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
U-S ^Headquarters LID, ,,K.
10^ r Mail code 3404T   " '
^Pennsylvania Avenue NW
   Washington, DC 20460
       202-566-0556
       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 2  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.

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 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)(l) 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 2 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

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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 time-
series 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 smal! 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 gas-
and 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

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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 short-
term 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.

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t
                  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 CAS AC 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 CAS AC 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,
                                                               s
                                                           Dr. Rogene Henderson, Chair
                                                           Clean Air Scientific Advisory Committee

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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-analvsis 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.)

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     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 HOOF), Woodies Building, 1025 F Street, N.W., Room 3604, Washington,
DC 20004, Telephone: 202-343-9994)
                                       A-l

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           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

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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. Armislead (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 Veda!, 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

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                   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-l

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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-l 1
Dr. Frederick J. Miller	C-13
Dr. Maria Morandi	C-l5
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

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                                   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/R-
 05/004aF) 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

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                           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 03 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

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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 Oi 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 '(V
                                           C-5

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                                  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.  1 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-IB 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.
       1 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 smail  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

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                               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.
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                               Dr. Michael Klein man
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 (ug/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 self-
       medicate 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 03-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 LI 1 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
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       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 5 8(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
       RespirJ14(4):854-861.
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Liao D, Duan Y, Whitsel EA, Zheng ZJ, Heiss G, Chinchilli VM, et a). 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 at. 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 I: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.
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                               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
epidemiologica) studies of the fact that O3 needs to be considered as a surrogate index for the
photochemical mixture containing O3.1 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.  2,1.  3: change "nitrogen oxides (NOx)" to "nitrogen dioxide (NO2)."

p. 8-2, para.  1,1.  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.  2,1.  5: change "clean" to "cleaner."

p. 8-3, para.  3,1.  2: insert "finer scale" before "spatial."

p. 8-4, para.  2,1.  8: insert "due to springtime intrusions of stratospheric O3" after "Hemisphere."

p. 8-8, para.  2,1.  14: change "03" to "photochemical oxidant."

p. 8-8, para.  3,1.  4: delete "somewhat."

p. 8-15, para. 2,1. 4: insert "generally" before "having."

p. 8-25, para. 2,1. 7-12: A reference should be provided to support this statement.
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p. 8-63, para. 1,1. 8, 10, and 14: insert "onset" before "risk."

p. 8-69, para. 2,1. 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. 2,1. 12: add "below O.OSppm, and even below 0.06ppm" after "levels" (Spektor et
al. 1988).

p. 8-75, para. 2,1. 2: change "0.08" to "0.06"  (based on Adams 2006)

p. 8-75, para. 2,1. 12: delete "likely."

p. 8-75, para. 2,1. 13: insert (Thurston et al. 1997)" after "children."

p. 8-80, para. 1,1. 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. 2,1. 8: insert "short-term" before "responsiveness."
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                               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 lexicological, 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 03 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.
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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.
                          aS ^HeadquartersLibrary
                               Mail code 3404T
                          A)u Pennsylvania Avenue NW
                             Washington, DC 20460
                                202-566-0556
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                                 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 Ch 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 Oa 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
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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 mixturesrand . tThe
results..."

Page 8-21

Quote: "..most  important biological markers of Ch-induced injury response mechanisms in both
humans..."
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                                 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-biologicaliy 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, tt 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
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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.
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                                  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 fuil 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)
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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 .OSppm.

