UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF THE ADMINISTRATOR

SCIENCE ADVISORY BOARD

March 30, 2011

EPA-CASAC-11-004

The Honorable Lisa P. Jackson 

Administrator 

U.S. Environmental Protection Agency 

1200 Pennsylvania Avenue, N.W.

Washington, D.C.20460

Subject: Clean Air Scientific Advisory Committee (CASAC) Response to Charge 

Questions on the Reconsideration of the 2008 Ozone National Ambient Air 

Quality Standards

Dear Administrator Jackson:

This letter provides comments of the Clean Air Scientific Advisory Committee (CASAC) 

in response to the charge questions submitted in the January 26, 2011 memorandum from the 

Office of Air Quality Planning and Standards (OAQPS). The questions are related to the current 

reconsideration of the 2008 proposed National Ambient Air Quality Standard (NAAQS) for 

Ozone. 

Previous Comments by CASAC

As you know, CASAC has an extensive, recent record of providing independent peer 

review on the Agency’s technical documents related to the Ozone NAAQS. From 2005 to 2008, 

CASAC reviewed two drafts of the Staff Paper, two drafts of the Criteria Document, two drafts 

of the risk assessment and two drafts of the exposure assessment. As stated in our letters of 

October 24, 2006, March 26, 2007 and April 7, 2008 to former Administrator Stephen L. 

Johnson, CASAC unanimously recommended selection of an 8-hour average ozone NAAQS 

within the range of 60 to 70 ppb (Henderson, 2006, 2007 and 2008). On March 12, 2008, EPA 

published its decision to revise the National Ambient Air Quality Standards (NAAQS) for 

Ozone, revising the 8-hour “primary” ozone standard1

 1

An 8-hour averaging time and a form based on the annual fourth-highest daily maximum 8-hour concentration, 

averaged over 3 years, were adopted in 1997 and retained in the 2008 rulemaking.

, designed to protect public health, to a 

level of 75 ppb. In response, CASAC offered comments in a letter to former Administrator 

Johnson on April 7, 2008 to the effect that CASAC did not endorse the new primary ozone 

standard (75 ppb) as being sufficiently protective of public health (Henderson, 2008).
ii

In response to EPA’s reconsideration of the 2008 Ozone NAAQS and the proposal 

published on January 19, 2010, CASAC reaffirmed its support for the selection of an 8-hour 

average ozone NAAQS within the 60 – 70 ppb range. In our letter of February 19, 2010 (Samet, 

2010), we reiterated support for this range and referred to the supporting evidence as presented in 

Air Quality Criteria for Ozone and Related Photochemical Oxidants (March 2006) and Review 

of the National Ambient Air Quality Standards for Ozone: Policy Assessment of Scientific and 

Technical Information (Environmental Protection Agency, 2007). 

While we are concerned that EPA’s most recent request for additional CASAC advice is 

redundant with our past reviews, we nonetheless are pleased for the opportunity to reaffirm our 

previous advice and we are submitting this letter and the attached consensus advice to further 

assist EPA as it takes action following this additional scientific input from CASAC. 

Here we reaffirm that the evidence from controlled human and epidemiological studies 

strongly supports the selection of a new primary ozone standard within the 60 – 70 ppb range for 

an 8-hour averaging time. As enumerated in the 2006 Criteria Document and other companion 

assessments, the evidence provides firm and sufficiently certain support for this recommended 

range for the standard. 

Key Findings

Although the Clean Air Act mandates the selection of a standard that has an adequate 

“margin of safety,” the practical application of this term requires a policy judgment. The 

scientific evidence that was assembled by EPA and reviewed by CASAC shows no “threshold” 

or level below which there is no risk of decrement in lung function following short-term 

exposure to ozone. 

As you give consideration to the revision of the NAAQS, we offer the following 

summary of findings in the evidence available through 2006. Supporting evidence can be found 

in the attached responses to charge questions. 

• The evidence available on dose-response for effects of ozone shows associations 

extending to levels within the range of concentrations currently experienced in the United 

States.

• There is scientific certainty that 6.6-hour exposures with exercise of young, healthy, nonsmoking adult volunteers to concentrations ≥ 80 ppb cause clinically relevant decrements 

of lung function. 

• Some healthy individuals have been shown to have clinically relevant responses, even at 

60 ppb. 

• Since the majority of clinical studies involve young, healthy adult populations, less is 

known about health effects in such potentially ozone sensitive populations as the elderly, 

children and those with cardiopulmonary disease. For these susceptible groups, 
iii

decrements in lung function may be greater than in healthy volunteers and are likely to 

have a greater clinical significance. 

• Children and adults with asthma are at increased risk of acute exacerbations on or shortly 

after days when elevated ozone concentrations occur, even when exposures do not exceed 

the NAAQS concentration of 75 ppb.

• Large segments of the population fall into what EPA terms a “sensitive population 

group,’’ i.e., those at increased risk because they are more intrinsically susceptible 

(children, the elderly, and individuals with chronic lung disease) and those who are more 

vulnerable due to increased exposure because they work outside or live in areas that are 

more polluted than the mean levels in their communities. 

Public Comments

There were 57 public comments presented during the teleconferences on February 18, 

2011 and March 3, 2011. As always, we welcome public input into our deliberations. Some 

commenters pointed out that even in the range of 60 – 70 ppb, there would be selected members 

of the population who would continue to be at risk, and thus a standard set in this range would 

contain a reduced margin of safety for these vulnerable populations. Some raised questions about 

the evidence showing effects at the lower end of the concentration range in the U.S. Other public 

comments addressed topics outside the scope of our specific deliberations around the charge 

questions. For your information, concerns were expressed about potential deleterious economic 

consequences of a more stringent NAAQS, including adverse impacts on jobs and commerce, 

and the practical issues of implementation. Other comments concerned the possibility of 

deferring any change in the 2008 standard until the newer evidence has been considered. The 

uncertainties involved in establishing "policy relevant background" for this naturally occurring as

well as internationally-transported pollutant also received comments. 

Evidence Considered by CASAC

At EPA’s request, our deliberations were constrained to the evidence assembled in the 

prior review that ended in 2008, i.e. a science record that closed in 2006. This constraint 

imposed an artificial boundary on our discussions. The public comments, however, were not so 

limited. While we appreciate the depth and scope of the public’s interest in ozone regulation, we 

recognize that the topics raised and newer information could not be incorporated into our 

deliberations given our instructions from EPA and the process that has been used for assembling 

and reviewing evidence in considering a NAAQS revision. Although some written comments 

from individual panelists include more recent studies, CASAC consensus responses to the charge 

questions and this letter are based on the literature considered in the last ozone NAAQS review. 

Conclusion

Again, we reaffirm our unanimous recommendation expressed in former CASAC 

Chairperson Henderson’s 2008 letter to former Administrator Johnson, to set the ozone NAAQS 

within the range of 60 to 70 ppb for an 8-hour averaging time. In that range, CASAC finds that 
iv

the evidence is sufficiently certain to be confident of public health benefits and additional 

protection for susceptible groups. 

Sincerely, 

/signed/

Dr. Jonathan M. Samet

Chair

Clean Air Scientific Advisory Committee

Enclosures
v

NOTICE

This report has been written as part of the activities of the EPA’s Clean Air Scientific Advisory 

Committee (CASAC), a federal advisory committee independently chartered to provide 

extramural scientific information and advice to the Administrator and other officials of the EPA. 

CASAC provides balanced, expert assessment of scientific matters related to issues and 

problems facing the Agency. This report has not been reviewed for approval by the Agency and, 

hence, the contents of this report do not necessarily represent the views and policies of the EPA, 

nor of other agencies within the Executive Branch of the federal government. In addition, any 

mention of trade names of commercial products does not constitute a recommendation for use. 

CASAC reports are posted on the EPA website at http://www.epa.gov/CASAC. 
vi

U.S. Environmental Protection Agency

Clean Air Scientific Advisory Committee

Ozone Review Panel for the Reconsideration of the 2008 NAAQS

CHAIR

Dr. Jonathan M. Samet, Professor and Flora L. Thornton Chair, Department of Preventive 

Medicine, University of Southern California, Los Angeles, CA

MEMBERS

Mr. George A. Allen, Senior Scientist, Northeast States for Coordinated Air Use Management 

(NESCAUM), Boston, MA

Dr. John R. Balmes, Professor, Department of Medicine, Division of Occupational and 

Environmental Medicine, University of California, San Francisco, CA

Dr. Joseph D. Brain, Cecil K. and Philip Drinker Professor of Environmental Physiology, 

Department of Environmental Health, Harvard School of Public Health, Harvard University, 

Boston, MA

Dr. Ellis B. Cowling, University Distinguished Professor At-Large Emeritus, Colleges of 

Natural Resources and Agriculture and Life Sciences, North Carolina State University, Raleigh, 

NC

Dr. H. Christopher Frey, Professor, Department of Civil, Construction and Environmental 

Engineering, College of Engineering, North Carolina State University, Raleigh, NC

Dr. William (Jim) Gauderman, Professor, Department of Preventive Medicine, University of 

Southern California, Los Angeles, CA

Dr. Jack Harkema, Professor, Department of Pathobiology, College of Veterinary Medicine, 

Michigan State University, East Lansing, MI

Dr. Rogene Henderson, Senior Scientist Emeritus, Lovelace Respiratory Research Institute, 

Albuquerque, NM

Dr. Philip Hopke, Bayard D. Clarkson Distinguished Professor, Department of Chemical and 

Biomolecular Engineering, Clarkson University, Potsdam, NY

Dr. Michael T. Kleinman, Professor, Department of Medicine, Division of Occupational and 

Environmental Medicine, University of California, Irvine, Irvine, CA

Dr. Allan Legge, President, Biosphere Solutions, Calgary, Alberta, CANADA
vii

Dr. Morton Lippmann, Professor, Nelson Institute of Environmental Medicine, New York 

University School of Medicine, Tuxedo, NY

Dr. Frederick J. Miller, Independent Consultant, Independent Consultant, Cary, NC

Dr. Maria Morandi, Assistant Professor, Division of Environmental and Occupational Health, 

