Summary of EPA Responses to Interagency Working Comments on Draft 

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(1) Comment

Page 32

Air quality model simulations estimate that peak O3 levels will continue to improve over 

the next decade as additional reductions in O3 precursors from power plants, motor 

vehicles, and other sources are realized. 

In addition to being affected by changing emissions, future O3 concentrations will also be 

affected by climate change. Modeling studies in EPA’s Interim Assessment (U.S. EPA, 

2009b) and cited in support of the 2009 Endangerment Finding (74 FR 66,496; Dec. 15, 

2009) show that, while the impact is not uniform, simulated climate change causes 

increases in summertime O3 concentrations over substantial regions of the country, with 

increases tending to occur during higher peak pollution episodes in the summer. These 

increases in O3 pollution over broad areas of the U.S., including in the largest 

metropolitan areas with the worst O3 problems, increase the risk of morbidity and 

mortality. Children, older adults, and people with asthma or other lung diseases are 

among the most vulnerable to these O3-related health effects. If unchecked, climate 

change has the potential to offset some of the improvements in O3 air quality, and 

therefore some of the improvements in public health, that are expected from reductions in 

emissions of O3 precursors.

EPA Response: The “disconnect” arises because both efforts look at separate individual 

effects in isolation. Our analyses focus on what will happen as emissions changes 

(climate held constant); the climate assessments focus on what will happen as climate 

changes (emissions held constant). We’ve tried to clarify through text edits.

(2) Comment

Page 33: 

The EPA may consider proximity to background levels as a factor in the decision whether 

and how to revise the NAAQS when considering levels within the range of 

reasonable values supported by the air quality criteria and judgments of the 

Administrator. ATA III, 283 F. 3d at 279.

EPA Response: The Administrator has not used background concentrations as part of 

the basis for her proposed decisions on the O3 NAAQS. 

(3) Comment

Page 37:

Therefore, the conclusions in the PA strive to reflect an interpretation of the available 

scientific evidence and exposure/risk information that neither overstates nor understates 

the strengths and limitations of that evidence and information.

Commented [A1]: Please explain more clearly (in the text) the 

potential disconnect between the predictions for this regulation and 

those associated with the Endangerment Finding. For instance, this 

a function of different baseline assumptions? 

Commented [A2]: Does the Administrator use this flexibility in 

the current proposal? If so, please point us to that text.
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EPA Response: We have added text to indicate that the PA conclusions on the 

interpretation of the evidence reflect the views of EPA staff, and that they have been 

reviewed by the CASAC panel.

(4) Comment

Page 39:

The categories considered in evaluating the evidence for these potential at-risk factors are 

“adequate evidence,” “suggestive evidence,” “inadequate evidence,” and “evidence of no 

effect.” These categories are discussed in more detail in the ISA (U.S. EPA, 2013, 

chapter 8, Table 8-1). 

EPA Response: We have added additional clarifying discussion of the ISA’s framework 

for at-risk factors, along with appropriate references to the ISA. 

(5) Comment

Page 49:

4) New epidemiologic studies provide expanded evidence for respiratory effects 

associated with long-term or repeated O3 concentrations (e.g., seasonal average of 1-or 8-

hour daily max concentrations). Recent studies demonstrate interactions between exercise 

or different genetic variants and both new-onset asthma in children and increased 

respiratory symptom effects in individuals with asthma; additional studies of respiratory 

morbidity and mortality support the association between long-term exposure to O3 and a

range of respiratory health effects. 

(5) New evidence of risk factors (i.e., people with certain genetic variants related to 

antioxidant status or inflammation, and people with reduced intake of antioxidant 

nutrients) strengthens our understanding of the potential modes of action from O3-

induced effects. 

1. Overview of Mechanisms

The purpose of this section is to describe what appear to be the key events and 

pathways that contribute to health effects resulting from both short-term and long-term 

exposures to O3. The information in this section draws from section 5.3 of the ISA (U.S. 

EPA, 2013). Mode of action refers to a sequence of key events and processes that result 

in a given toxic effect. Elucidation of mechanisms provides a more detailed 

understanding of these key events and processes. Experimental evidence elucidating 

modes of action and/or mechanisms contributes to our understanding of the biological 

plausibility of adverse O3-related health effects, including respiratory effects and effects 

outside the respiratory system (U.S. EPA, 2013, Chapters 6 and 7). 

Figure 3.1 in the PA (U.S. EPA, 2014c) shows what research suggests are the key 

events in the toxicity pathway of O3 that are described briefly here and in more detail in 

section 3.1.1 of the PA. The initial key event is the formation of secondary oxidation 

products in the respiratory tract (U.S. EPA, 2013, section 5.3). This mainly involves 

direct reactions with components of the extracellular lining fluid (ELF). Although the 

Commented [A3]: Please provide more discussion here about

the categorization scheme, as it is critical to understanding later 

sections of the document.

Commented [A4]: Shouldn’t this be “suggest” in order to be 

consistent with wording on page 55 that says “may modify the risk”? 
Summary of EPA Responses to Interagency Working Comments on Draft 

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ELF has inherent capacity to quench (based on individual antioxidant capacity), this 

capacity can be overwhelmed, especially with exposure to elevated concentrations of O3. 

The resulting secondary oxidation products transmit signals to the epithelium, pain 

receptive nerve fibers and, if present, immune cells (i.e., eosinophils, dendritic cells and 

mast cells) involved in allergic responses. Thus, the effects of O3 are mediated by 

components of ELF and by the multiple cell types found in the respiratory tract. Further, 

oxidative stress is an implicit part of this initial key event. 

EPA Response: We have made several edits in this section in response to reviewers’ 

comments, with edits appropriately reflecting the ISA’s characterization of the degree of 

certainty in the evidence. 