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).  1 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.
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                                  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 ozone-
induced 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 ozone-
induced 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.
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                                  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.7.1 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).
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                               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 Os exposures for the general population tend to be reasonably well correlated
with monitored ambient Cb 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 Os 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 Os monitoring data
appear to provide the most useful index of human Oa exposure currently available to help
characterize health outcomes associated with Oa 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

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                               Dr. Barbara Zielinska


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

By Barbara Zielinska, April 30,2006

In general, 1 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 Oi concentrations
measured outdoors at community monitoring sites provide the most useful index of human O}
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  03  exposure
monitor measurements may serve as "surrogate indices of exposures to broader Oa -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.
                                         C-24

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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
Ozone
to
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 tc
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 generaDy cycle  annually. The intent of this review is to examine die 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 direshold (the  intenxposure interval (Figure 1  a). Ambient
exposures are variable in nature, with daily and seasonal variations in concentration (Figure 1 b-d) (USEPA,
1996). As die 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  nea:r
background.
                                                                                           D-l

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                       Otrl
                                   \J
                      Figure 1. Defining tame exposure p.iwncicrs. a
                      mng  ,; pci concern,. dun,lion rf tati.
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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
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                                                                                            D-2

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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 pprn 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 die 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.
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                                                                                                D-3

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                               BWLOGIC RESPONSE
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                           Kijur. 7. Dimf bnxidiiolai of rni cxrasal n> I pj uzunc for 6 haws per <
                           per wdc fur JOmooUa (A) (lar eqinis 150|m) Bone B-t> identify Kgio* shown'
                           higher nugmficMioi imam bslow. DilUI Hid termini! hroochiolar epithelium (BO
                           l|>j>rui BumcwhM flanuted (epilhelul thiciUKM i|l>incinlly dcttcutd in Knninnl
                           tuoochiota (fcpr cqU 15urn). BmiKhtolifUilion o( [he iJvn.lv dua (D.K) tjnohtJ
                           Ittpophnie mi IMbpbstic epilhefium >Ui afak Mfla. (P)OFr  il. |Wn He-
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                 EXPOSURE
                                                          M
                                         1
              5MOLOGIC RESPOHse
                                                                           MLOOCIIEIKXIH
                                                                                                  I
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                                                         Ffctorf 9. Graphic reprcscniaitofi or UK response of Ihe central senna of mt K^npoMt
                                                         6 or 27 d>s fotliwing mi imtiai J-d*j cKpoui 10 O.K ppm oxene. Increasing iht
                                                         inicrexjHrturc interval due* nut ftppciir (o change Ihe *calc injury phase, U'fopper a
                   DAILY EXPOSURE
liiimii
                                                                       EXPOSURE
                                                           I       I
                                                               mmtta
                                                                    BIOLOGIC RESPONSE
                  EPISODIC EXPOSURE
                                                           I   I * (# a u
  Figure 111. Sotwmilii' H daily anj cpi^nitc pMlcnts ftf cxfwtun: lu wl.iJ
  vvp-l S liour put day to It YJ ^ni UA>IC Iw 4 tml i( 90 divv ifldu -,-t J
                                                                  hk fcprtseiitttioii of ihc rapunM of regimen bronchioles uf khcsm
                                                         ^'IJQrfElgf Ofoed 1o OL25 ppra for 8 hour* per day daily for \S ntanttn or in Bhc
                                                         ~       cyfila. Tobtl hin collagen is vignincatillv tncreAscJ in nonkryE
                                                                           i (Hyde cl tl., IW5)
        In an exposure regimen with a longer interexposure interval, Ban 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 recover)' 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
                                                     Headquarters Library
                                                    a/I code 3404T
                                              '-C> Pennsylvania Avenue NW
                                              Washington, DC  20460
                                                   202-566-0556

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                                                            IHIMMIIII
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                                                                                            rs
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Siimmary and Conclusions
        The response of the respkatory 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 ol
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 or
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

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Acknowledgements

       This work is funded by NIEHS ES 00628,09681, RR00169, and T32 ES 7059 (Paige)