School of Public Health, University of Texas, Houston, TX

Dr. Charles Plopper, Professor, Department of Anatomy, Physiology and Cell Biology, School 

of Veterinary Medicine, University of California, Davis, California

Mr. Richard L. Poirot, Environmental Analyst, Air Pollution Control Division, Department of 

Environmental Conservation, Vermont Agency of Natural Resources, Waterbury, VT

Dr. Armistead (Ted) Russell, Professor, Department of Civil and Environmental Engineering, 

Georgia Institute of Technology, Atlanta, GA

Dr. Elizabeth A. (Lianne) Sheppard, Professor, Biostatistics and Environmental & 

Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA

Dr. Frank Speizer, Edward Kass Professor of Medicine, Channing Laboratory, Harvard 

Medical School, Boston, MA

Dr. Helen Suh, Program Area Director, Environmental Health, Public Health Division, National 

Opinion Research Corporation (NORC) at the University of Chicago, Boston, MA

Dr. James Ultman, Professor, Chemical Engineering, Bioengineering Program, Pennsylvania 

State University, University Park, PA

Dr. Sverre Vedal, Professor, Department of Environmental and Occupational Health Sciences, 

School of Public Health, University of Washington, Seattle, WA

Dr. Kathleen Weathers, Senior Scientist, Cary Institute of Ecosystem Studies, Millbrook, NY

Dr. Barbara Zielinska, Research Professor, Division of Atmospheric Sciences, Desert Research 

Institute, Reno, NV

SCIENCE ADVISORY BOARD STAFF

Dr. Holly Stallworth, Designated Federal Officer, Science Advisory Board Staff Office, 

Washington, DC 
viii

U.S. Environmental Protection Agency

Clean Air Scientific Advisory Committee

(CASAC)

CHAIR

Dr. Jonathan M. Samet, Professor and Flora L. Thornton Chair, Department of Preventive 

Medicine, University of Southern California, Los Angeles, CA

MEMBERS

Mr. George Allen, Senior Scientist, NESCAUM (Northeast States for Coordinated Air Use 

Management), Boston, MA

Dr. Joseph D. Brain, Cecil K. and Philip Drinker Professor of Environmental Physiology, 

Department of Environmental Health, Harvard School of Public Health, Harvard University, 

Boston, MA

Dr. H. Christopher Frey, Professor, Department of Civil, Construction and Environmental 

Engineering, College of Engineering, North Carolina State University, Raleigh, NC

Dr. Armistead (Ted) Russell, Professor, Department of Civil and Environmental Engineering, 

Georgia Institute of Technology, Atlanta, GA

Dr. Helen Suh, Program Area Director, Environmental Health, Public Health Division, National 

Opinion Research Corporation (NORC) at the University of Chicago, Boston, MA

Dr. Kathleen Weathers, Senior Scientist, Cary Institute of Ecosystem Studies, Millbrook, NY

SCIENCE ADVISORY BOARD STAFF

Dr. Holly Stallworth, Designated Federal Officer, Science Advisory Board Staff Office, 

Washington, D.C.
1

CASAC Consensus Responses to Charge Questions

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 controlled human exposures to ozone were carried out in rigorous fashion by 

established investigators at distinguished institutions. They used state-of-the-art 

techniques to measure pulmonary function changes and changes in lung inflammation 

based on biomarkers in bronchoalveolar-lavage fluids. These studies have produced 

substantial data on the acute effects of short-term exposures to this respiratory irritant and 

the results were quite consistent over a wide range of ozone concentrations and exposure 

durations. While CASAC did not consider the findings of recent publications (post-2006) 

in reaching this judgment, it was aware that the results of these more recent studies were 

consistent with those of the earlier studies that formed the basis for our judgments on the 

effects produced by controlled human exposures. 

In interpreting these findings, we note that most of the studies that influenced our 

judgments on the proposed range involved healthy adult subjects and required exercise as 

a necessary factor for revealing adverse responses to ozone. Exercise promotes higher 

levels of ventilation as well as switching from predominantly nasal to oral breathing. 

These factors increase the penetration of ozone into the lungs, thereby increasing 

respiratory responses relative to quiet breathing. Since many Americans have occupations 

that require them to work outdoors while others exercise outdoors for recreation, these 

studies reflect the exposure circumstances of many people in the United States. This is an 

important consideration in establishing the primary NAAQS. There is also a substantial 

literature demonstrating that children with asthma participate in team sports and other 

forms of strenuous exercise as a regular part of their school and after-school activities. 

For such children, who represent a sensitive population, the pulmonary function 

decrements and inflammation observed in exercising healthy adults most likely 

underestimate the effects of a given ozone exposure. 

There are substantial complementary epidemiological data that have the strength, 

compared with clinical studies, of being based on responses in generally much larger 

numbers of participants with a wider range of susceptibility. In chamber studies, 

exposures are limited to ozone alone. While ambient ozone measurements used in 

epidemiological studies are reasonably specific to ozone, there are other strong 

photochemical oxidants in the ambient air as well. This is considered a strength of the 

epidemiological data since ozone is not, per se, a criteria pollutant. Rather it was selected 

to serve as an indicator for the Photochemical Oxidant NAAQS, and the health effects of 

the mixture in natural settings may be larger than if the exposure were only to ozone. The 

health-related functional and inflammatory changes measured in panel studies of people 

exposed to ozone outdoors are also seen in the controlled chamber exposure studies with 
2

ozone alone. Since these effects are not known to occur with ambient air exposures to 

realistic concentrations of these other photochemical co-pollutants, their presence may 

serve to exacerbate rather than simply add to the effects of the ozone in the ambient 

mixture. Thus, within the range of ozone concentrations under consideration (60 to 70 

ppb) over which the ratio of ozone to other photochemical oxidants is unlikely to change, 

reducing the ozone NAAQS is likely to reduce the effects of the photochemical oxidant 

mixture as a whole.

The effects observed in epidemiological studies are reasonably specific to ozone. 

However, as discussed above, they can also be influenced by the presence of other strong 

photochemical oxidants in the ambient air, and thus the health effects in natural settings 

may be larger than expected from clinical experiments with exposure only to ozone. 

Another potential difference between controlled exposure and epidemiological studies is 

the reaction products from ozone once it enters indoor environments. These reaction 

products include a wide range of gas-phase respiratory irritants and ultra-fine particles. 

Epidemiological studies take these other oxidants into account to some greater or lesser 

extent with respect to the correlations of the other ambient oxidants with ozone.It should 

also be noted that central monitors, particularly those placed in urban areas, have ozone 

concentrations that are lower than those further from the urban core because nitric oxide 

in motor vehicle emissions scavenges ozone, thereby lowering ozone concentrations 

within traffic corridors. Thus, ozone levels recorded by central site monitors may not 

accurately index the near-ground exposure of most individuals in the population.

Taken together, results of controlled human studies and the epidemiological studies 

strongly support the selection of a new primary ozone 8-hour concentration limit that is 

well below the 1997 limit of 80 ppb over an 8-hour averaging time. There is scientific 

certainty that 6.6-hour exposures to ozone at concentrations ≥ 80 ppb with intermittent 

exercise, cause clinically relevant decrements of lung function in groups of young, 

healthy volunteers, and in one controlled human exposure study there were “clinically 

relevant” effects in some individuals at 60 ppb. “Clinically relevant” effects are 

decrements >10%, a decrease in lung function considered clinically relevant by the 

American Thoracic Society. The results of multiple epidemiological studies also show 

that children and adults with asthma are at increased risk of acute exacerbations of 

asthma on or shortly after days when ozone concentrations are elevated above 

background but less than 80 ppb, and there is no evidence of a threshold concentration 

limit below which there are no adverse effects in sensitive subpopulations. Given the 

results of EPA’s exposure and risk assessments, setting a new NAAQS in the range of 60 

to 70 ppb is appropriate, but would provide little margin of safety at its upper end.

In summary, the strengths of the evidence from controlled human exposure and 

epidemiological studies enumerated in the Criteria Document and its update were 

substantial, and the evidence is more than adequate to support the recommended range 

for the NAAQS of 60 to 70 ppb. The limitations of the evidence from controlled human 

exposure and epidemiological studies were well and appropriately stated in the Staff 

Paper.
3

Thus, considering the available evidence and the findings of the exposure and risk 

assessment, a substantial number of susceptible individuals are at risk and the degree of 

protection afforded to them would increase as the NAAQS is lowered. The evidence 

available suggests that an adequate margin of safety cannot be achieved for all and that a 

level should be set that reduces the at-risk population to a minimally acceptable number, 

with a reasonable degree of certainty. The unanimous recommendation of CASAC, 

given in Chairperson Henderson’s 2008 letter to the Administrator was to set the NAAQS 

within the range of 60 to 70 ppb. In that range, CASAC found that the evidence was 

sufficiently certain to be confident of public health benefits and additional protection for 

susceptible groups. We are still in agreement with that conclusion.
4

2. Recognizing that controlled human exposure studies at 80 ppb O3 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 FEV1, how should the results of these studies inform our 

understanding the health effects to healthy adults at exposures levels from 60 to 70 

ppb? 

Results from earlier studies at 80 ppb ozone and above were reviewed in earlier Criteria 

Documents and were primarily summarized in less detail in the current Criteria 

Document. Dosimetry of ozone is relevant to extrapolations from higher to lower 

concentrations. Several articles have pointed out that pulmonary function (McDonnell, 

et. al., 1997) and other response indicators (Mudway and Kelly 2004) are related to 

exposure concentration, ventilation rate and exposure duration, among other variables. 

The responses at levels below 80 ppb in the Adams and other studies are consistent with 

predictions using dosimetric and effective dose calculations that were influenced by 

results obtained at 80 ppb and higher concentrations. 

