UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

 WASHINGTON D.C. 20460 

OFFICE OF THE ADMINISTRATOR 

SCIENCE ADVISORY BOARD 

June 05, 2006 

EPA-CASAC-06-007 

Honorable Stephen L. Johnson 

Administrator 

U.S. Environmental Protection Agency 

1200 Pennsylvania Avenue, NW 

Washington, DC 20460 

Subject: Clean Air Scientific Advisory Committee’s (CASAC) Teleconference Meeting 

to Provide Additional Advice to the Agency Concerning Chapter 8 (Integrative 

Synthesis) of the Final Ozone Air Quality Criteria Document (AQCD) 

Dear Administrator Johnson: 

EPA’s Clean Air Scientific Advisory Committee (CASAC or Committee), supplemented 

by subject-matter-expert Panelists — collectively referred to as the CASAC Ozone Review Panel 

(Ozone Panel) — met via a public teleconference on May 12, 2006, to provide additional advice 

to the Agency concerning Chapter 8 (Integrative Synthesis) of EPA’s Final Air Quality Criteria 

for Ozone and Related Photochemical Oxidants (Second External Review Draft), Volumes I, II, 

and III, (EPA/600/R-05/004aF-cF, February 2006), also known as the Final Ozone Air Quality 

Criteria Document (AQCD). The current Clean Air Scientific Advisory Committee roster is 

found in Appendix A of this report, and the CASAC Ozone Review Panel roster is attached as 

Appendix B. Panel members’ individual review comments are provided in Appendix C. 

The members of the Ozone Panel are in general agreement that, in its development of the 

Integrative Synthesis chapter in the Final Ozone AQCD, the Agency has been reasonably 

successful in assembling the relevant information and incorporating findings from atmospheric 

sciences, toxicology, human clinical studies and epidemiology. Nevertheless, in view of the 

acknowledged role of the Ozone AQCD in informing the 2nd draft Ozone Staff Paper and, 

ultimately, potential revisions to the national ambient air quality standards (NAAQS) for ozone, 

the CASAC is of the opinion that there are some important issues that are not presented well, or 

at all, in this chapter. These include: the utility of time-series studies in assessing the risks from 

ozone exposure; the problem of exposure measurement error in ozone mortality time-series 

studies; use of ozone as a surrogate marker for other toxic photochemical pollutants; a general 

downplaying of animal-to-human extrapolation studies; and the need for inclusion of welfare 

issues (i.e., leading to the establishment of secondary standards for criteria air pollutants) in an 

integrative synthesis chapter. Each of these issues is discussed in greater detail below. 

1 
1. Background 

The CASAC, comprising seven members appointed by the EPA Administrator, was 

established under section 109(d)(2) of the Clean Air Act (CAA or “Act”) (42 U.S.C. § 7409) as 

an independent scientific advisory committee, in part to provide advice, information and 

recommendations on the scientific and technical aspects of issues related to air quality criteria 

and NAAQS under sections 108 and 109 of the Act. Section 109(d)(1) of the CAA requires that 

EPA carry out a periodic review and revision, where appropriate, of the air quality criteria and 

the NAAQS for “criteria” air pollutants such as ozone. The CASAC, which is administratively 

located under EPA’s Science Advisory Board (SAB) Staff Office, is a Federal advisory 

committee chartered under the Federal Advisory Committee Act (FACA), as amended, 5 U.S.C., 

App. The Ozone Panel consists of the seven members of the chartered (statutory) CASAC, 

supplemented by sixteen technical experts. 

EPA is in the process of updating, and revising where appropriate, the AQCD for ozone 

and related photochemical oxidants published in 1996. This teleconference was a continuation 

of the Ozone Panel’s peer review of the revised Ozone AQCD in this present NAAQS review 

cycle for ozone. In the CASAC’s final letter/report to you from the Ozone Panel’s December 6­

7, 2005 meeting (EPA-CASAC-06-003, dated February 10, 2006, posted at the following URL: 

http://www.epa.gov/sab/pdf/casac_ozone_casac-06-003.pdf), we advised you that: 

“... given the critical importance of the exposure and human health effects integrative 

synthesis chapter in the development of the 2nd draft Ozone Staff Paper, after EPA issues the 

final Ozone AQCD on February 28, 2006, the CASAC will determine whether there is a need to 

convene a public meeting to conduct any additional review of Chapter 8.” 

On March 21, 2006, the Agency’s National Center for Environmental Assessment 

(NCEA-RTP) published the Final Ozone AQCD. After canvassing the members of the Ozone 

Panel, we decided that, despite the fact that the AQCD has already been finalized, it would be 

beneficial to hold a public teleconference meeting to provide additional advice to the Agency 

concerning the integrative synthesis chapter of the Final Ozone AQCD in order to inform EPA’s 

preparation of the 2nd draft Ozone Staff Paper and, ultimately, the proposed NAAQS for ozone. 

2. CASAC’s Additional Advice Concerning Chapter 8 of the Final Ozone AQCD 

It is the assessment of the CASAC that, in its development of the Integrative Synthesis 

chapter in the Final Ozone AQCD, EPA has taken a fairly standard approach to putting together 

the relevant information, and incorporating findings from atmospheric sciences, toxicology, 

human clinical studies and epidemiology. In general, this is done reasonably successfully. 

Unfortunately, there are some issues that are important when considering revisions to the 

NAAQS that are not presented well, or at all, and that have substantial implications for the 

Ozone Staff Paper. A discussion of the major issues is presented below and, as previously noted, 

individual comments of Ozone Panel members are attached. 

Utility of Time-Series Studies 

The first area of concern is how time-series studies are used in assessing the risks from 

ozone exposure. While the epidemiological evidence on the health effects of ozone constitute 

2
only a fraction of the totality of the scientific knowledge based on ozone health effects, this 

evidence plays a disproportionately large role in the policymaking process. The ozone timeseries studies, particularly the mortality time-series studies, could potentially play an especially 

important role in this process, as they did for particulate matter (PM), and therefore deserve 

special attention. An issue that needs to be confronted relates to the utility of these time-series 

studies in the NAAQS-setting process. Motivation for this concern is partly based on the 

observation that time-series findings indicate associations of mortality with not only PM and 

ozone, but with all of the criteria pollutants (see Stieb et al., J. Air Waste Manage. Assoc. 2002, 

2003; the complete references are below). 

Since it is unlikely that each of these pollutants will have similar short-term effects on 

mortality, these findings suggest that while the time-series study design is a powerful tool, being 

able to detect very small effects that could not be detected using other designs, it is also a blunt 

tool. The Clean Air Act requires that NAAQS be set for individual criteria air pollutants using 

the best available science. Because results of time-series studies implicate all of the criteria 

pollutants, findings of mortality time-series studies do not seem to allow us to confidently 

attribute observed effects specifically to individual pollutants. This raises concern about the 

utility of these types of studies in the current NAAQS-setting process and could serve to 

motivate interest in taking a broader perspective on regulating air pollution that incorporates the 

entire mixture of community air pollutants. 

Time-series studies typically make use of data from available air pollution monitoring 

network sites in which concentrations of various subsets of the criteria pollutants are measured. 

Study findings focus on identification of associations between day-to-day variation in these 

concentrations and daily mortality. Not only is the interpretation of these associations 

complicated by the fact that the day-to-day variation in concentrations of these pollutants is, to a 

varying degree, determined largely by meteorology, the pollutants are often part of a large and 

highly-correlated mix of pollutants, only a very few of which are measured. For the ozone and 

other photochemical oxidant NAAQS, this pollutant mix includes a large number of both gasand particle-phase photochemical oxidant pollutants. Unfortunately, we have only limited 

information on the specific chemical composition, toxicity and, equally importantly, the 

population exposure of oxidant pollutants other than ozone. 

Error in Estimating Exposure to Ozone 

The Ozone Staff Paper should consider the problem of exposure measurement error in 

ozone mortality time-series studies. It is known that personal exposure to ozone is not reflected 

adequately, and sometimes not at all, by ozone concentrations measured at central outdoor 

monitoring sites. Typically, personal exposures are much lower than the ambient concentrations, 

and can be dramatically lower depending on time-activity patterns, housing characteristics and 

season. In addition, and of particular importance for the ozone time-series studies, there can be 

no correlation between personal concentrations of ozone measured over time and concentrations 

measured at central outdoor sites. The population that would be expected to be potentially 

susceptible to dying from exposure to ozone is likely to have ozone exposures that are at the 

lower end of the ozone population exposure distribution, in which case this population would be 

exposed to very low concentrations of ozone indeed, and especially so in winter. Therefore it 

3
seems unlikely that the observed associations between short-term ozone concentrations and daily 

mortality are due solely to ozone itself. 

Another implication of ozone measurement error that is relevant to the NAAQS-setting 

process is that this degree of measurement error would be expected to have a substantial impact 

on the ability to detect a threshold of the concentration-response relationship below which no 

ozone effects are discernible. Pollutant exposure measurement error obscures true thresholds in 

the concentration-response relationship, and this effect worsens with increasing degrees of 

measurement error. Since threshold assumptions are incorporated in the Agency’s risk 

assessment and risk analyses, this issue will need to be addressed. 