References

Barr BC, Hyde DM, Plopper CQ Dungworth DL (1990) A comparison of Terminal airway remodeling in
    chronic daily versus episodic ozone exposure. Toxicology and Applied Pharmacology 106:384-407.
Castleman WL, Dungworth DL, Schwartz LW, Tyler WS (1980) Acute respiratory bronchioiitis: An
    ultrastructural and autoradiographic study of epithelial cell injury and renewal in Rhesus monkeys
    exposed to ozone. American Journal of Pathology 98:811-840.
Chang LY, Huang Y, Stockstill BL, Graham JA, Grose EC, Menache MQ Miller FJ, Costa DL, Crapo JD
    (1992) Epithelial injury and interstitial fibrosis in the proximal alveolar regions of rats chronically
    exposed to a simulated pattern  of urban  ambient  ozone.  Toxicology and Applied Pharmacology
    115:241-252.
Gelzleichter TR, Witschi H, Last JA (1992)  Concentration-response relationships  of rat lungs to exposure
   to oxidant air pollutants: A critical test of Haber's  law for ozone and nitrogen  dioxide. Toxicology and
   Applied Pharmacology 112:73-80.
Harkema JR, Plopper CQ Hyde-DM, St. George JA, Wilson DW, Dungworth DL (1993)  Response of
   Macaque bronchiolar epithelium to ambient concentrations of ozone. American Journal  of Pathology
   143(3)857-866.
Hyde DM, Plopper CQ Harkema JR, St. George JA, Tyler WS, Dungworth DL (1989) Ozone-induced
   structural changes in the monkey respiratory system. In: Schneider T, Lee SD, Welters GJR, Grant LD
   (Editors), Atmospheric Ozone  Research and its Policy Implications,  Elsevier  Science Publishers B.V,
   Amsterdam, pp. 523-532.
Paige RC, and Plopper CG (1999)  Acute and Chronic Effects of Ozone in Animal Models. In: S Holgate,
   H Koren, J Samet, and R Maynard (Editors), Air Pollutants and Effects on Human Health. Academic
   Press Ltd, London. In Press.
Plopper CQ Chow CK, Dungworth DL, Brummer M, Nemeth TJ  (1978) Effect of  low level of ozone on
   rat lungs: II. Morphological responses during recovery and re-exposure. Experimental and Molecular
   Pathology 29:400-411.
Plopper CQ Chu FP, Haselton CJ, Peake J, Wu J,  Pinkerton KE (1994)  Dose-dependent tolerance to
   ozone: 1. Tracheobronchial  epithelial reorganization in  rats  after 20  months' exposure. American
   Journal of Pathology 144(2):404-421.
PlopperCQ Hatch GE, Wong V, Duan X, WeirAJ, Tarkington BK, Devlin RB, Becker S, Buckpitt AR
   (1998) Relationship of inhaled ozone concentration to  acute tracheobronchial epithelial injury, site-
   specific ozone dose, and glutathione depletion in Rhesus monkeys. American Journal of Respiratory
   Cell and Molecular Biology 19:387-399.
Schwartz LW Dungworth DL, Mustafa MG, Tarkington BK, Tyler WS (1976) Pulmonary responses to rats
   to ambient  levels of ozone. Laboratory Investigation 34(6):565-578.
USEPA (U.S.  Environmental Protection Agency) (1996) Air Quality  Criteria  for  Ozone and Other
   Photochemical  Oxidants. Research  Triangle  Park,  NC:  Office  of Health  and  Environmental
   Assessment, Environmental Criteria and Assessment Office; report no.  EPA/600/P-93/004cF. 3v.
                                                                                           D-8

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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

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                    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 2   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.

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 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)(l) 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 2" 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

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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 time-
series studies, particularly the mortality time-series studies, could potentially play an especially
important role in this process, as they did for paniculate 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 gas-
and 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

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 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 short-
term 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.

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       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 CAS AC 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,
                                                Dr. Rogene Henderson, Chair
                                                Clean Air Scientific Advisory Committee

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References:

Stieb, DM; Judek, S; Burnett, RT. Meta-analvsis 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-analvsis 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.)

