[Federal Register: July 11, 2007 (Volume 72, Number 132)]
[Proposed Rules]
[Page 37817-37919]
[DOCID:fr11jy07-19]

-----------------------------------------------------------------------

Part II

Environmental Protection Agency

-----------------------------------------------------------------------

40 CFR Part 50

National Ambient Air Quality Standards for Ozone; Proposed Rule

-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 50

[EPA-HQ-OAR-2005-0172; FRL-8331-5]
RIN 2060-AN24

National Ambient Air Quality Standards for Ozone

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: Based on its review of the air quality criteria for ozone
(O3) and related photochemical oxidants and national ambient
air quality standards (NAAQS) for O3, EPA proposes to make
revisions to the primary and secondary NAAQS for O3 to
provide requisite protection of public health and welfare,
respectively, and to make corresponding revisions in data handling
conventions for O3.
    With regard to the primary standard for O3, EPA proposes
to revise the level of the 8-hour standard to a level within the range
of 0.070 to 0.075 parts per million (ppm), to provide increased
protection for children and other ``at risk'' populations against an
array of O3-related adverse health effects that range from
decreased lung function and increased respiratory symptoms to serious
indicators of respiratory morbidity including emergency department
visits and hospital admissions for respiratory causes, and possibly
cardiovascular-related morbidity as well as total nonaccidental and
cardiopulmonary mortality. The EPA also proposes to specify the level
of the primary standard to the nearest thousandth ppm. The EPA solicits
comment on alternative levels down to 0.060 ppm and up to and including
retaining the current 8-hour standard of 0.08 ppm (effectively 0.084
ppm using current data rounding conventions).
    With regard to the secondary standard for O3, EPA
proposes to revise the current 8-hour standard with one of two options
to provide increased protection against O3-related adverse
impacts on vegetation and forested ecosystems. One option is to replace
the current standard with a cumulative, seasonal standard expressed as
an index of the annual sum of weighted hourly concentrations, cumulated
over 12 hours per day (8 a.m. to 8:00 p.m.) during the consecutive 3-
month period within the O3 season with the maximum index
value, set at a level within the range of 7 to 21 ppm-hours. The other
option is to make the secondary standard identical to the proposed
primary 8-hour standard. The EPA solicits comment on specifying a
cumulative, seasonal standard in terms of a 3-year average of the
annual sums of weighted hourly concentrations; on the range of
alternative 8-hour standard levels for which comment is being solicited
for the primary standard, including retaining the current secondary
standard, which is identical to the current primary standard; and on an
alternative approach to setting a cumulative, seasonal secondary
standard(s).

DATES: Written comments on this proposed rule must be received by
October 9, 2007.

ADDRESSES: Submit your comments, identified by Docket ID No. EPA-HQ-
OAR-2005-0172, by one of the following methods:
     http://www.regulations.gov: Follow the on-line instructions for

submitting comments.
     E-mail<EMAIL_ADDRESS>     Fax:<PHONE_NUMBER>.
     Mail: Docket No. EPA-HQ-OAR-2005-0172, Environmental
Protection Agency, Mail code 6102T, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460. Please include a total of two copies.
     Hand Delivery: Docket No. EPA-HQ-OAR-2005-0172,
Environmental Protection Agency, EPA West, Room 3334, 1301 Constitution
Ave., NW., Washington, DC. Such deliveries are only accepted during the
Docket's normal hours of operation, and special arrangements should be
made for deliveries of boxed information.
    Instructions: Direct your comments to Docket ID No. EPA-HQ-OAR-
2005-0172. The EPA's policy is that all comments received will be
included in the public docket without change and may be made available
online at http://www.regulations.gov, including any personal information

provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through http://www.regulations.gov

or e-mail. The http://www.regulations.gov Web site is an ``anonymous access''

system, which means EPA will not know your identity or contact
information unless you provide it in the body of your comment. If you
send an e-mail comment directly to EPA without going through
http://www.regulations.gov, your e-mail address will be automatically captured

and included as part of the comment that is placed in the public docket
and made available on the Internet. If you submit an electronic
comment, EPA recommends that you include your name and other contact
information in the body of your comment and with any disk or CD-ROM you
submit. If EPA cannot read your comment due to technical difficulties
and cannot contact you for clarification, EPA may not be able to
consider your comment. Electronic files should avoid the use of special
characters, any form of encryption, and be free of any defects or
viruses. For additional information about EPA's public docket, visit
the EPA Docket Center homepage at http://www.epa.gov/epahome/dockets.htm
.

    Docket: All documents in the docket are listed in the
http://www.regulations.gov index. Although listed in the index, some

information is not publicly available, e.g., CBI or other information
whose disclosure is restricted by statute. Certain other material, such
as copyrighted material, will be publicly available only in hard copy.
Publicly available docket materials are available either electronically
in http://www.regulations.gov or in hard copy at the Air and Radiation Docket

and Information Center, EPA/DC, EPA West, Room 3334, 1301 Constitution
Ave., NW., Washington, DC. The Public Reading Room is open from 8:30
a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. The
telephone number for the Public Reading Room is<PHONE_NUMBER> and the
telephone number for the Air and Radiation Docket and Information
Center is<PHONE_NUMBER>.
    Public Hearings: The EPA intends to hold public hearings around the
end of August to early September in several cities across the country,
and will announce in a separate Federal Register notice the dates,
times, and addresses of the public hearings on this proposed rule.

FOR FURTHER INFORMATION CONTACT: Dr. David J. McKee, Health and
Environmental Impacts Division, Office of Air Quality Planning and
Standards, U.S. Environmental Protection Agency, Mail code C504-06,
Research Triangle Park, NC 27711; telephone:<PHONE_NUMBER>; fax: 919-
541-0237; e-mail<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

General Information

What Should I Consider as I Prepare My Comments for EPA?