Ozone as a Surrogate for Other Toxic Agents 

At least two questions arise from these observations that are relevant to the ozone 

NAAQS-setting process: (1) What chemical agent or agents are at least partly responsible for 

the observed associations between ozone and mortality in the time-series studies?; and (2) Do we 

require an immediate answer to this question of whether ambient ozone adequately serves as a 

surrogate marker that, when controlled, effectively mitigates health impacts of this entire mix of 

pollutants? One possible explanation for the observed associations of ozone with mortality is 

that ozone itself may be serving as a marker for other agents that are contributing to the shortterm exposure effects on mortality. This would require that outdoor concentrations of these 

agents are correlated over time with outdoor ozone concentrations, which is to be expected if 

they are products of the same atmospheric processes that lead to ozone formation, and that these 

outdoor pollutant concentrations are better correlated with personal exposures than is the case for 

ozone itself. 

We have very little information on these last two issues at this time to make a strong 

argument for this, although it is a plausible argument. It should be noted that the observed 

associations pertain to total mortality, which implies that ozone is causing acute effects on the 

cardiovascular system, and not merely on the respiratory system. As indicated in Chapter 8 of 

the air quality criteria document, our understanding of cardiovascular effects of ozone is 

currently very limited compared to our understanding of ozone’s effects on the lung. 

Animal-to-Human Extrapolation 

The Integrative Synthesis chapter touches upon animal-to-human extrapolation issues in a 

number of places, with the general theme being one of concern that such extrapolations cannot 

be accomplished for ozone. The Ozone Panel did not agree with the extent to which these 

extrapolations are downplayed, and offers the following comments, primarily for the benefit of 

Agency staff who are involved in the development of the 2nd draft Ozone Staff Paper. The 

experiments by Hatch discussed on page 8-31 of the Final Ozone AQCD give the reader the 

impression that rats are more sensitive to ozone than are humans. However, if one adjusts for 

ventilation differences between exercising humans and resting rats and body mass differences, 

the relationships between inhaled dose and biological responses in these studies are in reasonably 

good agreement. 

4
In addition, the statement found on page 8-16 that “some” subjects are reproducible over 

time in their response to ozone is deceptive. The work of McDonnell and his EPA colleagues 

clearly shows that the vast majority of subjects are reproducible over time in their response to 

ozone exposure. Moreover, the 1996 publication by Overton et al. shows that anatomical dead 

space accounts for the major part of heterogeneity among subjects seen in acute pulmonary 

function responses in human clinical studies. 

The chapter inconsistently presents the case for and against animal-to-human 

extrapolation by first contending that physiological differences lead to large uncertainties in such 

extrapolations, and subsequently stating the agreement between the species is sufficient to 

support a common mode of action for ozone in producing biological effects. The latter is, in fact, 

the more appropriate interpretation in view of the commonality of pulmonary function changes, 

protein in lavage fluid, and a number of other biological endpoints between animals and humans. 

In the preparation of the 2nd draft Ozone Staff Paper, EPA staff should pay particular attention to 

the book chapter published by Ozone Panel member Dr. Charles Plopper (“Time-response 

profiles: Implications for injury, repair and adaptation to ozone”; complete reference below) 

concerning the importance of the relationship between ozone exposure in different scenarios and 

the resulting biological responses (found in Appendix D). This gives rise to exposure/dosimetry 

issues in terms of the pattern of biological response, and most likely requires a translation of the 

animal exposures via a dosimetry model for full application to assessing human equivalent 

exposure scenarios. 

Inclusion of Welfare Issues in Integrative Chapters 

The members of CASAC understand that the exposures and adverse effects of criteria 

pollutants on public health have been the principal focus of the Agency’s traditional sense of 

responsibility to the people of the United States. But the U.S. Congress, in passing the Clean Air 

Act Amendments of 1970, established that both public-health-based primary standards and 

public-welfare-based secondary standards for criteria air pollutants should be set as part of the 

NAAQS. Thus, the integrative chapters for criteria pollutants need to include discussion of 

issues related to the setting of the both the primary and secondary standards. 

The issues addressed above have direct implications for the Ozone Staff Paper, and 

should be given thoughtful consideration in drafting the next version. They are particularly 

relevant to the ozone risk assessment and risk analyses in which mortality time-series studies 

have previously played a central role. The CASAC plans to have a general discussion of the 

utility of time-series epidemiology studies for risk assessment purposes in a meeting at a later 

date. We look forward to providing additional advice on this important issue in the future. As 

always, we wish the Agency staff well in this important endeavor. 

 Sincerely, 

/Signed/ 

Dr. Rogene Henderson, Chair 

 Clean Air Scientific Advisory Committee 

5
References: 

Stieb, DM; Judek, S; Burnett, RT. Meta-analysis of time-series studies of air pollution and 

mortality: Effects of gases and particles and the influence of cause of death, age, and season 

Journal of the Air & Waste Management Association, 52 (4): 470-484, 2002 

Stieb, DM; Judek, S; Burnett, RT. Meta-analysis of time-series studies of air pollution and 

mortality: Update in relation to the use of generalized additive models 

Journal of the Air & Waste Management Association, 53 (3): 258-261, 2003 

Plopper, C.G., R. Paige, E. Schelegle, A. Buckpitt, V. Wong, B. Tarkington, L. Putney and D. 

Hyde. (2000) Time-response profiles: Implications for injury, repair and adaptation to ozone, 

pp. 23-37. In U. Heinrich and U. Mohr, (Eds.), Relationships Between Acute and Chronic 

Effects of Air Pollution. ILSI Press: Washington, DC. 

Appendix A – Roster of the Clean Air Scientific Advisory Committee 

Appendix B – Roster of the CASAC Ozone Review Panel 

Appendix C – Review Comments from Individual CASAC Ozone Review Panel Members 

Appendix D – “Time-response Profiles: Implications for Injury, Repair, and Adaptation to 

Ozone” (Hopper et al.) 

6 
Appendix A – Roster of the Clean Air Scientific Advisory Committee 

U.S. Environmental Protection Agency 

Science Advisory Board (SAB) Staff Office 

Clean Air Scientific Advisory Committee (CASAC) 

CHAIR 

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

Albuquerque, NM 

MEMBERS 

Dr. Ellis Cowling, University Distinguished Professor-at-Large, North Carolina State 

University, Colleges of Natural Resources and Agriculture and Life Sciences, North Carolina 

State University, Raleigh, NC 

Dr. James D. Crapo, Professor, Department of Medicine, National Jewish Medical and 

Research Center, Denver, CO 

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

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

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

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

Medical School, Boston, MA 

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

Institute, Reno, NV 

SCIENCE ADVISORY BOARD STAFF 

Mr. Fred Butterfield, CASAC Designated Federal Officer, 1200 Pennsylvania Avenue, N.W., 

Washington, DC, 20460, Phone: 202-343-9994, Fax: 202-233-0643 (butterfield.fred@epa.gov) 

(Physical/Courier/FedEx Address: Fred A. Butterfield, III, EPA Science Advisory Board Staff 

Office (Mail Code 1400F), Woodies Building, 1025 F Street, N.W., Room 3604, Washington, 

DC 20004, Telephone: 202-343-9994) 

A-1 
Appendix B – Roster of the CASAC Ozone Review Panel 

U.S. Environmental Protection Agency 

Science Advisory Board (SAB) Staff Office 

Clean Air Scientific Advisory Committee (CASAC) 

CASAC Ozone Review Panel 

CHAIR 

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

Albuquerque, NM 

MEMBERS 

Dr. John Balmes, Professor, Department of Medicine, University of California San Francisco, 

University of California – San Francisco, San Francisco, California 

Dr. Ellis Cowling*, University Distinguished Professor-at-Large, North Carolina State 

University, Colleges of Natural Resources and Agriculture and Life Sciences, North Carolina 

State University, Raleigh, NC 

Dr. James D. Crapo*, Professor, Department of Medicine, National Jewish Medical and 

Research Center, Denver, CO 

Dr. William (Jim) Gauderman, Associate Professor, Preventive Medicine, Medicine, 

University of Southern California, Los Angeles, CA 

Dr. Henry Gong, Professor of Medicine and Preventive Medicine, Medicine and Preventive 

Medicine, Keck School of Medicine, University of Southern California, Downey, CA 

Dr. Paul J. Hanson, Senior Research and Development Scientist, Environmental Sciences 

Division, Oak Ridge National Laboratory (ORNL), Oak Ridge, TN 

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

Michigan State University, East Lansing, MI 

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

Engineering, Clarkson University, Potsdam, NY 

Dr. Michael T. Kleinman, Professor, Department of Community & Environmental Medicine, 

University of California – Irvine, Irvine, CA 

Dr. Allan Legge, President, Biosphere Solutions, Calgary, Alberta, Canada 

B-1 
Dr. Morton Lippmann, Professor, Nelson Institute of Environmental Medicine, New York 

University School of Medicine, Tuxedo, NY 

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

Dr. Maria Morandi, Assistant Professor of Environmental Science & Occupational Health, 

Department of Environmental Sciences, School of Public Health, University of Texas – Houston 

Health Science Center, Houston, TX 

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

of Veterinary Medicine, University of California – Davis, 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, Georgia Power Distinguished Professor of Environmental 

