### Summary of Interagency Working Comments on Draft Language under

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

1 Page 32

Air quality model simulations estimate that peak O 3 levels will continue to improve over
the next decade as additional reductions in O 3 precursors from power plants, motor vehicles, and
other sources are realized. In addition to being affected by changing emissions, future O 3 concentrations will also be affected by climate change. Modeling studies in EPA’s Interim Assessment (U.S. EPA, 2 009b) 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
O 3 concentrations over substantial regions of the country, with in creases tending to occur during higher peak pollution episodes in the summer. These increases in O 3 pollution over broad areas of the U.S., including in the largest metropolitan areas with the worst O 3 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 O 3
- related health effects. If unchecked , climate change has the potential to offset some of the improvements in O 3 air quality, and therefore some of the improvements in public health, that are expected from reductions in emissions of O 3
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 pr oposal? 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.

### Summary of Interagency Working Comments on Draft Language under

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2 Page 49 :

4) New epidemiologic studies provide expanded evidence for respiratory effects associated with long

- term or repeated O 3 concentrations (e.g., seasonal average of 1

- or 8

- hour daily max concentrations). Recent studies demonstrate interactions between exercise or different genetic
variants an d 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 O 3 and a range of respiratory health e ffects. (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 fro m O 3
- 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 O 3

. The information in th is 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

pro cesses. Experimental evidence elucidating modes of action and/or mechanisms contributes to our understanding of the biological plausibility of adverse O 3
- 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 O 3 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 compon ents 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 O 3 . The resulting seconda ry 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 O 3 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 c ontrolled human exposure studies conducted in young, healthy adults with moderate
exertion have reported FEV 1 decrements and pulmonary inflammation in some subjects following prolonged exposures to O 3 concentrations as low as 60 ppb , and respiratory symptoms in some subjects during the fifth and six exercise periods following exposures to concentra tions 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 as at 72 ppb

. 1 Epidemiologic studies provide evidence that increases in ambient O 3
exposure s 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., FEV 1 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 p revious reviews CASAC has
endorsed these conclusions

Bottom of page 6 2 :

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% FEV 1 decrements is 25% following exposure to 80 ppb O 3 and 10% following exposure to 60 ppb O 3 (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 interind ividual 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 O 3 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 O 3 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

1 Scheleg le et al. (2009) reported a statistically significant increase in respiratory symptoms in healthy adults at a target O 3 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 c hange, 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 O 3 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 l ow O 3 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% FEV 1 decrements is 25% following exposure to 80 ppb O 3 and 10% following exposure to 60 ppb O 3 (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 num ber (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 par ticipants 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 amb ient O 3 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 FEV 1 decrements greater than 10% following 6.6 hour exposure to 60 ppb O 3 , and that 22% would experience such decrements following exposure to 80 ppb O 3 (U.S. EPA, 2013, p. 6

- 18 and Figure 6

- 3). The model developed by Schelegle et al. (2012) predicts that, for a prolonge d (6.6 hours) O 3 exposure with moderate, quasi

- continuous exercise, the average dose of onset for FEV 1 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
individual s 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 O 3 (U.S. EPA, 2013, p. 6

- 16), which is consistent with the threshold FEV 1 responses repo rted by McDonnell et al. (2012).

Page 66:

Among outdoor workers, Brauer et al. (1996 ) found a robust association with daily 1

- hour max O 3 concentrati ons less than 40 ppb. Ulmer et al. (1997 ) found a robust association in
schoolchildren with 30

- minute maximum O 3 concentrations less than 60 ppb. For 8

- hour average
O 3 concentrations, associations with lung function decr ements 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 t T hese 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 O 3 during intermittent, moderate exertion.

Page 71 :

Most controlled human exposure studies have reported that asthmatics experience larger O 3
- 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 p rediction/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

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5 2 00 ppb O 3 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 O 3 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 O 3
- induced inflammatory response in induced sputum , though pretreatment did not prevent FEV 1 decrements ( Vagaggini et al., 2001; 2007 ) . In contrast, Stenfors et al. (2002 ) did not detect a difference in the O 3
- 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 :

Th e data suggest that as a whole the healthy population, on average, may have small inflammatory responses following exposure to near

- ambient levels of O 3 , though there may be a
sizable subpopulation that is very sensitive to low levels of O 3

.

Page 74 :

The limi ted epidemiologic evidence reviewed in the 2006 O 3 AQCD ( U.S. EPA, 2006a )
demonstrated an association between short

- term increases in ambient O 3 concentrations and airways inflammation in children (1

- hour max O 3 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 . I t 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 O 3

.