In considering the public health implications of the controlled studies relevant to ozone 

health effects, CASAC notes that the participants were healthy, non-smoking young 

adults. Chamber studies of asthmatic and non-asthmatic subjects exposed to ozone at 

relatively high concentrations showed that the reductions in forced expiratory volume in 

1 second (FEV1) and mid-maximal expiratory flow (MMEF) were significantly greater in 

the subjects with asthma than in those without asthma (Kreit et. al., 1989). For ethical 

reasons, controlled exposure studies are designed to limit effects to only those that are 

relatively mild and reversible, including decrements in pulmonary function and evidence 

of inflammatory changes. One characteristic response to low ozone exposure levels is 

mucosal neutrophilic cell inflammation probably mediated by phospholipid-derived 

products and by epithelial cell-derived chemokines and cytokines (Bromberg and Koren, 

1995). This response may be poorly correlated with lung function changes, perhaps 

because the time course of development for these responses is different from that for 

changes in FEV1 or because the mechanism of ozone-induced reduction in lung function 

may not be related to airway inflammation. In fact, some individuals may exhibit 

inflammation without significant changes in pulmonary function. However, the data 

showing elevated levels of inflammatory cytokines, infiltration of inflammatory cells 

(macrophages and neutrophils) and evidence of oxidative changes provide important 

components of biological plausibility and advance our understanding of the mechanisms 

by which ozone affects health. The data also provide mechanistic support for the 

observed epidemiological associations with regard to exacerbations of asthma at 

concentrations below 80 ppb. The inflammatory effects are likely to be more serious for 

individuals with chronic lung diseases. The exposure chamber studies showed that 

individuals with chronic obstructive pulmonary disease had significantly greater losses of 

pulmonary function (19% from their baseline) than did healthy controls when exposed to 

ozone during light exercise (Gong et. al., 1997). While these studies are often performed 

at exposure concentrations higher than typical ambient conditions, they serve to identify 

disease-relevant mechanisms and underscore the inherent variability of even healthy adult 

populations with respect to their responses to ozone. It is important that we consider this 
5

person-to-person variability in sensitivity to ozone as we examine whether the current or 

proposed ambient concentration ranges provide an adequate margin of safety for sensitive 

subpopulations.
6

3. How should the results of the controlled human exposure studies at 60 ppb O3, 

showing effects on FEV1 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 60 

to 70 ppb? 

The results of only one controlled human exposure study of the effect of ozone at 

concentrations <80 ppb were available for the committee to consider (Adams et. al., 

2006). This study was well-designed and conducted with appropriate methods. The 

authors reported a statistically significant group mean decrement in FEV1 of 4.7% after 

6.6-hour exposure to 80 ppb as compared to the response to filtered air (a 1.35% increase 

in FEV1). They also reported a group mean decrement in FEV1 of 1.5% after 6.6-hour 

exposure to 60 ppb ozone that was not significantly different from the response to filtered 

air. However, eight of the 30 subjects in the Adams et al. study experienced decrements 

in FEV1>5% and two had decrements >10%, a decrease in lung function considered 

clinically relevant by the American Thoracic Society (American Thoracic Society, 2000). 

The results of the Adams et al. study fit well with those from multiple other studies of the 

effect of ozone on lung function at concentrations ≥80 ppb, which have consistently 

shown that some individuals are more sensitive to this effect of ozone than others

(McDonnell et. al., 1997). The results of the Adams et al. study also have been carefully 

reanalyzed by EPA investigators (Brown, et. al., 2007), and this reanalysis showed a 

statistically significant group effect on FEV1 after 60 ppb ozone exposure.

In addition to FEV1, Adams et. al. also assessed respiratory symptoms. While no 

statistically significant difference in symptoms was detected for a square-wave exposure 

to 60 ppb ozone for 6.6 hours compared to filtered air, there was a statistically significant 

increase in symptoms after a triangular exposure to ozone that averaged 60 ppb over 6.6 

hours.

As discussed at length in the Criteria Document and Staff Paper, there is no evidence for 

a threshold below which ozone does not affect lung function. The magnitude of the effect 

of ozone diminishes with decreasing concentration, but does not reach the comparison 

level associated with exposure to ozone-free filtered air. Furthermore, there is a great 

degree of variability of response magnitude among the healthy individuals studied, with 

some having clinically relevant responses, even at 60 ppb. 
7

4. With respect to the information from controlled human exposure studies at 60 ppb 

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. 

The inset plot of the Adams data 

(Adams 2006), derived from Figure 8-2 

of Volume I of “Air Quality Criteria for 

Ozone and Related Photochemical 

Oxidants, 2006”, shows an 

approximately normal distribution in the 

ozone-induced decrements in FEV1 with 

exposure to 0.060 ppm (60 ppb). The 

consistency of effects across ozone 

exposure levels within the Adams study, 

as well as the consistency with effects 

observed in an earlier independent study 

(McDonnell et al. 1991), supports the validity of the observed deficits in FEV1 at 60 ppb 

from the Adams study. In other words, the evidence suggests that prolonged exposure to 

60 ppb ozone causes a general shift in the distribution of FEV1 towards lower values. 

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 (7%) into 

the region of clinical importance (>10% decrement).

All of the Adams study subjects were healthy adult 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 60 ppb ozone. 

A 10% decrement in FEV1 can lead to 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 lead to moderate to severe respiratory 

symptoms. The exposure and risk assessment conducted for the last review of the ozone 

NAAQS clearly 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 60 ppb were to be adopted, some sensitive individuals could still be 

exposed to concentrations that could cause them to have a clinically relevant decrement 

in lung function.

The experimental study results in healthy subjects essentially preclude extension of these 

studies to groups that may be more sensitive because of the ethics of carrying out clinical 

studies in diseased individuals. Thus, without having specific studies among asthmatics 

and children at these levels of exposure, it is prudent, in spite of the uncertainty, that EPA 
8

select an exposure level below the current standard (closer to the 60 ppb level) to “protect 

public health with an adequate margin of safety, including the need to protect susceptible 

populations.”
9

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?

As discussed above, the findings from clinical studies of healthy volunteers may 

underestimate the risks in groups considered potentially susceptible. In the controlled 

human exposure studies carried out at concentrations of 80ppb ozone and below, a 

percentage of healthy subjects have lung function changes much higher than the average 

response (e.g., FEV1 changes >10 %). While FEV1 changes >10% may not prevent 

healthy individuals from pursuing their normal daily activities, individuals with 

compromised lungs, such as persons with asthma, may incur significant health impacts 

with reductions of this magnitude. As CASAC has commented in the past to EPA, 

evidence is accumulating that persons with asthma, the elderly, and particularly children, 

are more sensitive and experience larger decrements in lung function due to ozone 

exposure than do healthy adult volunteers. 

In addition, epidemiological studies considered in the last review showed adverse effects 

of ozone on various health endpoints (e.g., emergency department visits and increased 

hospital admissions for respiratory illness) at relatively low exposure levels. These 

findings and the results of the clinical studies suggest the possibility of ozone effects 

down to the lower end of the 60-70 ppb range. CASAC concluded at the last review that 

the lower range of consideration for revision of the NAAQS should be 60 ppb ozone, 

acknowledging inherently that margin of safety considerations would be better met at 60 

ppb than at 70 ppb ozone. Moreover, since the relative strength of the evidence is weaker 

at lower ozone concentrations (see # 6 below for comments on the epidemiological 

evidence), a range of 60 to 70 ppb ozone allows the Administrator 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 with some margin of safety.
10

6. 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? 

While epidemiological studies are inherently more uncertain as exposures and risk 

estimates decrease (due to the greater potential for biases to dominate small effect 

estimates), specific evidence in the literature does not suggest that our confidence on the 

specific attribution of the estimated effects of ozone on health outcomes differs over the 

proposed range of 60-70 ppb. In framing our answer to this question, we note that the 

range covered is quite narrow and we would not anticipate major differences in the 

characteristics of the pollution mixture across this range. 

Several distinct classes of epidemiological studies are relevant in this rangeand some 

examples are given below. For instance, mortality effects for ozone have been found in 

time-series studies in communities where mean ambient concentrations are well below 

the proposed range (e.g., Vedal et al 2003). Exercise-induced decrements in lung 

function, known to be causally related to ozone in controlled exposure studies, have been 

observed in field studies of healthy volunteers. For instance, in a cross-sectional study, 

Korrick et al. (1998) found that hikers on Mount Washington experienced significant 

decreases in FEV1 after prolonged exercise on days when ozone averaged 40 ppb (range 

21 to 74 ppb). The magnitude of these decrements increased as mean ozone levels 

increased and it was nearly fourfold higher for persons with asthma than for persons 

without asthma. Panel studies of campers are yet another class of field studies that have 

shown effects on children’s lung function are associated with ambient ozone. For 

example, in a panel of healthy children, Spektor et al. (1988) showed significant 

reductions in FEV1 associated with one-hour average ambient ozone, even when 

restricted to days with ozone below 60 ppb. Similarly, in panels of children with 

moderate to severe asthma attending summer camp, Thurston et al.(1997) reported not 

only respiratory function changes, but also more clinically significant responses, 

including increases in physician prescribed rescue medication and respiratory symptoms. 

In yet another class of epidemiological studies, health care utilization for asthma has been 

shown to decrease when ozone concentrations decreased. For example, Friedman et al 

(2001) found that 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. In this study, the relative risk of asthma events 

increased stepwise at cumulative ozone concentrations 60 to 89 ppb and 90 ppb or more 

compared with ozone concentrations of less than 60 ppb. The reduction of the adverse 

effects on asthma in this study was dependent on reduction of ozone exposures to levels 

below 60 ppb. 