Engineering, Environmental Engineering Group, School of Civil and Environmental 

Engineering, Georgia Institute of Technology, Atlanta, GA 

Dr. Elizabeth A. (Lianne) Sheppard, Research Associate Professor, Biostatistics and 

Environmental & Occupational Health Sciences, Public Health and Community Medicine, 

University of Washington, Seattle, WA 

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

Medical School, Boston, MA 

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

State University, University Park, PA

Dr. Sverre Vedal, Professor of Medicine, Department of Environmental and Occupational 

Health Sciences, School of Public Health and Community Medicine, University of Washington, 

Seattle, WA

Dr. James (Jim) Zidek, Professor, Statistics, Science, University of British Columbia, 

Vancouver, BC, Canada 

Dr. Barbara Zielinska*, Research Professor, Division of Atmospheric Science, Desert Research 

Institute, Reno, NV 

SCIENCE ADVISORY BOARD STAFF 

Mr. Fred Butterfield, CASAC Designated Federal Officer, 1200 Pennsylvania Avenue, N.W., 

Washington, DC, 20460, Phone: 202-343-9994, Fax: 202-233-0643 (butterfield.fred@epa.gov) 

* Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by the EPA 

Administrator 

B-2 
Appendix C – Review Comments from 

Individual CASAC Ozone Review Panel Members 

This appendix contains the preliminary and/or final written review comments of 

the individual members of the Clean Air Scientific Advisory Committee (CASAC) 

Ozone Review Panel who submitted such comments electronically. The comments are 

included here to provide both a full perspective and a range of individual views 

expressed by Panel members during the review process. These comments do not 

represent the views of the CASAC Ozone Review Panel, the CASAC, the EPA Science 

Advisory Board, or the EPA itself. The views of the CASAC Ozone Review Panel and 

the CASAC as a whole are contained in the text of the report to which this appendix is 

attached. Panelists providing review comments are listed on the next page, and their 

individual comments follow. 

C-1
Panelist Page # 

Dr. Ellis Cowling......................................................................................... C-3 

Dr. William (Jim) Gauderman...........................................................................C-4

Dr. Henry Gong........................................................................................... C-6 

Dr. Rogene Henderson.................................................................................. C-7 

Dr. Michael T. Kleinman............................................................................... C-8

Dr. Morton Lippmann .................................................................................. C-11

Dr. Frederick J. Miller................................................................................... C-13

Dr. Maria Morandi........................................................................................ C-15

Dr. Charles Plopper....................................................................................... C-17

Dr. Frank Speizer........................................................................................ C-19

Dr. James Ultman........................................................................................... C-21

Dr. Sverre Vedal..........................................................................................C-22

Dr. James (Jim) Zidek .................................................................................. C-23

Dr. Barbara Zielinska ................................................................................... C-24

C-2
Dr. Ellis Cowling 

Dr. Ellis Cowling 

North Carolina State University 

May 1, 2006 

Review of the Integrated Synthesis Chapter (Chapter 8) in the Final (2006) Criteria Document 

for Ozone and Related Photochemical Oxidants 

My major concern about the Integrative Synthesis Chapter (Chpater 8) for the Final Air 

Quality Criteria Document for Ozone and Related Photochemical Oxidants (EPA/600/R05/004aF) is its exclusive focus on “Ozone Exposure and [Public] Health Effects.” Integrative 

Synthesis is at least as much needed with regard to “Ozone Exposure and Public Welfare 

Effects” as it is on “Ozone Exposure and Public Health Effects.” 

All of us on CASAC understand that the exposures and adverse effects of criteria pollutants 

on public health have been the principal focus of EPA’s traditional sense of the Agency’s sense 

of responsibility to the people of the United States. But many of us also believe that the intent of 

the US Congress in passing the Clean Air Act Amendments of 1970 was to establish both: 

 public-health based Primary Standards, and also 

 public-welfare based Secondary Standards 

for Criteria Pollutants as part and parcel of the National Ambient Air Quality Standards. 

The language of the Clean Air Act is quite explicit with regard to both the public-health 

effects and public welfare effects of criteria pollutants – the Congress directed that the 

Administrator of EPA shall: 1) identify air pollutants that “in his judgment, may reasonably be 

anticipated to endanger public health and welfare,” and 2) define National Ambient Air Quality 

Standards that are “requisite to protect the public welfare from any known or anticipated adverse 

effects associated with the presence of [the] pollutant in the ambient air.” 

The phrase “known or anticipated” provides both a significant degree of discretion, and a 

substantial responsibility for the Administrator to use prudent professional judgment in dealing 

with uncertainties and deficiencies in available scientific evidence regarding the exposure and 

effects of ozone and other photochemical oxidants on crops, forests, and natural ecosystems and 

their relationship to values held dear by the people of our country. 

Thus, we hope that the Integrative Synthesis Chapters of all future Criteria Documents, (and 

Staff Papers based on these Criteria Documents), will include Integrative Synthesis Chapters that 

are indeed inclusive – chapters that describe the science that undergirds wise public policy 

decisions aimed at protecting both the public-health concerns and interests of our people -- as 

well as the public-welfare concerns and interests of our people. 

C-3
Dr. William (Jim) Gauderman 

Chapter 8, Integrative Synthesis 

Jim Gauderman 

5/12/05 

Throughout the document, the term ‘inconclusive’ is used to denote non-significant. A large, 

well-conducted study that finds no significant association should not be characterized as 

inconclusive. Smaller studies that do not find a significant association should also be 

characterized as such, perhaps with a caveat about low power. 

Consistent units (ppm or ppb) should be used throughout 

8-9, line 13: replace ‘an optimal’ with ‘the’ 

8-12, line -9: eliminate ‘sham’ and remove parentheses from ‘clean air’. Two lines down, 

replace ‘versus more closely mimicking’ with ‘rather than’ 

8-14: The last sentence that carries over onto 8-15 does not make sense. 

8-15: I found the paragraph beginning with ‘New uptake...’ unsatisfying in that it did not 

provide a clear summary of the directions of differences. For example, rather than saying there 

were gender differences, the paragraph should indicate whether effects were higher for males or 

females. This would not take much space and would improve the value of this summary 

paragraph. 

8-29, Table 8-1: ‘Interindividual variability’ is not a susceptibility factor. Eliminate ‘being 

recognized’. 

8-33, line 13: Why focus only on studies from U.S. and Canada? Despite this caveat, the 

document goes on to reference studies from Europe, for example on 8-38 and 8-58. 

8-40, line -4: define ‘per standardized O3 increment’ 

8-41, line -10: replace ‘quantitative results’ with ‘quantitatively equivalent results’ 

8-43, line -5: ‘analyses’ should be ‘analysis’ 

8-44, line 5: This sentence seems like a copout. If this is the case, how can we move forward to 

consider a revised standard? If the difficulty of finding a threshold below 0.08 is what is meant, 

this should be stated more explicitly 

8-47, line -9: replace ‘pulmonary function’ with ‘response’ 

C-4 
8-50, line 7: replace ‘cross-section’ with ‘longitudinal’. In the last paragraph, caveats should be 

included to point out the high exposure levels to which the monkeys were exposed and the 

limited relevance of these levels to current ambient O3 levels. 

8-53, lines 6, 7: replace ‘fine’ with ‘ultrafine’ 

8-54, line -3: replace ‘of’ with ‘to’ 

8-60, line 11: replace ‘smaller increases’ with ‘growth deficits’. 

8-61, line 9: replace ‘diminished’ with ‘smaller’ here and 13 lines below. 

8-79, line 10: insert ‘exposure to current ambient levels of’ between ‘long-term’ and ‘O3’ 

C-5
Dr. Henry Gong 

COMMENTS ON CHAPTER 8 (INTEGRATIVE SYNTHESIS) 

Draft AQCD, February 2006. 

Henry Gong, Jr., M.D., 4/30/06 (revised 5/1/06) 

I have reviewed the revised chapter 8. I also concur with the comments by several CASAC 

colleagues (Drs. Vedal, Zidek, and Lippmann). 

The Staff has generally produced an improved chapter (integration) with sharper focus and 

exposition on key issues such as those posed by the review in December 2005. The “integration” 

will always remain a challenging task but I am comfortable with the current version, in 

particular, in the area of the clinical studies. 

Specific Comments: 

1. I am pleased that Dr. Adams’ recently published study was reviewed accordingly since 

we lack many clinical studies using such low ozone exposure concentrations. The 

inclusion of Fig 8-1B is an excellent example of the pitfalls of relying on group means 

and the concept of adjusting for filtered-air responses (“ozone-induced”). The total 

number of subjects in Adams’ studies remains much smaller than in McDonnell’s study. 

I wonder if one can calculate post hoc the expected real effect size versus the probability 

of finding a statistically significant effect for Dr. Adams’ studies with ozone levels at 

0.04 and 0.06 ppm, given the small number of subjects and inherent variability of FEV1 

responses. This calculation might provide some measure of confidence about a “true 

negative.” 

2. Page 8-50/1st para: “There are no data available from controlled human chamber studies 

that evaluated chronic exposure regimens.” This sentence is unnecessary and should 

probably be deleted. The statement is misleading since its interpretation relies on your 

perspective. One reaction is that it is obviously impractical and unethical to study 

subjects inside an environmental chamber for 5 or 10 years! Some investigators have 

reported intrasubject reproducibilty of ozone responsiveness over months (McDonnell 

and Bedi, I believe) but not over years. However, aging is an unavoidable factor since 

people apparently develop less ozone responsiveness with aging. 