(6) Comment

Page 54:

Recent controlled human exposure studies conducted in young, healthy adults with 

moderate exertion have reported FEV1 decrements and pulmonary inflammation in some 

subjects following prolonged exposures to O3 concentrations as low as 60 ppb, and 

respiratory symptoms in some subjects during the fifth and six exercise periods following 

exposures to concentrations as low asat 72 ppb.

1 Epidemiologic studies provide evidence 

that increases in ambient O3 exposures can result in are associated with lung function 

decrements, increases in respiratory symptoms, and pulmonary inflammation in children 

with asthma; increases in respiratory-related hospital admissions and emergency 

department visits; and increases in respiratory mortality.

EPA Response: Here and elsewhere (where similar comments are made), we do not 

agree with the addition of the word “some” in this context. This sentence is discussing 

group mean changes in lung function, as reported in the published studies. This sentence 

is not discussing the proportion of study subjects experiencing decrements of a particular 

magnitude. In parts of the notice where we are discussing the proportion of study subjects 

experiencing decrements of a particular magnitude (i.e., see II.B.2.a.i), we have inserted 

text to indicate that, based on the data available at 60 ppb, 1% of subjects experienced 

decrements > 20%. 

Here and elsewhere, we also do not agree with adding reference to the fifth and sixth 

exercise periods, as we are referring to effects following 6.6 hour exposures (i.e., 

comparison of pre- and post-exposure changes). We have inserted language to clarify that 

the effects discussed here were measured following the 6.6 hour exposure period. 

 

1Schelegle et al. (2009) reported a statistically significant increase in respiratory symptoms in 

healthy adults at a target O3 exposure concentration of 70 ppb, averaged over the study period. 

For this 70 ppb target exposure concentration, Schelegle et al. (2009) reported that the actual 

mean exposure concentration was 72 ppb.

Commented [A5]: Should this word be deleted?

Commented [A6]: Should this be “appear to be”

Commented [A7]: To be consistent with the details provided on 

pages 58-61 it seems some nuance is needed in this sentence - there 

should be a consistent way of clarifying that these studies we are 

talking about small group effects in a small percentage of people, 

and , only 1 or 2 people with gt 20%,.

From page 58.

As discussed below, group mean changes in lung function are often 

small, especially following exposures to relatively low O3

concentrations (e.g., 60 ppb). 

From page 63:

Based on these studies, the weighted average proportion (i.e., based 

on numbers of subjects in each study) of young, healthy adults with 

>10% FEV1 decrements is 25% following exposure to 80 ppb O3 and 

10% following exposure to 60 ppb O3 (U.S. EPA, 2013, page 6-19).1
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Suggested change to “are associated with” made.

(7) Comment

Top of page 62:

decrements (e.g., FEV1 decrements > 10 percent but < 20 percent, lasting up to 24 hours) 

would likely interfere with normal activity for many individuals, and would likely result 

in more frequent use of medication (75 FR 2973, January 19, 2010). In previous reviews 

CASAC has endorsed these conclusions

EPA Response: Edits made.

(8) Comment 

Bottom of page 62: 

EPA Response: We have inserted text into section II.B.2.a.i to indicate that, of the data 

available at 60 ppb O3, 1% of subjects had > 20% decrement in FEV1. The new text also 

notes that the McDonnell et al. (2012) paper predicts that 1% of people exposed to 60 

ppb O3 would have > 20% decrements in FEV1. 

(9) Comment 

Page 63: 

Across Based on these studies, the weighted average proportion (i.e., based on numbers 

of subjects in each study) of young, healthy adults with >10% FEV1 decrements is 25% 

following exposure to 80 ppb O3 and 10% following exposure to 60 ppb O3 (U.S. EPA, 

2013, page 6-19).2 The ISA notes that responses within an individual tend to be 

reproducible over a period of several months, indicating that interindividual differences 

reflect differences in intrinsic responsiveness. Given this, the ISA concludes that “a 

considerable fraction” of healthy individuals experience clinically meaningful decrements 

in lung function when exposed for 6.6 hours to 60 ppb O3 during quasi continuous, 

moderate exertion (U.S. EPA, 2013, section 6.2.1.1, p. 6-20).

As discussed above and in the ISA (U.S EPA, 2013, Section 5.3.2), secondary oxidation 

products formed following O3 exposures can activate neural reflexes leading to decreased 

lung function. Two new quantitative models (McDonnell et al., 2012; Schelegle et al., 

2012), discussed in section 6.2.1.1 of the ISA (U.S. EPA, 2013, p. 6-15), included 

mathematical approaches to simulate the hypothesized protective effect of antioxidants in 

 

2 The ISA also notes that by considering responses uncorrected for filtered air exposures, during 

which lung function typically improves (which would increase the size of the change, pre-and 

post-exposure), 10% is an underestimate of the proportion of healthy individuals that are likely 

to experience clinically meaningful changes in lung function following exposure for 6.6 hours to 

60 ppb O3 during intermittent moderate exertion (U.S. EPA, 2012, section 6.2.1.1). 

Commented [A8]: Suggest using scientific references rather than 

a prearmble to a proposal that was not finalized. Please address all 

instances in the preamble.

Commented [A9]: Please state in the preamble the number (or 

percentage) of individuals in Kim et al and the number (or percent) 

in Schlegle et al. that had deficits in FEV1 that were between 15 

and 20 percent.

Commented [A10]: Is EPA planning to make the data from the 

Kim study available to the public (consistent with OMB’s M-13-13). 

Given the requirement to make the de-identified data available to the 

public, we encourage EPA to do so when the NPRM is released.

Commented [A11]: Please point us to where in the preamble 

discussion of the HERA this (that only a small portion of the 

participants responded) is taken into account in the extrapolation to 

the population (i.e., do the exposure assessments assume 100% of 

the people would respond at a given level?).