Our confidence that the effects from epidemiological studies are attributable to ozone is 

also bolstered by the recognition that the endpoints of concern do not change at the lower 

levels of the proposed range. While it may be difficult to disentangle the effect of a 

single pollutant in epidemiological studies, the evidence regarding ozone-related health 

effects from epidemiological studies is consistent with the evidence from controlled 

exposure studies that involve ozone alone. Indeed, evidence from observational studies of 
11

individuals exercising outdoors indicates ozone may have even stronger lung function 

effects than those estimated in controlled exposure studies, suggesting the possibility that 

a mixture of photochemical oxidants may be more toxic than ozone alone. Finally, 

whether or not the effects attributed to ozone in epidemiological studies are specific to 

ozone vs. the entire photochemical oxidant pollutant mixture, 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 of the proposed range.
12

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 60 and 70 ppb. Considering the patterns of change in the estimates of 

exposures of concern at and above the 60 and 70 ppb 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 first issue is the estimated change in exposures for alternative standards across the 

proposed range of 60 to 70 ppb. Table 1 (included here) in the January 19, 2010 

Proposed Rule (75 Federal Register 11, p. 2978) presents the modeled number and 

percentage of children with exposure (defined as at least one 8-hr average exposure per 

year with moderate or greater level of exercise) at each of three ozone benchmark levels 

of concern (80, 70 and 60 ppb) for ozone standards ranging from the old standard of 84 

ppb to a lowest standard of 64 ppb, for the 12 urban areas in aggregate. It is important to 

note that use of a benchmark level of concern assumes that exposures below the 

benchmark are not harmful to anyone. Since no estimates are presented down to the 

lower end of the proposed range, i.e., 60 ppb, we cannot directly answer the question for 

the entire proposed range of the standard, based on these model estimates. However, at 

least for levels of concern of 70 ppb or greater, because the number and percent exposed 

is either zero or exceedingly small when meeting a standard of 64 ppb, depending on the 

year, it can be inferred that even fewer would be exposed if a standard of 60 ppb was met. 

For a level of concern of 60 ppb, for the year with the lowest concentrations that were 

considered (2004), essentially no exposures were estimated to occur when meeting the 

standard of 64 ppb, whereas for the year with the higher concentrations that were 

considered (2002), it was estimated that around 5% of children would be exposed, 

implying that even fewer would be exposed if a standard of 60 ppb was met. Some 

individual city estimates of exposure were lower while others were higher than these 

aggregate estimates. Based on earlier uncertainty and sensitivity analyses carried out by 

EPA, and relative to uncertainty in health effect estimates, the extent of uncertainty in 

these exposure estimates is acceptable. 

The second issue relates to the public health significance of reductions in exposure for the 

range of standards from 70 to 60 ppb. Public health significance is directly addressed by 

the risk assessment for selected endpoints (see responses to charge question #8) and can 

only be partially assessed based on exposure alone. For endpoints for which it was not 

possible to carry out a quantitative risk assessment (e.g., pulmonary inflammation and 

bronchial hyper-responsiveness), public health significance is gauged in light of the 

toxicologic, human clinical and epidemiological findings. Toxicologic data (i.e., animal 

experimental data) are not particularly helpful in this regard. In the absence of 

demonstrable effects in human clinical studies (in normal individuals or those with mild 

disease) on other than lung function decrements for exposure concentrations less than 80 

ppb, we can only infer effects at lower concentrations and in the more severely diseased. 

Findings from epidemiological studies are less causally conclusive, but indicate effects at 

substantially lower concentrations than were used in the experimental studies. The 
13

benchmark levels in Table 1 correspond to greater degrees of uncertainty about health 

impacts going from 80 down to 60 ppb. Part of this uncertainty relates to the scant 

human clinical data that were available for consideration at exposure concentrations 

below 80 ppb, and the data available are largely limited to effects on lung function. 

Uncertainty also comes from the reliance on epidemiological (non-experimental) findings 

at the lower concentrations. Therefore, while (in Table 1) the predicted number exposed 

increases at every level of the standard as the benchmark level of concern is reduced, the 

public health impact of this increase in number exposed becomes less certain. One could 

argue that since there is no clear threshold for ozone effects, increases in the number 

exposed by lowering the benchmark level of concern translates directly into increased 

numbers of health effects. This ignores not just increasing uncertainty, but also the fact 

that “exposure” at the decreasing benchmark levels results in an increasingly smaller 

percentage of people who will experience health effects at the decreasing levels of 

exposure. These latter percentages are difficult to estimate for endpoints other than, 

perhaps, acute lung function changes. Consequently, the public health significance is 

difficult to gauge for these other endpoints.

What then can be said about the public health significance of exposures at the different 

benchmark levels of concern across the different standards being considered? (The 

response to charge question #8 directly addresses the question of public health 

significance based on quantitative risk assessment.) It is prudent to assume that for at 

least some segments of the population, adverse effects (in addition to acute lung function 

effects) occur at levels below 80 ppb and, making use of epidemiologic observations, that 

there is no obvious threshold, with effects occurring even at and below the benchmark 

level of concern of 60 ppb. Indeed, the concept of a benchmark level of concern is 

inconsistent with the concept of no threshold. It should be understood that use of Table 1 

to make inferences about the public health significance of various standards involves 

assuming there is a threshold at the benchmark level of concern. Making use ofTable 1, 

in the year with the higher ozone concentrations (2002), less than 20% of children will 

experience at least one day at an exposure of concern of 60 ppb at a standard of 70 ppb, 

and only a small fraction of these children will be expected to experience an effect on 

these other health endpoints (e.g., pulmonary inflammation and bronchial 

hyperresponsiveness). At a standard of 64 ppb, approximately 5% of children will be 

exposed, of whom only a fraction will be sensitive. Therefore, at the posed lowest 

concentration of concern (60 ppb), a further reduction in the standard from 70 ppb is 

estimated to have a small public health impact. However, the absence of a threshold 

means that levels below 60 ppb are also of concern. Consequently, this and any other 

analysis that assumes a level of concern of 60 ppb is an underestimate of the true public 

health impact. 
14
15

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 64 ppb. 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 the proposed range? 

Please consider this question in light of the scientific evidence as a whole. 

As indicated in our previous comments, CASAC had a number of concerns relating to the 

mortality estimates in the ozone risk assessment, and did not consider those mortality 

estimates sufficiently robust to serve as the sole basis for establishing a new NAAQS. 

However, based primarily on the morbidity effects in the risk assessment components of 

the 2007 Staff Paper, CASAC previously and unanimously concluded that "Beneficial 

effects in terms of reduction of adverse health effects were calculated to occur at the 

lowest concentration considered (i.e., 0.064 ppm)." (Henderson, 10/24/06, p.4).

Table 2 from the January 19, 2010 Proposed Rule (75 Federal Register 11, p. 2983) is 

provided below as background for addressing this charge question. With regard to 

protecting the public health, the numbers of children aged 5-18 who would suffer at least 

a once per year drop in their pulmonary function of a potentially clinically relevant 

amount with 6-hour ambient air ozone concentrations at 74-64 ppb is estimated to be 

between 340,000 and 180,000 in the worse case vs 130,000 and 70,000 in the best case 

scenarios (as estimated from 15 urban sites). Among children with asthma over this same 

exposure range, potentially important decreases in pulmonary function would occur in 

5% to 1.5% of all children with asthma (estimated from 5 urban sites). It is not clear that 

2002 is the “worse case” or that 2004 is the “best case,” but these two scenarios provide 

bounds. Since estimates were not presented down to the lower end of the proposed 

range, i.e., 60 ppb, we cannot, based on the model results available, answer the charge 

question for the entire proposed range of the standard. However, the available estimates, 

which represent a substantial fraction of at-risk children, would represent a significant 

public health impact. Reduction of the NAAQS to 60 ppb would further reduce the 

number of people affected. 

As discussed at length in the Criteria Document and Staff Paper, there is no evidence of a 

threshold, i.e., the magnitude of the effects measured in clinical studies diminishes with 

decreasing ozone concentration, but does not reach the functional level associated with 

exposure to ozone-free clean air. Furthermore, there is a great degree of variability of 

response magnitude among the individuals studied, with some having clinically-relevant 

responses, even at 60 ppb, and more of them with such responses at higher 

concentrations. Importantly, these clinical studies were carried out in normal healthy 

adults, and even in these volunteers from 7-20%had clinically relevant changes in 

pulmonary function or symptoms. These findings suggest that comparable ozone 

exposures to more sensitive people could lead to more adverse health effects in the 

substantial proportion of the population with lung disease. 
16
17

Works Cited

Adams, W.C. 2006. Comparison of chamber 6.6-h exposures to 0.04-0.08 PPM ozone via 

square-wave and triangular profiles on pulmonary responses. Inhalation Toxicology.

18(2):127-136.

American Thoracic Society. 2000. What constitutes an adverse health effect of

air pollution? American Journal of Respiratory and Critical Care Medicine.161:665-673.

Brown, J. S. The effects of ozone on lung function at 0.06 ppm in healthy adults. June 

14, 2007. Memo to the Ozone NAAQS Review Docket. EPA-HQ-OAR-2005-0172-

0175. Available online at: 

http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_cr_td.html

Bromberg, P.A. and H.S. Koren, 1995. Ozone-induced human respiratory dysfunction 

and disease. Toxicology Letters. 82-83:307-16.

Environmental Protection Agency. 2007. Review of the national ambient air

quality standards for ozone: assessment of scientific and technical information.

OAQPS staff paper. July 2007. Research Triangle Park, NC: Office

of Air Quality Planning and Standards; EPA report no. EPA–452/R–07–007.

Friedman, M.S., K.E. Powell, L. Hutwagner, L.M. Graham, W.G. Teague. 2001. Impact 

of changes in transportation and commuting behaviors during the 1996 Summer Olympic 

Games in Atlanta on air quality and childhood asthma. Journal of the American Medical 

Association. 285:897-905.

Gong, H., Jr. et. al., 1997. Responses of older men with and without chronic obstructive 

pulmonary disease to prolonged ozone exposure.Archives of Environmental Health. 

52(1):18-25.

Henderson, R. 2006. Letter from CASAC Chairman Rogene Henderson to EPA

Administrator Stephen Johnson. October 24, 2006, EPA–CASAC–07–001.

Henderson, R. 2007. Letter from CASAC Chairman Rogene Henderson to EPA

Administrator Stephen Johnson. March 26, 2007, EPA–CASAC–07–002.

Henderson, R. 2008. Letter from CASAC Chairman Rogene Henderson to EPA

Administrator Stephen Johnson. April 7, 2008, EPA–CASAC–08–009.

Kreit, J.W., et. al., 1989. Ozone-induced changes in pulmonary function and bronchial 

responsiveness in asthmatics. Journal of Applied Physiology. 66(1):217-22.
18

Korrick, S.A.L. M. Neas, D.W. Dockery, D.R. Gold, G.A. Allen, L.B. Hill, K.D. 

