2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -1- 

### Contents

George Allen ................................................................................................................... ......................2

John Balmes .................................................................................................................... ......................6

James Gauderman ...................................................................................................................... .........10

Rogene Henderson ............................................................................................................... ...............12

Philip K. Hopke................................................................................................................ ...................15

Morton Li ppmann ................................................................................................................ ...............18

Fred Miller.................................................................................................................... .......................22

Lianne Sheppard................................................................................................................ ..................23

Frank Sp eizer.................................................................................................................. .....................24

Helen Suh ...................................................................................................................... ......................27

James Ultman ................................................................................................................... ...................302-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -2- 

### George Allen

Caveat: With regard to the range of ozone c oncentrations under cons ideration, these comments

assume the form of th e NAAQS will remain uncha nged from what was pr omulgated in the 2008 rule. Any change in the form (daily averag e 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 ev idence 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?

As with nearly all other pollutants, the expo sure-response relationship is stronger and more scientifically robust as you go to higher concentrations. This holds for both controlled human exposures and epidemiological studies. Both appr oaches have their limitations, especially toward the lower end of the proposed range. The contro lled exposure studies usually do not include sensitive and vulnerable populations (SVP) as subjec ts; 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 markers such as FE V1 and inflammatory markers th at 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 confou nding from other pollutants and uncontrolled variables; these factors would us ually bias effect results toward the null. However, since the ambient ozone measurements used in epidemiologi cal studies are 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 studies where other strong oxid ants are presumably no t 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 indoor s (Weschler, Atmospheri c Environment 38 (2004)

5715

B 5716); these include a wide range of gas-phase re spiratory irritants and ultra-fine particles.

Q2. Recognizing that contro lled human exposure studies at 0.080 ppm O3 and above have provided evidence of other health effects, in cluding inflammation and increased airway responsiveness which may occur through different ph ysiological mechanisms than the reduction in FEV1, how should the results of these studies info rm our understanding the health effects to healthy adults at exposures levels from 0.060 to 0.070 ppm?2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -3- As noted in the background material included in th ese charge questions, the available data suggest that there probably is a reasonably A smooth exposure-response curve @ going from .080 to .060 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 th e controlled human exposure studi es at 0.060 ppm O3, showing effects on FEV1 and respiratory symptoms, in th e 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 studies support the concept of a reasonably smooth exposure-response curve down to these levels as opposed to a health effect threshold near .060 ppm.

Q4. With respect to the inform ation from controlled human expos ure studies at 0.060 ppm O3, what is the scientific importan ce of the small, group mean FE V1 decrements relative to the findings that 7 to 20% of the subj ects experienced FEV1 decrements $ 10%? Please consider this question from both a public health and a clinical perspective.

For healthy adult subjects in co ntrolled human exposure studies, these FEV1 decrements indicate some biological response, but the clinical significance of this is unclear especially in light of some studies showing inflammatory re sponses without FEV1 decremen ts. From a public health perspective, where SVP would be expected to ha ve an enhanced response to exposures to these concentrations, these results may have more im portance. Ideally, controlled human exposure studies would be conducted at these levels using SV P, but that has risks of adverse outcomes in the study subjects, making such studies difficult to do.

Q5. The evidence, including th at summarized above, indicates th at susceptible populations may have greater responses than healthy people. In lig ht of this evidence, ho w 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 stud ies conducted on healthy adults provide a A best case @ (least health effect) scenario rela tive to SVP. Epidemiological st udies that focus on SVP would be expected to show greater health effects for a given concentration, but are subject to the confounding factors noted above. The best approach may be a A weight of evidence @ scenario that2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -4- assesses the consistency (or lack thereof) across these very different approaches to quantifying

ozone health effects.

Q6. To what extent does your co nfidence 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 previously, the uncertain ty (or confidence if you wish) of any exposure study decreases as the exposure concentrations decrease. For epid emiological 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 pa rticular 0.060 and 0.070 ppm. Considering the patterns of change in the es timates of exposures of concern at and above the 0.060 and 0.070 ppm benchmark levels, and the uncertainties a nd 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?

There is little doubt that reduced exposure, both in size of SVP exposed and the concentrations they are exposed to, has some pub lic health benefit as you go fro m .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 remain ing exposures with health effect s across the proposed range in

SVP.

Q8. EPA's quantitative risk assessment estimated the numbers of occurrences of various ozone

related health effects associated w ith just meeting alternative standa rd 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 stan dard 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 sta ndards across the proposed range? Please consider this question in light of the sc ientific evidence as a whole.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -5- This is really a policy question, not a science questi on. There is likely some risk (i.e., not 0) for

SVP even at the low end of the proposed range. This is not uni que to ozone; some residual risk is present for every NAAQS pollutant , since none of them (except maybe CO) have 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 vari ous ranges considered. The science can only take the process so far, and after that it becomes a po licy 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 reconsideration of the 2008 ozone NAAQS is constrai ned to the literature available during that NAAQS review process, it is worth noting that more r ecent studies over the last 4-5 years support and perhaps strengthen the scientific justification for an oz one NAAQS in the range of .060 to .070 ppm.