Commented [A12]: Should this word be “hypothesizes” or 

“predicts”? If not, should “are likely to” or “could” be inserted 

between “healthy individuals” and “experience”?

Commented [A13]: Consider replacing with full sentence from 

ISA. 
Summary of EPA Responses to Interagency Working Comments on Draft 

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the ELF at lower ambient O3 concentrations, and include a threshold below which 

changes in lung function do not occur. 

EPA Response: Section II.C.3.a of the preamble discusses the approach taken in the 

HREA to estimating lung function risks. Risk estimates are based on the available 

scientific evidence for the relationship between O3 exposures and lung function 

responses. 

We have made changes to these paragraphs consistent with the specific edits suggested 

by reviewers. 

(10) Comment

Page 65

Specifically, the model developed by McDonnell et al. (2012) predicts that 9% of healthy 

exercising adults would experience FEV1 decrements greater than 10% following 6.6 

hour exposure to 60 ppb O3, and that 22% would experience such decrements following 

exposure to 80 ppb O3 (U.S. EPA, 2013, p. 6-18 and Figure 6-3). The model developed 

by Schelegle et al. (2012) predicts that, for a prolonged (6.6 hours) O3 exposure with 

moderate, quasi-continuous exercise, the average dose of onset for FEV1 decrement 

would be reached following 4 to 5 hours of exposure to 60 ppb, and following 3 to 4 

hours of exposure to 80 ppb. However, 14% of the individuals had a dose of onset that 

was less than 40% of the average. Those individuals would reach their dose of onset 

following 1 to 2 hours of exposure to 50 to 80 ppb O3 (U.S. EPA, 2013, p. 6-16), which is 

consistent with the threshold FEV1 responses reported by McDonnell et al. (2012). 

EPA Response: We have edited this paragraph to clarify that results discussed are 

presented in studies by McDonnell et al. (2012) and Schelegele et al. (2012). With 

respect to the Schelegle et al. study, the percentages presented were derived for each 

subject based on their data; thus, not predicted based on a model.

(11) Comment

Page 66:

Among outdoor workers, Brauer et al. (1996) found a robust association with daily 

1-hour max O3 concentrations less than 40 ppb. Ulmer et al. (1997) found a robust 

association in schoolchildren with 30-minute maximum O3 concentrations less than 

60 ppb. For 8-hour average O3 concentrations, associations with lung function 

decrements in children with asthma were found to persist at concentrations less than 

80 ppb in a U.S. multicity study (Mortimer et al., 2002) and less than 51 ppb in a study 

conducted in the Netherlands (Gielen et al., 1997).

EPA Response: We have clarified in text. 

Commented [A14]: Throughout this paragraph, please clarify 

whether EPA is extrapolating to the population vs. if the McDonnell 

article does this. 

Commented [A15]: Shouldn’t this be: “are predicted to have”

Commented [A16]: Shouldn’t this be “would be predicted to 

reach”?

Commented [A17]: Please clarify in text whether these are all 

statistically significant findings? 
Summary of EPA Responses to Interagency Working Comments on Draft 

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(12) Comment 

Page 68: 

EPA extrapolates that tThese studies also indicate that, on average, 10% of young, 

healthy adults experience clinically meaningful decrements in lung function when 

exposed for 6.6 hours to 60 ppb O3 during intermittent, moderate exertion. 

EPA Response: We have reworded to indicate that this result is based on the data in the 

referenced studies. 

(13) Comment

Page 71:

Most controlled human exposure studies have reported that asthmatics experience larger 

O3-induced inflammatory responses than non-asthmatics. Specifically, asthmatics 

exposed to 200 ppb O3 for 4-6 hours with exercise show significantly more neutrophils in 

bronchoalveolar lavage fluid (BALF) than similarly exposed healthy individuals 

(Scannell et al., 1996; Basha et al., 1994). Bosson et al. (2003) reported significantly 

greater expression of a variety of pro-inflammatory cytokines in asthmatics, compared to 

healthy subjects, following exposure to 200 ppb O3 for 2 hours. In addition, research 

available in the last review, combined with a recent study newly available in this review, 

indicates that pretreatment of asthmatics with corticosteroids can prevent the O3-induced 

inflammatory response in induced sputum, though pretreatment did not prevent FEV1

decrements (Vagaggini et al., 2001; 2007). In contrast, Stenfors et al. (2002) did not 

detect a difference in the O3-induced increases in neutrophil numbers between 15 subjects 

with mild asthma and 15 healthy subjects by bronchial wash at the 6 hours postexposure 

time point, although the neutrophil increase in the asthmatic group was on top of an 

elevated baseline. 

EPA Response: We have edited to clarify this issue. Of the six studies cited, four found 

significant effects of O3 on symptoms. Bosson et al. (2003) and Stenfors et al. (2002) 

only looked at inflammatory markers and did not investigate respiratory symptoms.

(14) Comment 

Page 73:

The data suggest that as a whole the healthy population, on average, may have small 

inflammatory responses following exposure to near-ambient levels of O3, though there 

may be a sizable subpopulation that is very sensitive to low levels of O3. 

EPA Response: Wed edited the text to indicate that this was the study authors’ 

conclusion, and added the direct quote from the study. 

(15) Comment

Commented [A18]: Please clarify in text whether it is EPA that 

is hypothesizing or making a prediction/extrapolation. 

Commented [A19]: This paragraph and the next couple talk 

about inflammatory responses, which is appropriate given the 

section, but did the authors of any of these studies also monitor 

respiratory symptoms? Given the argument that asthmatics are more 

likely to have larger responses, it seems that at 200ppb large 

decrements (per the ATS defn) would be important for the reader to 

understand whether symptoms were observed.

If the stronger evidence for differences is available from the last 

review, rather than citing the proposal for the reconsideration, please 

cite the studies upon which this argument is based. 