Kimball, B.A. Rosner, F.E. Speizer. 1998. Effects of ozone and other pollutants on the 

pulmonary function of adult hikers. Environmental Health Perspectives. 106: 93-99.

McDonnell, W.F. et. al. 1997. Prediction of ozone-induced FEV1 changes. Effects of 

concentration, duration, and ventilation. American Journal of Respiratory and Critical 

Care Medicine.156(3 Pt 1):715-22.

McDonnell, W.F., H.R. Kehrl, S. Abdul-Salaam, P.J. Ives, L.J. L.J. Folinsbee, R.B. 

Devlin, et al. 1991. Respiratory response of humans exposed to low levels of ozone for 

6.6 hours. Archives of Environmental Health. 46(3):145-150.

Mudway, I.S. and F.J. Kelly. 2004. An investigation of inhaled ozone dose and the 

magnitude of airway inflammation in healthy adults. American Journal of Respiratory 

and Critical Care Medicine. 169(10):1089-95.

Samet, J. 2010. Letter from CASAC Chairman Jonathan M. Samet to EPA

Administrator Lisa Jackson. February 19, 2010. EPA–CASAC–10–007. 

Spektor, D.M., M. Lippmann, P. J. Lioy, G.D. Thurston, K. Citak, D.J. James, N. Bock, 

F.E. Speizer, and C. Hayes. 1988. Effects of ambient ozone on respiratory function in 

active normal children. American Review of Respiratory Disease. 137:313-320.

Thurston, G.D., M. Lippmann, M.B. Scott, J.M. Fine. 1997. Summertime haze air 

pollution and children with asthma. American Journal of Respiratory and Critical Care 

Medicine. 155:654-660.

Vedal, S., M. Brauer, R. White, J. Petkau. 2003. Air pollution and daily mortality in a 

city with low levels of pollution. Environmental Health Perspectives. 111:45-51.
A-1

Individual Panelist Comments

Table of Contents

Mr. George Allen ............................................................................................................................. A-2

Dr. John Balmes............................................................................................................................... A-6

Dr. Joe Brain................................................................................................................................... A-10

Dr. James Gauderman.................................................................................................................... A-13

Dr. Rogene Henderson................................................................................................................... A-15

Dr. Philip K. Hopke ....................................................................................................................... A-18

Dr. Michael T. Kleinman ............................................................................................................... A-19

Dr. Morton Lippmann.................................................................................................................... A-24

Dr. Fred Miller ............................................................................................................................... A-28

Dr. Lianne Sheppard ...................................................................................................................... A-29

Dr. Frank Speizer ........................................................................................................................... A-30

Dr. Helen Suh................................................................................................................................. A-33

Dr. James Ultman........................................................................................................................... A-36

Dr. Sverre Vedal............................................................................................................................. A-39

Dr. Barbara Zielinska ..................................................................................................................... A-41
A-2

Mr. 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.

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?

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 controlled 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 markers such as FEV1 and inflammatory markers that 

epidemiological studies cannot (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 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 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) 5715–5716); these include a wide range of gas-phase 

respiratory irritants and ultra-fine particles.

 2. 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 the 

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 available data 

suggest that there probably is a reasonably “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 
A-3

of thresholds. And as with all other aspects of the science, this assumption is weaker at .060 than 

at .070 ppm.

3. 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 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.

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.

For healthy adult subjects in controlled 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 responses without FEV1 decrements. From a public health 

perspective, where SVP would be expected to have an enhanced response to exposures 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.

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?

The results of controlled human exposure studies conducted on healthy adults provide 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 concentration, but are subject to the 

confounding factors noted above. The best approach may be a “weight of evidence” scenario 

that assesses the consistency (or lack thereof) across these very different approaches to 

quantifying ozone health effects.

6. 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 previously, the uncertainty (or confidence if you wish) of any exposure study decreases 

as the exposure concentrations decrease. For epidemiological studies, the effects of confounders 

are 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.
A-4

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?

There is little doubt that reduced exposure, both in size of SVP exposed 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 remaining exposures with health effects across the proposed range in 

SVP.

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 the proposed range? Please consider this 

question in light of the scientific evidence as a whole.

This is really a policy 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) 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 various ranges considered. The science can only take 

the process so far, and after that it becomes 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 reconsideration 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 the 

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 overreport 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 
A-5

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 measurements of 

NAAQS pollutants have various biases associated with them, sometimes positive (NO2, nontrace 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 “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.
A-6

Dr. John Balmes

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 human 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, setting 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 O3 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 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?

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 

concentrations 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 O3, 

showing effects on FEV1 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?

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 

experienced 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 individuals are more 

sensitive to this effect of ozone than others. The selection of a NAAQS for ozone needs to 

consider an adequate margin of safety to protect the most sensitive subgroup of individuals. 
A-7

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 statistically 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 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.

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 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 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 concentrations 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, 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?

Controlled 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 increased 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 susceptibility 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 with 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 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?

While the effects of ozone cannot be easily isolated from the effects of other pollutants in 
A-8

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 cumulative 

ozone concentrations 0.060 to 0.089 ppm and 0.090 ppm or more compared with ozone 

concentrations of less than 0.060 ppm. The reduction of the adverse 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. Therefore, 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 the 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 ozone 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 effects on mortality in the exposure and risk 

assessment components of the 2007 Staff Paper. The evidence regarding the ozone exposuremortality relationship has grown stronger since the publication of the Staff Paper (e.g., Jerrett et 

al., 2009) and a mortality effect was seen at concentrations below the current standard.
A-9

References Cited:

Brown JS, Bateson TF, McDonnell WF. 2008. Effects of exposure to 0.06 ppm ozone on FEV1

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, Burnett RT, Pope CA 3rd, Ito K, Thurston G, Krewski D, Shi Y, Calle E, Thun M. 

2009. Long-term ozone exposure and mortality. N Engl J Med 360:1085-1095.

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, Walby 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 180:265-272.
A-10

Dr. Joe Brain

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 quality of the controlled human exposures to ozone is extremely good. Established 

investigators at distinguished institutions did their best to measure pulmonary function changes. 

There are even some bronchoalveolar lavage data. In general, there are more data here than for 

many other regulated and unregulated pollutants. At the same time, there are limitations worth 

considering. They are primarily carried out in healthy, young, non-smoking volunteers. Data for 

susceptible populations are modest at best. It should also be noticed that most of the studies 

involve exercise as a necessary component to reveal responses to ozone. Of course, many 

Americans exercise, so that’s not irrelevant. But it is important to keep in mind that higher 

levels of ventilation, and especially switching from nose to mouth breathing, have a substantial 

effect on ozone responses. Finally, the issue of adaptation has generally not been addressed. On 

the one hand, when humans are chronically exposed to steady-state levels of ozone, they may 

adapt, and their responses may be diminished. On the other hand, if they have not seen these 

levels of ozone recently, responses may be greater. There is also a considerable amount of 

epidemiologic data as well. This has the advantage of more diverse subjects, but typically less 

invasive responses – primarily limited to pulmonary function studies. As noted elsewhere, in 

contrast to chamber studies where exposures are limited to ozone, epidemiologic studies 

inevitably involve a mixture of pollutants. Identifying changes relating to ozone only may be 

difficult or impossible.

2. 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 the 

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?

The database reviewed and summarized is consistent with past evaluations, but emphasizes the 

fact that responses to ozone can be seen within the proposed range of 0.06-0.07 ppm, especially 

when exercise is included.

3. 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 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 data mentioned above, especially inflammation, are important. If responses to ozone were 

completely limited to reversible pulmonary function changes, we would be less concerned. 
A-11

However, chronic inflammation and the presence of increased neutrophils and neutrophil elastase 

raise concerns. Chronic inflammation and resulting increased levels of reactive oxygen species 

(ROS) may result in cumulative irreversible damage. These changes raise concerns about 

increases in morbidity and mortality caused by chronic exposure to ozone.

Unfortunately, the number of studies at 0.06 ppm of ozone are more limited than those at higher 

concentrations of ozone. Like other pollutants, our confidence about the magnitude of health 

effects increases as we go to higher levels. However, the limited studies that do exist at 0.06 

ppm ozone demonstrate that there are responses among some individuals. Like PM2.5, there is 

the absence of a clearly defined threshold. Instead, we can always find a susceptible group that 

responds to lower and lower levels.

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.

We must not only look at average responses to a given pollutant exposure. We need to take into 

consideration the entire distribution of responses, particularly that of outliers. We must protect 

even a minority of exposed subjects, if they experience significant declines in pulmonary 

function. The existence of susceptible subgroups will usually drive standard setting.

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?

As indicated above, the presence of susceptible populations and the magnitude of their increased 

responsiveness is a key factor in regulation setting. As the question suggests, an advantage of 

epidemiologic studies is that they usually encompass a wider range of populations including 

older, younger, and sicker individuals. In contrast, the chamber studies typically exclude these 

much more susceptible populations. Asthmatics have been studied to a certain extent. However, 

it is also true that epidemiologic studies generally don’t utilize exercise to the same degree as 

chamber studies for ozone. Moreover, the sickest individuals probably spend less time out of 

doors where ozone levels are highest. The answer to question five is that both chamber studies 

and epidemiologic studies need to be considered and integrated.

6. 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 the question implies, out confidence in attributing the effects observed in epidemiologic 

studies to ozone alone is usually limited and decreases with progressively lower levels of ozone. 

As the question implies, ozone never exists by itself in outside air. There are other sources of 

oxidant injury, as well as other pollutants known to produce some of the same effects, such as 

decreases in pulmonary function. Ozone concentrations/exposures throughout the day definitely 
A-12

have a “signature” because of the important role of sunlight in generating ozone from other 

gaseous pollutants. Then the time course of some acute responses may be helpful in identifying 

the role of ozone per se. More generally, however, this dilemma suggests that we should be 

thinking more and more about the aggregate effects of different types of air pollution, such as 

those that collectively produce oxidant injury.

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 eductions in exposures of concern, as well as the exposures 

remaining, for alternative standards across the proposed range?