Some interested parties have ra ised 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 netw ork 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 expo sure-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 me asurements of NAAQS pollutants have various biases associated with them, so metimes 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 me thod. In this context, I am not concerned with the reported

biases in the UV method. However, since there may be effectiv e ways to reduce the biases in this method, EPA may want to consider additional specif ications for the testing of UV ozone analyzers in the Federal Equivalent Method (FEM) regulations to assess this issue.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -6- 

### John Balmes

1. What is your advice on the overall strengt hs and limitations of the evidence from controlled human exposure and epidemiologica l 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 human and epidemiologi cal studies strongly supports the selection of a new primary ozone st andard that is well below the 1997 standard of 0.08 ppm over an 8-hour av eraging time. There is scient ific certainty that 6.6-hour exposures to concentrations ≥ 0.08 ppm with intermittent exerci se cause clinically relevant decrements of lung function in young, healthy vo lunteers. The resul ts of multiple epidemiological studies al so show that children and adults wi th asthma are at increased risk

of acute exacerbations of this disease on or shortly after days when ozone conc entrations 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, setting a new NAAQS in the ra nge of 0.060 to 0.070 is appropriate.

2. Recognizing that controlled hum an 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 diff erent physiological mechanisms than the

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

The results of studies that show that exposu re to ozone at 0.080 ppm and above causes airway inflammation, increase d permeability, and increas ed responsiveness provide mechanistic support for the observed epid emiological associations with regard to

exacerbations of asthma at concentrations below 0.080 ppm. Th e mechanism of ozoneinduced decrements in lung function may not be related to airway inflammation.

3. How should the results of the controll ed 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 health y adults at exposure levels from 0.060 to 0.070 ppm?

At the time of the last EPA rev iew 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 experienced decreases ≥ 10%, which have been previously determined to be2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -7- of clinical relevance. These re sults fit well with those from mu ltiple other studies of ozone’s effect on lung function at concentrations ≥ 0.080 ppm, which have co nsistently shown that

some individuals are more sensitive to this effe ct of ozone than others. The selection of a NAAQS for ozone needs to consid er an adequate margin of safety to protect the most sensitive subgroup of individu als. Since the scientific ev idence was reviewed for the preparation of the 2006 Criteria Document for Ozone, the result s of the Adams et al. (2006) study have been carefu lly reanalyzed (Brown et al., 2008) and actually show a statistically significant group effect. In addition, two oth er 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 cont rolled human exposure studies at 0.060 ppm O 3

, what is the scientific importan ce 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 pub lic health and a clin ical perspective.

From a clinical perspective, 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 chroni c obstructive pulmonary disease have decreased ventilatory reserve (i.e., decreased ba seline FEV1) such that a ≥ 10% decrement could be associated with moderate to severe respiratory symptoms. Fr om a public health perspective, the exposure

and risk assessment conducted for the last revie w of the ozone NAAQS cl early document 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 concentrat ions that could cause them to have a clinically relev ant decrement in lung function.

5. The evidence, including that summarized abo ve, indicates that su sceptible 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 epidemio logical studies of susceptibl e groups, to inform a judgment on the effects of ozone exposure on susceptible populations?

Controlled human exposure studies have shown th at 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 increased risk of

exacerbations of their disease on or shortl y after days with el evated ambient ozone concentrations. Taken together, the results of these studies provide strong evidence that people with asthma are a subgro up of the population with increased suscep tibility 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 populati on of children and adults wi th asthma. Older individuals with pre-existing lung and heart disease, wh o 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 he althy young adults who have been studied to2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -8- date.

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 com pared to the higher levels?

While the effects of ozone cannot be easily is olated from the effects of other pollutants in epidemiological studies, health care utilization for asthma has been shown to decrease when

ozone concentrations are decreas ed. For example, when traffi c density was decreased during the Summer Olympic Games in Atlanta in 19 96, there was significantly decreased use of pediatric care for asthma that co rrelated best with a reduction in peak ozone concentrations (Friedman et al., 2001). In this study, the relative risk of asthma events increased stepwise at

cumulative ozone concentrations 0.060 to 0.0 89 ppm and 0.090 ppm or more compared with

ozone concentrations of less th an 0.060 ppm. The reduction of the adverse effects on asthma in this study was dependent on reduction of ozone exposures to le vels below 60 ppb.

7. EPA’s exposure assessment quantified the number of all children and asthmatic children likely to be exposed to specific benchmark l evels of ozone, includi ng in particular 0.060 and 0.070 ppm. Considering the patterns of chan ge in the estimates of exposures of concern at and above the 0.060 and 0.070 ppm be nchmark levels, and the uncertainties

and limitations in the es timates, what is the relative im portance from a public health perspective of the estimated re ductions 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 lin ear with no threshold, at least th rough 0.060 ppm. Therefore, it

is reasonable to assume a si milar exposure-response relatio nship for exacerbations of asthma. Considering the patterns of change in the estimates of expo sures at alternative standards, as well as the uncert ainties and limitations of the estimates, it is likely that susceptible individuals would st ill be adversely affected at a NAAQS of 0.060 ppm, although

the number of such individual s would be substantially lowe r than at higher alternate

standards.

8. EPA’s quantitative risk assessment estimated the numbers of occurrences of various ozone related health effects a ssociated with just meeting al ternative standar d 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 alterna tive standard levels, and the

uncertainties and limitations in the estimates, what is th e relative impor tance from a public health perspective of the estimated reductions in risk, as well as the risk remaining, for alternative standards across th e proposed range? Please consider this question in light of the scie ntific evidence as a whole.