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     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. EHis 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, Gary, 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 HOOF), Woodies Building, 1025 F Street, N.W., Room 3604, Washington,
DC 20004, Telephone: 202-343-9994)
                                       A-l

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           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-l

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Dr. Morton Lippmann, Professor, Nelson Institute of Environmental Medicine, New York
University School of Medicine, Tuxedo, NY

Dr. Frederick J. Miller*, Consultant, Gary, 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 (butterfieid.fred@.epa.gov)
* Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by the EPA
  Administrator
                                         B-2

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                   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-l

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Panelist                                                                      Paee#
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

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                                   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/R-
05/004aF) 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 CAS AC 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

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                           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 O} 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

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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 63 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 '(V
                                           C-5

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                                  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

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                               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

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                               Dr. Michael Klein man
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 (ug/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 self-
       medicate before seeing a physician.  In addition, this discussion needs to be integrated
       with observations of duration of O3 episodes.  03 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 OS-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 LI 1 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 ai. 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

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       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 03 and that the O3 effects might be masked by other
       pollutants whereas this is less of a problem during the high 03 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(I):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 5 8(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
       RespirJ14(4):854-861.
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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): 13 54-1360.
                                 u.o EPA Headquarters Library
                                       Mail code 3404T
                                  200 Pennsylvania Avenue NW
                                    Washington, DC 20460
                                        202-566-0556
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                               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
epidemiologicai studies of the fact that 03 needs to be considered as a surrogate index for the
photochemical mixture containing 03.1 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.  2,1.  3: change "nitrogen oxides (NOx)" to "nitrogen dioxide (NO2)."

p. 8-2, para.  1,1.  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.  2,1.  5: change "clean" to "cleaner."

p. 8-3, para.  3,1.  2: insert "finer scale" before "spatial."

p. 8-4, para.  2,1.  8: insert "due to springtime intrusions of stratospheric O3" after "Hemisphere."

p. 8-8, para.  2,1.  14: change "O3" to "photochemical oxidant."

p. 8-8, para.  3,1. 4: delete "somewhat."

p. 8-15, para. 2,1.4: insert "generally" before "having."

p. 8-25, para. 2,1. 7-12: A reference should be provided to support this statement.
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p. 8-63, para. 1,1. 8, 10, and 14: insert "onset" before "risk."

p. 8-69, para. 2,1. 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. 2,1 12:  add "below O.OSppm, and even below 0.06ppm" after "levels" (Spektor et
al. 1988).

p. 8-75, para. 2,1. 2: change "0.08" to "0.06"  (based on Adams 2006)

p. 8-75, para. 2,1. 12:  delete "likely."

p. 8-75, para. 2,1. 13:  insert (Thurston et al. 1997)" after "children."

p. 8-80, para. 1,1. 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. 2,1. 8: insert "short-term" before "responsiveness."
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                               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 03 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.
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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.
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                                 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 Chwere 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 pprn, 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 O?exposure
ad 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

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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^-aftd . tThe
results..."

Page 8-21

Quote: "..most important  biological markers of Cb-induced injury response mechanisms in both
humans..."
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                                 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

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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.
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                                  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)
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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

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                                  Dr. James UJtman
                             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 ozone-
induced 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 ozone-
induced 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.
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                                  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.7.1 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 -1 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).
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                               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 Osexposures for the general population tend to be reasonably well correlated
with monitored ambient Oi 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 Cb 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 Os monitoring data
appear to provide the most useful index of human Os exposure  currently available to help
characterize health outcomes associated with Oaexposures 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.
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                               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 63 concentrations
measured outdoors at community monitoring sites provide the most useful index of human Oj
exposure (page 8-8 and 8-JO). 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  03 exposure
monitor measurements may serve as "surrogate indices of exposures to broader 03 -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'1 (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 die 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 (Gelzleichtei:
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 irtterexposure interval (Figure 1 a).  Ambient
exposures are variable in nature, with daily and  seasonal variations in concentration (Figure 1  b-d) (USEPA,
1996). As die 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-l