C-6
Dr. Rogene Henderson 

Comments on Chapter 8 

Rogene Henderson 

My major comment is on the content of the chapter. If it is too late to consider my 

suggested changes, I would hope they might be taken into account for subsequent integrative 

chapters in CDs. 

I think the purpose of this integrative chapter is to facilitate the development of the Staff 

Paper. The main concerns are whether ozone causes specific health effects and, if so, AT 

WHAT LEVEL OF EXPOSURE. Based on these findings, the Staff Paper will attempt to 

discern whether the current regulatory levels for ozone need to be altered. 

 I found Chapter 8 placed much emphasis on what health effects are induced, but did not 

focus enough on the level of exposure required to induce the effects. For example, the first 27 

pages of the chapter are a summary (repeat) of what was said in earlier chapters. I did not think it 

needed, or at least not in such a lengthy form. There is a shortened version of this summary 

starting on page 8-73 (sort of a summary of a summary) and it might serve as a better starting 

point than the detailed repeated report in the initial part of the chapter. Another approach might 

be to develop a summary table with references to the place in earlier chapters where the study is 

described in detail. 

The lack of focus on the level causing the effects can be seen in the tables. In Table 8-1, 

8-2, and 8-3, we need a column(s) indicating the level of ozone exposure associated with the 

effects. The exposure level is key to setting the regulations. 

C-7
Dr. Michael Kleinman 

Dr. Michael Kleinman 

Chapter 8 Comments 

General Comments 

This chapter is very comprehensive but loses focus. It could be significantly shortened. It might 

be useful to focus on the integrated findings that directly support the recommendations for 

revisions to the NAAQS that are presented in the Staff Paper. It is important to clearly establish 

that the data used to support the recommendations are coherent, consistent and rational. 

Specific Comments 

Pg 8-31 L9-11 The Hatch findings need to be placed in context with the dosimetry information, 

i.e. after adjustment for ventilation differences between exercising humans and resting 

rats and body mass differences, the relationships between inhaled dose (μg/kg bw) and 

biological response for humans and rats are in agreement. The way this is presented 

suggests that the rat is 5 times less sensitive than the humans, which is not true! 

Pg 8-32 L 8-10 I assume that this information relates to ambient as opposed to laboratory 

exposures. If so one needs to acknowledge that there might be some efforts to selfmedicate before seeing a physician. In addition, this discussion needs to be integrated 

with observations of duration of O3 episodes. O3 episodes are rarely a 1 day event. The 

controlled study data clearly show that effects of O3 are worse on the second day of an 

intermittent exposure. By the third day there may be some attenuation of responses. To 

further complicate things, there may be cumulative effects as well as progressive effects 

that relate to lags. The paragraph should be expanded to take these factors into account. 

Pg 8-36 L5 It should be noted that observation of attenuation of O3-induced inflammatory 

response (Kopp et al. 1999) was consistent with earlier pulmonary function studies (Linn 

et al. 1988) which showed that individuals in Los Angeles were responsive to controlled 

O3 exposure in the spring but that the response was attenuated when measured in the fall 

after a summer of relatively high ambient O3 exposures. Sensitivity to O3 was recovered 

by the following spring indicating that response attenuation is transient. 

Pg 8-36 L11 The basis for stating why “these findings must ... be considered inconclusive” 

should be presented. For example, ... due to possible confounding by PM2.5, elemental 

carbon and NO2 (Chan et al. 2005; Holguin et al. 2003; Liao et al. 2004; Park et al. 

2005). 

Pg 8-37 L5-6 Several studies showed an association between ambient ozone exposures and 

emergency room visits for respiratory disease (Bates et al. 1990; Castellsague et al. 1995; 

Cody et al. 1992; Ponce de Leon et al. 1996; Stieb et al. 1996). The statement could lead 

one to presume that the association is due to lack of control for confounding by 

C-8
temperature. There should some more detailed explanation or interpretation offered. For 

example, could it be noted that reasons for finding relationships with warm weather 

ozone exposure but not for year-round exposure might be that during winter there is less 

photochemical production of O3 and that the O3 effects might be masked by other 

pollutants whereas this is less of a problem during the high O3 season? 

Pg 8-38 L28-30 Should some statement be made that given the significant associations between 

mortality and exposures at or below 98th percentile 8-h max O3 levels of 80-85 ppb there 

is little or no margin of safety offered by the current NAAQS? 

Pg 8-42 L 20-21 In terms of public health it is important to note that the percent of individuals 

showing decreased pulmonary function showed a dose-related response with respect to 

O3 at levels of 0.06 ppm. The group mean differences rely on only part of the entire data 

set. It might be more useful in the establishment of health protective standards to use all 

the data in a regression format to better estimate the region for which significant numbers 

of individuals might experience adverse effects. 

Pg 8-43 L 9-10 Again, relating to margin of safety, these findings suggest that the current 

standard is less protective than it should be. Shouldn’t this be one of the conclusions in 

the Staff Paper?? 

Pg 8-43 L 27 Change to “A more formal threshold analysis...” 

Pg 8-44 L 5 Perhaps it would be more accurate to state that there is insufficient evidence to 

support a threshold for adverse effects of O3. Furthermore, if there is a threshold, the 

data seem to indicate that it would be lower than the current 8-h standard of 80 ppb. 

Bates DV, Baker-Anderson M, Sizto R. 1990. Asthma attack periodicity: a study of hospital 

emergency visits in Vancouver. Environ Res 51(1):51-70. 

Castellsague J, Sunyer J, Saez M, Anto JM. 1995. Short-term association between air pollution 

and emergency room visits for asthma in Barcelona. Thorax 50(10):1051-1056. 

Chan CC, Chuang KJ, Su TC, Lin LY. 2005. Association between nitrogen dioxide and heart 

rate variability in a susceptible population. Eur J Cardiovasc Prev Rehabil 12(6):580-586. 

Cody RP, Weisel CP, Birnbaum G, Lioy PJ. 1992. The effect of ozone associated with 

summertime photochemical smog on the frequency of asthma visits to hospital 

emergency departments. Environ Res 58(2):184-194. 

Holguin F, Tellez-Rojo MM, Hernandez M, Cortez M, Chow JC, Watson JG, et al. 2003. Air 

pollution and heart rate variability among the elderly in Mexico City. Epidemiology 

14(5):521-527. 

Kopp MV, Ulmer C, Ihorst G, Seydewitz HH, Frischer T, Forster J, et al. 1999. Upper airway 

inflammation in children exposed to ambient ozone and potential signs of adaptation. Eur 

Respir J 14(4):854-861. 

C-9
Liao D, Duan Y, Whitsel EA, Zheng ZJ, Heiss G, Chinchilli VM, et al. 2004. Association of 

higher levels of ambient criteria pollutants with impaired cardiac autonomic control: a 

population-based study. Am J Epidemiol 159(8):768-777. 

Linn WS, Avol EL, Shamoo DA, Peng RC, Valencia LM, Little DE, et al. 1988. Repeated 

laboratory ozone exposures of volunteer Los Angeles residents: an apparent seasonal 

variation in response. Toxicol Ind Health 4(4):505-520. 

Park SK, O'Neill MS, Vokonas PS, Sparrow D, Schwartz J. 2005. Effects of air pollution on 

heart rate variability: the VA normative aging study. Environ Health Perspect 

113(3):304-309. 

Ponce de Leon A, Anderson HR, Bland JM, Strachan DP, Bower J. 1996. Effects of air pollution 

on daily hospital admissions for respiratory disease in London between 1987-88 and 

1991-92. J Epidemiol Community Health 50 Suppl 1:s63-70. 

Stieb DM, Burnett RT, Beveridge RC, Brook JR. 1996. Association between ozone and asthma 

emergency department visits in Saint John, New Brunswick, Canada. Environ Health 

Perspect 104(12):1354-1360. 

C-10
Dr. Morton Lippmann 

Comments of Dr. Morton Lippmann 

NYU School of Medicine 

April 17, 2006 

Chapter 8 (Integrative Synthesis) of Final Ozone AQCD 

I’ve read through Chapter 8 of the Feb. 2006 draft of the Ozone CD, and find it to be generally 

satisfactory. It could be condensed somewhat if time and resources permitted tighter editing. 

Also, it should be more consistent in its use of ozone concentrations. There are many places 

where they are in ppm, others where they are in ppb, and still others where they are in ppm, with 

ppb in parentheses. Also, “in vivo” and “in vitro” should be italicized. 

My major criticism is that there is not nearly enough emphasis in the discussion of the 

epidemiological studies of the fact that O3 needs to be considered as a surrogate index for the 

photochemical mixture containing O3. I point this out first in my note for page 8-2 below. There 

needs to be a new introduction to the discussion of the epidemiology that explains why this 

distinction is needed in the integrative discussion of the laboratory-based studies and the field 

and larger population epidemiology. This was an issue discussed by the CASAC ozone Panel at 

our last meeting, and I sensed that we felt it was important for NCEA to implement it when 

revising Chapter 8. 