In addition to what I have stat ed in my responses to the previo us seven questions, it is also important to consider the effect of reductions in exposures to ozone on mortality with the alternate standards. Although the evidence from epidemiologi cal studies of ozone-related2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -9- mortality published prior to 200 6 was not considered sufficientl y robust by CASAC to serve as the basis for a new NAAQS, EP A estimated effects on mortalit y in the exposure and risk assessment components of the 2007 Staff Paper. The evidence regardi ng the ozone exposuremortality relationship has grown stronger si nce the publication of the Staff Paper (e.g., Jerrett et al., 2009) and a morta lity effect was seen at conc entrations below the current

standard.

References Cited:

Brown JS, Bateson TF, McDonnell WF. 2008. Effect s of exposure to 0. 06 ppm ozone on FEV 1 in humans: A secondary analysis of ex isting 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 th e 1996 Summer Olympic Games in Atlanta on air quality and childhood asthma. JAMA 285:897-905.

Jerrett M, Burnett RT, Pope CA 3r d, Ito K, Thurston G, Krewski D, Shi Y, Calle E, Thun M. 2009. Long-term ozone exposure and mort ality. N Engl J Med 360:1085-1095.

Kim CS, Alexis NE, Rap pold AG, Kehrl H, Hazucha Mj, Lay JC, Schmitt MT, Case M, Devlin RB, Peden DB, Diez-Sanchez D. 2011. Lung function and inflamma tory responses in healthy young adults exposed to 0.06 ppm ozone for 6.6 h ours. Am J Respir Crit Care Med Jan 7 [Epub ahead of print].

Schelegle ES, Morales CA, Walby WF, Marion S, Allen RP. 6.6-hour inhalation of ozone concentration from 60 to 87 part s per million in healthy humans. 20 09. Am J Respir Crit Care Med

180:265-272.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -10- 

### 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 fr om 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 ob served following 6.6 hr squa re wave exposure to 0.060 ppm O3 compared to 6.6 hr filt ered air (FA) exposure. The statistical analysis by EPA was based on a straightforwar d paired comparison, and they conservatively used a nonparametric sign test to obt ain a p-value of 0.002 for the 0.06 ppm vs. FA comparison. Alternative, more powerful anal ytic methods using either a Wi lcoxon signed-rank test or a aired t-test yielded even lower p-values in the EPA analysis. The EPA comparison remained significant afte r a Bonferroni correction for multip le comparisons. The original analysis of the data by Adam s did not find a significant di fference in FEV1 between the 0.06 and FA exposure conditions. Howeve r, that analysis wa s based on a Scheffe correction for multiple comparisons, which is kn own to have very low power for the type of pairwise comparisons conduct ed 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 condu cted, 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 rela tive to FA exposure.

Of the 30 study subjects in Adams, 24 show ed 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, the consiste ncy of effects across O3 exposure levels, as well as the consistency wi th 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. In other words, it is likely that prolonged exposure to 0.06 ppm O3 causes a general shi ft in the distribution of FEV1 towards lower values. The following plot of the Adams data , derived from Figure 8-2 of Vo lume I of the “Air Quality
Criteria for Ozone and Rela ted Photochemical Oxidants, 2006” document, shows an approximate normal distribution in the O3-ind uced changes in FEV1 with exposure to 0.06 ppm.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -11- 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 Adam s study subjects were healthy volunteers. From a public health st andpoint, these results suggest that a large number of individuals in the g eneral population (that are othe rwise healthy), are likely to experience FEV1 deficits greater than 10% with prol onged exposure to 0.06 ppm O3. Although most healthy indivi duals can probably sustain a short-term 10-15% decline in

FEV1 with little or no no ticeable effect, it is not clear how they mi ght be affected in the longer term if they experien ce repeated lung function deficits due to 0.06 ppm or greater O3 exposures over multiple days or weeks. Based on several othe r controlled exposure studies, we might expect that O3-induced FEV1 deficits in subjects with an existing respiratory condition (e.g. as thma) would be shifted even furt her to the right compared to the above figure. A 10-15% (or greater) polluti on-related deficit in FE V1 in an individual with an existing respiratory co ndition is large en ough that it could cause a clinically observable response.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -12- 

### Rogene Henderson

February 9, 2011

1. What is your advice on the overall strengths and limitations of the evidence from controlled human exposure and epidemiological studies and th e 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 safe ty, including the need to protect susceptible populations, such as children and people with asthma?

I reviewed the previous correspondence betwee n 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 risk a ssessments, 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 exposu re studies provide the most di rect evidence of the health

effects on humans and the studi es 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 yo ung 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 a dults exposed to 0.060 ppm ozon e for 6.6 hours.) Asthmatic persons are known to be more se nsitive to ozone than are heal thy 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 thes e studies inform our understa nding the health effects to healthy adults at exposures levels from 0.060 to 0.070 ppm?

These additional health-effect en dpoints should definitely be taken into account in setting the

standards to the extent that information is av ailable. The recent pub lication by Kim et al. (2011) provides information on both types of endpoints endpoints.

3. How should the results of the controlle d human exposure studi es 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 a bove, 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. an d 0.060 form a continuum of

levels of effect that must all be considered in setting a standard with a margin of safety. The2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -13- results of the 0.06 ppm exposures provide incre ased confidence and decreased uncertainty

about the health effects of ozon e exposure at that concentration. Thus it essential that the

results of the controlled human ex posure studies at 0.060 ppm be taken into consideration for the understanding of the health effects of ozone in the rang e of 0.070-0.060 ppm.