As indicated before, focusing on susceptible individuals is appropriate. Children represent a 

familiar and important susceptible class. Even at rest. their ventilation per kilogram is higher 

than that of adults. Moreover, they tend to be much more active and more likely to be 

exercising. Moreover, if there are chronic, cumulative changes produced by ozone, there is a 

longer period of lifespan ahead for children where these effects may become manifest. The 

existing data and these considerations of children and other susceptible groups suggest that 

continued reduction of ozone exposures will produce public health benefits. Of course, attention 

to other sources of oxidant injury from other air pollutants should be emphasized as well.

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 the proposed range? Please consider this 

question in light of the scientific evidence as a whole.

I believe that each year brings additional scientific evidence documenting the importance of 

ozone exposures, both acute and chronic, at progressively lower levels. Maintaining or perhaps 

lowering the ozone standard will reduce the numbers of people who suffer from ozone-induced 

adverse health effects. I also agree with the suggestion that even tighter regulatory standards will 

not eliminate ozone-induced changes entirely – especially in the most susceptible groups. 

Because of variations in susceptibility and exposure, no threshold for ozone effects is likely. 

Moreover, there is no plausible scenario to reduce ozone levels to zero, given the multiplicity of 

industrial and natural sources.
A-13

Dr. James Gauderman

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 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 pvalues 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 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 the 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%) experienced 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 

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 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 and 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 
A-14

clinically interesting (>10%). All of the Adams study subjects 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 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 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. 
A-15

Dr. Rogene Henderson

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 between 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 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 O3 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 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?

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 O3, 

showing effects on FEV1 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 levels 

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 it essential that the 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.
A-16

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.

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 viewpoint, 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 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 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 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 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?

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

assessments indicate that the number of children and asthmatic children exposed to ozone levels 

of concern is significant from a public health viewpoint.

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-17

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 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. 
A-18

Dr. Philip K. Hopke

The charge questions provided to the ozone panel revolve primarily around 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 

respect 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 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 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 round of review. Then a better informed judgment 

can be rendered.
A-19

Dr. Michael T. Kleinman

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?

a. Controlled Human Exposure:

Controlled human studies to O3 were, in large part, conducted with volunteers that were 

relatively young, in good physical condition and were non-smokers. The proposed range 

of 0.060 to 0.070 ppm was identified after a thorough and intensive review of the 

available studies and was an important part of the data used to identify that range 

(Horstman et al., 1990, Adams, 2003b, a, 2006). However that data did not stand alone 

and was view in context with population studies that showed significant effects at and 

perhaps below the selected range and mechanistic studies that provided evidence of 

biological plausibility. 

b. Epidemiological Studies: Epidemiological studies and panel studies with sensitive 

populations, e.g. asthmatic adolescents) have demonstrated significant effects at 

exposures that were within, and sometimes below, the proposed range of O3 

concentrations. There was adequate discussion of the strengths and weaknesses of this 

study in the ISA and risk documents that were previously reviewed. 

c. Advice: Given the points in a and b above, and the fact that subsequent studies (Schelegle 

et al., 2009, Kim et al., 2011) did not negate the previous conclusions, there is not 

adequate reason to alter the Panel’s prior advice to the Administrator. 

2. 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 the 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?

A characteristic response to low O3 levels is mucosal neutrophilic inflammation probably 

mediated by phospholipid-derived products and by epithelial cell-derived chemokines and 

cytokines (Bromberg and Koren, 1995). This response may be poorly correlated with lung 

function changes because the time course of development for these responses is different from 

that for changes in FEV1. However these data provide important components of the biological 

plausibility and advance our understanding of the mechanisms by which O3 affects health. It 

should be noted that inflammatory effects are likely to be more serious for individuals with 

chronic lung diseases. This is consistent with the exposure chamber study findings that 

individuals with chronic obstructive pulmonary disease had significantly greater losses of 

pulmonary function (19% from their baseline) than did healthy controls when exposed to O3

during light exercise (Gong et al., 1997). While these studies are often performed at exposure 

concentrations higher than typical ambient conditions, they serve to identify disease-relevant 

mechanisms and also to underscore the inherent variability of even healthy populations with 

respect to their responses to O3. It is important that we consider this variability as we examine 
A-20

whether the current or proposed ambient concentration ranges provide an adequate margin of 

safety for sensitive individuals in the population.

3. 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

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?

As stated in the charge document, “The controlled human exposure studies at 0.060 ppm O3 are 

limited, with only two published studies (Adams 2003a and 2006) available from one 

investigator. However, the Adams studies are well-designed and employed an exposure protocol 

that was consistent with earlier studies (Horstman et al., 1990; McDonnell et al., 1991). At the 

0.080 ppm level, the subjects did not appear to be more responsive to O3 than subjects in 

previous studies, as the observed response was similar to that of previous studies (Horstman et 

al., 1990, Mcdonnell et al., 1991, Adams, 2003b, a, 2006). Although of much smaller magnitude, 

the temporal pattern of the 0.060 ppm response was generally consistent with the temporal 

patterns of response to higher concentrations of O3 in this and other studies. These findings are 

not unexpected because the previously observed group mean FEV1 responses to 0.080 ppm were 

in the range of 6–9% suggesting that exposure to lower concentrations of O3 would result in

smaller, but real group mean FEV1 decrements, i.e., the responses to 0.060 ppm O3 are consistent

with the presence of a smooth exposure-response curve with responses that do not end abruptly

below 0.080 ppm (75 FR 2950)”. A graph showing an exponential fit (R2=0.87) to the group 

mean changes in FEV1 from the Adams et al. (2006) study only are shown as the solid line in 

context with data from more recent studies demonstrates that the previous conclusions remain 

valid. The dashed linen is an exponential fit (R2=0.85) to all the data.
A-21

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.

The human exposure studies used relatively small populations of healthy, non-smoking young 

individuals. The within group variability of this preselected relatively homogeneous population 

might underestimate that of the population at large. The 7-20 percent of individuals with 

changes in pulmonary function that would be considered to be clinically relevant (i.e. 10%) 

should have great weight in the evaluation of potential public health risk, especially for the less 

homogeneous population at large.

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?

There are very few controlled human studies that have been conducted with susceptible groups . 

The Gong, et al. (1997) study showed that for some outcomes individuals with COPD were 

considerably more susceptible to O3 effects than were healthy individuals, when results were 
A-22

expressed in terms of changes from their respective baseline levels. Individuals with COPD 

have diminished respiratory reserves and are likely to have less capacity to compensate for 

adverse environmental effects. This might be intensified when such individuals are under some 

stress, such as the light exercise imposed during the Gong et al. (1997) study. Thus one should 

consider that even though the potential benefits accruing from reducing O3 exposures below the 

current standard might be considered small based on responses of healthy subjects, there might 

still be important benefits for individuals with compromised lungs and hearts. 

6. 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?

It has been very difficult to apportion effects in epidemiological studies between O3 and copollutants. However some studies that examined multiple pollutant models (i.e. O3 and 

particulate matter) have shown independent effects of O3. There might be a seasonal 

characteristic since the strongest associations between O3 and health outcomes occur in the warm 

season months. The uncertainties at lower concentrations are greater. However the 

epidemiological studies are consistent with the controlled human studies which do not suffer 

from multiple pollutant interactions. Thus reducing O3 concentrations will be expected to reduce 

adverse effects, especially in more susceptible members of the population.

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 exposures of concern are at levels at which controlled studies found significant pulmonary 

function changes in health adults. Asthmatic children and others with pre-existing heart and lung 

diseases are likely to be more susceptible to effects of O3 than are healthy young adults. Some 

epidemiological studies have identified effects at or below those levels. The panel’s previous 

deliberations and the EPA assessments were based on an intensive search of the scientific 

literature at the time (2005 and earlier). The conclusions drawn remain valid and are, in fact, 

substantiated by more recent studies. The reduction of ozone exposures is important from the 

public health perspective.

8. EPA’s quantitative risk assessment estimated the numbers of occurrences of various ozonerelated 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 the proposed

range? Please consider this question in light of the scientific evidence as a whole.
A-23

The previous deliberations of this panel concluded “Beneficial effects in terms of reduction of 

adverse health effects were calculated to occur at the lowest concentration considered (i.e., 0.064 

ppm). (Henderson, 10/24/06, p.4).” The potential benefits accrued to literally thousands of 

individuals when combined improvements with respect to mortality and morbidity were 

considered. This is important from the public health standpoint. (Also see previous points).

Adams WC (2003a) Comparison of chamber and face mask 6.6-hour exposure to 0.08 ppm 

ozone via square-wave and triangular profiles on pulmonary responses. Inhal Toxicol 

15:265-281.

Adams WC (2003b) Relation of pulmonary responses induced by 6.6-h exposures to 0.08 ppm 

ozone and 2-h exposures to 0.30 ppm ozone via chamber and face-mask inhalation. Inhal 

Toxicol 15:745-759.

Adams WC (2006) Comparison of chamber 6.6-h exposures to 0.04-0.08 PPM ozone via squarewave and triangular profiles on pulmonary responses. Inhal Toxicol 18:127-136.

Bromberg PA, Koren HS (1995) Ozone-induced human respiratory dysfunction and disease. 

Toxicol Lett 82-83:307-316.

Gong H, Jr., Shamoo DA, Anderson KR, Linn WS (1997) Responses of older men with and 

without chronic obstructive pulmonary disease to prolonged ozone exposure. Arch 

Environ Health 52:18-25.

Horstman DH, Folinsbee LJ, Ives PJ, Abdul-Salaam S, McDonnell WF (1990) Ozone 

concentration and pulmonary response relationships for 6.6-hour exposures with five 

hours of moderate exercise to 0.08, 0.10, and 0.12 ppm. Am Rev Respir Dis 142:1158-

1163.

Kim CS, Alexis NE, Rappold AG, Kehrl H, Hazucha MJ, Lay JC, Schmitt MT, Case M, Devlin 

RB, Peden DB, Diaz-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.

Mcdonnell WF, Kehrl HR, Abdulsalaam S, Ives PJ, Folinsbee LJ, Devlin RB, Oneil JJ, 

Horstman DH (1991) Respiratory Response of Humans Exposed to Low-Levels of Ozone 

for 6.6 Hours. Archives of Environmental Health 46:145-150.