The following are some specific corrections and suggested edits: 

p. 8-1, para. 2, l. 3: change “nitrogen oxides (NOx)” to “nitrogen dioxide (NO2).” 

p. 8-2, para. 1, l. 5-7: change “whereas less attention is accorded to the distinctly much more 

limited available information on other photochemical oxidants, e.g., PAN or H2O2.” to “and on 

O3 as an index of the mixture of photochemical oxidants, including PAN, H2O2, and oxygen 

containing radicals, for which much more limited information is available.” 

p. 8-3, para. 2, l. 5: change “clean” to “cleaner.” 

p. 8-3, para. 3, l. 2: insert “finer scale” before “spatial.” 

p. 8-4, para. 2, l. 8: insert “due to springtime intrusions of stratospheric O3” after “Hemisphere.” 

p. 8-8, para. 2, l. 14: change “O3” to “photochemical oxidant.” 

p. 8-8, para. 3, l. 4: delete “somewhat.” 

p. 8-15, para. 2, l. 4: insert “generally” before “having.” 

p. 8-25, para. 2, l. 7-12: A reference should be provided to support this statement. 

C-11
p. 8-63, para. 1, l. 8, 10, and 14: insert “onset” before “risk.” 

p. 8-69, para. 2, l. 12: insert “Thurston et al. (1997) showed that asthmatic children did receive a 

physician-ordered increase in medication in proportion to the ambient O3 concentration.” before 

“Such.” 

p. 8-74, para. 2, l. 12: add “below 0.08ppm, and even below 0.06ppm” after “levels” (Spektor et 

al. 1988). 

p. 8-75, para. 2, l. 2: change “0.08” to “0.06” (based on Adams 2006) 

p. 8-75, para. 2, l. 12: delete “likely.” 

p. 8-75, para. 2, l. 13: insert (Thurston et al. 1997)” after “children.” 

p. 8-80, para. 1, l. 3: change “increased risk of mortality” to “reduced longevity.” (This is to 

distinguish between the evidence from the time-series studies of daily mortality, and the lack of 

evidence for increased annual mortality.) 

p. 8-80, para. 2, l. 8: insert “short-term” before “responsiveness.” 

C-12 
Dr. Frederick J. Miller 

Dr. Fred J. Miller 

May 18, 2005 

Integrative Synthesis: Ozone Exposure and Health Effects 

Chapter 8 

General Comments 

This second version of the integrative synthesis chapter is greatly improved over the first. The 

collective evidence for ozone health effects based upon dosimetry, animal toxicological, human 

clinical, and epidemiological data is well presented and laid out in a logical manner. The sections 

of the chapter are inconsistent in their use of references, a situation that a final edit could correct. 

Despite the improvements, there are a number of points made in the chapter that are either 

incorrect or that would benefit from expansion or rewording if it were not for the fact that the 

Ozone Criteria Document has already been finalized. Nonetheless, the following comments are 

offered so that EPA staff charged with development of the Ozone Staff Paper can benefit from 

them. 

• The discussion of Policy Relevant Backgrounds does not bring out that these values are 

dependent on the time of the year. In addition, I would echo the comments of Dr. Zidek 

concerning the influence of measurement error on PRB values and their usefulness in 

assessing risk. 

• The section on dosimetry still does not discuss one of the most important findings since 

the last CD, namely that anatomical dead space is a major driver of the delivered dose of 

ozone and probably accounts for a major part of the heterogeneity seen in responses in 

human clinical studies. I noted this in my comments on the first draft of this chapter. 

• The statement is made on page 8-8 that ambient and personal exposures are well 

correlated. As Dr. Zidek noted in his comments, the available studies do not support a 

strong conclusion on this point. 

• At the start of Section 8.3.1, the statement is made that “Children tend to be more active 

outside and, therefore, often manifest a higher breathing rate than most adults”. The fact 

is that children have a higher basal rate period. So the sentence is somewhat misleading. 

• On page 8-12, the statement is made that “Earlier animal toxicology studies were carried 

out using relatively high O3 exposure concentrations/doses that do not reflect “real 

world” exposure scenarios”. This was in reference to studies available for the 1996 

AQCD. This statement is incorrect. The EPA chronic O3 study conducted in the 1980s 

mimicked real world patterns and started with a background exposure of only 0.06 ppm. 

• There are discrepancies on pages 8-13 and 8-14 concerning animal to human 

extrapolations. First it is contended that molecular differences between animals and 

humans lead to large uncertainties in animal to human extrapolations. Yet on the next 

page, there is discussion purporting a common mode of action for O3 between animals 

and humans. In the opinion of this reviewer, extrapolation for various endpoints is quite 

possible, has been done successfully in the past, and is done a disservice by the 

statements of the author(s) of this section. Some of the examples and discussion in 

Chapter 4 support the practicality of animal to human extrapolation for ozone effects. 

C-13
• In the last paragraph on page 8-14, the statement is made that newer studies show that 

uptake decreases as airflow rate increases. This observation has been known since the 

1970s based upon the work of Aharonson and also by Frank and colleagues. 

• On page 8-16, the statement is made that some subjects are reproducible over time in 

their response to ozone. I would submit that the work of McDonnell and colleagues 

shows that the vast majority of subjects are reproducible over time in their response to 

ozone exposures. Thus, the use of “some subjects” is misleading. 

• Triangle exposures (p. 8-19) are said to reflect ambient patterns better than square wave 

exposures, which is correct. However, has the length of time to the peak of the triangle in 

the exposure studies been truly reflective of “real world” patterns? The reasonableness of 

triangle versus square wave exposure scenarios most likely varies depending upon 

geographic location, particularly across the United States. 

• In Figure 8-3, the authors should have made clear in the legend that these resolution times 

relate to brief exposures to ozone. 

• On page 8-31, some aspects of animal to human extrapolation are discussed. Here would 

have been a good place to make reference to studies on protein in lavage fluid and how 

dosimetry models have been used to integrate the experimental findings across species. 

This presumes that this material was reworded in Chapter 4 in response to my comments 

on the August 2005 version of Chapter 4. 

• “Tolerance” is used incorrectly in multiple places in this integrative synthesis chapter. 

Tolerance has a very specific definition arising from animal toxicological studies wherein 

exposure to a lower level of a chemical imparted protection from effects when animals 

were subsequently exposed to higher concentrations of the chemical. The authors should 

have stuck with “attenuation” in describing the diminishing or lack of occurrence of 

changes with repeated ozone exposures. 

C-14
Dr. Maria Morandi 

Comments on Chapter 8 – Maria T. Morandi 

Chapter 8 appears to give more weight to the cardiovascular and mortality effects (Sections 8-3 

on page 8-27 to 8-32; pages 8-36 to 8-39 and section on cardiovascular effects, and section 

8.6.3) studies than the Panel considered scientifically appropriate given the available evidence 

and uncertainties, the latter being especially important with regards to exposure estimate error. 

The other consideration, as discussed by the Panel, is the discrepancy between the levels of 

ozone at which exposure-effects are observed in chamber studies of acute lung function, and the 

significantly lower measurements (compared to the chamber exposures and outdoor 

concentrations) reported by studies that have conducted personal exposure measurements of 

ozone, and the results of epidemiology studies of acute effects that use the ambient 

measurements as the surrogate for exposures. These differences suggest that ozone may be acting 

at least in part as a surrogate for other oxidants that are formed via chemical reactions leading to 

ozone formation and accumulation. 

Page 8-3 

Quote: “Median values of daily 1-h max O3 were typically much higher in large urban areas or in 

areas downwind of them. For example, in Houston, TX they approached 0.20 ppm during the 

same 2000-2004 period.” 

The text appears to imply that the median values of daily-1-h max of ozone for Houston in the 

2000-2004 period approached 0.20 ppm, which cannot not be correct. 0.20 ppm is reasonable 

as the maximum 1-hr concentration over the period, not the median of the 1-hour max. On pages 

8-4 and 8-5 the text says that 1-hour maximum values approach 0.20 ppm in the Eastern US and 

California, the latter been similar to maxima in Houston. 

Page 8-8 

Quote: “Thus, activity level is an important consideration in determining potential O3 exposure 

and dose received” 

Exposure is concentration X time only. Potential dose is concentration X time X inhalation rate 

(such as minute volume); inhalation rate varies with activity level. 

Section 8.3 

1st two paragraphs: This section needs to be tempered regarding the assumption that ambient 

measurements are a good estimate of personal exposures in a population. This is a reasonable 

assumption in many, but not all, cases. Thus, there could be significant exposure estimate errors 

when comparing exposure-response across different subgroups in a population, or across 

different populations, because correlations between outdoor and indoor concentrations may not 

be necessarily high everywhere. For example, in Houston, which has a very high utilization of 

C-15
conventional air conditioning (and, consequently, very low indoor ozone concentrations in a 

large fraction of homes during the ozone season), the ambient concentrations may not be good 

indicators of personal exposures for a large proportion of the population because the indoor 

residential concentrations remain essentially unchanged - frequently at or below the detection 

limit of the ozone monitor- while the outdoor concentration varies significantly increasing, 

peaking, and declining during the day (see prior versions of the AQD for citations to the 1980 

Houston Asthma Study). In other cities where natural ventilation or evaporative AC 

predominates, outdoor concentrations are indeed a better surrogate of personal exposures 

because they correlate with the indoor concentrations. Perhaps the text should be modified to 

indicate that the outdoor concentrations are the only available index (rather than “most useful”) 

of exposure distributions at this time. 