4. With respect to the inform ation from controlled human ex posure 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 no t comment on that aspect. From a public health viewpoint, I think the effect is significant. The Clean Air Act req uires that a margin of safety be taken into account, and from a public health viewpoin t, the 0.060 level does induce adverse health effects in a portion of the heal thy community and those effects ar e likely to be greater in the asthmatic population.

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 c onducted 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 epidemiology data showing increased use of medication, school absences, and hospital admissions is one way to evaluate the respons e of sensitive populatio ns to ozone. The controlled 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 th e 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 unce rtainties increase. However, the effects of ozone exposure can best be considered as a cont inuum, with decreasing incidence or severity with decreasing exposure. Ho wever, the endpoints of conc ern remain the same, providing some confidence that the effects are due mainly to ozone.

7. . EPA’s exposure assessment quantified the numbe r of all children and asthmatic children likely to be exposed to specific benchmark levels of ozone, including in partic ular 0.060 a nd 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, a nd the uncertainties and limitations in the estimates, what is the relative importance from a public health perspect ive 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 rea sonable and made with the be st data available. The2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -14- assessments indicate that the number of child ren and asthmatic childr en exposed to ozone levels of concern is significant from a public health viewpoint.

8. . EPA’s quantitative risk assessment estimated the numbers of occurrenc es of various ozone

related health effects associated with just meeting alternative sta ndard levels down to a standard level of 0.064 ppm. Considering the patterns of change in the estimate s of health effects in the risk

assessment at the alternative stan dard 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 st andards across the proposed range? Please consider this question in light of the sc ientific evidence as a whole.

The CASAC took into a ccount 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 expo sures, one could have

confidence in the observed e ffects. I am still in agreemen t with that conclusion.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -15- 

### Philip K. Hopke

The charge questions provided to the ozone pane l revolve primarily around the toxicological and epidemiological evidence for the adverse health ef fects 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 oxidant s in the ambient atmosphere. Epidemiology would take these ot her oxidants into account to some greater or lesser extent with respect to the covariance of the other ambient ox idants with ozone. Howe ver, central monitors particularly monitors typically placed in downwind locations in urban area s to avoid significant titration effects of motor vehicle emissions, ma y not be an adequate measure of population exposure across that urban area.

We also have to recognize the full extent of th e change made with the promulgation of the 2008 ozone NAAQS. By changi ng the reported precision of the m easurements, we have effectively lowered the standard 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 ye t been fully felt. Give n that there is another review underway and this review is not supposed to take new literatu re 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 reex amine all of the body of information available as part of the current round of review. Th en 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 fr om 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 ob served following 6.6 hr squa re wave exposure to 0.060 ppm O3 compared to 6.6 hr filt ered air (FA) exposure. The statistical analysis by EPA was based on a straightforwar d paired comparison, and they conservatively used a nonparametric sign test to obt ain a p-value of 0.002 for the 0.06 ppm vs. FA comparison. Alternative, more powerful anal ytic methods using either a Wi lcoxon signed-rank test or a paired t-test yielded even lo wer p-values in the EPA anal ysis. The EPA comparison remained significant afte r a Bonferroni correction for multip le comparisons. The original analysis of the data by Adam s did not find a significant di fference in FEV1 between the 0.06 and FA exposure conditions. Howeve r, that analysis wa s based on a Scheffe correction for multiple comparisons, which is known to have very lo w power for the type of pairwise comparisons conduct ed by Adams compared to other well-known methods for2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -16- multiple-testing correction (Kirk, 1982). Thus , from my understanding of the statistical analyses that have been condu cted, 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 rela tive to FA exposure.

Of the 30 study subjects in Adams, 24 show ed 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, the consiste ncy of effects across O3 exposure levels, as well as the consistency wi th 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. In other words, it is likely that prolonged exposure to 0.06 ppm O3 causes a general shi ft in the distribution of FEV1 towards lower values. The following plot of the Adams data , derived from Figure 8-2 of Vo lume I of the “Air Quality
Criteria for Ozone and Rela ted Photochemical Oxidants, 2006” document, shows an approximate normal distribution in the O3-ind uced 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 Adam s study subjects were healthy volunteers. From a public health st andpoint, these results suggest that a large number of individuals in the g eneral population (that are othe rwise healthy), are likely to experience FEV1 deficits greater than 10% with prol onged exposure to 0.06 ppm O3. Although most healthy indivi duals can probably sustain a short-term 10-15% decline in

FEV1 with little or no no ticeable effect, it is not clear how they mi ght be affected in the longer term if they experien ce repeated lung function deficits due to 0.06 ppm or greater O3 exposures over multiple days or weeks. Based on several othe r controlled exposure studies, we might expect that O3-induced FEV1 deficits in subjects with an existing respiratory condition (e.g. as thma) would be shifted even furt her to the right compared to the above figure. A 10-15% (or greater) polluti on-related deficit in FE V1 in an individual with an existing respiratory co ndition is large en ough that it could cause a clinically observable response.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -17- 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 judg ment on the effects of ozone exposure on susceptible populations?

