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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.

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.

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.

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). 

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.

Commented [A3]: Please provide more discussion here 

about the categorization scheme, as it is critical to 

understanding later sections of the document.
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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 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. 

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 

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

consistent with wording on page 55 that says “may modify the 

risk”? 

Commented [A5]: Should this word be deleted?

Commented [A6]: Should this be “appear to be”
Summary of Interagency Working Comments on Draft Language under 

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3

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.

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

Bottom of page 62: 

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 the ELF at lower 

 

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.

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 [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

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 Interagency Working Comments on Draft Language under 

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4

ambient O3 concentrations, and include a threshold below which changes in lung function do not 

occur. 

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). 

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).

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. 

Page 71:

Most controlled human exposure studies have reported that asthmatics experience larger O3-

induced inflammatory responses than non-asthmatics. Specifically, asthmatics exposed to 

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? 

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. 
Summary of Interagency Working Comments on Draft Language under 

EO12866/13563 Interagency Review. Subject to Further Policy Review.

5

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 proinflammatory 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. 

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. 

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).

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. 

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). 

Page 80:

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. 

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”?
Summary of Interagency Working Comments on Draft Language under 

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6

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.

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 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). 

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.

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 

Commented [A24]: We are having trouble tracing this 

conclusion. The results cited in prior sections suggests high 

inter-individual 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.

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? 
Summary of Interagency Working Comments on Draft Language under 

EO12866/13563 Interagency Review. Subject to Further Policy Review.

7

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 

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. 

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 long-term 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.

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). 

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 

Commented [A28]: By more studies that show similar 

results. 

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 geneenvironment 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 Interagency Working Comments on Draft Language under 

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8

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.

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

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

Page 135:

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 

de-identified form) available to the public as part of the docket 

for the NPRM? 

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? 
Summary of Interagency Working Comments on Draft Language under 

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9

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). 

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. 

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).

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).

Page 145:

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. 

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. 
Summary of Interagency Working Comments on Draft Language under 

EO12866/13563 Interagency Review. Subject to Further Policy Review.

10

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). 

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). 

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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:

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 5F-5). 

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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 .

Commented [A47]: Consider adding “please see discussion 

below regarding uncertainties associated with these numbers.”
Summary of Interagency Working Comments on Draft Language under 

EO12866/13563 Interagency Review. Subject to Further Policy Review.

11

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 exposureresponse 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

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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

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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 exposure-response 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 

 

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

section 3.2.3.1). 

Commented [A48]: Per prior discussion, in addition to 

“inter-individual 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)?

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. 
Summary of Interagency Working Comments on Draft Language under 

EO12866/13563 Interagency Review. Subject to Further Policy Review.

12

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 nonasthmatics (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 non-asthmatic 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). 

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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 welldesigned) 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). 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.