Commented [A20]: This sentence appears to be the conclusion 

to this section. It is not clear to us from the evidence cited that the 

end of this sentence shouldn’t read something like:

... though some asthmatics and potentially with other respiratory 

conditions may be more sensitive to low levels of O3. 
Summary of EPA Responses to Interagency Working Comments on Draft 

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Page 74:

The limited epidemiologic evidence reviewed in the 2006 O3 AQCD (U.S. EPA, 2006a) 

demonstrated an association between short-term increases in ambient O3 concentrations 

and airways inflammation in children (1-hour max O3 of approximately 100 ppb).

EPA Response: We edited to use the word “reported.” 

(16) Comment

Page 77:

People with asthma are generally more sensitive to bronchoconstricting agents than those 

without asthma, and the use of an airway challenge to inhaled bronchoconstricting agents 

is a diagnostic test in asthma. 

EPA Response: We added a reference. 

(17) Comment

Page 78: 

Airway hyperresponsiveness is linked with the accumulation and/or activation of 

eosinophils in the airways of asthmatics, which is followed by production of mucus and a 

late-phase asthmatic response (75 FR 2970, January 19, 2010). 

EPA Response: Appropriate references added. 

(18) Comment

Page 80: 

These results from controlled human exposure studies indicate that sub-populations of 

healthy study subjects consistently experience larger than average lung function 

decrements, greater than average inflammatory responses and pulmonary injury as 

expressed by increased epithelial permeability, and greater than average airway 

responsiveness, and that these effects are mediated by apparently different physiologic 

pathways.

EPA Response: We have clarified this sentence in order to better link it to the rest of the 

paragraph. 

(19) Comment

Page 82:

In controlled human exposure studies available in the last review as well as newly 

available studies, statistically significant increases in group mean respiratory symptom 

Commented [A21]: It seems odd to use the term “demonstrated” 

for limited evidence (maybe “reported” would work better?) 

Commented [A22]: Please provide a reference here. 

Commented [A23]: Rather than the 2010 proposal for 

reconsideration, please provide more technical detail, as this seems 

an important component of your argument. If there are not separate 

references here (other than those below), perhaps this first sentence 

should be somewhat less definitive – for instance, did you mean: 

“which is assumed to be (or could be) followed by late-phase 

asthmatic response”?

Commented [A24]: We are having trouble tracing this 

conclusion. The results cited in prior sections suggests high interindividual responses, and that only a small proportion of healthy 

individuals would be expected to respond, but it isn’t clear to us that 

these results mean that a “subpopulation” “consistently” experiences 

larger than average airway responsiveness. ” Indeed, the literature 

cited above seems to imply that those who display some of the 

symptoms don’t necessarily display others . 

Commented [A25]: Earlier in the paragraph EPA refers to 

“markers of epithelial injury.” Is thiswhat is being referred to here? 

If so, suggest being consistent. Either way, it seems that the point of 

this section is that some people will show these precursors to overt 

effects without evidence of FEV1 or symptom changes.
Summary of EPA Responses to Interagency Working Comments on Draft 

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scores have been consistently reported in healthy adult volunteers engaged in 

intermittent, moderate exertion following 6.6 hour exposures to average O3

concentrations at or above 72 ppb (Adams, 2003; Adams, 2006; Schelegle et al., 2009). 

Such symptoms have been reported to increase with increasing O3 exposure 

concentrations, duration of exposure, and activity level (McDonnell et al., 1999). 

Results have been less consistent for lower exposure concentrations. A recent 

study by Schelegle et al. (2009) reported a statistically significant increase in respiratory 

symptoms in healthy adults following 6.6 hour exposures to an average O3 concentration 

of 72 ppb during the fifth and six exercise periods, but not 60 ppb. Kim et al. (2011) also 

did not find statistically significant increases in respiratory symptoms following 

exposures of healthy adults to 60 ppb O3. Adams (2006) reported an increase in 

respiratory symptoms in healthy adults during a 6.6 hour exposure protocol with an 

average O3 exposure concentration of 60 ppb. This increase was significantly different 

from initial respiratory symptoms, but not from filtered air controls. The findings for 

O3-induced respiratory symptoms in controlled human exposure studies, and the evidence 

integrated across disciplines describing underlying modes of action, provide biological 

plausibility for epidemiologic associations observed between short-term increases in 

ambient O3 concentration and increases in respiratory symptoms (U.S. EPA, 2013, 

section 6.2.4). 

EPA Response: We have edited this section for transparency and consistency. 

References: Schelegele et al. (2009) at 72 ppb; Adams (2003 and 2006) and Schelegele et 

al. (2009) at 80 ppb.

See comment 6 for response to suggested text edits. 

(20) Comment

Page 93 -94: Small point – there are two references that are listed as U.S. 2013; we 

assume they should both be U.S. EPA 2013.

EPA Response: Edits made. 

(21) Comment

Page 95:

In summary, recent epidemiologic studies support and reinforce the epidemiologic 

evidence for O3-associated respiratory hospital admissions and emergency department 

visits from the last review. In addition, the evidence for associations with respiratory 

mortality has been strengthened considerably since the last review, with the addition of 

several large multicity studies. The biological plausibility of the associations reported in 

these studies is supported by the experimental evidence for respiratory effects.

b. Respiratory effects – long-term 

Commented [A26]: Since there has only been one study 

between 72 and 79 ppb, we think that this information would be 

conveyed more transparently if this sentence was confined to levels 

at or above 80ppb where the use of the term “consistently” is 

appropriate. 

This would be more consistent with the text in the conclusion –

beginning bottom of page 85 –

“Although studies that have become available since the last review 

have not reported increased respiratory symptoms in young, healthy 

adults following exposures with moderate exertion to 60 ppb, one 

recent study did report increased symptoms following exposure to 

70 ppb O3.”