Response -- In many ways, the lowest exposure level of 0.06 ppm sh owing some symptom changes and statistically significa nt lung function changes in healt hy subjects in an EPA analysis conducted for the last O3 NAAQS review represented a greate st lower bound on the ozone concentration of public health c oncern. In all of the controlled hu man exposure stud ies at 0.08-ppm ozone and below, a reasonable percentage of h ealthy 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 normal daily activities, individuals with compromised lungs, such as asth matics, incur significant health impacts with such lung function changes. As CASAC has noted in the past to th e Agency, evidence is ac cumulating that persons with asthma, and particularly child ren, 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 di scussed in the last review were
showing O 3 -related effects on various health endpoint s (e.g., emergency department visits, increased hospital emissions, and mo rtality increases) at relatively lo w exposure levels leads one to

conclude that O 3 may cause effects even below 0.06 ppm. Since strengthening such a conclusion would need additional data from new studies, the CASAC concluded at the last review that the
lower range of consideration for revi sion of the NAAQS should be 0.060 ppm O 3 . By doing so, the
CASAC felt that margin of safety considera tions would better be me t 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 Administ rator to place her judgment on the weight that any uncertainties and limitations in the science play in selecting an exposure level protective of public health.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -18- 

### Morton Lippmann

9. What is your advice on the overall strengt hs and limitations of the evidence from controlled human exposure and epidemiologica l 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 strengths of the evidence from controlle d human exposure and epidemiological studies

enumerated in the Criteria Document and it s update were substant ial, and more than adequate to support the reco mmended range for the NAAQS of 0.060 to 0.070 ppm. The

limitations of the evidence fr om controlled human exposure and epidemiological studies were well and appropriately stated in the Staff Pape r. These limitations have subsequently been substantially reduced since CASAC’s last co mmentary of April 7, 2008 (EPA-CASAC-08- 009) concerning the “Final rule” by the findings in peer-reviewed papers that have provided

further evidence of the risks of inhaled ozone to normal in dividuals (Brown et al. 2008; Schelegle et al. 2009; Kim et al. in press), and in children and adul ts with asthma at concentrations well below 0.080 ppm (Lin et al. 2008; Moore et al. 2008; Islam et al. 2009; Silverman and Ito 2010).

10. Recognizing that controlled hum an 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 diff erent physiological mechanisms than the

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

These results demonstrate that there are subclinical responses to ozone inhalation that contribute to the physiological responses that are more readily measured in studies focused on clinically-relevant indices. Th ey also provide results that provide a mechan istic basis for

the functional effects and inc reased morbidity and mortality.

11. How should the results of the controll ed 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 health y adults at exposure levels from 0.060 to 0.070 ppm?

As discussed at length in the Criteria Docume nt and Staff Paper, there is no evidence of a threshold, i.e., the magnitude of the effect diminishes with decreasing ozone concentration,

but does not reach the functional level associat ed with exposure to ozone-free clean air. Furthermore there is a grea t degree of variability of response magnitude among the2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -19- individuals studied, with some having clinically-relevant resp onses, even at 0.060 ppm, and more of them with such responses at higher co ncentrations. Since the numbers of subjects exposed in the each of the cont rolled chamber studies at each concentratio n have been small, extrapolation to the much larg er general population indicates that a very large number of

individuals would have substantia l responses, even though they would constitu te only about 10% of the population. Schelege et al. (2009) show that FEV1 decrements >20% can occur at

0.060 as well as at 0.070 and 0 .080 ppm.

12. With respect to the information from cont rolled human exposure studies at 0.060 ppm O 3

, what is the scientific importan ce 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 pub lic health and a clin ical perspective.

See my response to #3 above.

13. The evidence, including that summarized abo ve, indicates that su sceptible 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 epidemio logical studies of susceptibl e groups, to inform a judgment on the effects of ozone exposure on susceptible populations?

Epidemiological studies generally show responses comparable to those observed in controlled human exposure studies conducted on healthy adults, but at lower ozone concentrations. This is partly due to the pres ence of less healthy, i. e., more susceptible people in the general population, but also due, at le ast in part, to the influence of prior days’ exposures, and to evidence that ambient air containing other poll utants that can exacerbate the responses. Thus, the chamber studies underestimate popu lation responses that are known to be associated with ozone exposu res. A margin-of-safety is need ed to compensate for the

understatement of effect from the chamber exposure studies.

14. 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 com pared to the higher levels?

I do not have confidence that the effects observed in epidemiological studies are attributable specifically to O 3 , as noted above. However, the effects are characteristic of those produced by ozone, and not associated with other pollutan ts in the ambient air, at least at the levels

found there. Thus reduction of the adverse health effects is dependent on reduction of ozone

exposures.

15. EPA’s exposure assessment quantified the number of all children and asthmatic children likely to be exposed to specific benchmark l evels of ozone, includi ng in particular 0.060 and 0.070 ppm. Considering the patterns of chan ge in the estimates of exposures of concern at and above the 0.060 and 0.070 ppm be nchmark levels, and the uncertainties

and limitations in the es timates, what is the relative im portance from a public health2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -20- perspective of the estimated re ductions in exposures of concern, as well as the exposures remaining, for alternative standards across the proposed range?

