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### Contents

George Allen

................................ ................................ ................................ ................................ ........ 2

John Balmes

................................ ................................ ................................ ................................ ......... 6

James Gauderman

................................ ................................ ................................ .......................... 10

Rogene Henderson

................................ ................................ ................................ ............................ 12

Philip K. Hopke

................................ ................................ ................................ ................................ . 15

Lianne Sheppard

................................ ................................ ................................ ............................... 18

Frank Speizer

................................ ................................ ................................ ................................ ..... 19

Helen Suh

................................ ................................ ................................ ................................ ........... 222

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### George Allen

Caveat: With regard to the range of ozone concentrations under consideration, these comments assume the form of the NAAQS will remain unchanged from what was promulgated in the 2008 rule. Any change in the form (daily average duration, percentile, multi

- year averaging) will change the effects of a standard even if the numerical value (e.g., .060 to .070 ppm) remains the

same.

Q 1. What is your advice on the overall strengths and limitations of the evidence from controlled human exposure and epidemiolo gical studies and the results of the exposure and risk assessments, in the context of EPA's selection of a standard level within the proposed range that would be requisite to protect public health with an adequate margin of safety, including the need to protect susceptible populations, such as children and people with asthma?

As with nearly all other pollutants, the exposure

- response relationship is stronger and more scientifically robust as you go to higher concentrations. This holds for both controll ed human exposures and epidemiological studies. Both approaches have their limitations, especially toward the lower end of the proposed range. The controlled exposure studies usually do not include sensitive and vulnerable populations (SVP) as subjects; this makes it more difficult to extrapolate results to the SVP that the NAAQS is intended to protect. The bias here is to underestimate the effects of a given concentration on SVP. These types of studies do allow detailed assessment of physiological mark ers such as FEV1 and inflammatory markers that epidemiological studies can not (usually) assess. Epidemiological studies do include SVP, although they are usually not constrained to this group. These studies have much greater exposure mis

- classification than controlled exposure studies, and potential confounding from other pollutants and uncontrolled variables; these factors would usually bias effect results toward the null. However, since the ambient ozone measurements used in epidemiological studies ar e reasonably specific to ozone, they are actually an indicator of strong oxidants in the air, and thus the health effects may be larger than if the exposure were only to ozone. This is different than the ozone concentrations used in controlled exposure st udies where other strong oxidants are presumably not present; thus these studies may underestimate the reported ozone health effects relative to epidemiological studies. Another potential difference between controlled exposure and epidemiological studies is the reaction products from ozone once it gets indoors (Weschler, Atmospheric Environment 38 (2004)

5715 B 5716); these include a wide range of gas

- phase respiratory irritants and ultra

- fine particles.

Q2. Recognizing that controlled human exposure studies at 0.080 ppm O3 and above have provided evidence of other health effects, including inflammation and increased airway responsiveness which may occur through different physiological mechanisms than t he reduction in FEV1, how should the results of these studies inform our understanding the health effects to healthy adults at exposures levels from 0.060 to 0.070 ppm?

As noted in the background material included in these charge questions, the availab le data suggest that there probably is a reasonably A smooth exposure

- response curve @ going from .080 to .0602

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- ppm. This does not imply that this holds at even lower levels, since that gets into the issue of thresholds. And as with all other aspects of the science, this assumption is weaker at .060 than at .070 ppm.

Q3. How should the results of the controlled human exposure studies at 0.060 ppm O3, showing effects on FEV1 and respiratory symptoms, in the context of the larger body of evidence from

cont rolled human exposure studies, mentioned above, inform our understanding of the health effects to healthy adults at exposure levels from 0.060 to 0.070 ppm?

These studies support the concept of a reasonably smooth exposure

- response curve down to these

l evels as opposed to a health effect threshold near .060 ppm.

Q4. With respect to the information from controlled human exposure studies at 0.060 ppm O3, what is the scientific importance of the small, group mean FEV1 decrements relative to the findings that 7 to 20% of the subjects experienced FEV1 decrements **∃** 10%? Please consider this question from both a public health and a clinical perspective.

For healthy adult subjects in controlled human exposure studies, these FEV1 decrements indicate

some bi ological response, but the clinical significance of this is unclear especially in light of some studies showing inflammatory responses without FEV1 decrements. From a public health perspective, where SVP would be expected to have an enhanced response to e xposures to these concentrations, these results may have more importance. Ideally, controlled human exposure studies would be conducted at these levels using SVP, but that has risks of adverse outcomes in the study subjects, making such studies difficult to do.

Q5. The evidence, including that summarized above, indicates that susceptible populations may have greater responses than healthy people. In light of this evidence, how can we appropriately use the results of controlled human exposure studies conducted on healthy adults, as well as the epidemiological studies of susceptible groups, to inform a judgment on the effects of ozone exposure on susceptible populations? The results of controlled human exposure studies conducted on healthy adults provide a A best

case @ (least health effect) scenario relative to SVP. Epidemiological studies that focus on SVP would be expected to show greater health effects for a given conce ntration, but are subject to the confounding factors noted above. The best approach may be a A weight of evidence @ scenario that assesses the consistency (or lack thereof) across these very different approaches to quantifying

ozone health effects.2

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- Q6. To what extent does your confidence that the effects observed in epidemiological studies are attributable specifically to O3 lessen or otherwise change, if at all, at the lower levels in the proposed range as compared to the higher levels?

As noted pre viously, the uncertainty (or confidence if you wish) of any exposure study decreases as the exposure concentrations decrease. For epidemiological studies, the effects of confounders is likely to be larger at .060 than .070 ppm. However, it = s a reasonable assumption that this factor would bias observed health effects toward the null, not strengthen them.

Q7. EPA's exposure assessment quantified the number of all children and asthmatic children likely to be exposed to specific benchmark levels of ozone, including in particular 0.060 and 0.070 ppm. Considering the patterns of change in the estimates of exposures of concern at and above the 0.060 and 0.070 ppm benchmark levels, and the uncertainties and limitations in the estimates, what

is the relative i mportance from a public health perspective of the estimated reductions in exposures of concern, as well as the exposures remaining, for alternative standards across the proposed range?