Comment re: this text from page 85-86: for conssitency with the 

prior discussion of Schelegel 2009, suggest using “72” in the text, 

and footnoting the “70” rather than vis vers.

Commented [A27]: In the conclusion to this section and the 

introduction to the next section we note that the term “strengthen 

considerably,” is used, but what it means seems to differ somewhat. 

Does CASAC refer to both bodies of post 2006 literature the same 

way? 

Commented [A28]: By more studies that show similar results. 
Summary of EPA Responses to Interagency Working Comments on Draft 

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Since the last review, the body of evidence indicating the occurrence of 

respiratory effects due to long-term O3 exposure has been considerably strengthened. 

This evidence is discussed in detail in the ISA (U.S. EPA, 2013, Chapter 7) and 

summarized below for new-onset asthma and asthma prevalence, asthma hospital 

admissions, pulmonary structure and function, and respiratory mortality. 

EPA Response: We have removed the word “considerably” in both cases. 

(22) Comment

Page 96:

Asthma is a heterogeneous disease with a high degree of temporal variability. The on-set, 

progression, and symptoms can vary within an individual’s lifetime, and the course of 

asthma may vary markedly in young children, older children, adolescents, and adults. In 

the previous review, longitudinal cohort studies that examined associations between longterm O3 exposures and the onset of asthma in adults and children indicated a direct effect 

of long-term O3 exposures on asthma risk in adults (McDonnell et al., 1999, 15-year 

follow-up; Greer et al., 1993, 10-year follow-up) and effect modification by O3 in 

children (McConnell et al., 2002). Since that review, new evidence has become available 

about the association between long-term exposures to O3 and new-onset asthma that has 

increased our understanding of the gene-environment interaction and the mechanisms and 

biological pathways most relevant to assessing O3-related effects.

EPA Response: With respect to the first point, we do not agree with the reviewers’ 

suggestion and the suggested change is outside the scope of what this paragraph is 

intended to convey. With respect to the second point, we have made edits consistent with 

the suggested language.

(23) Comment

Page 103/104

The association between increased O3 concentrations and increased risk of death from 

respiratory causes was insensitive to the use of different models and to adjustment for 

several ecologic variables considered individually. The authors reported that when 

seasonal averages of 1-hour daily maximum O3 concentrations ranged from 33 to 104 

ppb, there was no statistical deviation from a linear concentration-response relationship 

between O3 and respiratory mortality across 96 U.S. cities (U.S. EPA, 2013, section 7.7). 

However, the authors also reported “limited evidence” for an effect threshold at an O3 

concentration of 56 ppb (p=0.06). 

EPA Response: We have added clarifying text elaborating on the analyses presented by 

Jerrett et al. (2009).

Commented [A29]: More studies, but they seem to show 

equivocal results.

Commented [A30]: This paragraph may benefit by a sentence 

that highlights the fact that despite significant research, the scientific 

community has not been able to identify any specific causal factors 

for new-onset asthma. 

Commented [A31]: The construction of this sentence implies 

that we know what causes asthma, and we are just trying to link it to 

ozone. Consider something like: 

“Since that review, additional studies have examined the association 

...; the results of these studies can be interpreted in the context of

our increased understanding of the potential gene-environment 

interactions, mechanisms, and biological pathways associated with 

incident asthma. 

Commented [A32]: Given the extent to which the Jerrett 2009 

analysis is relied upon in the Administrator’s conclusions (it is cited 

16 times in that section), it would seem reasonable to provide the 

reader with more discussion of the variety of analyses that were 

conducted on alternative thresholds explored by the authors –we are 

not sure this sentence does justice to the author’s work. .
Summary of EPA Responses to Interagency Working Comments on Draft 

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(24) Comment

Page 107: Featured quote from IASe:

The evaluation of new multicity studies that examined the association between 

short-term O3 exposures and mortality found evidence that supports the 

conclusions of the 2006 AQCD. These new studies reported consistent positive 

associations between short-term O3 exposure and all-cause (nonaccidental) 

mortality, with associations persisting or increasing in magnitude during the warm 

season, and provide additional support for associations between O3 exposure and 

cardiovascular and respiratory mortality.

EPA Response: The quote highlighted by commenters is referring to O3-associated 

mortality. The point being made is that there is new evidence in this review for 

associations with mortality, including additional studies of cause-specific mortality (i.e., 

respiratory and cardiovascular). The inconsistent evidence discussed in the preceding 

section is for O3-associated cardiovascular morbidity. 

(25) Comment

Page 117:Evidence new to this review indicates that 6.6-hour exposures to 60 ppb O3

during moderate exertion can result in pulmonary inflammation in some young healthy 

adults. As discussed in section 3.1.2 above, the initiation of inflammation can be 

considered as evidence that injury has occurred. Inflammation induced by a single O3

exposure can resolve entirely, but that continued acute inflammation can evolve into a 

chronic inflammatory state (ISA, U.S. EPA, 2013, p. 6-76), which is clearly adverse.

Responses measured in controlled human exposure studies indicate that the range of 

effects elicited in humans exposed to ambient O3 concentrations include: decreased 

inspiratory capacity; mild bronchoconstriction; rapid, shallow breathing pattern during 

exercise; and symptoms of cough and pain on deep inspiration (U.S. EPA, 2013, section 

6.2.1.1). Some young, healthy adults exposed to O3 concentrations ≥ 60 ppb, while 

engaged in 6.6 hours of intermittent moderate exertion, develop reversible, transient 

decrements in lung function. In addition, depending upon the concentration and duration 

of exposure, some healthy adults , experienced symptoms of breathing discomfort, and 

inflammation if minute ventilation or duration of exposure is increased sufficiently (U.S. 

