability has been observed for lung 

### 14
function decrements, symp tomatic responses, pulmonary inflammation, AHR, and altered 

### 15
epithelial permeability in healthy adults exposed to O 3 ( Que et al., 2011 ; Holz et al., 

### 16

2005 ; McDonnell, 1996 ) . These responses to O 3 exposure in healthy individuals tend to 

### 17
be reproducible within a given individual over a period of several months indicating 

### 18
differences in the intrinsic responsiveness ( Holz et al., 2005 ; Hazucha et al., 2003 ; Holz 

### 19

et al., 1999 ; McDonnell et al., 1985b )

. 

### 20

### Draft

– Do Not Cite or Quote 8

- 38 June 2012 Limitations include the challenge of evaluating effect measure modification in 

### 1
epidemiologic studies with widespread po pulations with variation in numerous factors. 

### 2
For a number of the factors described below, there are few available studies. Many 

### 3
toxicological and controlled human exposure studies are the only ones that have 

### 4

examined certain factors and therefore have not been replicated. In considering 

### 5
epidemiologic studies conducted in other countries, it is possible that those populations 

### 6
may differ in SES or other demographic indicators, thus limiting generalizability to a 

### 7
U.S. population. Additionally, many epidemiolo gic studies that stratify by factors of 

### 8
interest have small sample sizes, which can decrease precision of effect estimates. 

### 9

These challenges and limitations in evaluating the factors that can increase risk for 

### 10
experiencing O 3 - related health effects may co ntribute to conclusions that evidence for 

### 11
some factors, such as genetic factors, sex, SES, and obesity provided “suggestive” 

### 12
evidence of potentially increased risk. In addition, for a number of factors listed in 

### 13

Tab le 8

- 5 the evidence was inadequate to draw conclusions about potential increase in 

### 14
risk of effects. Overall, the factors most strongly supported as contributing to potentially 

### 15

increased risk o f O 3 - related effects among various populations and lifestages were related 

### 16
to asthma, age group (children and older adults), dietary factors, and working outdoors. 

### 17

### Draft

– Do Not Cite or Quote 8

- 39 June 2012 

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