There is little doubt that reduced exposure, both in size of SVP expo sed and the concentrations they are exposed to, has some public health benefit as you go from .070 to .060 ppm. However, it is difficult to quantify the changes in public health benefits across this range of concentrations. There will always be some rema ining exposures with health effects across the proposed range in

SVP.

Q8. EPA's quantitative risk assessment estimated the numbers of occurrences of various ozone related health effects associated with just meeting alternative standard levels down to a standard level of 0.064 ppm. Considering the patterns of change in the estimates of health effects in the risk assessment at the alternative standard levels, and the uncertainties and limitations in the estimates, what is the relative importance from a p ublic health perspective of the estimated reductions in risk, as well as the risk remaining, for alternative standards across the proposed range? Please consider this question in light of the scientific evidence as a whole.2

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- This is really a po licy question, not a science question. There is likely some risk (i.e., not 0) for SVP even at the low end of the proposed range. This is not unique to ozone; some residual risk is present for every NAAQS pollutant, since none of them (except maybe CO) h ave a clear effect threshold. The quantitative risk assessment does not provide a bright line; it only provides guidance to the best estimate of risk at the various ranges considered. The science can only take the process so far, and after that it become s a policy judgment that weighs the estimated (and more uncertain at the lower end of the range) health benefits against the difficulty of implementing effective control strategies to meet any given NAAQS.

Additional Comments.

Although the reconsiderati on of the 2008 ozone NAAQS is constrained to the literature available during that NAAQS review process, it is worth noting that more recent studies over the last 4

- 5 years support and perhaps strengthen the scientific justification for an ozone NAAQS in th e range of .060 to .070 ppm.

Some interested parties have raised the question of the quality of the ozone data used in the epidemiologic studies, saying that there are common situations where the UV absorption measurement method normally used in the ozone monitoring network can significantly over

- report ozone concentrations. There is evidence that this can happen, but it is unclear if this a significant factor in the overall ozone exposure

- health effect relationship. Additionally, the difference

between chamber studies and ambient air exposures with the additional load of strong oxidants not being included in the measurement further reduces the implications of a modest issue with the UV method. It should also be noted that nearly all ambient air measurem ents of NAAQS pollutants have various biases associated with them, sometimes positive (NO2, non

- trace CO, SO2 when NO is elevated, sometimes negative (the PM2.5 FRM, depending how it is run), sometimes biases between different FRMs for PM10 (the SSI Hi

- Vol A war @ in the 1980's), and sometimes just very goofy (the Hi

- Vol FRM for lead). Some of these biases are as large or larger than the likely positive bias from the UV ozone method. In this context, I am not concerned with the reported

biases in the UV method. However, since there may be effective ways to reduce the biases in this method, EPA may want to consider additional specifications for the testing of UV ozone analyzers in the Federal Equivalent Method (FEM) regulations to assess this issue.2

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### John B **almes**

1. What is your advice on the overall strengths and limitations of the evidence from controlled human exposure and epidemiological studies and the results of the exposure and risk assessments, in the context of EPA's selection of a standard level within the proposed range that would be requisite to protect public health with an adequate margin of safety, including the need to protect susceptible populations, such as children and people with asthma?

Taken together, the evidence from controlled huma n and epidemiological studies strongly supports the selection of a new primary ozone standard that is well below the 1997 standard of 0.08 ppm over an 8

- hour averaging time. There is scientific certainty that 6.6

- hour exposures to concentrations ≥0.08 ppm with intermittent exercise cause clinically relevant decrements of lung function in young, healthy volunteers. The results of multiple epidemiological studies also show that children and adults with asthma are at increased risk

of acute exacerbations of this disease on or shortly after days when ozone concentrations are elevated above background but remain below 0.08 ppm. Given the need to protect public health with an adequate margin of safety and the results of EPA’s exposure and risk
assessments, sett ing a new NAAQS in the range of 0.060 to 0.070 is appropriate.

2. Recognizing that controlled human exposure studies at 0.080 ppm O 3 and above have provided evidence of other health effects, including inflammation and increased airway responsiveness which may occur through different physiological mechanisms than the

reduction in FEV 1 , how should the results of these studies inform our understanding the health effects to healthy adults at exposures levels from 0.060 to 0.070 ppm?

The results of studies that show that exposure to ozone at 0.080 ppm and above causes airway inflammation, increased permeability, and increased responsiveness provide mechanistic support for the observed epidemiological associations with regard to

exacerbations of asthma at concent rations below 0.080 ppm. The mechanism of ozone

induced decrements in lung function may not be related to airway inflammation.

3. How should the results of the controlled human exposure studies at 0.060 ppm O 3
, showing effects on FEV 1 and respiratory sympt oms, in the context of the larger body of evidence from controlled human exposure studies, mentioned above, inform our understanding of the health effects to healthy adults at exposure levels from 0.060 to 0.070 ppm?

At the time of the last EPA review of the evidence on the health effects of ozone, only the study of Adams et al. (2006) provided data on exposures at concentrations ≤0.080 ppm. Although that study as published reported a non

- significant group decrease (~3%) in FEV1, several subjects experien ced decreases ≥10%, which have been previously determined to be of clinical relevance. These results fit well with those from multiple other studies of ozone’s effect on lung function at concentrations ≥0.080 ppm, which have consistently shown that

some i ndividuals are more sensitive to this effect of ozone than others. The selection of a2

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- NAAQS for ozone needs to consider an adequate margin of safety to protect the most sensitive subgroup of individuals. Since the scientific evidence was reviewed for the preparation of the 2006 Criteria Document for Ozone, the results of the Adams et al. (2006) study have been carefully reanalyzed (Brown et al., 2008) and actually show a statistically significant group effect. In addition, two other studies have shown st atistically significant

decrements in FEV1 after 6.6

- hour exposures to 0.070 ppm (Schelgele et al., 2009) and 0.060 ppm (Kim et al., 2011), respectively.

4. With respect to the information from controlled human exposure studies at 0.060 ppm O 3
, what is the scientific importance of the small, group mean FEV 1 decrements relative to the findings that 7 to 20% of the subjects experienced FEV 1 decrements ≥ 10%? Please consider this question from both a public health and a clinical perspective.