Schelegle ES, Morales CA, Walby WF, Marion S, Allen RP (2009) 6.6-hour inhalation of ozone 

concentrations from 60 to 87 parts per billion in healthy humans. Am J Respir Crit Care 

Med 180:265-272.
A-24

Dr. Morton Lippmann

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 strengths of the evidence from controlled human exposure and epidemiological studies 

enumerated in the Criteria Document and its update were substantial, and more than adequate to 

support the recommended range for the NAAQS of 0.060 to 0.070 ppm. The limitations of the 

evidence from controlled human exposure and epidemiological studies were well and 

appropriately stated in the Staff Paper. These limitations have subsequently been substantially 

reduced since CASAC’s last commentary 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 individuals (Brown et al. 2008, (which was included in the 

final docket and can be officially cited in our CASAC letter); as well as newer work, which we 

cannot officially cite, i.e., Schelegle et al. 2009; Kim et al. in press), and in recent work on 

children and adults 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). 

2. 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 the 

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?

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 clinicallyrelevant indices. They also provide results that provide a mechanistic basis for the functional 

effects and increased morbidity and mortality.

3. 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 

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?

As discussed at length in the Criteria Document 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 associated with exposure to ozone-free clean air. Furthermore 

there is a great degree of variability of response magnitude among the individuals studied, with 

some having clinically-relevant responses, even at 0.060 ppm, and more of them with such 

responses at higher concentrations. Since the numbers of subjects exposed in the each of the 

controlled chamber studies at each concentration have been small, extrapolation to the much 

larger general population indicates that a very large number of individuals would have 

substantial responses, even though they would constitute only about 10% of the population. 
A-25

Schelege et al. (2009) show that FEV1 decrements >20% can occur at 0.060 as well as at 0.070 

and 0.080 ppm.

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.

See my response to #3 above.

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?

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 presence of less healthy, i.e., more susceptible people in the general population, 

but also due, at least in part, to the influence of prior days’ exposures, and to evidence that 

ambient air containing other pollutants that can exacerbate the responses. Thus, the chamber 

studies underestimate population responses that are known to be associated with ozone 

exposures. A margin-of-safety is needed to compensate for the understatement of effect from the 

chamber exposure studies.

6. 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?

I do not have confidence that the effects observed in epidemiological studies are attributable 

specifically to O3, as noted above. However, the effects are characteristic of those produced by 

ozone, and not associated with other pollutants 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. 

It is highly informative that associations of effects with O3 ambient concentrations at 0.060 ppm 

and below were seen in adults and children engaged in recreational exercise programs. In a 

cross-sectional study, Korrick et al. (1998) found hikers on Mount Washington experienced 

significant decreases in FEV1 after prolonged exercise on days when ozone averaged 0.040 ppm 

(range 0.021 to 0.074 ppm). The magnitude of these decrements increased as mean ozone levels 

increased and it was nearly fourfold higher for persons with asthma than for persons without 

asthma. Panel studies of campers are yet another class of field studies that have shown effects on 

children’s lung function were associated with ambient ozone. For example, in a panel of healthy 

children, Spektor et al. (1988) showed significant reductions in FEV1 associated with one-hour 

average ambient ozone, even when restricted to days with ozone below 0.060 ppm. Similarly, in 

panels of children with moderate to severe asthma attending summer camp, Thurston et al. 

(1997) reported not only respiratory function changes, but also more clinically significant 

responses, including increases in physician prescribed rescue medication and respiratory 
A-26

symptoms.

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?

Since the most reasonable assumption concerning the ozone exposure response relationship is 

linear with no threshold, it is important to reduce ozone exposures 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 either 0.060 or 0.070 will only reduce the numbers of people with adverse health 

effects, and will not eliminate such effects.

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 the proposed range? Please consider this question in light of the scientific evidence as 

a whole.

See my response to #3 above.

References Cited:

Brown JS, Bateson TF, & McDonnell WF. Effects of exposure to 0.06 ppm ozone on FEV1 in 

humans: A secondary analysis of existing data. Environ. Health Perspect. 116:1023-1026 

(2008).

Islam T, McConnell R, Gauderman WJ, Avol E, Peters 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, Rappold 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).

Korrick, S.A. L. M. Neas, D.W. Dockery, D.R. Gold, G.A. Allen, L.B. Hill, K.D. Kimball, B.A. 

Rosner, F.E. Speizer. 1998. Effects of ozone and other pollutants on the pulmonary function of 

adult hikers. Environmental Health Perspectives 106: 93-99.
A-27

Lin S, Liu X, Le LH, and Hwang 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, Brajer V, Alcorn S, & Tager 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 parts per million in healthy humans. Am. J. Respir. Crit. Care Med.

180:265-272 (2009).

Silverman RA, Ito K. Age related association of fine particles and ozone with severe acute 

asthma in New York City. J. Allergy and Clin. Immunol. 125:367-373 (2010).

Spektor, D.M., M. Lippmann, P. J. Lioy, G.D. Thurston, K. Citak, D.J. James, N. Bock, F.E. 

Speizer, and C. Hayes. 1998. Effects of ambient ozone on respiratory function in

active normal children. American Review of Respiratory Disease 137:313-320.

Thurston, G.D., M. Lippmann, M.B. Scott, J.M. Fine. 1997. Summertime haze air

pollution and children with asthma. American Journal of Respiratory and Critical Care

Medicine 155:654-660.
A-28

Dr. 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 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 and 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 normal 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 particularly children, are more sensitive and experience larger decrements in 

lung function due to O3 exposure than do healthy volunteers. 

This, coupled with the fact that a number of epidemiology studies discussed in the last review 

were showing O3-related effects 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 O3 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 revision of the NAAQS should be 0.060 ppm O3. 

By doing so, the CASAC felt that margin of safety considerations would better be met than at 

0.070 ppm O3. Moreover, since the relative strength of the science is weaker as one lowers the 

O3 concentration under consideration, a range of 0.060 to 0.070 ppm O3 allows the Administrator 

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.
A-29

Dr. Lianne Sheppard

Individual comments:

I still fully agree with the advice provided by CASAC in its letters of October 24, 2006 (EPACASAC-07-001), March 26, 2007 (EPA-CASAC-07-002), and February 10, 2010 (EPACASAC-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 contributed to 

my updated understanding of the evidence available in the 2008 review.
A-30

Dr. Frank Speizer

Preliminary Comments

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?

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 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 diseased 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—more 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...”

2. 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 the 

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?

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 because 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 protected 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. 

3. 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 

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 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 
A-31

that the data are consistent with the lower end of the range being more protective than the upper 

end. 

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.

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. 

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?

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 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 exposures

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. 

6. 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?

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 greater variability rather than confounding by additional pollutants and thus the effects noted 

seem attributable to ozone pollution. 

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 
A-32

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?

As indicated in the discussion 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 children. 

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 population the Administrator is willing to leave at risk. 

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 the proposed range? Please consider this question in light of the scientific evidence as 

a whole.

From the Fed Reg TABLE 3—NUMBER AND PERCENT OF ALL AND ASTHMATIC 

SCHOOL AGE CHILDREN IN 12 URBAN AREAS ESTIMATED TO EXPERIENCE 8-

HOUR OZONE EXPOSURES ABOVE 0.060 AND 0.070 PPM WHILE AT MODERATE OR 

GREATER EXERTION,ONE OR MORE TIMES PER SEASON ASSOCIATED WITH JUST 

MEETING ALTERNATIVE 8-HOUR STANDARDS BASED ON ADJUSTING 2002 AND 

2004 AIR QUALITY DATA1 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 

is 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 numbers 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.
A-33

Dr. 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 controlled 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 human exposure studies by Adams 

(2002, 2006) show statistically 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 findings. 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 levels 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 O3 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 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?

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 O3, showing 

effects on FEV1 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 

of safety determinations. 

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.
A-34

For individuals with pre-existing respiratory disease, a 10% decrement in FEV1 is 

significant. 

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.

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 

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?

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 O3 levels. Confounding by other pollutants is 

certainly of concern. However, ozone mediated impacts have been observed for a variety 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 correlations 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 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 no 

threshold in ozone-mediated impacts. As a result, even with uncertainty in the benchmark 

exposures, it is likely that a significant fraction of asthmatic children will remain exposed to 

ozone exposures above the benchmark level.
A-35

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 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 limitations may outweigh, or at the least counteract, any 

concerns regarding uncertainty in the risk estimates. 
A-36

Dr. James Ultman

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?

Clinical Studies. Has several strengths including accurate and precise administration of exposure 

gas mixtures and patterns of exposure. The methods of measuring lung function and biological 

responses are also accurate, and precise, and are generally standardized between different 

laboratories. The medical and physiological states of the subjects are well-defined. 

Weaknesses include the use of ozone exposure levels that are usually 0.08 ppm or above. Only 

two studies (Adams 2002,2006) were conducted in the range 0.06-0.07 ppm ozone being 

considered for the new standard. Also, due to ethical concerns, the large majority of all clinical 

studies are performed on healthy or young subjects or subjects with mild respiratory disease. 

Moreover, only a handful clinical studies elucidate the role of copollutants in the exposure gas 

mixture, and sponses are observable only when exercise is superimposed on exposure.

Epidemiological Studies. A major strength is data that are drawn from large and diverse 

populations that include people of all ages and all states of health. Another strength is the use of 

morbidity endpoints (e.g., hospital admissions from asthma exacerbation) that directly elucidate 

the clinical importance of the exposure. Although a strength of these studies is exposure to real 

world gas mixtures, this results in a major problem in separating out the effect of ozone alone 

from its other copollutants; this can result in an overestimation of the ozone health effect. 

Another weakness is the need to utilize exposure data from above-ground monitoring sites; this 

can also cause an overestimation of the health effect. 

2. 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 the 

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?