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                        Hi-l
                                     "P0*"" parameters. a) Nluarucs !hc pwamrtcrs dunaci-
                                     **'- *lii ,3 la,g.h of dm, taween expun
                                 ,, 1VJSlphie "*'<""'' of daily <.. in .mbiaw
                      urn .nntnili. (US1-.PA. IW), 4 Shows ihr dily vriion of ozone toncetilrs-
                                              '
           minimum and maximum
           ~ ** """ of
                                                            mtMiircd  un
                                                              lluoush Dc'
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, 1 999, 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
        0115
                0>y>
Wfm Z, Graphic reprfvciilalion of tht biologic icspoore lo c
npMurt. i) epithelial ictjnnu k} m|>   "  "
                                                                                             D-2

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continues. If exposure ceases, the affected compartments will revert to pie-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  pprn 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.
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                                      EXPOSURE
                                  encode RESPONSE
                          I'LLJLLLJ
                               J  4  5
                                         BIOLOGIC RESPONSE
                                    S  6  7
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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
hj'perplasia in response to  a relatively  standard long-term exposure  protocol is illustrated by Harkema et
al.,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 1 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

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                           Hture 7. Ditttl bnmchioia of nu atpoxxl  I ppjn none for 6 hours per Mly decreased in lenmiul
                           bronchiole! flr cqujk 15pm) Cnmchiolanoiion r chc ilvtolv duct [D !) inviihtxl
                           li)pcrj>liKic utd rattapkaK ejniliclHjtti ttv afuh Mjttii. (Plopfvr et >l 1994) He-
                           pnaxi. with permiisnm, from Ploppcr il.. I9W. DOM dcpcndtm tola-ana lo ozone:
                           I. TniKhcobrondtuil epithelial rco(gfnii/*ct-M~lll. 6 Ajntrian SOCKIV fa btvestiiut-
                           (i Pllhology.                              '      ^
        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  foi  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. Re-
exposure 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

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                 EXFOSlME
              BKM.OCIC wsroiise
   in the wklv insure seam  n 9* i>1>m ,,, In: 4 lia!  0.25 ppm F 8 hours per day duly fur IS iimahs  in altc
                                                          :>4DiMUk eycfcf. Tool hng coRaccn is Hfincficaraly increased in racntej f
                                                          -&k
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                                                           lite*
          pc. . fe, Mv c
              ,nwi ,1* kb,^ fi^^, .
                                                       flim 14. tawmt at the temwul bcooOiiotir tpittelnim K> > XHI| e>^e  Croat *< fim t)le of on** apamc. ibs pi*t"
                                                            i nomal (al Alto the Tim re-(HuM; dl>; lh  (r^rai^ >. Alto *e jec
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A cknowledgements
       This work is funded by NIEHS ES 00628, 09681, RR00169, and T32 ES 7059 (Paige)
References

Barr BC, Hyde DM, Plopper CQ Dungworth DL (1990) A comparison of Terminal airway remodeling in
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Castleman WL, Dungworth DL, Schwartz LW, Tyler WS (1980) Acute respiratory bronchiolitis: An
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Chang LY, Huang Y, Stockstill BL, Graham JA, Grose EC, Menache MQ Miller FJ, Costa DL, Crapo JD
    (1992) Epithelial injury and interstitial fibrosis in the  proximal alveolar regions of rats chronically
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Gelzleichter TR, Witschi H, Last JA (1992) Concentration-response relationships of rat lungs to exposure
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Harkema JR, Plopper CQ Hyde. DM, St.  George JA, Wilson DW,  Dungworth DL (1993) Response of
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Hyde DM, Plopper CQ Harkema JR, St.  George JA, Tyler WS, Dungworth DL (1989) Ozone-induced
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Plopper CQ Chu FP, Haselton CJ, Peake J, Wu J, Pmkerton KE  (1994)  Dose-dependent tolerance to
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Schwartz LW Dungworth DL, Mustafa MG, Tarkington BK, Tyler WS (1976) Pulmonary responses to rats
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USEPA (U.S. Environmental  Protection Agency) (1996)  Air  Quality  Criteria for  Ozone  and Other
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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.
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