From a clinical pe rspective, a 10% decrement in FEV1 is often associated with respiratory symptoms, especially in individuals with pre

- existing pulmonary or cardiac disease. For example, people with chronic obstructive pulmonary disease have decreased ventilatory reserve ( i.e., decreased baseline FEV1) such that a ≥10% decrement could be associated with moderate to severe respiratory symptoms. From a public health perspective, the exposure and risk assessment conducted for the last review of the ozone NAAQS clearly documen t that a substantial proportion of the U.S. population is exposed to levels of ozone at the various alternative standards considered. This means that even if a NAAQS of 0.060 ppm were to be selected, some sensitive individuals could still be exposed to co ncentrations that could cause them to have a clinically relevant decrement in lung function.

5. The evidence, including that summarized above, indicates that susceptible populations may have greater responses than healthy people. In light of this evidence, h ow can we appropriately use the results of controlled human exposure studies conducted on healthy adults, as well as the epidemiological studies of susceptible groups, to inform a judgment on the effects of ozone exposure on susceptible populations?

Contr olled human exposure studies have shown that individuals with asthma have enhanced responses to ozone, in terms of both airway inflammation and lung function decrements with exercise. Epidemiological studies have shown that such individuals are at increas ed risk of exacerbations of their disease on or shortly after days with elevated ambient ozone concentrations. Taken together, the results of these studies provide strong evidence that people with asthma are a subgroup of the population with increased sus ceptibility to ozone. Given the effects on lung function that have been documented in healthy adults exposed to

ozone at concentrations ≤0.080 ppm, a NAAQS with a margin of safety is necessary to protect the susceptible population of children and adults w ith asthma. Older individuals with pre

- existing lung and heart disease, who have not been adequately investigated in controlled human exposure studies, as well as young children who cannot participate in such studies, may also be more susceptible than the healthy young adults who have been studied to

date.

6. To what extent does your confidence that the effects observed in epidemiological studies2

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- are attributable specifically to O 3 lessen or otherwise change, if at all, at the lower levels in the proposed ra nge as compared to the higher levels?

While the effects of ozone cannot be easily isolated from the effects of other pollutants in epidemiological studies , health care utilization for asthma has been shown to decrease when ozone concentrations are decreased. For example, when traffic density was decreased during the Summer Olympic Games in Atlanta in 1996, there was significantly decreased use of pediatric care for asthma that correlated best with a reduction in peak ozone concentrations (Friedman et al., 2001). In this study, the relative risk of asthma events increased stepwise at

cu mulative ozone concentrations 0.060 to 0.089 ppm and 0.090 ppm or more c ompared with

ozone concentrations of less than 0.0 60 pp m. The reduction of the adver se effects on asthma in this study was dependent on reduction of ozone exposures to levels below 60 ppb

.

7. EPA’s exposure assessment quantified the number of all children and asthmatic children likely to be exposed to specific benchmark levels of ozone, including in particular 0.060 and 0.070 ppm. Considering the patterns of change in the estimates of exposures of concern at and above the 0.060 and 0.070 ppm benchmark levels, and the uncertainties and limitations in the estimates, what is the relative importance from a public health perspective of the estimated reductions in exposures of concern, as well as the exposures remaining, for alternative standards across the proposed range?

The cumulative evidence to date on the ozone exposure

- lung function response relationship strongly suggests that it is linear with no threshold, at least through 0.060 ppm. Theref ore, it is reasonable to assume a similar exposure

- response relationship for exacerbations of asthma. Considering the patterns of change in the estimates of exposures at alternative standards, as well as the uncertainties and limitations of the estimates, it is likely that susceptible individuals would still be adversely affected at a NAAQS of 0.060 ppm, although the number of such individuals would be substantially lower than at higher alternate

standards

.

8. EPA’s quantitative risk assessment estimated the numbers of occurrences of various ozone related health effects associated with just meeting alternative standard levels down to a standard level of 0.064 ppm. Considering the patterns of change in the estimates of health effects in the risk assessment at the alternative standard levels, and the uncertainties and limitations in the estimates, what is the relative importance from a public health perspective of the estimated reductions in risk, as well as the risk remaining, for alternative standards across t he proposed range? Please consider this question in light of the scientific evidence as a whole.

In addition to what I have stated in my responses to the previous seven questions, it is also important to consider the effect of reductions in exposures to o zone on mortality with the alternate standards. Although the evidence from epidemiological studies of ozone

- related mortality published prior to 2006 was not considered sufficiently robust by CASAC to serve as the basis for a new NAAQS, EPA estimated effe cts on mortality in the exposure and risk assessment components of the 2007 Staff Paper. The evidence regarding the ozone exposure

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- mortality relationship has grown stronger since the publication of the Staff Paper (e.g., Jerrett et al., 2009) and a mortal ity effect was seen at concentrations below the current

standard.

References Cited:

Brown JS, Bateson TF, McDonnell WF. 2008. Effects of exposure to 0.06 ppm ozone on FEV 1 in humans: A secondary analysis of existing data. Environ Health Perspect 116 :1023

- 1026

.

Friedman MS, Powell KE, Hutwagner L, Graham LM, Teague WG. 2001. Impact of changes in transportation and commuting behaviors during the 1996 Summer Olympic Games in Atlanta on air quality and childhood asthma. JAMA 285 :897

- 905.

Jerrett M, Bur nett RT, Pope CA 3rd, Ito K, Thurston G, Kre wski D, Shi Y, Calle E, Thun M. 2009. Long

- term ozone exposure and mortality. N Engl J Med 360 :1085

- 10 95.

Kim CS, Alexis NE, Rappold AG, Kehrl H, Hazucha Mj, Lay JC, Schmitt MT, Case M, Devlin RB, Peden DB, Diez

- Sanchez D. 2011. Lung function and inflammatory responses in healthy young adults exposed to 0.06 ppm ozone for 6.6 hours. Am J Respir Crit Care Med Jan 7 [Epub ahead of print]

.

Schelegle ES, Morales CA, Wa lby WF, Marion S, Allen RP. 6.6

- hour inhalation of ozone concentration from 60 to 87 parts per million in healthy humans . 2009. Am J Respir Crit Care Med

1 80:265

- 272.2

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### James **Gauderman**

Charge Question # 4. With respect to the information from controlled human exposure studies at 0.060 ppm O3, what is the scientific importance of the small, group mean FEV1
decrements relative to the findings that 7 to 20% of the subjects experienced FEV1
decrements ≥ 10%? Please consider this question from both a public health and a clinical perspective.