    1. Submitting CBI. Do not submit this information to EPA through
http://www.regulations.gov or e-mail. Clearly mark the part or all of the

information that you claim to be CBI. For CBI information in a disk or
CD ROM that

you mail to EPA, mark the outside of the disk or CD ROM as CBI and then
identify electronically within the disk or CD ROM the specific
information that is claimed as CBI. In addition to one complete version
of the comment that includes information claimed as CBI, a copy of the
comment that does not contain the information claimed as CBI must be
submitted for inclusion in the public docket. Information so marked
will not be disclosed except in accordance with procedures set forth in
40 CFR part 2.
    2. Tips for Preparing Your Comments. When submitting comments,
remember to:
     Identify the rulemaking by docket number and other
identifying information (subject heading, Federal Register date and
page number).
     Follow directions--The Agency may ask you to respond to
specific questions or organize comments by referencing a Code of
Federal Regulations (CFR) part or section number.
     Explain why you agree or disagree, suggest alternatives,
and substitute language for your requested changes.
     Describe any assumptions and provide any technical
information and/or data that you used.
     If you estimate potential costs or burdens, explain how
you arrived at your estimate in sufficient detail to allow for it to be
reproduced.
     Provide specific examples to illustrate your concerns, and
suggest alternatives.
     Explain your views as clearly as possible, avoiding the
use of profanity or personal threats.
     Make sure to submit your comments by the comment period
deadline identified.

Availability of Related Information

    A number of documents relevant to this rulemaking are available on
EPA Web sites. The Air Quality Criteria for Ozone and Related
Photochemical Oxidants (Criteria Document) (two volumes, EPA/ and EPA/,
date) is available on EPA's National Center for Environmental
Assessment Web site. To obtain this document, go to http://www.epa.gov/ncea
, and click on ``Ozone.'' The Staff Paper, human exposure and

health risk assessments, vegetation exposure and impact assessment, and
other related technical documents are available on EPA's Office of Air
Quality Planning and Standards (OAQPS) Technology Transfer Network
(TTN) Web site. The Staff Paper is available at http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_cr_sp.html
, and the exposure and risk

assessments and other related technical documents are available at
http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_cr_td.html. EPA

will be making available corrected versions of the final Staff Paper
and human exposure and health risk assessment technical support
documents on these same EPA Web sites on or around July 16, 2007. These
and other related documents are also available for inspection and
copying in the EPA docket identified above.

Table of Contents

    The following topics are discussed in this preamble:
I. Background
    A. Legislative Requirements
    B. Related Control Requirements
    C. Review of Air Quality Criteria and Standards for
O3
II. Rationale for Proposed Decision on the Primary Standard
    A. Health Effects Information
    1. Mechanisms
    2. Nature of Effects
    3. Interpretation and Integration of the Health Evidence
    4. O3-Related Impacts on Public Health
    B. Human Exposure and Health Risk Assessments
    1. Exposure Analyses
    2. Quantitative Health Risk Assessment
    C. Conclusions on the Adequacy of the Current Primary Standard
    1. Background
    2. Evidence- and Exposure/Risk-Based Considerations
    3. CASAC Views
    4. Administrator's Proposed Conclusions Concerning Adequacy of
Current Standard
    D. Conclusions on the Elements of the Primary Standard
    1. Indicator
    2. Averaging Time
    3. Form
    4. Level
    E. Proposed Decision on the Primary Standard
III. Communication of Public Health Information
IV. Rationale for Proposed Decision on the Secondary Standard
    A. Vegetation Effects Information
    1. Mechanisms Governing Plant Response to Ozone
    2. Nature of Effects
    3. Adversity of Effects
    B. Biologically Relevant Exposure Indices
    C. Vegetation Exposure and Impact Assessment
    1. Exposure Characterization
    2. Assessment of Risks to Vegetation
    D. Conclusions on the Adequacy of the Current Standard
    1. Background
    2. Evidence- and Exposure/Risk-Based Considerations
    3. CASAC Views
    4. Administrator's Proposed Conclusions Concerning Adequacy of
Current Standard
    E. Conclusions on the Elements of the Secondary Standard
    1. Indicator
    2. Cumulative, Seasonal Standard
    3. 8-Hour Average Standard
    F. Proposed Decision on the Secondary Standard
V. Creation of Appendix P--Interpretation of the NAAQS for Ozone
    A. Data Completeness
    B. Data Handling and Rounding O3 Conventions
VI. Ambient Monitoring Related to Proposed Revised Standards
VII. Statutory and Executive Order Reviews
References

I. Background

A. Legislative Requirements

    Two sections of the Clean Air Act (CAA) govern the establishment
and revision of the NAAQS. Section 108 (42 U.S.C. 7408) directs the
Administrator to identify and list ``air pollutants'' that ``in his
judgment, may reasonably be anticipated to endanger public health and
welfare'' and whose ``presence * * * in the ambient air results from
numerous or diverse mobile or stationary sources'' and to issue air
quality criteria for those that are listed. Air quality criteria are
intended to ``accurately reflect the latest scientific knowledge useful
in indicating the kind and extent of identifiable effects on public
health or welfare which may be expected from the presence of [a]
pollutant in ambient air * * *.''
    Section 109 (42 U.S.C. 7409) directs the Administrator to propose
and promulgate ``primary'' and ``secondary'' NAAQS for pollutants
listed under section 108. Section 109(b)(1) defines a primary standard
as one ``the attainment and maintenance of which in the judgment of the
Administrator, based on such criteria and allowing an adequate margin
of safety, are requisite to protect the public health.'' \1\ A
secondary standard, as defined in section 109(b)(2), must ``specify a
level of air quality the attainment and maintenance of which, in the
judgment of the Administrator, based on such criteria, is requisite to
protect the public welfare from any known or anticipated adverse
effects associated with the presence of [the] pollutant in the ambient
air.'' \2\
---------------------------------------------------------------------------