Section 8.3.2: 

This section does not mention at all the impact of HVAC systems on indoor ozone 

concentrations, which is more than just due to low AER. In residences or commercial buildings 

with HVAC systems, a large fraction of the indoor air re-circulates in the ductwork which 

provides additional surfaces for ozone decay and reactions with materials deposited in the filter. 

Some additional editorial suggestions: 

Page 8-12:

 “...to help identify potential mechanisms(s) of action...” 

“Since then a few newer, more recent human clinical and... air pollutant mixtures; and . tThe 

results...” 

Page 8-21 

Quote: “..most important biological markers of O3-induced injury response mechanisms in both 

humans...” 

C-16
Dr. Charles Plopper 

CASAC-Chapter 8 

Integrative Synthesis: Ozone Exposure and Health Effects 

Comments by C.G. Plopper 

One of the fundamental issues missing in the overview of the section (8.4.1) dealing with 

Integration of Experimental and Epidemiologic Evidence is a discussion of the patterns of 

biologically relevant exposure conditions. The issues which are involved include establishing the 

biological impact when: 

1) The peak exposure concentration exceeds the threshold necessary to produce a response 

an acute biological response; 

2) the duration of the exposure period where the peak exceeds the threshold for acute 

biological response; 

3) The number peak days that reach biologically relevant concentrations with less than 24 

hour intervals of non-biologically responsive concentrations; 

4) The extent of this interpeak interval. 

When peaks are separated by 24 hours or less (usually approximately 18 hours) the biological 

response is less as exposure progresses than if the interexposure interval extends beyond seven 

days. Short interexposure periods (less than 24 hours) during multiple repeated exposure results 

in the production of a phenomenon called tolerance. In other words, a repeated history of 

exposures above the threshold on successive days results in a depression of the acute response 

and decreased sensitivity. An additional aspect of this response is that once a series of these 

exposure regimens have occurred in which repeated peak days last over a significant period of 

time, generally 4-7 days, the biological response will be altered when additional exposures occur 

in the future. 

It is difficult to address the cross cutting issues relevant to assessment/interpret of ozone health 

effects without including the relationship between exposure scenarios and the biological 

response. The chapter as written does not clearly separate acute responses, versus chronic 

responses, versus the development of tolerance and how exposure history influences both acute 

and chronic responses. While this section summarizes earlier animal studies, it does not really 

address the exposure/dosimetry issue in terms of the pattern of biological response. 

There are discussions throughout section 8.4.1 and .2 which refer to doses and assessments, but 

do not clearly differentiate how the pattern of exposure can influence the measurements. This is 

especially critical for the section on lung inflammation. The paragraph ending at the top of page 

8-36 is a good example of how the exposure scenario impacts the biological response and how 

this alters the endpoints that are measured physiologically. 

It would be helpful for the discussion to break out the differences between long term exposure 

and chronic effects, because the effects depend on the population exposed, the history, and the 

pattern of exposure during the acute phases of response. In section 8.6.2 no mention is made of 

the fact that exposure history for subjects in the human studies were not addressed. The same 

situation was true when the bottom of page 8-50 which discusses long term infant studies, but 

C-17
does not include the studies of young adult rhesus monkeys which found essentially the same 

time of response. 

In the beginning of section 8.7 there is a discussion of the susceptible and vulnerable populations 

and issues which may alter susceptibility. The issue of exposure history is ignored in this section. 

Some discussion somewhere needs to be included, because this is a critical factor in judging the 

level of sensitivity of populations and dictates whether individuals will appear more or less 

susceptible to chronic injury. 

The same is true for the discussion on page 8-58 and on pages 8-60 and 8-61, especially the last 

paragraph in section 8.7.2. 

C-18
Dr. Frank Speizer 

Comments on Chapter 8, Feb. 2006 Final Ozone AQCD 

Submitted by Frank E. Speizer, MD 

General Comment: 

The organization of the chapter works well. I particularly like the way the added new 

data are presented as an extension of the 1996 document. Notably, no negative or inconsistent 

findings are mentioned until the epidemiology section. Does this mean that there are no tox or 

human exposure studies that are null, or is the publication bias stronger than in the epi field? 

Some discussion of this is warranted. 

The integrated discussion of the possible mechanisms from tox and human studies as 

related to the epidemiological finding is a useful addition in pulling the data together. The 

summary of the finding is complete. What are missing are staff recommendations for a standard. 

I would have thought that the concluding section of this chapter should contain this discussion. 

Is it still to come? When will we have a chance to see it? 

Specific Comments: 

Page 8.2, first full para, line 8: Take out word “various” 

Page 8.2, last paragraph. Whole paragraph is totally redundant with last sentence of previous 

paragraph and can be left out. 

Page 8.3, section 8.2.1, lines 8-9. I think this should be qualified with something like “except for 

Los Angeles and Houston as well as other sites in California”. 

Page 8.12, first full paragraph. It doesn’t make sense to leave out Chapter 7 in this intro 

paragraph, particularly since the title of the section includes Epidemiology and 2 paragraphs later 

on page 8.13, the Epidemiology studies are introduced. 

Page 8.17,text lines 5-6: suggest take out “and seem physiologically insignificant”. This is 

simply catering to the lack of understanding of group mean differences and the rest of the 

sentence adequately addresses the issue. 

Page 8.18, last para, line 1: “triangular exposure profile” is jargon. Needs to be defined up front 

rather than at end of paragraph on page 8.19. 

Page 8.20, last para, line 8: Change “common” to “Spirometric” 

Page 8.21, last para, line 1: Take out word “most”

Page 8.34, second full para, lines 8-9: Take out sentence, already said above. 

Page 8.34, last para, line 2: Change 40.3ppb (SD 15.2) to .04ppm (SD .015) 

C-19 
Page 8.38, para 1, line 6: This is a bit of overstatement. Most of the studies presented were not 

really “designed specifically to examine the effects of O3”... I think the word “specifically” 

might be removed without changing the meaning of the sentence and would be more accurate. 

Page 8.39, para 1, lines 14-18: These two sentences may lead to confusion. I think I know what 

the author is trying to say, but there is a whole science about omission and commission in using 

underlying and contributory cause of death. None of it has to do with causality as expressed 

here. The fact that a contributory cause of death may be the underlying cause and is 

misclassified has little to due with causality as related to air pollution. (It is for this reason that 

many authors use cardiopulmonary when doing analysis of air pollution health effects, and can 

use cardiovascular since it represents more than 60% of the total.) The last sentence presumes 

the coding rules are being ignored. Suggest simply leave off the last two sentences. 

Page 8.55, second full para, last line: Agree with statement but I did not see many O3 epi 

studies quoting exposures below .08ppm. 

Page 8.67, 8.68, Tables 8.2 and 8.3: Not clear that the definitions of small, moderate and large 

are correct for change in bronchoresponsiveness. Footnote says a 100% change equivalent to a 

50% decrease in PD20. (I recognize that this table is reproduced from 1996, but that doesn’t 

mean it should be accepted without comment). I would have thought a 20% decrease in PD20 

was significant, and adjusting up from there would change cut off points. Similarly for changes 

with airways resistance, the cuts offs are too high. 

C-20
Dr. James Ultman 

Comments on Revised Chapter 8 

James Ultman 

May 20, 2006 

It is apparent that considerable effort has gone into the development and refinement of this 

chapter, and it does provide a useful (but unnecessarily lengthy) summary of the previous 

chapters and their annexes. 

The authors of the chapter successfully demonstrate that there is a strong homology of ozoneinduced responses between animals and people, implying that the underlying biological 

mechanisms are similar among the different species. On the other hand, the authors point out 

that there are differences in gene transcription between animals and man, implying that ozoneinduced responses may not occur by the same mechanisms. In addition, the chapter says very 

little concerning the application of dosimetry to bridge the gap between exposure, dose and 

response. Overall, this chapter should have sent a much clearer message that we have the tools 

to perform quantitative interspecies or intraspecies extrapolations using quantitative dosimetric 

analyses. 

I would hope that the staff document would, in fact, not hesitate to use such analyses, where 

appropriate. A particular situation that comes to mind is the extrapolation of health effects 

observed in adults to the comparable effects in children by taking into account differences in 

lung sizes and ventilation rates. 

Also, I strongly agree with Rogene Henderson’s comment that there are no definitive statements 

in the chapter regarding specific exposure levels at which ozone-induced health effects of 

various types are likely occur. Thus, very little explicit guidance is provided to those developing 

the Staff Document. 

C-21
Dr. Sverre Vedal 

Comments on Feb 2006 draft Ozone Criteria Document, chapter 8 (Integrative Synthesis) 

This version of chapter 8 has improved its focus on observational study effects at or below the 

current NAAQS, and it continues to do a good job in integrating findings from different 

disciplines. But, in my opinion, some major issues that would seem to be critical for moving 

ahead with the Staff Paper are not handled well. 