In the re

- analysis of Adams (2006) study of 30 subjects by EPA ( Brown

, 2007) , a small but statistically significant decline in FEV1 was observed. Specifically, a 2.85% mean O3

- induced decline in FEV1 was observed following 6.6 hr square wave exposure to 0.060

pp m O3 compared to 6.6 hr filtered air (FA) exposure. The statistical analysis by EPA was based on a straightforward paired comparison, and they conservatively used a nonparametric sign test to obtain a p

- value of 0.002 for the 0.06 ppm vs. FA comparison. Alternative, more powerful analytic methods using either a Wilcoxon signed

- rank test or a paired t

- test yielded even lower p

- values in the EPA analysis. The EPA comparison remained significant after a Bonferroni correction for multiple comparisons. The o riginal analysis of the data by Adams did not find a significant difference in FEV1 between the 0.06 and FA exposure conditions. However, that analysis was based on a Scheffe correction for multiple comparisons, which is known to have very low power for t he type of pairwise comparisons conducted by Adams compared to other well

- known methods for multiple

- testing correction (Kirk, 1982). Thus, from my understanding of the statistical analyses that have been conducted, I would argue that the analysis by EPA should be preferred to that of Adams for the specific comparison of the FEV1 effects of 0.06 ppm exposure relative to FA exposure.

Of the 30 study subjects in Adams, 24 showed some evidence for an O3

- induced decline in FEV1, and 2 of the 30 (7%) experi enced a decline greater than 10%. Although the sample size is relatively small, the consistency of effects across O3 exposure levels, as well as the consistency with effects observed by an earlier independent study (McDonnell, 2002), indicates that the ob served deficits in FEV1 at the 0.060 ppm from the Adams study are not spurious. In other words, it is likely that prolonged exposure to 0.06 ppm O3 causes a general shift in the distribution of FEV1 towards lower values. The following plot of the Adams d ata, derived from Figure 8

- 2 of Volume I of the “ Air Quality Criteria for Ozone and Related Photochemical Oxidants, 2006 ” document, shows an approximate normal distribution in the O3

- induced changes in FEV1 with exposure to 0.06 ppm.2

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- Althoug h the mean decrement is less than 3% and would not be considered clinically important, the shift to the right in this distribution pushes a fraction of subjects into the region that becomes clinically interesting (>10%). All of the Adams study subjects we re healthy volunteers. From a public health standpoint, these results suggest that a large number of individuals in the general population (that are otherwise healthy), are likely to experience FEV1 deficits greater than 10% with prolonged exposure to 0.0 6 ppm O3. Although most healthy individuals can probably sustain a short

- term 10

- 15% decline in FEV1 with little or no noticeable effect, it is not clear how they might be affected in the longer term if they experience repeated lung function deficits due to 0.06 ppm or greater O3 exposures over multiple days or weeks. Based on several other controlled exposure studies, we might expect that O3

- induced FEV1 deficits in subjects with an existing respiratory condition (e.g. asthma) would be shifted even furth er to the right compared to the above figure. A 10

- 15% (or greater) pollution

- related deficit in FEV1 in an individual with an existing respiratory condition is large enough that it could cause a clinically observable response.2

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### Rogene Henderson

Febr uary 9, 2011

1. What is your advice on the overall strengths and limitations of the evidence from controlled human exposure and epidemiological studies and the results of the exposure and risk assessments,

in the context of EPA's selection of a standard level within the proposed range that would be requisite to protect public health with an adequate margin of safety, including the need to protect susceptible populations, such as children and people with asthma?

I reviewed the previous correspondence betw een CASAC and the Agency as well as the Federal Register notice of the reconsideration of the 2008 primary NAAQS for ozone and found that the evidence from controlled human exposures and epidemiological studies, as well as the results of the exposure and r isk assessments, fully supported the selection of the primary ozone standard in the range of 0.060 to 0.070 ppm to protect public health with a margin of safety. Human exposure studies provide the most direct evidence of the health

effects on humans and the studies clearly show that adverse effects occur in some healthy adults after exposure for 6.6 hr to 0.060 ppm ozone. This finding has recently been confirmed in clinical studies in 59 healthy young adults exposed to 0.060 ppm ozone for 6.6 hours (Kim et al., dol:10.1164/rccm.201011

- 18130C, Lung function and inflammatory responses in healthy young adults exposed to 0.060 ppm ozone for 6.6 hours.) Asthmatic persons are known to be more sensitive to ozone than are healthy persons. Therefore, to provide some margin of safety, the standard must take into consideration these sensitive subpopulations.

2.. Recognizing that controlled human exposure studies at 0.080 ppm O 3 and above have provided evidence of other health effects, including inflammation and increased airway responsiveness which may occur through different physiological mechanisms than the reduction in

FEV 1 , how should the results of these studies inform our understanding the health effects to healthy adults at exposures levels from 0.060 to 0.070 ppm?

These additional health

- effect endpoints should definitely be taken into account in setting the standards to the extent that information is available. The recent publication by Kim et al. (2011) provides information on both types of endpoints endpoints.

3. How should the results of the controlled human exposure studies at 0.060 ppm O 3 , showing

effects on FEV 1 and respiratory symptoms, in the context of the larger body of evidence from controlled human exposure studies, mentioned above, inform our understanding of the health effects to healthy adults at exposure levels from 0.060 to 0.070 ppm?

The results of human controlled exposures to 0.080. 0.070. and 0.060 form a continuum of

lev els of effect that must all be considered in setting a standard with a margin of safety. The results of the 0.06 ppm exposures provide increased confidence and decreased uncertainty about the health effects of ozone exposure at that concentration. Thus i t essential that the2

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- results of the controlled human exposure studies at 0.060 ppm be taken into consideration for the understanding of the health effects of ozone in the range of 0.070

- 0.060 ppm.

4. With respect to the information from controlled human e xposure studies at 0.060 ppm O 3 , what is the scientific importance of the small, group mean FEV 1 decrements relative to the findings that 7 to 20% of the subjects experienced FEV 1 decrements ≥ 10%? Please consider this question from both a public health and a clinical perspective.