    \1\ The legislative history of section 109 indicates that a
primary standard is to be set at ``the maximum permissible ambient
air level * * * which will protect the health of any [sensitive]
group of the population,'' and that for this purpose ``reference
should be made to a representative sample of persons comprising the
sensitive group rather than to a single person in such a group'' [S.
Rep. No. 91-1196, 91st Cong., 2d Sess. 10 (1970)].
    \2\ Welfare effects as defined in section 302(h) (42 U.S.C.
7602(h)) include, but are not limited to, ``effects on soils, water,
crops, vegetation, man-made materials, animals, wildlife, weather,
visibility and climate, damage to and deterioration of property, and
hazards to transportation, as well as effects on economic values and
on personal comfort and well-being.''

---------------------------------------------------------------------------

    The requirement that primary standards include an adequate margin
of safety was intended to address uncertainties associated with
inconclusive scientific and technical information available at the time
of standard setting. It was also intended to provide a reasonable
degree of protection against hazards that research has not yet
identified. Lead Industries Association v. EPA, 647 F.2d 1130, 1154 (DC
Cir 1980), cert. denied, 449 U.S. 1042 (1980); American Petroleum
Institute v. Costle, 665 F.2d 1176, 1186 (D.C. Cir. 1981), cert.
denied, 455 U.S. 1034 (1982). Both kinds of uncertainties are
components of the risk associated with pollution at levels below those
at which human health effects can be said to occur with reasonable
scientific certainty. Thus, in selecting primary standards that include
an adequate margin of safety, the Administrator is seeking not only to
prevent pollution levels that have been demonstrated to be harmful but
also to prevent lower pollutant levels that may pose an unacceptable
risk of harm, even if the risk is not precisely identified as to nature
or degree. The CAA does not require the Administrator to establish a
primary NAAQS at a zero-risk level or at background concentration
levels, see Lead Industries Association v. EPA, 647 F.2d at 1156 n. 51,
but rather at a level that reduces risk sufficiently so as to protect
public health with an adequate margin of safety.
    In addressing the requirement for an adequate margin of safety, EPA
considers such factors as the nature and severity of the health effects
involved, the size of the population(s) at risk, and the kind and
degree of the uncertainties that must be addressed. The selection of
any particular approach to providing an adequate margin of safety is a
policy choice left specifically to the Administrator's judgment. Lead
Industries Association v. EPA, 647 F.2d at 1161-62; Whitman v. American
Trucking Associations, 531 U.S. 457, 495 (2001) (Breyer, J., concurring
in part and concurring in judgment).
    In setting standards that are ``requisite'' to protect public
health and welfare, as provided in section 109(b), EPA's task is to
establish standards that are neither more nor less stringent than
necessary for these purposes. Whitman v. American Trucking
Associations, 531 U.S. 457, 473. In establishing ``requisite'' primary
and secondary standards, EPA may not consider the costs of implementing
the standards. Id. at 471. As discussed by Justice Breyer in Whitman v.
American Trucking Associations, however, ``this interpretation of Sec.
109 does not require the EPA to eliminate every health risk, however
slight, at any economic cost, however great, to the point of
``hurtling'' industry over ``the brink of ruin,'' or even forcing
``deindustrialization.'' Id. at 494 (Breyer J., concurring in part and
concurring in judgment) (citations omitted). Rather, as Justice Breyer
explained:

    The statute, by its express terms, does not compel the
elimination of all risk; and it grants the Administrator sufficient
flexibility to avoid setting ambient air quality standards ruinous
to industry.
    Section 109(b)(1) directs the Administrator to set standards
that are ``requisite to protect the public health'' with ``an
adequate margin of safety.'' But these words do not describe a world
that is free of all risk--an impossible and undesirable objective.
(citation omitted). Nor are the words ``requisite'' and ``public
health'' to be understood independent of context. We consider
football equipment ``safe'' even if its use entails a level of risk
that would make drinking water ``unsafe'' for consumption. And what
counts as ``requisite'' to protecting the public health will
similarly vary with background circumstances, such as the public's
ordinary tolerance of the particular health risk in the particular
context at issue. The Administrator can consider such background
circumstances when ``deciding what risks are acceptable in the world
in which we live.'' (citation omitted).
    The statute also permits the Administrator to take account of
comparative health risks. That is to say, she may consider whether a
proposed rule promotes safety overall. A rule likely to cause more
harm to health than it prevents is not a rule that is ``requisite to
protect the public health.'' For example, as the Court of Appeals
held and the parties do not contest, the Administrator has the
authority to determine to what extent possible health risks stemming
from reductions in tropospheric ozone (which, it is claimed, helps
prevent cataracts and skin cancer) should be taken into account in
setting the ambient air quality standard for ozone. (citation
omitted).
    The statute ultimately specifies that the standard set must be
``requisite to protect the public health'' ``in the judgment of the
Administrator,'' Sec.  109(b)(1), 84 Stat. 1680 (emphasis added), a
phrase that grants the Administrator considerable discretionary
standard-setting authority.
    The statute's words, then, authorize the Administrator to
consider the severity of a pollutant's potential adverse health
effects, the number of those likely to be affected, the distribution
of the adverse effects, and the uncertainties surrounding each
estimate. (citation omitted). They permit the Administrator to take
account of comparative health consequences. They allow her to take
account of context when determining the acceptability of small risks
to health. And they give her considerable discretion when she does
so.
    This discretion would seem sufficient to avoid the extreme
results that some of the industry parties fear. After all, the EPA,
in setting standards that ``protect the public health'' with ``an
adequate margin of safety,'' retains discretionary authority to
avoid regulating risks that it reasonably concludes are trivial in
context. Nor need regulation lead to deindustrialization.
Preindustrial society was not a very healthy society; hence a
standard demanding the return of the Stone Age would not prove
``requisite to protect the public health.''
    Although I rely more heavily than does the Court upon
legislative history and alternative sources of statutory
flexibility, I reach the same ultimate conclusion. Section 109 does
not delegate to the EPA authority to base the national ambient air
quality standards, in whole or in part, upon the economic costs of
compliance.