Since the most reasonable assumption concerning the ozone exposure resp onse relationship is linear with no threshold, it is important to reduce ozone ex posures by reducing the NAAQS

in order to reduce the adverse health effects. However, it must be kept in mind that reductions of the NAAQS to eith er 0.060 or 0.070 will only re duce the numbers of people with adverse health effects, and will not eliminate such effects.

16. EPA’s quantitative risk assessment estimated the numbers of occurrences of various ozone related health effects a ssociated with just meeting al ternative standar d 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 alterna tive standard levels, and the

uncertainties and limitations in the estimates, what is th e relative impor tance from a public health perspective of the estimated reductions in risk, as well as the risk remaining, for alternative standards across th e proposed range? Please consider this question in light of the scie ntific evidence as a whole.

See my response to #3 above.

References Cited:

Brown JS, Bateson TF, & McDonnell WF. Effect s of exposure to 0.06 ppm ozone on FEV 1 in humans: A secondary analysis of existing data. Environ. Health Perspect. 116 :1023-1026 (2008).

Islam T, McConnell R, Gauder man WJ, Avol E, Pe ters JM, and Gilliland F, Ozone, oxidant defense genes, and risk of asthma during adolescence. Am. J. Respir. Crit. Care Med. 177(4):388- 395 (2009).

Kim CS, Alexis NE, Rap pold AG, Kehrl H, Hazucha Mj, Lay JC, Schmitt MT, Case M, Devlin RB, Peden DB, Diez-Sanchez D. 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. (in press).

Lin S, Liu X, Le LH, and Hwan g S-A. Chronic exposure to ambient ozone and asthma hospital admissions among children. Environ. Health Perspect. 116 :1725-1730 (2008).

Moore K, Neugebauer R, Lurmann F, Hall J, Braj er V, Alcorn S, & Ta ger I. Ambient ozone concentrations cause increased hospitalizations for asthma in children: An 18-year study in

Southern California. Environ. Health Perspect. 116 :1063-1070 (2008).

Schelegle ES, Morales CA, Walby WF, Marion S, Allen RP. 6.6-hour inhalation of ozone concentration from 60 to 87 pa rts per million in healthy humans. Am. J. Respir. Crit. Care Med. 180:265-272 (2009).2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -21- Silverman RA, Ito K. Age related association of fi ne particles and ozone with severe acute asthma in New York City. J. Allergy and Clin. Immunol. 125:367-373 (2010).2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -22- 

### Fred Miller

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 judg ment on the effects of ozone exposure on susceptible populations?

Response -- In many ways, the lowest exposure level of 0.06 ppm sh owing some symptom changes and statistically significa nt lung function changes in healt hy subjects in an EPA analysis conducted for the last O3 NAAQS review represented a greate st lower bound on the ozone concentration of public health c oncern. In all of the controlled hu man exposure stud ies at 0.08-ppm ozone and below, a reasonable percentage of h ealthy 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 normal daily activities, individuals with compromised lungs, such as asth matics, incur significant health impacts with such lung function changes. As CASAC has noted in the past to th e Agency, evidence is ac cumulating that persons with asthma, and particularly child ren, 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 di scussed in the last review were
showing O 3 -related effects on various health endpoint s (e.g., emergency department visits, increased hospital emissions, and mo rtality increases) at relatively lo w exposure levels leads one to

conclude that O 3 may cause effects even below 0.06 ppm. Since strengthening such a conclusion would need additional data from new studies, the CASAC concluded at the last review that the
lower range of consideration for revi sion of the NAAQS should be 0.060 ppm O 3 . By doing so, the
CASAC felt that margin of safety considera tions would better be me t 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 Administ rator to place her judgment on the weight that any uncertainties and limitations in the science play in selecting an exposure level protective of public health.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -23- 

### Lianne Sheppard

February 11, 2011

Individual comments : I still fully agree with the advi ce provided by CASAC in its le tters of October 24, 2006 (EPACASAC-07-001), March 26, 2007 (EPA -CASAC-07-002), and Februa ry 10, 2010 (EPA-CASAC10-007). My opinion has been stre ngthened by the experience I ha ve 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 yo ur confidence that the effects obser ved 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?

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 a nd found ozone-related health effects. These include time series studies, field studies, and panel studies. The st rengths 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 diffic ult to tease out the effects of a si ngle pollutant in epidemiological studies, there is evidence regarding ozone-relate d health effects from epidemiological studies

that is consistent with the ev idence from controlled exposure st udies. 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 pop ulation 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.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -24- 

### 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 epidemiologi cal studies and the results of the exposure and risk assessments, in the context of EPA's selectio n 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?

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 second that so me 7-20% of the subjects experienced what I would consider very significan t lung function decreases (> 10 %) and or moderate respiratory symptoms. These findings essential preclude, because of the ethics of carrying out clinical studies in diseased individuals, from extending these st udies 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 prud ent that, in spite of the uncertain ty—more later on this issue—that EPA is justified to select an exposure level below th e 0.080pppm (and I would say closer to the 0.060 ppm level) to “protect public health with an adequate margin of safet y, including the need to protect susceptible populations...”