I am not a clinician, so will not comment on that aspect. From a public health viewpoint, I think the effect is significant. The Clean Air Act requires that a margin of safety be taken into account, and from a public health v iewpoint, the 0.060 level does induce adverse health effects in a portion of the healthy community and those effects are likely to be greater in the asthmatic population.

5. The evidence, including that summarized above, indicates that susceptible populat ions may have greater responses than healthy people. In light of this evidence, how can we appropriately use the results of controlled human exposure studies conducted on healthy adults, as well as the epidemiological studies of susceptible groups, to info rm a judgment on the effects of ozone exposure on susceptible populations.

The epidemiology data showing increased use of medication, school absences, and hospital admissions is one way to evaluate the response of sensitive populations to ozone. The

co ntrolled human exposures gives you a ceiling level which is higher than the level that would be protective of sensitive populations

.

6. To what extent does your confidence that the effects observed in epidemiological studies are attributable specifically to O 3 lessen or otherwise change, if at all, at the lower levels in the proposed range as compared to the higher levels?

For any pollutant, as one goes down the dose

- response curve to lower levels of exposure,

confidence in the effects seen decrease and uncertainties increase. However, the effects of ozone exposure can best be considered as a continuum, with decreasing incidence or severity with decreasing exposure. However, the endpoints of concern remain the same, providing

some confidence that the e ffects are due mainly to ozone.

7. . EPA’s exposure assessment quantified the number of all children and asthmatic children likely to be exposed to specific benchmark levels of ozone, including in particular 0.060 and 0.070 ppm. Considering the patterns o f change in the estimates of exposures of concern at and above the 0.060 and 0.070 ppm benchmark levels, and the uncertainties and limitations in the estimates, what is the relative importance from a public health perspective of the estimated reductions in exposures of concern, as well as the exposures remaining, for alternative standards across the proposed range?

The exposure assessments were reasonable and made with the best data available. The

assessments indicate that the number of children and asthm atic children exposed to ozone levels of concern is significant from a public health viewpoint.2

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- 8. . EPA’s quantitative risk assessment estimated the numbers of occurrences of various ozone related health effects associated with just meeting alternative standard levels down to a standard level of 0.064 ppm. Considering the patterns of change in the estim ates of health effects in the risk assessment at the alternative standard levels, and the uncertainties and limitations in the estimates, what is the relative importance from a public health perspective of the estimated reductions in risk,

as well as the r isk remaining, for alternative standards across the proposed range? Please consider this question in light of the scientific evidence as a whole.

The CASAC took into account the uncertainties associated with assessing the risks to low

levels of ozone and concluded that in a range of 0.060 to 0.070 ppm exposures, one could have confidence in the observed effects. I am still in agreement with that conclusion.2

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### Philip K. Hopke

The charge questions provided to the ozone panel revolve primarily arou nd the toxicological and epidemiological evidence for the adverse health effects of exposure to ozone and other oxidants. One critical aspect that I believe is generally lost in the discussion is the presence of other photochemical oxidants. Thus, if we are looking at controlled exposures to ozone alone, we will be underestimating the effects of the total collection of oxidants in the ambient atmosphere. Epidemiology would take these other oxidants into account to some greater or lesser extent with

respe ct to the covariance of the other ambient oxidants with ozone. However, central monitors particularly monitors typically placed in downwind locations in urban areas to avoid significant titration effects of motor vehicle emissions, may not be an adequate measure of population exposure across that urban area.

We also have to recognize the full extent of the change made with the promulgation of the 2008 ozone NAAQS. By changing the reported precision of the measurements, we have effectively

lowered the st andard from 84 ppb to 75.4 ppm and not from 80 to 75 ppb. This difference is a relatively large reduction whose effects have not yet been fully felt. Given that there is another review underway and this review is not supposed to take new literature into account, my recommendation would be that the standard not be lowered any further than 70.0 ppb, the upper end of the range judged as likely to be protective of public health, and reexamine all of the body of information available as part of the current rou nd of review. Then a better informed judgment can

be rendered.

Charge Question # 4. With respect to the information from controlled human exposure studies at 0.060 ppm O3, what is the scientific importance of the small, group mean FEV1
decrements relative to the findings that 7 to 20% of the subjects experienced FEV1
decrements ≥ 10%? Please consider this question from both a public health and a clinical perspective.

In the re

- analysis of Adams (2006) study of 30 subjects by EPA ( Brown

, 2007) , a small
but statistically significant decline in FEV1 was observed. Specifically, a 2.85% mean O3

- induced decline in FEV1 was observed following 6.6 hr square wave exposure to 0.060 ppm O3 compared to 6.6 hr filtered air (FA) exposure. The statistical analysis by E PA was based on a straightforward paired comparison, and they conservatively used a nonparametric sign test to obtain a p

- value of 0.002 for the 0.06 ppm vs. FA comparison. Alternative, more powerful analytic methods using either a Wilcoxon signed

- rank te st or a paired t

- test yielded even lower p

- values in the EPA analysis. The EPA comparison remained significant after a Bonferroni correction for multiple comparisons. The original analysis of the data by Adams did not find a significant difference in FEV 1 between the 0.06 and FA exposure conditions. However, that analysis was based on a Scheffe correction for multiple comparisons, which is known to have very low power for the type of pairwise comparisons conducted by Adams compared to other well

- known me thods for multiple

- testing correction (Kirk, 1982). Thus, from my understanding of the statistical analyses that have been conducted, I would argue that the analysis by EPA should be2

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- preferred to that of Adams for the specific comparison of the FEV1 effec ts of 0.06 ppm exposure relative to FA exposure.

Of the 30 study subjects in Adams, 24 showed some evidence for an O3

- induced decline in FEV1, and 2 of the 30 (7%) experienced a decline greater than 10%. Although the sample size is relatively small, t he consistency of effects across O3 exposure levels, as well as the consistency with effects observed by an earlier independent study (McDonnell, 2002), indicates that the observed deficits in FEV1 at the 0.060 ppm from the Adams study are not spurious. I n other words, it is likely that prolonged exposure to 0.06 ppm O3 causes a general shift in the distribution of FEV1 towards lower values. The following plot of the Adams data, derived from Figure 8

- 2 of Volume I of the “ Air Quality
Criteria for Ozone an d Related Photochemical Oxidants, 2006 ” document, shows an approximate normal distribution in the O3

- induced changes in FEV1 with exposure to 0.06 ppm.