Id. at 494-496.
    Section 109(d)(1) of the CAA requires that ``not later than
December 31, 1980, and at 5-year intervals thereafter, the
Administrator shall complete a thorough review of the criteria
published under section 108 and the national ambient air quality
standards * * * and shall make such revisions in such criteria and
standards and promulgate such new standards as may be appropriate * *
*.'' Section 109(d)(2) requires that an independent scientific review
committee ``shall complete a review of the criteria * * * and the
national primary and secondary ambient air quality standards * * * and
shall recommend to the Administrator any new * * * standards and
revisions of existing criteria and standards as may be appropriate * *
*.'' This independent review function is performed by the Clean Air
Scientific Advisory Committee (CASAC) of EPA's Science Advisory Board.

B. Related Control Requirements

    States have primary responsibility for ensuring attainment and
maintenance of ambient air quality standards once EPA has established
them. Under section 110 of the Act (42 U.S.C. 7410) and related
provisions, States are to submit, for EPA approval, State
implementation plans (SIPs) that provide for the attainment and
maintenance of such standards through control programs directed to
emission sources. The majority of man-made NOX and VOC
emissions that contribute to O3 formation in the United
States come from three types of sources: mobile sources, industrial
processes (which include consumer and commercial products), and the
electric

power industry.\3\ Mobile sources and the electric power industry were
responsible for 78 percent of annual NOX emissions in 2004.
That same year, 99 percent of man-made VOC emissions came from
industrial processes (including solvents) and mobile sources. Emissions
from natural sources, such as trees, may also comprise a significant
portion of total VOC emissions in certain regions of the country,
especially during the O3 season, which are considered
natural background emissions.
---------------------------------------------------------------------------

    \3\ See EPA report, Evaluating Ozone Control Programs in the
Eastern United States: Focus on the NOX Budget Trading Program,
2004.
---------------------------------------------------------------------------

    EPA has developed new emissions standards for many types of
stationary sources and for nearly every class of mobile sources in the
last decade to reduce O3 by decreasing emissions of
NOX and VOC. These programs complement State and local
efforts to improve O3 air quality and meet current national
standards. Under the Federal Motor Vehicle Control Program (FMVCP, see
title II of the CAA, 42 U.S.C. 7521-7574), EPA has established new
emissions standards for nearly every type of automobile, truck, bus,
motorcycle, earth mover, and aircraft engine, and for the fuels used to
power these engines. EPA also established new standards for the smaller
engines used in small watercraft, lawn and garden equipment. Recently
EPA proposed new standards for locomotive and marine diesel engines.
Benefits from engine standards increase modestly each year as older,
more-polluting vehicles and engines are replaced with newer, cleaner
models. In time, these programs will yield substantial emission
reductions. Benefits from fuel programs generally begin as soon as a
new fuel is available.
    The reduction of VOC emissions from industrial processes has been
achieved either directly or indirectly through implementation of
control technology standards, including maximum achievable control
technology, reasonably available control technology, and best available
control technology standards; or are anticipated due to proposed or
upcoming proposals based on generally available control technology or
best available controls under provisions related to consumer and
commercial products. These standards have resulted in VOC emission
reductions of almost a million tons per year accumulated starting in
1997 from a variety of sources including combustion sources, coating
categories, and chemical manufacturing. The EPA is currently working to
finalize new federal rules, or amendments to existing rules, that will
establish new nationwide VOC content limits for several categories of
consumer and commercial products, including aerosol coatings,
architectural and industrial maintenance coatings, and household and
institutional commercial products. These rules will take effect in
2009, and will yield significant new reductions in nationwide VOC
emissions--about 200,000 tons per year. Additionally, in O3
nonattainment areas, we anticipate reductions of an additional 25,000
tons per year following completion of control technique recommendations
for 3 additional consumer and commercial product categories. These
emission reductions primarily result from solvent controls and
typically occur where and when the solvent is used, such as during
manufacturing processes.
    The power industry is one of the largest emitters of NOX
in the United States. Power industry emission sources include large
electric generating units and some large industrial boilers and
turbines. The EPA's landmark Clean Air Interstate Rule (CAIR), issued
on March 10, 2005, permanently caps power industry emissions of
NOX in the eastern United States. The first phase of the cap
begins in 2009, and a lower second phase cap begins in 2015. By 2015,
EPA projects that the CAIR and other programs in the Eastern U.S. will
reduce power industry O3 season NOX emissions in
that region by about 50 percent and annual NOX emissions by
about 60 percent from 2003 levels.
    With respect to agricultural sources, the U.S. Department of
Agriculture (USDA) has approved conservation systems and activities
that reduce agricultural emissions of NOX and VOC. Current
practices that may reduce emissions of NOX and VOC include
engine replacement programs, diesel retrofit programs, manipulation of
pesticide applications including timing of applications, and animal
feeding operations waste management techniques. The EPA recognizes that
USDA has been working with the agricultural community to develop
conservation systems and activities to control emissions of
O3 precursors.
    These conservation activities are voluntarily adopted through the
use of incentives provided to the agricultural producer. In cases where
the States need these measures to attain the standard, the measures
could be adopted. The EPA will continue to work with USDA on these
activities with efforts to identify and/or improve the control
efficiencies, prioritize the adoption of these conservation systems and
activities, and ensure that appropriate criteria are used for
identifying the most effective application of conservation systems and
activities.
    The EPA will work together with USDA and with States to identify
appropriate measures to meet the primary and secondary standards,
including site-specific conservation systems and activities. Based on
prior experience identifying conservation measures and practices to
meet the PM NAAQS requirements, the EPA will use a similar process to
identify measures that could meet the O3 requirements. The
EPA anticipates that certain USDA-approved conservation systems and
activities that reduce agricultural emissions of NOX and VOC
may be able to satisfy the requirements for applicable sources to
implement reasonably available control measures for purposes of
attaining the primary and secondary O3 NAAQS.