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), perha ps 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 exp ressed 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 O 3 concentrations at or above 72 ppb (Adams, 2003; Adams, 2006; Schelegle et al., 2009). Such symptoms have been reported to increase with increasing O 3 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 aver age O 3 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 O 3

. Adams (2006) repor ted an increase in respiratory symptoms in healthy adults during a 6.6 hour exposure protocol with an average O 3 exposure concentration of 60 ppb. This increase was significantly different from initial respiratory symptoms, but not from filtered air contro ls.
The findings for O 3
- 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 O 3 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
O 3
- 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

re sponsiveness

. ” 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 c onsistent. 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 s entence 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 O 3 .”

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

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7 strengthened considerably since the last review, with the addition of severa l 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 indica ting the occurrence of respiratory effects due to long

- term O 3 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 h eterogeneous 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 th e previous review, longitudinal cohort studies that examined associations between long

- term O 3 exposures and the onset of asthma in adults and children indicated a direct effect of long

- term O 3 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 O 3 in children (McConnell et al., 2002). Since that review, new evidence has become available about the association between long

- term exposures to O 3 and

new

- onset asthma that has increased our understanding of the gene

- environment interaction and the mechanisms and biological pathways most relevant to assessing O 3
- related effects.

Page 103/104

The association between increased O 3 concentrations and increased risk of deat h 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 O 3 concentrations ranged from 33 to 104 ppb, there was no statistical deviation
from a linear concentration

- response relationship between O 3 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 thre shold at an O 3 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 O 3 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 m a y benefit by a sentence that highlights the fact that despite significant research, the scientific community has not been able to identify any specific causal facto rs 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 potentia l 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 Interagency Working Comments on Draft Language under

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8 associations between short

- term O 3 exposure and all

- cause (nonaccidental) mortality, with associations persisting or incr easing in magnitude during the warm season, and provide additional support for associations between O 3 exposure and cardiovascular and respiratory mortality

.

Page 117 :

Evidence new to this review indicates that 6.6

- hour exposures to 60 ppb O 3 during m oderate 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 O 3 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 O 3 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 O 3 concentrations ≥ 60 ppb, while engaged in 6.6 hours of intermittent moderate exertion, develop reversible, transient decrements in lung function

. In addition,
d epending 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 th e FEV 1 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% FEV 1 decrements. Moreover, consistent with the findings of the ISA (U.S. EPA, 2013, section 6.2.1.1), CASAC concl uded 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 respirat ory 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
ad v ersity of effects at different O 3 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 c onsistent 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 differ ence.

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 func tion 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 plau sibility 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 proportio n 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 O 3 are reported to the public during the O 3 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 O 3 . People are advised to reduce exposure depending on the predicted O 3 levels and the likelihoo d 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

- O 3 days. Staying indoors to reduce exposure is not recommended until air quality reaches th e 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 O 3 , while at specified exert ion 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 O 3
- attributable effects (U.S. EPA, 2013, Chapter 8).

Page 144 :

In the HREA, population exposures to ambient O 3 concentrations are estimated using the current

ve rsion of the Air Pollut ants 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
O 3 , including the temporal and spatial distribution s of people and O 3 concentrations throughout an urban area, the variation of O 3 concentrations within various microenvironment s , 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) uni nsured 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 des ignated 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 exerc ise 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., p age 133 states:

“ Overall, the ISA (U.S. EPA 2013) concludes adequate evidence is available indicating that older adults are at increased risk of O 3 - 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 w ere 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

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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 O 3 exposures at those benchmark concentration s . 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 O 3 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 O 3 have been reported to decrease lung function and to increase airwa y inflammation. Exposures of healthy adults to 72 ppb O 3 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 O 3 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, or and decreased lung host defense were reported (U.S. EPA, 2014c, section 3.1.2.1).

Page 147:

As discussed below, the interindividual variability in responsiveness following exposures of
concern means that only a subs et 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 o f 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. Estimate s smaller than 50 were rounded downward

to zero (from U.S. EPA, 2014a, Appendix 5F Table 5F

- 5).

Page 14 9 :

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

- tha t “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 discussio n 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 O 3 standards, the PA also notes important uncertainties in these estimates. For example, d ue to variability in responsiveness, only a subset of individuals who experience exposures at or above a benchmark
concentration can be expected to experience health ef fects. G iven 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 cann ot be translated into quantitative estimates of the number of people likely to experience specific health effects. 4

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 dimens tion of the potential implications of this uncertainty for exposure estimates, the HREA reports the results of limited exposure model sensitivity analyses

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 O 3
- induced lung function decrements. An uncertainty with p articular 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 exh ibit the same lung function response following O 3 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 FEV 1 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 child ren reported O 3
- 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 respons e 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 a t 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 th is 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 O 3
- 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 O 3
- 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 O 3
- 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 subje cts 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 O 3
- induced lung
function decrements than the healthy adults used to develop exposure

- response relationships, the HREA could underestimate the impacts of O 3 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 O 3 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). 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.