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

decrements in pulmonary function and also elevates various biological responses such as airway 

inflammation. Because lung function decrements and airway inflammation occur by different 

mechanisms and do not necessarily appear together in the same subject or occur in the same 

time-frame in a given subject, functional endpoints such as FEV1 are probably not directly 

related to biological endpoints such as eosinophilia. Thus, although significant FEV1 decrements 

at ozone exposure levels of 0.04 and 0.06 ppm were documented in the literature up to 2008 

(Adams 2002, 2006), one cannot conclude that the same would be true of airway inflammation. 

3. 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 

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? 
A-37

Data from two clinical studies on healthy young subjects (Adams 2002,2006), provides evidence 

that 0.06 ppm ozone causes a pre-to-post exposure decrement in FEV1 relative to that in clean 

air. The reanalysis of Adams 2006 study by Brown(2), in particular, indicates that a 6.6 hr 

exposure to a square-wave or variable ozone concentration pattern with intermittent exercise 

results in a 3% decrease in FEV1 with 2/30 exhibiting a decrement greater than 10%. In 

susceptible subjects, we expect that the FEV1 decrement under the same exercise and exposure 

conditions would be even greater, possibly reaching a clinically significant level.

An exposure-response curve was developed in the Staff Paper of January 2007 using several 

different scenarios regarding the nature of the function (figure 5-3). The results indicate that 

Adam’s subject-averaged data at 0.04 and 0.06 ppm ozone exposure fit very well with data 

obtained at higher ozone exposure levels in his lab (California) as well as in EPA’s clinical 

laboratory (Chapel Hill). The distribution of responses among subjects at ozone levels at 0.08 

ppm and above also appears to be similar between the two labs (table 5-3). This coherence of a 

substantial amount data at 0.08 ppm and above, together with the plausibility of the exposureresponse curve that passes through the more limited data at 0.06 and 0.04 ppm gives us 

confidence that clinically importance FEV1 responses can occur in moderately exercising 

subjects at 0.06 ppm ozone exposure. 

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.

Though it only occurs in 7-20% of the subjects, the observation of decrements in FEV1>10% at 

0.06 ppm ozone exposure is an important indicator of a possible health effect in sensitive 

individuals. The probabilistic exposure-response curve in the staff paper of January 2007 (Fig. 

5-4) further supports the expectation that, even in a “healthy” population, there will be some 

individuals whose lung function is adversely affected by a single 8 hour exposure that includes 

intermittent moderate exercise.

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?

In this connection, it is useful to consider the exposure-dose-response paradigm. While exposure 

refers to inhaled concentration, dose is closely related to the product of minute ventilation with 

inhaled concentration. Importantly, increasing the level of physical activity increases minute 

ventilation. This, in turn, can increase the severity of pulmonary function or biological responses 

without changing exposure concentration.

In natural settings, susceptible people (e.g.,asthmatics or the aged) may avoid or even be 

incapable of the hour-long bouts of moderate exercise that are produced by healthy subjects 

during clinical studies. Thus, at comparable ozone exposure levels, respiratory dose to 
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susceptible individuals would be smaller than the dose to healthy exercising individuals. 

However, susceptible people will (by definition) react with a greater response to a given inhaled 

dose of ozone. Because of these counteracting effects, the exposure-response behavior found for 

healthy subjects in clinical studies(e.g., Fig. 5-4, Staff paper, January 2007) is a reasonable basis 

for estimating the exposure-response of susceptible populations. 

6. 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 concentration levels are reduced, uncertainties in personal exposure as well endpoints 

attributed to ozone alone would generally increase.

 
A-39

Dr. Sverre Vedal

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 first issue is the estimated change in exposures for alternative standards across the proposed 

range of 0.060 to 0.070 ppm. Table 1 in the Proposed Rules (p. 2978 in the Federal Register 

January 19, 2010) presents modeled number and percentage of children with exposure (defined 

as at least one 8-hr average exposure per year with moderate or greater level of exercise) at each 

of three ozone benchmark levels of concern (0.080, 0.070 and 0.060 ppm) for ozone standards 

ranging from the old standard of 0.084 to a lowest standard of 0.064 ppm, for the 12 urban areas 

in aggregate. Since no estimates are presented down to the lower end of the proposed range, i.e.,

0.060 ppm, we cannot directly answer the question for the entire proposed range of the standard, 

based on these model estimates. However, at least for levels of concern of 0.070 or greater, 

because the number and percent exposed is either zero or exceedingly small when meeting a 

standard of 0.064, depending on the year, it can be inferred that even fewer are exposed were a 

standard of 0.060 to be met. For a level of concern of 0.060, for the year with the lowest 

concentrations (2004), no exposures are estimated to occur when meeting the standard of 0.064, 

whereas for the year with the higher concentrations (2002), it is estimated that around 5% of 

children will be exposed, implying that even fewer will be exposed were a standard of 0.060 to 

be met. Some individual city estimates of exposure were lower while others were higher than 

these aggregate estimates. Based on earlier uncertainty and sensitivity analyses carried out by 

EPA, and relative to uncertainty in health effect estimates, uncertainty in these exposure 

estimates is acceptable. 

The second issue relates to the public health significance of reductions in exposure for the range 

of standards from 0.070 to 0.060. Some of the public health significance is addressed by the risk 

assessment for selected endpoints (see responses to charge question #8). For endpoints for 

which it was not possible to carry out a quantitative risk assessment, we must infer public health 

significance in light of the toxicologic, human clinical and epidemiological findings. 

Toxicologic data (i.e., animal experimental data) are largely not helpful in this regard. In the 

absence of demonstrable effects in human clinical studies (in normals or those with mild disease) 

on other than lung function decrements for exposure concentrations less than 0.080 ppm, we are 

left inferring effects at lower concentrations and in the more severely diseased. Findings from 

epidemiological studies are less certain, but indicate effects at substantially lower concentrations 

than were used in the experimental studies. The benchmark levels in Table 1 correspond to 

greater degrees of uncertainty going from 0.080 down to 0.060. Part of this uncertainty relates to 

the precious little human clinical data at exposure concentrations below 0.080, and what exists is 

essentially limited to effects on lung function. Another part of the uncertainty relates to the 

reliance on epidemiological (non-experimental) findings at the lower concentrations. Therefore, 
A-40

while (in Table 1) the predicted number exposed increases for every level of the standard as the 

benchmark level of concern is reduced, the public health impact of this increase in number 

exposed becomes less certain. One could argue that since there is no clear threshold for ozone 

effects, increases in the number exposed translates directly into increases in health effects. This 

ignores not just increasing uncertainty, but also the fact that “exposure” at the decreasing 

benchmark levels results in an increasingly smaller percentage of people affected at the 

decreasing levels of exposure. These latter percentages are difficult to estimate for endpoints 

other than, perhaps, acute lung function changes. So, the public health significance is difficult to 

gauge for these other endpoints.

What then can be said about the public health significance of exposures at the different levels of 

concern across the different standards? It is prudent to assume that for at least some segments of 

the population, adverse effects (in addition to acute lung function effects) occur at levels below 

0.080, and, making use of epidemiologic observations, that there is no obvious threshold for 

these effects with effects occurring even at the benchmark level of 0.060. At some concentration 

the number of individuals affected must be exceedingly small, although, because the number of 

days with lower benchmark levels is greater than with higher levels, a feature not captured by the 

exposure estimates in Table 1, the opportunities for exposure throughout the year are greater at 

the lower benchmark levels. This explains the observation from the risk assessment that the 

majority of adverse effects are due to exposures occurring at relatively lower concentrations.
A-41

Dr. Barbara Zielinska

The charge questions provided to the CASAC Ozone Panel members concern only 

adverse health effects of exposure to ozone. Since I am an atmospheric chemist I do not feel 

qualified to answer these questions. However, I would like to comment on another important 

aspect of NAAQS for ozone reconsideration, namely the uncertainties associated with 

establishing an appropriate policy relevant background (PRB). Since PRB is not directly 

measured, EPA relies on modeling to establish the range of PRB. In the 2006 Criteria Document 

and 2007 Staff Paper, which served as a basis for the setting of the ozone 2008 NAAQS, EPA 

relied on a global model (GEOS-Chem) with emphasis on a particular GEOS-Chem PRB 

simulation for the year 2001 (Fiore et al., 2003). The resulting modeled PRB range was reported 

to be 15- 35 ppb, depending on location and month. The newer versions of the GEOS-Chem 

model that are currently being used are greatly improved over the version used by Fiore et al 

(2003) for the 2001 simulation. They predict higher PRB levels and are more consistent with 

observational analysis. In addition, Parrish et al. (2009) found that ozone from Asia entering the 

US west coast increased at a rate of 3‐5 ppb during the past decade.

During the 2005 -2007 CASAC Ozone Panel deliberations, the uncertainties and 

inconsistencies of this model (Fiore et al., 2003) were discussed. The model did not agree with 

observations that indicated higher background ozone levels (often exceeding 50 ppb), and 

evidence of stratospheric intrusion events during the winter and spring seasons. Since EPA’s 

ozone risk estimates are sensitive to the assumed PRB level, it is important to recognize and 

reflect these model uncertainties in the risk analysis. In the CASAC letter of February 19, 2010, 

the Panel noted that as levels for ozone standards move closer to “background” levels, new 

issues may arise with implementation as background levels vary throughout the country and 

advised EPA to carefully consider these issues in the next ozone review cycle (letter from 

CASAC chair, Dr. Jonathan M. Samet, EPA-CASAC-10-007, February 19, 2010).

It must be acknowledged that the most recent information relevant to the PRB level was 

not available prior to 2006 and thus cannot be considered in the current reconsideration of the 

ozone NAAQS. Given the importance of this issue, the next periodic ozone NAAQS review 

cycle should take into account the newer information available on a background level of ozone, 

as well as newer health related research results. 

References:

Fiore, A., D. Jacob, H. Liu, R. Yantosca, T. Fairlie, Q. Li. 2003. Variability in surface ozone 

background over the United States: Implications for air quality. J. Geophys. Res., 108, 

D24, 4784.

Parrish, D.D., D.B. Miller, A.H. Goldstein. 2009. Increasing ozone in the marine boundary layer 

inflow at the west coasts of North America and Europe. Atmos. Chem. Phys., 9, 1303-

1323.