EPA, 2013, section 6.2.1.1). Among healthy subjects there is considerable interindividual 

variability in the magnitude of the FEV1 responses, but when data were combined across 

studies at 60 ppb (U.S. EPA, 2013, pp. 6-17 to 6-18), 10% of healthy subjects had >10% 

FEV1 decrements. Moreover, consistent with the findings of the ISA (U.S. EPA, 2013, 

section 6.2.1.1), CASAC concluded that “[a]sthmatic subjects appear to be at least as 

sensitive, if not more sensitive, than non-asthmatic subjects in manifesting ozone-induced 

pulmonary function decrements” (Frey, 2014c, p. 4). The combination of lung function 

decrements and respiratory symptoms, which has been considered adverse in previous 

Commented [A33]: We are having difficulty following how the 

preamble gets from the “inconsistent evidence” for ozone and CVD 

discussed in the prior section, to featuring the this quotation from the 

ISA that includes cardiovascular effects.

Commented [A34]: Edited to be consistent with next paragraph.

Commented [A35]: Did EPA mean “but it is hypothesized 

that...”? 

Commented [A36]: something like this additional text seems 

necessary given that not all studies examined all endpoints or found 

significant difference.

Commented [A37]: Will EPA be making this dataset (in a deidentified form) available to the public as part of the docket for the 

NPRM? 
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reviews, has been demonstrated in healthy adults following prolonged (6.6 hour) 

exposures, while at intermittent moderate exertion, to 72 ppb. For these types of effects, 

information from controlled human exposure studies, which provides an indication of the 

magnitude and thus potential adversity of effects at different O3 concentrations, combined 

with estimates of occurrences in the population from the HREA, provide information 

about their importance from a policy perspective.

EPA Response: We have made edits in these paragraphs, consistent with commenters’ 

suggestions as appropriate. 

(26) Comment

Page 135:

With regard to asthma, Table 3-7 in the PA (U.S. EPA, 2014c, section 3.1.5.2) 

summarizes information on the prevalence of current asthma by age in the U.S. adult 

population in 2010 (Schiller et al. 2012; children - Bloom et al., 2011). Individuals with 

current asthma constitute a fairly large proportion of the population, including more than 

25 million people. Asthma prevalence tends to be higher in children than adults. Within 

the U.S., approximately 8.2% of adults have reported currently having asthma (Schiller et 

al., 2012) and 9.5% of children have reported currently having asthma (Bloom et al., 

2011). 

EPA Response: This section is on the size of the at-risk population. We rely on the U.S. 

Census for information on the number of asthmatics. The Census does not provide the 

additional information that commenters have highlighted. However, added text to

reference the at-risk populations section for more information about variability in 

responsiveness for all at-risk groups.

We have added text indicating that asthma severity and medication use are potential 

sources of uncertainty when considering the response of asthmatics to O3 exposures.

(27) Comment

Page 137:

Forecasted and actual AQI values for O3 are reported to the public during the O3 season. 

The AQI advisories explicitly state that children, older adults, people with lung disease, 

and people who are active outdoors, may be at greater risk from exposure to O3. People

are advised to reduce exposure depending on the predicted O3 levels and the likelihood of 

risk. This advice includes being active outdoors when air quality is better, and reducing 

activity levels or reducing the time being active outdoors on high-O3 days. Staying 

indoors to reduce exposure is not recommended until air quality reaches the Very 

Unhealthy or Hazardous categories. 

Commented [A38]: It is not clear from the publication whether 

the same people are experiencing BOTH statistically significant 

changes in lung function when compared to clean air AS WELL AS 

symptoms (in the later exercise periods). Could EPA please clarify 

for us the number of participants in the study that had both 

significant decrements and reported symptoms?

Commented [A39]: The discussion above implies that the level 

of adversity is dependent on the subgroup of interest and the 

extrapolation to the implications for the most sensitive 

subpopulations. If that is the case, and (as indicated earlier) the key 

role of the controlled exposure studies is biological plausibility of 

effects at certain levels, are we correct in our understanding that 

EPA is saying that the results of these studies of healthy people are 

but one input into a designation of adversity? 

Commented [A40]: Per our discussion, we are wondering if it 

makes sense to assume all asthmatics are reactive to ozone. In 

addition to questions about sensitivity to air pollution (vs. other 

triggers), and baseline inter-individual variability, are there any 

statistics about the percentage of a) untreated asthmatics or b) 

uninsured or under-insured asthmatics, or c) the distribution of 

severity levels across asthmatics? 

We understand EPA was going to add such a discussion to the 

uncertainties section of the risk assessment discussion, but maybe it 

should be mentioned here as well? 

Commented [A41]: As we lower the NAAQS, the bar for 

unhealthy air is lowered, meaning more days will be designated as 

unhealthy. Is EPA concerned that advising more people to avoid 

physical activity on more days of the year trades off reducing 

something with a small risk (small decrements in lung function) vs 

increasing a fairly well known risk (lack of exercise and obesity)? It 

might be useful to take comment on this issue in the AQI section. 
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EPA Response: EPA works closely with state/local/tribal agencies and with the public 

health community, including the CDC, to develop public health communications 

materials for the AQI that appropriately balance concerns about the potential for air 

quality-related health effects with other lifestyle factors, such as physical activity, that 

can influence health. We do not believe it would be appropriate to take comment on this 

issue in the O3 proposal.

(28) Comment

Page 143:

The exposure assessment presented in the HREA (U.S. EPA, 2014a, Chapter 5) provides 

estimates of the number and percent of people exposed to various concentrations of 

ambient O3, while at specified exertion levels. The HREA estimates exposures in the 15 

urban study areas for four study groups, all school-age children (ages 5 to 18), asthmatic 

school-age children, asthmatic adults (ages 19 to 95), and all older adults (ages 65 to 95), 

reflecting the strong evidence indicating that these populations are at increased risk for 

O3-attributable effects (U.S. EPA, 2013, Chapter 8).