C. Review of Air Quality Criteria and Standards for O3

    Tropospheric (ground-level) O3 is formed from biogenic
and anthropogenic precursor emissions. Naturally occurring
O3 in the troposphere can result from biogenic organic
precursors reacting with naturally occurring nitrogen oxides
(NOX) and by stratospheric O3 intrusion into the
troposphere. Anthropogenic precursors of O3, specifically
NOX and volatile organic compounds (VOC), originate from a
wide variety of stationary and mobile sources. Ambient O3
concentrations produced by these emissions are directly affected by
temperature, solar radiation, wind speed and other meteorological
factors.
    The last review of the O3 NAAQS was completed on July
18, 1997, based on the 1996 O3 CD (U.S. EPA, 1996a) and 1996
O3 Staff Paper (U.S. EPA, 1996b). EPA revised the primary
and secondary O3 standards on the basis of the then latest
scientific evidence linking exposures to ambient O3 to
adverse health and welfare effects at levels allowed by the 1-hour
average standards (62 FR 38856). The O3 standards were
revised by replacing the existing primary 1-hour average standard with
an 8-hour average O3 standard set at a level of 0.08 ppm,
which is equivalent to 0.084 ppm using the standard rounding
conventions. The form of the primary standard was changed to the annual
fourth-highest daily maximum 8-hour average concentration, averaged
over three years. The secondary O3 standard was changed by
making it identical in all respects to the revised primary standard.
    Following promulgation of the revised O3 NAAQS,
petitions for review were

filed addressing a broad range of issues. In May 1999, in response to
those challenges, the U.S. Court of Appeals for the District of
Columbia Circuit held that EPA's approach to establishing the level of
the standards in 1997, both for the O3 and for the
particulate matter (PM) NAAQS promulgated on the same day, effected
``an unconstitutional delegation of legislative authority.'' American
Trucking Associations v. EPA, 175 F.3d 1027 (DC Cir., 1999). Although
the D.C. Circuit stated that ``factors EPA uses in determining the
degree of public health concern associated with different levels of
O3 and PM are reasonable,'' it remanded the rule to EPA,
stating that when EPA considers these factors for potential non-
threshold pollutants ``what EPA lacks is any determinate criterion for
drawing lines'' to determine where the standards should be set. Id. at
1034. Consistent with EPA's long-standing interpretation and DC Circuit
precedent, the court also reaffirmed prior rulings holding that in
setting the NAAQS, it is ``not permitted to consider the cost of
implementing those standards.'' Id. at 1040-41. The DC Circuit further
directed EPA to consider on remand the potential indirect beneficial
health effects of O3 pollution in shielding the public from
the effects of solar ultraviolet (UV) radiation, as well as the direct
adverse health effects of O3 pollution.
    Both sides filed cross appeals on the constitutional and cost
issues to the United States Supreme Court, and the Court granted
certiorari. On February 27, 2001, the U.S. Supreme Court issued a
unanimous decision upholding the EPA's position on both the
constitutional and the cost issues. Whitman v. American Trucking
Associations, 531 U.S. at 464, 475-76. On the constitutional issue, the
Court held that the statutory requirement that NAAQS be ``requisite''
to protect public health with an adequate margin of safety sufficiently
guided EPA's discretion, affirming EPA's approach of setting standards
that are neither more nor less stringent than necessary. The Supreme
Court remanded the case to the D.C. Circuit for resolution of any
remaining issues that had not been addressed by that Court's earlier
decisions. Id. at 475-76. On March 26, 2002, the D.C. Circuit Court
rejected all remaining challenges to the NAAQS, holding under
traditional standard of review that EPA ``engaged in reasoned decision-
making'' in setting the 1997 O3 NAAQS. Whitman v. American
Trucking Associations, 283 F.3d 355 (DC Cir. 2002).
    In response to the DC Circuit Court's remand to consider the
potential indirect beneficial health effects of O3 in
shielding the public from the effects of solar (UV) radiation, on
November 14, 2001, EPA proposed to leave the 1997 8-hour NAAQS
unchanged (66 FR 57267). After considering public comment on the
proposed decision, EPA reaffirmed the 8-hour O3 NAAQS set in
1997 (68 FR 614). Finally, on April 30, 2004, EPA issued an 8-hour
implementation rule that, among other things, provided that the 1-hour
O3 NAAQS would no longer apply to areas one year after the
effective date of the designation of those areas for the 8-hour NAAQS
(69 FR 23966).\4\ For most areas, the date that the 1-hour NAAQS no
longer applied was June 15, 2005. (See 40 CFR 50.9 for details.)
---------------------------------------------------------------------------

    \4\ On December 22, 2006, the D.C. Circuit vacated the April 30,
2004 implementation rule. South Coast Air Quality Management
District v. EPA, 472 F.3d 882. In March 2007, EPA requested the
Court to reconsider its decision.
---------------------------------------------------------------------------