Although the mean decrement is less than 3% and would not be considered clinically important, the shift to the right in this distribution pushes a fraction of subjects into the region that becomes clinically interesting (>10%). All of the Adams study subj ects were healthy volunteers. From a public health standpoint, these results suggest that a large number of individuals in the general population (that are otherwise healthy), are likely to experience FEV1 deficits greater than 10% with prolonged exposure to 0.06 ppm O3. Although most healthy individuals can probably sustain a short

- term 10

- 15% decline in FEV1 with little or no noticeable effect, it is not clear how they might be affected in the longer term if they experience repeated lung function defici ts due to 0.06 ppm or greater O3 exposures over multiple days or weeks. Based on several other controlled exposure studies, we might expect that O3

- induced FEV1 deficits in subjects with an existing respiratory condition (e.g. asthma) would be shifted eve n further to the right compared to the above figure. A 10

- 15% (or greater) pollution

- related deficit in FEV1 in an individual with an existing respiratory condition is large enough that it could cause a clinically observable response.2

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- Charge Question 5. The evidence, including that summarized above, indicates that susceptible populations may have greater responses than healthy people. In light of this evidence, how can we appropriately use the results of controlled human exposure studies conducted on healthy adults, as well as the epidemiological studies of susceptible groups, to inform a judgment on the effects of ozone exposure on susceptible populations?

Response

-- In many ways, the lowest exposure level of 0.06 ppm showing some symptom changes a nd statistically significant lung function changes in healthy subjects in an EPA analysis conducted for the last O3 NAAQS review represented a greatest lower bound on the ozone concentration of public health concern. In all of the controlled human exposure studies at 0.08

- ppm ozone and below, a reasonable percentage of healthy subjects have lung function changes much higher than the average response (e.g., FEV1 changes > 10 %). While FEV1 changes > 10% may still allow healthy individuals to go about their n ormal daily activities, individuals with compromised lungs, such as asthmatics, incur significant health impacts with such lung function changes. As CASAC has noted in the past to the Agency, evidence is accumulating that persons with asthma, and particula rly children, are more sensitive and experience larger decrements in lung

function due to O 3 exposure than do healthy volunteers.

This, coupled with the fact that a number of epidemiology studies discussed in the last review were
showing O 3 - related effec ts on various health endpoints (e.g., emergency department visits, increased hospital emissions, and mortality increases) at relatively low exposure levels leads one to

conclude that O 3 may cause effects even below 0.06 ppm. Since strengthening such a conc lusion would need additional data from new studies, the CASAC concluded at the last review that the
lower range of consideration for revision of the NAAQS should be 0.060 ppm O 3 . By doing so, the
CASAC felt that margin of safety considerations would better be met than at 0.070 ppm O 3

. Moreover, since the relative strength of the science is weaker as one lowers the O 3 concentration
under consideration, a range of 0.060 to 0.070 ppm O 3 allows the Administrator to place her judgment on the weight that any unce rtainties and limitations in the science play in selecting an exposure level protective of public health.2

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- 

### Lianne Sheppard

February 11, 2011

Individual comments I still fully agree with the advice provided by CASAC in its letters of October 24, 2006 (E PA

CASAC

- 07

- 001), March 26, 2007 (EPA

- CASAC

- 07

- 002), and February 10, 2010 (EPA

- CASAC

10

- 007). My opinion has been strengthened by the experience I have gained since 2008 through my continued involvement in air pollution and health research; this has cont ributed to my updated understanding of the evidence available in the 2008 review. :

Preliminary thoughts on a draft response to Charge Question 6 (for CASAC discussion) 6. To what extent does your confidence that the effects observed in epidemiological stu dies are attributable specifically to O 3 lessen or otherwise change, if at all, at the lower levels in the proposed range as compared to the higher levels? :

Possible points for CASAC’s response:

**•** The endpoints of concern do not change at the lower levels of the proposed range.

**•** Many of the epidemiological studies had mean exposures well below the proposed range of 0.070 ppm to 0.060 ppm and found ozone

- related health effects. These include time series studies, field studies, and panel studies. The strengths and weaknesses of these studies do not differ appreciably in the proposed range.

**•** The epidemiological evidence does not suggest a threshold exists for mean concentrations within or above the proposed range.

**•** While it is always difficult to tease out the e ffects of a single pollutant in epidemiological studies, there is evidence regarding ozone

- related health effects from epidemiological studies

that is consistent with the evidence from controlled exposure studies. This holds for the entire proposed range.

**•** While the effects attributed to ozone in epidemiological studies may not be specific to ozone, it is likely that reductions in population exposures to ozone will result in fewer adverse health effects. Our confidence in this statement does not change at the lower levels in the proposed

range.2

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- 

### Frank Speizer

Feb 8, 2011

Charge Question 1. What is your advice on the overall strengths and limitations of the evidence from controlled human exposure and epidemiological studies and the results of the exposure and risk assessments, in the context of EPA's selection of a standard level within the proposed range that would be requisite to protect public health with an adequate margin of safety, including the need to protect susceptible populations, such a s children and people with asthma?

Although the two Adams studies represent the only reported work at levels of exposure below 0.080 ppm of Ozone what has been pointed out and what is highly significant is that first the

studies were done in normals and s econd that some 7

- 20% of the subjects experienced what I would consider very significant lung function decreases (> 10%) and or moderate respiratory symptoms. These findings essential preclude, because of the ethics of carrying out clinical studies

in dis eased individuals, from extending these studies to what are likely to be an even more sensitive groups. Thus, without having specific studies among asthmatics and children at these levels of exposure it is most prudent that, in spite of the uncertainty

— mor e later on this issue

— that EPA is justified to select an exposure level below the 0.080pppm (and I would say closer to the 0.060 ppm level) to “protect public health with an adequate margin of safety, including the need to protect susceptible populations...”

Charge Question 2. Recognizing that controlled human exposure studies at 0.080 ppm O 3 and above have provided evidence of other health effects, including inflammation and increased airway responsiveness which may occur through different physiological me chanisms than the reduction in

FEV 1 , how should the results of these studies inform our understanding the health effects to healthy adults at exposures levels from 0.060 to 0.070 ppm?