EPA Response: We have removed the word “strong.” 

(29) Comment

Page 144:

In the HREA, population exposures to ambient O3 concentrations are estimated using the 

current version of the Air Pollutants Exposure (APEX) model. The APEX model 

simulates the movement of individuals through time and space and estimates their 

exposures to a given pollutant in indoor, outdoor, and in-vehicle microenvironments 

(U.S. EPA, 2014a, section 5.1.3). APEX takes into account important factors that 

contribute to total human exposure to ambient O3, including the temporal and spatial 

distributions of people and O3 concentrations throughout an urban area, the variation of 

O3 concentrations within various microenvironments, and the effects of exertion on 

breathing rate in exposed individuals (U.S. EPA, 2014a, section 5.1.3).

EPA Response: The activity pattern data used in the HREA exposure estimates has been 

updated for this review. Activity pattern data are from several individual studies 

conducted from 1982 through 2010 (see Table 5-3, Page 5-14 of REA). General statistics 

for the number of diaries within several broad categorizations, including how many from 

each of three decades (1980’s, 1990’s, and 2000’s) are provided in Appendix G, Table 

5G-1 (page 5G-3). Over half (54%) of all diary days are from the last decade, while only 

14% are pre-1990 (table 5G-1). Further, when using data provided in Table 5-3, at least 

60% of all school-age children’s diary days are from studies conducted since 2000. 

(30) Comment

Page 145:

Commented [A42]: “strong evidence” seems inconsistent with 

the characterization of “adequate evidence” used in the conclusions 

on pages 123-133 of the preamble, which conclude:

e.g., page 133 states:

“Overall, the ISA (U.S. EPA 2013) concludes adequate evidence is 

available indicating that older adults are at increased risk of 

O3-related health effects. “

Commented [A43]: Has the activity pattern data upon which the 

APEX model is based been updated? What year(s) are the activity 

pattern data and is there any reason to believe that activity patterns 

have changed significantly, particularly among children, since these 

data were collected, or are the compartments too large to be sensitive 

to such differences? We are thinking about children playing indoors 

on electronic devices. 
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The amount of weight to place on the estimates of exposures at or above specific

benchmark concentrations depends in part on the weight of the scientific evidence 

concerning health effects associated with O3 exposures at those benchmark

concentrations. It also depends on judgments about the importance, from a public health 

perspective, of the health effects that are known or can reasonably be inferred to occur as 

a result of exposures at benchmark concentrations (U.S. EPA, 2014c, sections 3.1.3, 

3.1.5). 

EPA Response: In several places in the notice we note the possibility for larger 

decrements following 8-hour exposures. With regard to ventilation rates, exposure 

estimates in the HREA are for people at elevated ventilation. We have added clarifying 

text to this paragraph to emphasize this point. 

(31) Comment

Page 145:

The lowest O3 exposure concentration for which controlled human exposure studies have 

reported respiratory effects in some healthy adults is 60 ppb, with more evidence 

supporting this benchmark concentration in the current review than in the last review. In 

healthy adults, exposures to 60 ppb O3 have been reported to decrease lung function and 

to increase airway inflammation. Exposures of healthy adults to 72 ppb O3 have been 

reported to result in larger average lung function decrements, compared to 60 ppb, as well 

as in increased respiratory symptoms in some subjects after fifth and sixth exercise 

periods.

3 Exposures of healthy adults to 80 ppb O3 have been reported to result in larger 

lung function decrements than following exposures to 60 or 72 ppb, and, depending upon 

the study, group means for increased airway inflammation, increased respiratory 

symptoms, increased airways responsiveness, orand decreased lung host defense were 

reported (U.S. EPA, 2014c, section 3.1.2.1). 

EPA Response: See response to comment #6 above.

(32) Comment

Page 147:

As discussed below, the interindividual variability in responsiveness following exposures 

of concern means that only a subset of individuals who are exposed at and above a given 

benchmark concentration would actually be expected to experience respiratory effects, 

however, Table 1 below (and the subsequent analyses) do not quantitatively adjust for 

such variability. .

Table 1, footnote 59:

 

3 As noted above, for the 70 ppb exposure concentration Schelegle et al. (2009) reported that the 

actual 6.6-hour mean exposure concentration was 72 ppb.

Commented [A44]: Would it be useful to note here the useful 

perspective provided by Schelegle et. al. 2009’s - that “if the 60 ppb 

ozone protocols were extended [than 6.6 hours, to be more 

consistent with the 8 hr standard]greater decrements might be 

achieved. A counter point to this possibility is the fact that the mean 

overall ventilations in Adams (2006) and this study are equal to or 

greater than mean ventilations that might be encountered during a 

day of heavy to severe manual labor among construction workers 

observed in Linn and colleagues (1993) and that this represents the 

higher end of ventilations that might be encountered in the normal 

population for a prolonged period.

Commented [A45]: Suggested edits or similar would carry 

through nuance that is provided earlier in the preamble. 

Commented [A46]: It isn’t clear from this sentence whether it is 

to be assumed that Table 1 accounts for the inter-individual 

variability (both due to genetics and due to whether or not child’s 

asthma is being adequately managed). Is there a way that the intent 

can be clarified in the text? For instance, see sample text .
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1 Numbers of children exposed in each urban case study area were averaged over the 

years 2006 to 2010. These averages were then summed across urban study areas. 

Numbers are rounded to nearest thousand unless otherwise indicated. Estimates smaller 

than 50 were rounded downward to zero (from U.S. EPA, 2014a, Appendix 5F Table 5F5). 

EPA Response: Table 1 presents results of the HREA analysis of exposures of concern, 

not estimates of health risk. 

We have added the suggested text in the footnote. 