1. The issue of exposure (or the lack of it) in the new mortality time series studies, studies that 

will likely play a central role in discussions on revising the standard, is not really touched on, as 

it was to some extent in Ch.7. I previously made extensive comments in this regard on Ch.7 and 

Ch.8 of the last draft, and will not repeat them now. The points remain relevant. I agree with 

Jim Zidek’s points on measurement error as well, and refer you to his comments. I would not 

relish the prospect of a risk analysis carried out by OAQPS on the basis of the time series 

mortality studies until the issue of exposure has been thoroughly aired. 

2. Exposure measurement error in the case of ozone will have a much more substantial effect on 

obscuring a concentration-response threshold than in the case of PM. This would seem to be an 

important issue when planning an ozone risk analysis, but is not mentioned. 

3. If we think, on the other hand, that ambient ozone concentration in observational studies is 

important more as a measure of photochemical pollutants in general, rather than as a measure of 

ozone exposure specifically, then this should be stated. Then an issue will become one of 

evaluating what evidence we have for exposure to, and effects of, these pollutants, about which I 

suspect we know relatively little. 

4. The bottom line on chronic effects puts more emphasis on the studies of seasonal lung 

function effects in children than those of longer-term effects - I think this is a misplaced 

emphasis. 

5. There are also some factual errors (e.g., the Gong study did in fact show increased heart rate 

due to ozone). 

C-22
Dr. James (Jim) Zidek 

COMMENTS ON CHAPTER 8 OF THE AQCD FOR OZONE 

Prepared by Jim Zidek, April 17, 2006 

The synthesis chapter seems quite well written. I have just a few comments limited to topics 

connected with comments I submitted during the Draft AQCD reviews. 

Page 8-7: In the revised AQCD, I was pleased to see some discussion of CTM estimation errors 

on page 2-21 and 2-22 and the need to evaluate them “by comparison with field data”. 

Moreover, interesting discussion of such errors for GEOS-CHEM has been included in Chapter 3 

(eg page 3.52) and even in the Executive Summary. Yet Chap 8 ignores them. This omission 

highlights the need to address them in the Staff paper and how they are to be accommodated in 

calculating the ozone standard. In particular, should the standard be raised, lowered of left 

unadjusted in view of that error in estimating the PRB? Would a big error lead to the adoption of 

a different PRB level than a small one? 

Page 8-8: Here we find the following statement: “Nevertheless, although substantial variability 

may exist among personal measurements, human exposure studies have observed that daily 

average personal O3 exposures for the general population tend to be reasonably well correlated 

with monitored ambient O3 concentrations.” This seems to be an example of the ecologic effect, 

making its relevance for the Staff paper doubtful. Moreover, it seems at odds with the preceding, 

“However” sentence. Finally, I would note that pages 3-72 & 3-73 give a mixed picture of this 

association. One study produced an insignificant or barely significant association, the other a 

significant association. Moreover the second found that “ambient O3 levels overestimated 

personal exposures 3- to 4-fold in the summer and 25-fold in the winter” hardly giving one 

confidence that the population average exposure is reasonably “well correlated” with ambient 

levels. 

Page 8-8: The next sentence to that above concludes: “Therefore, ambient O3 monitoring data 

appear to provide the most useful index of human O3 exposure currently available to help 

characterize health outcomes associated with O3 exposures of large population groups.” This 

sentence suggests indices other than ambient levels were considered and rejected but I cannot 

find such alternatives in the AQCD. Instead many indices (i.e., “metrics”) based on ambient 

monitoring measurements are discussed. 

The real aim of these two sentences seems to be support for ambient monitoring based criteria. 

Even more support appears in the “Thus” sentence in the middle of Page 8-10. However, based 

on the evidence offered in the AQCD, that support seems more tenuous than Chap 8 lets on. If 

additional evidence can be found, the Staff paper should cite it, as this is a contentious issue. It 

is one reason why APEX and other such methods have to be used in contexts like this to try to 

forecast the actual effect a change in the AQS might have on human exposure. 

C-23
Dr. Barbara Zielinska 

Comments on Chapter 8 (Integrative Synthesis) of the Ozone AQCD 

By Barbara Zielinska, April 30, 2006 

In general, I found Chapter 8 well written and informative. However, there are still some issues 

that are not represented adequately in this integrative synthesis. I agree with Jim Zidek that the 

uncertainties of the GEOS-CHEM global model estimates of Policy Relevant Background (PRB) 

should be mentioned in the integrative synthesis – this is important for the future ozone standard 

determination. I also think that the Section 8.3 on human exposures to ambient ozone has some 

problems. Although the Section mentions briefly the problems with estimating human exposure 

on the basis of central monitoring data, it still maintains that the ambient O3 concentrations 

measured outdoors at community monitoring sites provide the most useful index of human O3 

exposure (page 8-8 and 8-10). I don’t think that the AQCD provides strong evidences for such a 

statement. I’m also not sure if ambient O3 concentrations and/or (?) personal O3 exposure 

monitor measurements may serve as “surrogate indices of exposures to broader O3 –containing 

ambient mixtures of photochemical oxidants and/or other pollutants” (page 8-10). Which “other 

pollutants”? I don’t think that there are sufficient evidences provided in the Ozone AQCD 

supporting such a statement. 

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Appendix D – “Time-response Profiles: Implications for Injury, 

Repair, and Adaptation to Ozone” (Hopper et al.) 

Time-response Profiles: Implications for Injury, Repair, and Adaptation to 

Ozone 

C. PLOPPER, R. PAIGE, E. SCHELEGLE, A. BUCK-PITT, V WONG, B. TARKINGTON, L. PUTNEY, AND D. HYDE 

School of Veterinary Medicine and California Regional Primate Research Center, University of California, 

Davis, CA, USA 

Correspondence: Dr. Charles G. Plopper, School of Veterinary Medicine, Department of Anatomy, 

Physiology and Cell Biology, One Shields Avenue, UC Davis, Davis, CA 95616, USA 

Introduction 

The biological response of the respiratory system to exposure to oxidant air pollutants such as 

ozone follows a well-characterized pattern of cellular injury, inflammatory and repair events which is highly 

dependent upon the inhaled concentration and the length of the exposure. There is clear dose-response 

curve of acute injury for the initial exposure of naive animals and humans under experimental conditions. 

The initial cellular injury sets in motion a series of inflammatory and repair processes which follow a 

relatively uniform time course regardless of the extent of the acute injury, unless it is so massive as to be 

fatal. Under experimental conditions, these repair processes lead to the reestablishment of the pre-exposure 

steady-state within a finite period of time. Imposition of additional periods of exposure to injurious 

concentrations during the repair process alters the cellular events and leads to the establishment of a new 

steady-state where inflammation is markedly reduced and the cells which repopulate the injury site are 

resistant to further acute injury by oxidant gases. This is true regardless of how long the exposures are 

continued. Despite the very large number of long-term exposure studies, the utility of experimental animal 

studies for estimating the long-term risk to human populations of ambient exposure conditions appears 

limited. One of the limitations is that concentration multiplied by time does not equal effect (Gelzleichter 

et al., 1992). Depending on the measures used to assess effects, the response may actually appear to 

diminish over time. A second limitation is that ambient conditions are such that the periods when oxidant 

gas concentrations are elevated to levels which can produce injury are highly variable. The period below 

threshold concentrations can vary from as little as 18 hours to as long as many months. 

Additionally, these periods generally cycle annually. The intent of this review is to examine the issue 

of time in terms of the temporal characteristics of exposure conditions and the pattern of biological responses 

on which exposures are imposed. 

Exposure Pattern 

For the purposes of this discussion, exposure patterns will be characterized by three key parameters: 

concentration, duration of exposure (or exposure period), and the length of time between exposures when the 

concentration is below the biological response threshold (the interexposure interval (Figure 1 a). Ambient 

exposures are variable in nature, with daily and seasonal variations in concentration (Figure 1 b-d) (USEPA, 

1996). As the examples in Figure 1 illustrate, under ambient conditions the duration of exposure to 

elevated ozone concentrations on a daily basis is approximately 6 hours. The peak concentrations during 

this 6-hour period are highly variable by season. And there are many days, even during seasons 

associated with high average ambient levels, when the ambient concentration is very low or near 

background. 

D-1 
Biologic Response 

The response of the respiratory system to ozone exposure can be characterized in terms of the 

initial injury and inflammatory responses, followed by proliferation and repair of the epithelium at the 

site of injury. While there are a variety of biologic responses following ozone exposure, for the sake of 

comparison we will consider only the epithelial and inflammatory responses summarized in Figure 2. 

Initial responses include injury and death of ciliated cells in conducting airways and squamous 

epithelial cells in the centriacinar region of the parenchyma. This phase, which appears to occur within 

the first 8-12 hours of exposure, is associated with marked increases in intraluminal exudate that initially 

contains primarily epithelial cells and serum proteins, with minimal or no changes in the interstitium. 

This phase also includes degranulation of secretory cells. Subsequently, injured epithelium exfoliates and 

there is an increase in exudate containing inflammatory cells, primarily neutrophils and eosinophils. (See 

Paige and Plopper, 1999, for detailed review.) 

Proliferation of the epithelium, concurrent with downregulation of intraluminal exudates, marks 

the next stage of response. Significant numbers of inflammatory cells may still be found migrating 

through the epithelium at this stage, but within 7 days the acute inflammatory response is almost 

completely resolved. At this time, epithelial proliferation has greatly diminished, the epithelium is often 

hyperplastic, and proliferation of matrix components is in progress. After completion of this series of 

events, subsequent responses are dependent upon whether or not exposure to injurious concentrations 

D-2 
continues. If exposure ceases, the affected compartments will revert to pre-exposure steady-state within 

7-10 days. 