    The EPA initiated this current review in September 2000 with a call
for information (65 FR 57810) for the development of a revised Air
Quality Criteria Document for O3 and Other Photochemical
Oxidants (henceforth the ``Criteria Document''). A project work plan
(U.S. EPA, 2002) for the preparation of the Criteria Document was
released in November 2002 for CASAC and public review. EPA held a
series of workshops in mid-2003 on several draft chapters of the
Criteria Document to obtain broad input from the relevant scientific
communities. These workshops helped to inform the preparation of the
first draft Criteria Document (EPA, 2005a), which was released for
CASAC and public review on January 31, 2005; a CASAC meeting was held
on May 4-5, 2005 to review the first draft Criteria Document. A second
draft Criteria Document (EPA, 2005b) was released for CASAC and public
review on August 31, 2005, and was discussed along with a first draft
Staff Paper (EPA, 2005c) at a CASAC meeting held on December 6-8, 2005.
In a February 16, 2006 letter to the Administrator, the CASAC offered
final comments on all chapters of the Criteria Document (Henderson,
2006a), and the final Criteria Document (EPA, 2006a) was released on
March 21, 2006. In a June 8, 2006 letter (Henderson, 2006b) to the
Administrator, the CASAC offered additional advice to the Agency
concerning chapter 8 of the final Criteria Document (Integrative
Synthesis) to help inform the second draft Staff Paper.
    A second draft Staff Paper (EPA, 2006b) was released on July 17,
2006 and reviewed by CASAC on August 24 and 25, 2006. In an October 24,
2006 letter to the Administrator, CASAC provided advice and
recommendations to the Agency concerning the second draft Staff Paper
(Henderson, 2006c). A final Staff Paper (EPA, 2007) was released on
January 31, 2007. Around the time of the release of the final Staff
Paper in January 2007, EPA discovered a small error in the exposure
model that when corrected resulted in slight increases in the human
exposure estimates. Since the exposure estimates are an input to the
lung function portion of the health risk assessment, this correction
also resulted in slight increases in the lung function risk estimates
as well. The exposure and risk estimates discussed in this notice
reflect the corrected estimates, and thus are slightly different than
the exposure and risk estimates cited in the January 31, 2007 Staff
Paper.\5\ In a March 26, 2007 letter (Henderson, 2007), CASAC offered
additional advice to the Administrator with regard to recommendations
and revisions to the primary and secondary O3 NAAQS.
---------------------------------------------------------------------------

    \5\ EPA plans to make available corrected versions of the final
Staff Paper and the human exposure and health risk assessment
technical support documents on or around July 16, 2007 on the EPA
web site listed in the Availability of Related Information section
of this notice.
---------------------------------------------------------------------------

    The schedule for completion of this review is governed by a consent
decree resolving a lawsuit filed in March 2003 by a group of plaintiffs
representing national environmental and public health organizations,
alleging that EPA had failed to complete the current review within the
period provided by statute.\6\ The modified consent decree that governs
this review, entered by the court on December 16, 2004, provides that
EPA sign for publication notices of proposed and final rulemaking
concerning its review of the O3 NAAQS no later than March
28, 2007 and December 19, 2007, respectively. This consent decree was
further modified in October 2006 to change these proposed and final
rulemaking dates to no later than May 30, 2007 and February 20, 2008,
respectively. These dates for signing the publication notices of
proposed and final rulemaking were further extended to no later than
June 20, 2007 and March 12, 2008, respectively.
---------------------------------------------------------------------------

    \6\ American Lung Association v. Whitman (No. 1:03CV00778,
D.D.C. 2003).
---------------------------------------------------------------------------

    This action presents the Administrator's proposed decisions on the
review of the current primary and secondary O3 standards.
Throughout this preamble a number of conclusions, findings, and
determinations proposed by the Administrator are noted. While

they identify the reasoning that supports this proposal, they are not
intended to be final or conclusive in nature. The EPA invites general,
specific, and/or technical comments on all issues involved with this
proposal, including all such proposed judgments, conclusions, findings,
and determinations.

II. Rationale for Proposed Decision on the Primary Standard

    This section presents the rationale for the Administrator's
proposed decision to revise the existing 8-hour O3 primary
standard by lowering the level of the standard to within a range from
0.070 to 0.075 ppm, and to specify the standard to the nearest
thousandth ppm (i.e., to the nearest parts per billion). As discussed
more fully below, this rationale is based on a thorough review, in the
Criteria Document, of the latest scientific information on human health
effects associated with the presence of O3 in the ambient
air. This rationale also takes into account and is consistent with: (1)
Staff assessments of the most policy-relevant information in the
Criteria Document and staff analyses of air quality, human exposure,
and health risks, presented in the Staff Paper, upon which staff
recommendations for revisions to the primary O3 standard are
based; (2) CASAC advice and recommendations, as reflected in
discussions of drafts of the Criteria Document and Staff Paper at
public meetings, in separate written comments, and in CASAC's letters
to the Administrator; and (3) public comments received during the
development of these documents, either in connection with CASAC
meetings or separately.
    In developing this rationale, EPA has drawn upon an integrative
synthesis of the entire body of evidence, published through early 2006,
on human health effects associated with the presence of O3
in the ambient air. As discussed below in section II.A, this body of
evidence addresses a broad range of health endpoints associated with
exposure to ambient levels of O3 (EPA, 2006a, chapter 8),
and includes over one hundred epidemiologic studies conducted in the
U.S., Canada, and many countries around the world.\7\ In considering
this evidence, EPA focuses on those health endpoints that have been
demonstrated to be caused by exposure to O3, or for which
the Criteria Document judges associations with O3 to be
causal, likely causal, or for which the evidence is highly suggestive
that O3 contributes to the reported effects. This rationale
also draws upon the results of quantitative exposure and risk
assessments, discussed below in section II.B. Evidence- and exposure/
risk-based considerations that form the basis for the Administrator's
proposed decisions on the adequacy of the current standard and on the
elements of the range of proposed alternative standards are discussed
below in sections II.C and II.D, respectively.
---------------------------------------------------------------------------