Given the evidence of pathophysiologic changes in smaller airways with exposures at 0.08 ppm as well as the occurrence of pulmonary function changes in a substantial number of normal subjects, the only mechanism that would change these finding in diseased subjects if there were some way that the diseased airways, perhaps bec ause of the presence of excess mucus, would be “protected” from the potential oxidative effects of ozone. This seems highly unlikely in that disease subjects studied at 0.08 ppm and higher seem to respond more than normals and thus would not likely be

pro tected more at the lower levels to which normals have responded. Clearly, these experiments have not been done and one might argue that thus there is uncertainty; however, as indicated above such experiments might be considered unethical.

Charge Questi on 3. How should the results of the controlled human exposure studies at 0.060 ppm

O 3 , showing effects on FEV 1 and respiratory symptoms, in the context of the larger body of2

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- evidence from controlled human exposure studies, mentioned above, inform our under standing of the health effects to healthy adults at exposure levels from 0.060 to 0.070 ppm? Because these results represent a continuum of effects and it is unlikely that there is a threshold I would argue that the results are informative and suggest that EPA in carrying out its obligation must suggest a standard in the range indicated. I would argue that because there is no threshold that the data are consistent with the lower end of the range being more protective than the upper

end.

Charge Question 4. With respect to the information from controlled human exposure studies at 0.060 ppm O 3 , what is the scientific importance of the small, group mean FEV 1 decrements relative to the findings that 7 to 20% of the subjects experienced FEV 1 decrements ≥ 10%? Please consider this question from both a public health and a clinical perspective.

Please see answer to Charge Question 1 and 3. These small numbers of up to one

- fifth of normals of the studied populations having changes in lung function or symptoms of this magnitude strongly suggests that the susceptible population would respond even greater and could reach clinically significant responses that might result in emergency room visits and or hospitalizations.

Charge Question 5. The evidence, including t hat summarized above, indicates that susceptible populations may have greater responses than healthy people. In light of this evidence, how can we appropriately use the results of controlled human exposure studies conducted on healthy adults, as

well as th e epidemiological studies of susceptible groups, to inform a judgment on the effects of ozone exposure on susceptible populations?

It would be difficult to make an actual estimate of the difference in impact that might occur

between 7

- 20% of normals respo nding and even a similar if not greater number of diseased subjects who might have similar size responses. It would be reasonable to assume that the responses certainly would not be less frequent and are likely to be of greater magnitude or at least large enough to increase the likelihood that symptomatic responses would need to be treated. Given the substantial number of potentially at risk adults in the population and the distributions of possible exposures even at the lower level of the bounded exposur es it would be prudent to argue that there will be some individuals remaining at risk. The judgment is how large a population is the Administrator willing to tolerate as being still at risk, not whether she can protect the entire population of potentially susceptible individuals.

Charge Question 6. To what extent does your confidence that the effects observed in epidemiological studies are attributable specifically to O 3 lessen or otherwise change, if at all, at the lower levels in the proposed range as compared to the higher levels?

Clearly there is greater uncertainty at the lower bound of the range of exposure; however, whether this is due to the mixture of addition pollutants coming into play rather than simply more variability in response cannot be determined. The few cities in which there are essentially no alternative pollutants to consider or where seasonal selection has been used to minimize alternative pollutants still show similar effects, and thus the likely cause of the uncertainly relates to greater2

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- variability rather than confounding by additional pollutants and thus the effects noted seem attributable to ozone pollution.

Charge Question 7. EPA’s exposure assessment quantified the number of all children and asthmatic children likely to be exposed to specific benchmark levels of ozone, including in particular 0.060 and 0.070 ppm. Considering the patterns of change in the estimates of exposures of concern at and above the 0.060 and 0.070 ppm benchmark levels, and the uncertainties and

limi tations in the estimates, what is the relative importance from a public health perspective of the estimated reductions in exposures of concern, as well as the exposures remaining, for alternative standards across the proposed range?

As indicated in the di scussion across the 12 urban areas the assessment are considerably larger for the benchmark level of 0.60 ppm compared to the 0.070 ppm benchmark. However, they also note that the pattern of exposure is similar for all children and asthmatic school age ch ildren. The Administrator also stated that she must consider the public health impact in cities receiving considerably less protection associated with air quality just meeting the same standard. This is a difficult criteria to meet with a single standard . Thus it becomes prudent to weigh the impact of the exposure against the cost of meeting that standard. The science is clear that there will be children as risk at any reasonable standard chosen. Thus the public health consideration is how big a popula tion the Administrator is willing to leave at risk.

Charge Question 8. EPA’s quantitative risk assessment estimated the numbers of occurrences of various ozone related health effects associated with just meeting alternative standard levels down

to a st andard level of 0.064 ppm. Considering the patterns of change in the estimates of health effects in the risk assessment at the alternative standard levels, and the uncertainties and limitations in the estimates, what is the relative importance from a publi c health perspective of the estimated reductions in risk, as well as the risk remaining, for alternative standards across the proposed range? Please consider this question in light of the scientific evidence as a whole.

From the Fed Reg T ABLE 3

— N UMBER AND P ERCENT OF A LL AND A STHMATIC S CHOOL A GE C HILDREN IN 12
U RBAN A REAS E STIMATED TO E XPERIENCE 8

- H OUR O ZONE E XPOSURES A BOVE 0.060 AND 0.070 PPM W HILE AT M ODERATE OR G REATER E XERTION ,O NE OR M ORE T IMES PER S EASON A SSOCIATED W ITH J UST M EETING A LTERNATIVE 8

- H OUR S TANDARDS B ASED ON A DJUSTING 2002 AND 2004 A IR Q UALITY D ATA 1 2 This table not reproduced here suggests a wide range of at risk children dependent upon the choice of levels of exposure. Unfortunately, it is not clear that 2002 is the “worse case” or 2004 i s the “best case”. Nevertheless, with regard to protecting the public health the range of all children aged

5

- 18 between 0.064

- 0.074 is between 4.5 million and 950, 000 in the worse case vs 350,000 and 10,000 in the best case, with proportionately lower n umbers for asthmatic children. Clearly truth must lay somewhere in between. Even these lower numbers represent a substantial fraction of at risk children. Given the evidence of the pathophysiology, the clinical studies data in normals and

the likelihood that symptomatic subjects will respond to a greater degree, and the fact that there is no evidence for a threshold of effects, the prudent decision is to set a standard that is as protective of the public health with a margin of safety as mandated by law.2

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- 

### Helen Suh

1. What is your advice on the overall strengths and limitations of the evidence from controlled human exposure and epidemiological studies and the results of the exposure and risk assessments, in the context of EPA's selection of a standard level within the proposed range that would be requisite to protect public health with an adequate margin of safety, including the need to protect susceptible populations, such as children and people with asthma?