Effects of continued long-term exposure include persistent hyperplasia, low-grade chronic 

inflammation with few exudative cells (primarily macrophages), and increased synthesis of collagen. 

Short-term Exposures 

Very short exposures (as little as 2 hours) initiate the acute response to ozone (Figure 3) (Plopper 

et al., 1998). After 2 hours exposure to 1 ppm ozone there was a significant increase in abundance of 

necrotic cells corresponding with a significant decrease in abundance of intact epithelial cells. While 

polymorphonuclear leukocytes and eosinophils were significantly increased in number following a 2 

hour exposure to 1 ppm ozone, macrophages exhibited a significant decrease. 

When the exposure duration is increased (50-hour exposure of Rhesus monkeys to 0.8 ppm ozone) 

necrosis occurs immediately after the onset of exposure, peaks after about 12 hours of exposure and is 

completely resolved by 24 hours (Figure 4) (Castleman et al., 1980). Proliferation increases to maximum 

over the 2 days of exposure. After 50 hours of exposure, the acute necrotic phase is complete and repair 

has begun. 

As the length of time for the exposure episode is increased, the pattern of response changes. 

Schwartz et al., 1976 contrasted the biologic response in a continuous versus intermittent exposure. 

Rats were exposed to ozone for 7 days for either 8 hours per day (interexposure interval of 16 hours) or 

continuously (no interexposure interval). As the biologic response graphs illustrate (Figure 5), the early 

neutrophil infiltration is indistinguishable between the two exposure regimes. Epithelial hyperplasia is 

also equivalent in both exposure regimes, reaching maximum after 4 days of exposure and remaining 

elevated for the remainder of the 7 days. The key difference observed in this study was in the response of 

macrophages. An 8-hour per day exposure resulted in an increase in the number of alveolar macrophages, 

reaching maximum after about 3 days of exposure. In animals exposed for 24 hours per day, the same 

temporal relationship is observed with the maximum increase observed after about 3 days, but the number 

of macrophages is considerably greater than that observed in the 8 hour per day rats. Histopathology in 

the two different exposure groups is indistinguishable after the first 2 days. 

D-3 
Long-term Exposure 

If the exposure period is extended beyond one week, and the interexposure interval is kept short enough 

(less than 3 days) to prevent later phases of the repair cycle to occur, chronic lesions develop. Bronchiolar 

hyperplasia in response to a relatively standard long-term exposure protocol is illustrated by Harkema et 

a1.,1993 (Figure 6). Macaque monkeys were exposed to 0.30 ppm ozone for 8 hours per day for 90 days, 

resulting in bronchiolar hyperplasia and interstitial fibrosis. 

When the total exposure period is increased further hyperplastic lesions develop which are very similar to 

those observed in primates exposed everyday. Figure 7 illustrates the response of the rat terminal bronchiolar 

epithelium to a 20-month exposure 1 ppm ozone (6 hours per day, five days per week)(Plopper et al., 1994), 

including bronchiolarization of the alveolar duct (Figure 7). 

D-4 
In a modification of the above exposure regimen, rats were exposed for 78 weeks to a peak 

concentration of 0.25 ppm ozone over the course of 8 hours for 5 days per week, with a continuous 

baseline subthreshold concentration of 0.06 ppm ozone for 15 hours per day 7 days per week (Chang et 

al., 1992). Inflammation peaked early and resolved within the first few days of exposure (Figure 8). 

Fibroblast proliferation initiated shortly after the resolution of inflammation, peaked after about 1 week 

of exposure, and continued at a lower level for the remainder of exposure. Type I cell hyperplasia peaked 

after 1 week of exposure, resolved by 3 weeks, and started a gradual increase at about 6 weeks of 

exposure, reaching maximum severity over the course of 78 weeks. The latter underscores that with 

continued exposure, events that appear to resolve early recur. 

Extension of Interexposure Interval 

The next issue is what happens when the interval between exposures is increased to a sufficient 

length of time for repair to be complete (over 7 days). Plopper et al., 1978 (Figure 9) compared the 

response of rats exposed either 6 or 27 days after an initial 3 day exposure to ozone. Early responses to 

ozone included an influx of neutrophils followed by necrosis. The neutrophils resolved by the end of the 

3 day exposure. Necrosis reached maximum after day 3 and resolved by day 6 (3 days after cessation of 

exposure). Re-exposure on day 30 (27 days after cessation of exposure) results in the same pattern of 

neutrophil influx and necrosis. This is not necessarily surprising since the normal course of repair should 

result in an epithelium that is completely repaired more than three weeks after cessation of exposure. Reexposure on day 9 (6 days after cessation of exposure) yields a response similar to that observed in naive 

animals and in rats re-exposed 27 days after the initial exposure. For two exposure cycles, the acute 

inflammatory response and subsequent necrosis are the same as the initial exposure. 

D-5 
In an exposure regimen with a longer interexposure interval, Barr et al., 1990 (Figure 10) used an 

episodic exposure pattern of five 8-hour days of exposure to 0.95 ppm ozone followed by a 9-day 

recovery period. This pattern was repeated for a total of 90 days. Alternately, rats were exposed daily. 

While epithelial hypertrophy was not significantly different between daily and episodically exposed rats, the 

interstitial components were markedly different with a significant increase in interstitial thickness in 

episodically-exposed compared to daily-exposed rats. 

Additional increases in the length of time between exposures appears to further alter the biologic 

response. Hyde et al., 1989 (Figure 11) assessed total lung collagen and bronchiolar hyperplasia in Rhesus 

monkeys exposed to 0.25 ppm ozone. Monkeys were exposed 8 hours per day for either 18 continuous 

months or for alternating one-month periods. There was no discernable difference in the degree of 

bronchiolar hyperplasia in either exposure group, yet monkeys exposed on alternate months had 

considerably greater total lung collagen compared to monkeys exposed for 18 continuous months. This 

suggests that while the acute response (e.g., necrosis, inflammation) appears to be equivalent for 

subsequent exposures, the late responses involving repair may be altered. 

Given the previous data, it was apparent that an episodic exposure with an extended interexposure 

interval and multiple sampling points would provide a better understanding of the impact of variable 

exposure conditions on pathogenesis. Recently, we employed an exposure scenario similar to that of Barr 

et al., 1990, but with more frequent sampling. Rats were sampled at the beginning and end of each 5-day 

exposure period and at the end of each 9-day recovery period through day 29 (Figure 12). On the 5th day 

of the first exposure period, the epithelium appears hyperplastic (Figure 13c), yet the epithelium appears 

similar to control by 9 days after the first exposure period (Figure 14a). At the onset of the second set of 5-

day exposures, inflammation, necrosis and hyperplasia were attenuated compared to that observed in the first 

exposure (Figure 14b). Nine days after the second 5-day exposure period, bronchiolarization of the central 

acinus persists (Figure 15). 

D-6 
Summary and Conclusions 

The response of the respiratory system to oxidant air pollutants such as ozone is highly dependent on 

inhaled concentration and time. In ambient conditions, the synthesis of tropospheric ozone is cyclic in nature, 

with ozone concentrations rising highest in mid-afternoon and dropping lowest in the pre-dawn hours. 

Additionally, tropospheric ozone concentrations exhibit daily and even seasonal variations. However, most 

experimental studies employ exposure protocols with near-continuous exposures. The episodic nature of 

ambient exposure conditions in humans suggests that reliable assessments of risk must include a clear 

understanding of the impact of cyclic exposure conditions on biological time response profiles. The biological 

response of the respiratory system in naive animals to the initial ozone exposure follows a stereotypic cellular 

injury and inflammatory cycle. The imposition of additional oxidant stress by repeated exposure impacts 

the response variably, depending on the time during injury or repair when re-exposure occurs. The length 

of the interval between exposures appears to be more critical in determining the long-term impact of 

repeated exposures than the total duration of the exposure episode. Near-continuous exposure for a 

significant period of time (measured in months) fundamentally alters both the pattern of toxic cellular 

injury and the nature of the inflammatory response. Not only is the periodicity of the exposure important, 

but the duration of interexposure intervals also appears to effect biological response. The episodic nature 

of ambient exposure conditions appears to represent a greater health risk than would be expected based on 

extrapolation from experimental conditions relying on near-continuous exposure scenarios. 

D-7 
Acknowledgements 

This work is funded by NIEHS ES 00628, 09681, RR00169, and T32 ES 7059 (Paige) 

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NOTICE 

This report has been written as part of the activities of the U.S. Environmental 

Protection Agency’s (EPA) Clean Air Scientific Advisory Committee (CASAC), a 

Federal advisory committee administratively located under the EPA Science Advisory 

Board (SAB) Staff Office that is chartered to provide extramural scientific information 

and advice to the Administrator and other officials of the EPA. The CASAC is 

structured to provide balanced, expert assessment of scientific matters related to issue 

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 in the Executive Branch of the Federal 

government, nor does mention of trade names or commercial products constitute a 

recommendation for use. CASAC reports are posted on the SAB Web site at: 

http://www.epa.gov/sab. 

D-9