Charge Question 2. Recognizing that controlled hu man exposure studie s at 0.080 ppm O 3 and above have provided evidence of other health effect s, including inflammation and increased airway responsiveness which may occur th rough different physiological mech anisms 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 substantia l 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 because of th e presence of excess mucu s, would be “protected” from the potential oxidative effects of ozone. This seems highly un likely in that disease subjects studied at 0.08 ppm and higher seem to respond more than normals and thus would not likely be protected more at the lower levels to which no rmals 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 Question 3. How should the results of the contro lled human exposure studies at 0.060 ppm

O 3 , showing effects on FEV 1 and respiratory symptoms, in the context of the larger body of2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -25- 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? Because these results represent a c ontinuum of effects and it is unlik ely 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 bei ng more protective than the upper

end.

Charge Question 4. With respect to the information fr om controlled human exposure studies at 0.060 ppm O 3 , what is the scientific importanc e 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 Ques tion 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 re spond even greater and could reach clinically significant responses that might result in emer gency room visits and or hospitalizations.

Charge Question 5. The evidence, including that summariz ed 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 judg ment 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 responding 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 symp tomatic responses would need to be treated.

Given the substantial number of potentially at risk adults in th e population and the distributions of possible exposures even at the lo wer level of the bounded exposures it would be prudent to argue that there will be some individuals remaining at risk. The judgment is how large a population is th e Administrator willing to tolerate as being still at risk, not whether she can protect the entire population of po tentially susceptible individuals.

Charge Question 6. To what extent does your confid ence that the effects observed in epidemiological studies are a ttributable 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 pollutant s coming into play rath er than simply more variability in response cannot be determined. Th e 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 th e uncertainly relates to greater2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -26- variability rather than confounding by additiona l 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 spec ific benchmark levels of ozone, including in particular 0.060 and 0.070 ppm. Co nsidering the patterns of change in the estimates of exposures of concern at and above the 0. 060 and 0.070 ppm benchmark leve ls, 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?

As indicated in the discussion acro ss the 12 urban areas the assessment are considerably larger for the benchmark level of 0.60 ppm compared to the 0.070 ppm benchmark. Ho wever, they also note that the pattern of exposure is similar for all children and asthmatic school age children. The

Administrator also stated that she must consider the public health impact in cities receiving considerably less protection associated with air qua lity just meeting the same standard. This is a

difficult criteria to meet with a single standard. Thus it become s prudent to weigh the impact of the exposure against the cost of meetin g that standard. The science is clear that there will be children as risk at any reasonable standard chosen. T hus the public health consideration is how big a population 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 wi th just meeting alterna tive standard levels down to a standard level of 0.064 ppm. Considering th e patterns of change in the estimates of health effects in the risk assessment at the alter native 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 ri sk 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 rang e of at risk children dependent upon the choice of levels of exposure. Unfortunately, it is not clear that 2002 is the “wor se case” or 2004 is the “best case”. Nevertheless, with regard to protectin g the public health the ra nge of all children aged

5-18 between 0.064-0.074 is between 4.5 million a nd 950, 000 in the worse case vs 350,000 and 10,000 in the best case, with propor tionately lower numbers for asth matic children. Clearly truth must lay somewhere in between. Even these lowe r 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 de cision is to set a standard that is as protective of the public health with a margin of safety as mandated by law.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -27- 

### Helen Suh

1. What is your advice on the overall strengths and li mitations of the evid ence from controlled human exposure and epidemiological studies and the results of the exposure and risk assessments, in the context of EPA's selecti on of a standard level w ithin 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 a nd people with asthma?

The scientific evidence from controlled human e xposure and epidemiological studies and from the exposure and risk assessments supports a prim ary ozone standard (with a margin of safety)

between 0.060 to 0.070 ppm. The controlled human exposu re studies by Adams (2002, 2006) show statistically significant changes in lung function from a 6.6 ho ur exposure to 0.060 ppm

ozone. While these studies were limited in nu mber, they were well designed and results were consistent with those from prev ious studies, thus lending cred ibility to their findings. Of particular interest is the fact that a sma ll but important fraction of the study subjects experienced lung function decrem ents greater than 10% at ex posures to 0.060 ppm ozone. These findings suggest that the impacts of ozone exposures at these levels may be significant for individuals with pre-existing respiratory co nditions 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 have provided evidence of other health effects, including in flammation and increased airway responsiveness which may occur through diffe rent physiological mechanism s than the reduction in FEV 1 , how should the results of these studies inform our unde rstanding 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 co nsidering 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 a bove, inform our understanding of the health effects to healthy adults at exposur e 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 le ast as being central to margin of safety determinations.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -28- 4. With respect to the info rmation from controlled human ex posure studies at 0.060 ppm O 3

, what is the scientific importanc e 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.

For individuals with pre-existing respiratory diseas e, a 10% decrement in FEV1 is significant.

5. The evidence, including that summarized ab ove, 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 epidemiolo gical studies of susceptible gr oups, to inform a judgment on the effects of ozone exposure on susceptible populations.

Although the sample sizes are sm all, the variability in the resp onse observed for healthy adults in the controlled human studies can inform judg ments on the effects of ozone in susceptible populations. For example, the 7-20% of healthy adults who were found to have large ozonemediated 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 per centage of the susceptible population.

6. To what extent does your con fidence 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?

The uncertainty in the ep idemiological findings at low ozone levels is certainly greater than that at high ozone levels, with greater confiden ce 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 ha ve been observed for a variety of endpoints, including those such as school absences that ha ve 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 correlations between ozone and PM. Finally, additional support for epidemiological fi ndings is provided by results from controlled exposure studies.