    \7\ In its assessment of the epidemiological evidence judged to
be most relevant to making decisions on the level of the
O3 primary standard, EPA has placed greater weight on
U.S. and Canadian epidemiologic studies, since studies conducted in
other countries may well reflect different demographic and air
pollution characteristics.
---------------------------------------------------------------------------

    Judgments made in the Criteria Document and Staff Paper about the
extent to which relationships between various health endpoints and
short-term exposures to ambient O3 are likely causal have
been informed by several factors. As discussed below in section II.A,
these factors include the nature of the evidence (i.e., controlled
human exposure, epidemiological, and/or toxicological studies) and the
weight of evidence, which takes into account such considerations as
biological plausibility, coherence of evidence, strength of
association, and consistency of evidence.
    In assessing the health effects data base for O3, it is
clear that human studies provide the most directly applicable
information for determining causality because they are not limited by
the uncertainties of dosimetry differences and species sensitivity
differences, which would need to be addressed in extrapolating animal
toxicology data to human health effects. Controlled human exposure
studies provide data with the highest level of confidence since they
provide human effects data under closely monitored conditions and can
provide exposure-response relationships. Epidemiological data provide
evidence of associations between ambient O3 levels and more
serious acute and chronic health effects (e.g., hospital admissions and
mortality) that cannot be assessed in controlled human exposure
studies. For these studies the degree of uncertainty introduced by
confounding variables (e.g., other pollutants, temperature) and other
factors affects the level of confidence that the health effects being
investigated are attributable to O3 exposures, alone and in
combination with other copollutants.
    In using a weight of evidence approach to inform judgments about
the degree of confidence that various health effects are likely to be
caused by exposure to O3, confidence increases as the number
of studies consistently reporting a particular health endpoint grows
and as other factors, such as biological plausibility and strength,
consistency, and coherence of evidence, increase. Conclusions regarding
biological plausibility, consistency, and coherence of evidence of
O3-related health effects are drawn from the integration of
epidemiological studies with mechanistic information from controlled
human exposure studies and animal toxicological studies. As discussed
below, this type of mechanistic linkage has been firmly established for
several respiratory endpoints (e.g., lung function decrements, lung
inflammation) but remains far more equivocal for cardiovascular
endpoints (e.g., cardiovascular-related hospital admissions). For
epidemiological studies, strength of association refers to the
magnitude of the association and its statistical strength, which
includes assessment of both effects estimate size and precision. In
general, when associations yield large relative risk estimates, it is
less likely that the association could be completely accounted for by a
potential confounder or some other bias. Consistency refers to the
persistent finding of an association between exposure and outcome in
multiple studies of adequate power in different persons, places,
circumstances and times. For example, the magnitude of effect estimates
is relatively consistent across recent studies showing association
between short-term, but not long-term, O3 exposure and
mortality.
    Based on the information discussed below in sections II.A.1-II.A.3,
judgments concerning the extent to which relationships between various
health endpoints and ambient O3 exposures are likely causal
are summarized below in section II.A.3.c. These judgments reflect the
nature of the evidence and the overall weight of the evidence, and are
taken into consideration in the quantitative exposure and risk
assessments, discussed below in Section II.B.
    To put judgments about health effects that have been demonstrated
to be caused by exposure to O3, or for which the Criteria
Document judges associations with O3 to be causal, likely
causal, or for which the evidence is highly suggestive that
O3 contributes to the reported effects into a broader public
health context, EPA has drawn upon the results of the quantitative
exposure and risk assessments. These assessments provide estimates of
the likelihood that individuals in particular population groups that
are at risk for various O3-related physiological health
effects would experience ``exposures of concern'' and specific health
endpoints

under varying air quality scenarios (e.g., just meeting the current or
alternative standards), as well as characterizations of the kind and
degree of uncertainties inherent in such estimates.
    In this review, the term ``exposures of concern'' is defined as
personal exposures while at moderate or greater exertion to 8-hour
average ambient O3 levels at and above specific benchmark
levels which represent exposure levels at which O3-related
health effects are known or can reasonably be inferred to occur in some
individuals, as discussed below in section II.B.1.\8\ EPA emphasizes
that although the analysis of ``exposures of concern'' was conducted
using three discrete benchmark levels (i.e., 0.080, 0.070, and 0.060
ppm), the concept is more appropriately viewed as a continuum with
greater confidence and less uncertainty about the existence of health
effects at the upper end and less confidence and greater uncertainty as
one considers increasingly lower O3 exposure levels. EPA
recognizes that there is no sharp breakpoint within the continuum
ranging from at and above 0.080 ppm down to 0.060 ppm. In considering
the concept of exposures of concern, it is important to balance
concerns about the potential for health effects and their severity with
the increasing uncertainty associated with our understanding of the
likelihood of such effects at lower O3 levels.
---------------------------------------------------------------------------

    \8\ Exposures of concern were also considered in the last review
of the O3 NAAQS, and were judged by EPA to be an
important indicator of the public health impacts of those
O3-related effects for which information was too limited
to develop quantitative estimates of risk but which had been
observed in humans at and above the benchmark level of 0.08 ppm for
6-to 8-hour exposures * * * including increased nonspecific
bronchial responsiveness (for example, aggravation of asthma),
decreased pulmonary defense mechanisms (suggestive of increased
susceptibility to respiratory infection), and indicators of
pulmonary inflammation (related to potential aggravation of chronic
bronchitis or long-term damage to the lungs). (62 FR 38868)
---------------------------------------------------------------------------