(33) Comment

Page 149:

In considering exposure estimates within the context of the current and alternative O3

standards, the PA also notes important uncertainties in these estimates. For example, due 

to variability in responsiveness, only a subset of individuals who experience exposures at 

or above a benchmark concentration can be expected to experience health effects. Given 

the lack of sufficient exposure-response information for most of the health effects that 

informed benchmark concentrations, estimates of the number of people likely to 

experience exposures at or above benchmark concentrations generally cannot be 

translated into quantitative estimates of the number of people likely to experience specific 

health effects.4

EPA Response: We have added text to clarify that there are uncertainties in the 

responsiveness of asthmatics. 

(34) Comment

Page 150:

Uncertainties associated with the APEX exposure modeling also have the potential to be 

important (U.S. EPA, 2014a, section 5.5.2, Table 5-6). For example, the HREA 

concludes that exposures of concern could be underestimated for some individuals who 

are frequently and routinely active outdoors during the warm season (U.S. EPA, 2014a,

section 5.5.2).

...In order to evaluate one dimenstion of the potential implications of this uncertainty for 

exposure estimates, the HREA reports the results of limited exposure model sensitivity 

analyses

 

4 The exception to this is lung function decrements, as discussed below (and in U.S. EPA, 2014c, 

section 3.2.3.1). 

Commented [A47]: Consider adding “please see discussion 

below regarding uncertainties associated with these numbers.”

Commented [A48]: Per prior discussion, in addition to “interindividual variability” please discuss likelihood that it is children 

who do not have good asthma medication management that will 

respond, and the number of children in this subpopulation should be 

decreasing over time. Consider something like the following just 

before the sentence that begins “Given the lack of...”

For instance, only about 10% of the healthy subjects were predicted 

to show a response at 60 ppb. However, it is not clear how that 

would translate to asthmatics, given that they are assumed to be 

more sensitive – though not all asthmatics respond to the same 

triggers, and children who have appropriate asthma management 

may only respond at higher levels.

Formatted: Underline

Commented [A49]: Couldn’t they also be overestimated for 

children who spend much of their time indoors (e.g., children)?
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EPA Response: This section discusses the results of HREA sensitivity analyses 

evaluating the potential implications for exposure estimates of people staying indoors on 

high O3 days. 

We have made the 2nd edit suggested above. 

(35) Comment

Page 156:

Key uncertainties

As for exposures of concern discussed above, the PA also considers important 

uncertainties in estimates of lung function risk. In addition to the uncertainties noted for 

exposure estimates, the HREA identifies several key uncertainties associated with 

estimates of O3-induced lung function decrements. An uncertainty with particular 

potential to impact consideration of risk estimates stems from the lack of exposureresponse information in children. In the near absence of controlled human exposure data 

for children, risk estimates are based on the assumption that children exhibit the same 

lung function response following O3 exposures as healthy 18 year olds (i.e., the youngest 

age for which controlled human exposure data is available) (U.S. EPA, 2014a, section 

6.5.3). This assumption is justified in part by the findings of McDonnell et al. (1985), 

who reported that children 8-11 year old experienced FEV1 responses similar to those 

observed in adults 18-35 years old. In addition, as discussed in the ISA (U.S. EPA, 2013, 

section 6.2.1), summer camp studies of school-aged children reported O3-induced lung 

function decrements similar in magnitude to those observed in controlled human 

exposure studies using adults. In extending the risk model to children, the HREA fixes 

the age term in the model at its highest value, the value for age 18. This approach could 

result in either over- or underestimates of O3-induced lung function decrements in 

children, depending on how children compare to the adults used in controlled human 

exposure studies (U.S. EPA, 2014a, section 6.5.3). 

A related source of uncertainty is that the risk assessment estimates O3-induced 

decrements in asthmatics using the exposure-response relationship developed from data 

collected from healthy individuals. Although the evidence has been mixed (U.S. EPA, 

2013, section 6.2.1.1), several studies have reported larger O3-induced lung function 

decrements in asthmatics than in non-asthmatics (Kreit et al., 1989; Horstman et al., 

1995; Jorres et al., 1996; Alexis et al., 2000). On this issue CASAC noted that 

“[a]sthmatic subjects appear to be at least as sensitive, if not more sensitive, than nonasthmatic subjects in manifesting ozone-induced pulmonary function decrements” (Frey, 

2014c, p. 4). To the extent asthmatics experience larger O3-induced lung function 

decrements than the healthy adults used to develop exposure-response relationships, the 

HREA could underestimate the impacts of O3 exposures on lung function in asthmatics, 

including asthmatic children. The HREA notes that the magnitude this uncertainty might 

have on risk estimates remains unknown at this time (U.S. EPA, 2014a, section 6.5.4). 

EPA Response: Reviewers are correct in their understanding. 

Commented [A50]: Are we correct that this discussion is about 

the size of the change in lung function rather than the percentage of 

children expected to respond? Please also clarify in this section 

whether the percentage of children expected to respond the same as 

the percentage of adults who responded at each level? Please 

consider the comments provided in the context of the exposure 

assessment for this HREA as well. 
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(36) Comment

Page 160:

The PA also notes the HREA conclusion that lower confidence should be placed in the 

results of the assessment of respiratory mortality risks associated with long-term O3

exposures, primarily because that analysis is based on only one study (even though that 

study is well-designed) and because of the uncertainty in that study about the existence 

and level of a potential threshold in the concentration-response function (U.S. EPA, 

2014a, section 9.6).

EPA Response: The highlighted text refers specifically to respiratory mortality risk 

estimates based on the study by Jerrett et al. (2009). The Administrator additionally 

considers air quality analyses from the PA based on this study. We will review the 

Administrator’s rationale for consistency with regard to her consideration of this study. 

Commented [A51]: There seems to be a disconnect between the 

tone of this section (re: lower confidence for respiratory morbidity) 

and the extent to which the Administrator relies on the Jerrett 2009 

analysis in Administrator’s conclusions.