The scientific evidence from contr olled human exposure and epidemiological studies and from the exposure and risk assessments supports a primary ozone standard (with a margin of safety)

between 0.060 to 0.070 ppm. The controlled h uman exposure studies by Adams (2002, 2006)

show statistica lly significant changes in lung function from a 6.6 hour exposure to 0.060 ppm

ozone. While these studies were limited in number, they were well designed and results were consistent with those from previous studies, thus lending credibility to their findi ngs. Of particular interest is the fact that a small but important fraction of the study subjects experienced lung function decrements greater than 10% at exposures to 0.060 ppm ozone. These findings suggest that the impacts of ozone exposures at these l evels may be significant for individuals with pre

- existing respiratory conditions and must be considered to ensure adequate margin of safety for sensitive subpopulations.

2. Recognizing that controlled human exposure studies at 0.080 ppm O 3 and above h ave provided evidence of other health effects, including inflammation and increased airway responsiveness which may occur through different physiological mechanisms than the reduction in FEV 1 , how should the results of these studies inform our understandin g the health effects to healthy adults at exposures levels from 0.060 to 0.070 ppm?

It is reasonable to consider findings of sub

- clinical adverse impacts, such as increased inflammation and airway responsiveness, when considering adverse health impacts to healthy adults at exposures levels from 0.060 to 0.070 ppm . These findings are certainly pertinent to margin of safety considerations.

3. How should the results of the controlled human exposure studies at 0.060 ppm O 3 , showing effects on FEV 1 and respiratory symptoms, in the context of the larger body of evidence from controlled human exposure studies, mentioned above, inform our understanding of the health effects to healthy adults at exposure levels from 0.060 to 0.070 ppm?

These results provide important evidence that exposures to 0.060 ppm of ozone are harmful and are consistent with previous observations of no safe level for ozone exposures. Findings from Adams studies (2002, 2006) must be considered, at the least as being central to margin o f safety determinations.

4. With respect to the information from controlled human exposure studies at 0.060 ppm O 3
, what is the scientific importance of the small, group mean FEV 1 decrements relative to the2

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- findings that 7 to 20% of the subjects experienced FEV 1 decrements ≥ 10%? Please consider this question from both a public health and a clinical perspective.

For individuals with pre

- existing respiratory disease, a 10% decrement in FEV1 is significant.

5. The evidence, including that summa rized above, indicates that susceptible populations may have greater responses than healthy people. In light of this evidence, how can we appropriately use the results of controlled human exposure studies conducted on healthy adults, as well as the epidemi ological studies of susceptible groups, to inform a judgment on the effects of ozone exposure on susceptible populations.

Although the sample sizes are small, the variability in the response observed for healthy adults

in the controlled human studies can inform judgments on the effects of ozone in susceptible populations. For example, the 7

- 20% of healthy adults who were found to have large ozone

mediated responses in controlled exposure studies may provide an indication of the fraction of

individuals in the general population who may also be large responders. Ozone

- mediated response may comprise an even greater percentage of the susceptible population.

6. To what extent does your confidence that the effects observed in epidemiological studies are

att ributable specifically to O 3 lessen or otherwise change, if at all, at the lower levels in the proposed range as compared to the higher levels?

The uncertainty in the epidemiological findings at low ozone levels is certainly greater than that at high ozone levels , with greater confidence about the existence of health effects at the upper end and less confidence at lower O 3 levels

. Confounding by other pollutants is certainly of concern. However, ozone mediated impacts have been observed for a variet y of endpoints, including those such as school absences that have not been related to particulate matter (PM), perhaps the most important potential confounder. Further, ozone

- mediated impacts have been demonstrated in a number of locations, with varying c orrelations between ozone and PM. Finally, additional support for epidemiological findings is provided by results from controlled exposure studies.

7 . EPA’s exposure assessment quantified the number of all children and asthmatic children likely to be exposed to specific benchmark levels of ozone, including in particular 0.060 and 0.070 ppm. Considering the patterns of change in the estimates of exposures of concern at and above the 0.060 and 0.070 ppm benchmark levels, and the uncertainties and limita tions in the estimates, what is the relative importance from a public health perspective of the estimated reductions in exposures of concern, as well as the exposures remaining, for alternative standards across the proposed range?

The exposure assessment shows considerable temporal and spatial variability in exposure estimates, which is expected and which has important implications in determinations about adequate margin of safety. Given results from health studies, it is reasonable to assume no

threshold in ozone

- mediated impacts. As a result, even with uncertainty in the benchmark2

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- exposures, it is likely that a significant fraction of asthmatic children will remain exposed to ozone exposures above the benchmark level.

8 . EPA’s quantitative risk assessment estimated the numbers of occurrences of various ozone related health effects associated with just meeting alternative standard levels down to a standard level of 0.064 ppm. Considering the patterns of change in the estimates of health effects in the risk assessment at the alternative standard levels, and the uncertainties and limitations in the estimates, what is the relative importance from a public health perspective of the estimated reductions in risk, as well as the risk remaining, for altern ative standards across the proposed range? Please consider this question in light of the scientific evidence as a

whole.

The quantitative risk assessment showed public health significant reductions in risk in going from a 0.074 ppm to a 0.064 ppm standard . As acknowledged by the Administrator, reductions in risk may be even greater, as the risk assessment examined only a fraction of the observed health outcomes, with many unexamined health outcomes posing greater risks for sensitive subgroups. These lim itations may outweigh, or at the least counteract, any concerns regarding uncertainty in the risk estimates.