7 . EPA’s exposure assessment quantified the nu mber of all children and asthmatic children likely to be exposed to specific benchmark level s 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 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 no2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -29- threshold in ozone-mediated impacts. As a re sult, even with uncerta inty in the benchmark exposures, it is likely that a significant fracti on 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. C onsidering the patterns of change in the estimates of health effects in the risk assessment at the alter native 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 the proposed range? Please cons ider this question in light of the scientific evidence as a

whole.

The quantitative risk asse ssment showed public health signi ficant 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 ri sk assessment examined only a fraction of the observed health outcomes, with many unexamine d health outcomes posing greater risks for sensitive subgroups. These limitations may outwe igh, or at the least co unteract, any concerns regarding uncertainty in the risk estimates.2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -30- 

### James Ultman

Answers to Questions on Controlled Human Exposures

Charge question 1:

Strengths:

1. Objective,  accurate  and  precise  measurements  of  exposure  patter n  and  response endpoints.

2. Minimize  cofounding  influence  of  particulate  matter,  other  oxid ants  and  other copollutants on subject response.

3. Large  database  of  forced  expired  response  to  constant  ozone  exp osure  with intermittent exercise using fairly consistent protocols within labs and between labs.

4. Newest  studies  are  designed  for more  realistic  exposure  levels and  concentration

patterns.
Weaknesses:

1. Ethical  limitations  testing  subjects  that  have  severe  respirato ry  and/or

cardiovascular disease.

2. Usually not designed to model different exercise levels or mult iple daily exposures.

3. Large  majority  of  studies  on  ozone  concentrations  at  or  above  0 .08  ppm  and  on

constant exposure patterns.

4. Are  usually  not  specifically  designed  or  analyzed  to  examine  th e  health  effect  of ozone  exposure  relative  to  a  an  exposure  that  emulates  a  policy ‐relevant background.

Charge question 2:

Results  from  numerous  studies  indicate  that  exposure  to  0.08ppm ozone  and  greater

induces decrements in FEV 1 and also elevates various markers of inflammation.  Because lung  function  decrements  and  airway  inflammation  occur  by  diffe rent  mechanisms,  they are  not  directly  related  to  one  another.    Thus,  it  is  not  feasi ble  to  use  the  results  of inflammation  at  0.08    ppm  and  above  to  inform  our  understanding of  health  effects  at

lower concentrations.

There is one recent study(1)that reported a significant increas e in neutrophil counts in the sputum of healthy subjects during the day following a 0.06 ppm, 6.6 hour, ozone exposure.

Whether  or  not  this  observation  can  be  confirmed  in  another  stu dy  remains  to  be  seen. Even  with  this  scientific  uncertainty,  the  possibility  of  a  cli nically  consequential  airway inflammation  must  be  kept  in  mind  when  specifying  a  “margin  of safety”  in  the  ozone

standard.

Charge question 3:2-15-11 Preliminary Individual Comme nts on the Ozone Reconsideration These comments are preliminary and do no t represent consensus CASAC advice or EPA policy. Do not cite or quote.

Page -31- Data  from  two clinical studies, show  that exposure  to 0.06ppm o zone causes a significant pre‐to‐post  exposure  decrement  in  FEV 1 relative  to  that  in  clean  air.    The  reanalysis  of Adams  2006  study  by  Brown(2)  indicates  that  a  6.6  hr  exposure  t o  a  square‐wave  or variable ozone concentration pattern and intermittent exercise results in a 3% decrease in

FEV 1 with  2/30  subjects  exhibiting  a  decrement  greater  than  10%.    Fo r  a  constant  0.06 ppm exposure, Kim et et al. (2)reported a 2% decrease in the group mean FEV 1 with 3/59 subjects  exhibiting  a  decrement  greater  than  10%. In  a  third  study  (3),  the  group  mean

FEV 1 decrement during a 0.06 ppm  variable  ozone exposure pattern wa s not  statistically different  from  that  observed  during  clean  air  exposure.  Neverth eless,  6/31  subjects  had

FEV 1 decrements that were greater th an 10% relative to clean air.

Thus,  the  evidence  for  a  clinically  relevant  decrement  in  lung function  among  a subpopulation  of  subjects  is  coherent  among  these  studies  even though  statistical comparisons  of  the  group  means  are  equivocal.  Although  it  is  do ubtful  that  children, asthmatics and other susceptible populations would achieve the high workloads employed in  these  studies  (MV=20  L/m/m 2 body  surface  for  adults),  some  vulnerable  populations

such as outdoor laborers could would.

Charge question 4:

From a  clinical  perspective,  the  observation  of  decrements in  F EV 1 >10% is an important indicator of a possible health effect in a limited number of pa tients.  From a public health perspective, the group mean effect of long exposures at high wo rkloads on mechanical lung

function is minimimal.

1. Kim, C., et. Al. (2011). Lung function and inflamma tory responses in healthy you ng adults exposed to 0.06 ppm ozone f or 6.6 hours. Am J Resp Crit Care Med. (on‐line).

2. Brown,J.S. (2007) The effects of ozone on lung function at 0.06 ppm in healthy adults. Ozone NAAQS Review Docket (OAR‐2005‐0172).

3. Schelegle et al (2009). 6.6‐Hour inhalation of o zone concentrations from 60 to 87 parts per billion in healthy huma ns. Am J Resp Crit Care Med. 1 80:265‐272.