    Within the context of this continuum, estimates of exposures of
concern at discrete benchmark levels provide some perspective on the
public health impacts of O3-related health effects that have
been demonstrated in human clinical and toxicological studies but
cannot be evaluated in quantitative risk assessments, such as lung
inflammation, increased airway responsiveness, and changes in host
defenses. They also help in understanding the extent to which such
impacts have the potential to be reduced by meeting the current and
alternative standards. These O3-related physiological
effects are plausibly linked to the increased morbidity seen in
epidemiological studies (e.g., as indicated by increased medication use
in asthmatics, school absences in all children, and emergency
department visits and hospital admissions in people with lung disease).
Estimates of the number of people likely to experience exposures of
concern cannot be directly translated into quantitative estimates of
the number of people likely to experience specific health effects,
since sufficient information to draw such comparisons is not
available--if such information were available, these health outcomes
would have been included in the quantitative risk assessment. Due to
individual variability in responsiveness, only a subset of individuals
who have exposures at and above a specific benchmark level can be
expected to experience such adverse health effects, and susceptible
subpopulations such as those with asthma are expected to be affected
more by such exposures than healthy individuals. The amount of weight
to place on the estimates of exposures of concern at any of these
benchmark levels depends in part on the weight of the scientific
evidence concerning health effects associated with O3
exposures at and above that benchmark level. It also depends on
judgments about the importance from a public health perspective of the
health effects that are known or can reasonably be inferred to occur as
a result of exposures at and above the benchmark level. Such public
health policy judgments are embodied in the NAAQS standard setting
criteria (i.e., standards that, in the judgment of the Administrator,
are requisite to protect public health with an adequate margin of
safety).
    As discussed below in section II.B.2, the quantitative health risk
assessment conducted as part of this review includes estimates of risks
of lung function decrements in asthmatic and all school age children,
respiratory symptoms in asthmatic children, respiratory-related
hospital admissions, and non-accidental and cardiorespiratory-related
mortality associated with recent ambient O3 levels, as well
as risk reductions and remaining risks associated with just meeting the
current and various alternative O3 standards in a number of
example urban areas. There were two parts to this risk assessment: one
part was based on combining information from controlled human exposure
studies with modeled population exposure, and the other part was based
on combining information from community epidemiological studies with
either monitored or adjusted ambient concentrations levels. This
assessment not only provided estimates of the potential magnitude of
O3-related health effects, as well as a characterization of
the uncertainties and variability inherent in such estimates. This
assessment also provided insights into the distribution of risks and
patterns of risk reductions associated with meeting alternative
O3 standards.
    As discussed below, a substantial amount of new research has been
conducted since the last review of the O3 NAAQS, with
important new information coming from epidemiologic studies as well as
from controlled human exposure, toxicological, and dosimetric studies.
The newly available research studies evaluated in the Criteria Document
and the exposure and risk assessments presented in the Staff Paper have
undergone intensive scrutiny through multiple layers of peer review and
many opportunities for public review and comment. While important
uncertainties remain in the qualitative and quantitative
characterizations of health effects attributable to exposure to ambient
O3, the review of this information has been extensive and
deliberate. In the judgment of the Administrator, this intensive
evaluation of the scientific evidence has provided an adequate basis
for regulatory decision making. This review also provides important
input to EPA's research plan for improving our future understanding of
the effects of ambient O3 at lower levels, especially in at-
risk population groups.

A. Health Effects Information

    This section outlines key information contained in the Criteria
Document (chapters 4-8) and in the Staff Paper (chapter 3) on known or
potential effects on public health which may be expected from the
presence of O3 in ambient air. The information highlighted
here summarizes: (1) New information available on potential mechanisms
for health effects associated with exposure to O3; (2) the
nature of effects that have been associated directly with exposure to
O3 and indirectly with the presence of O3 in
ambient air; (3) an integrative interpretation of the evidence,
focusing on the biological plausibility and coherence of the evidence;
and (4) considerations in characterizing the public health impact of
O3, including the identification of ``at risk''
subpopulations.
    The decision in the last review focused primarily on evidence from
short-term (e.g., 1 to 3 hours) and prolonged ( 6 to 8 hours)
controlled-exposure studies reporting lung function decrements,
respiratory symptoms, and respiratory inflammation in humans, as well
as epidemiology studies reporting excess

hospital admissions and emergency department (ED) visits for
respiratory causes. The Criteria Document prepared for this review
emphasizes a large number of epidemiological studies published since
the last review with these and additional health endpoints, including
the effects of acute (short-term and prolonged) and chronic exposures
to O3 on lung function decrements and enhanced respiratory
symptoms in asthmatic individuals, school absences, and premature
mortality. It also emphasizes important new information from
toxicology, dosimetry, and controlled human exposure studies.
Highlights of the evidence include:
    (1) Two new controlled human-exposure studies are now available
that examine respiratory effects associated with prolonged
O3 exposures at levels below 0.080 ppm, which was the lowest
exposure level that had been examined in the last review.
    (2) Numerous controlled human-exposure studies have examined
indicators of O3-induced inflammatory response in both the
upper respiratory tract (URT) and lower respiratory tract (LRT), while
other studies have examined changes in host defense capability
following O3 exposure of healthy young adults and increased
airway responsiveness to allergens in subjects with allergic asthma and
allergic rhinitis exposed to O3.
    (3) Animal toxicology studies provide new information regarding
mechanisms of action, increased susceptibility to respiratory
infection, and the biological plausibility of acute effects and
chronic, irreversible respiratory damage.
    (4) Numerous acute exposure epidemiological studies published
during the past decade offer added evidence of ambient O3-
related lung function decrements and respiratory symptoms in physically
active healthy subjects and asthmatic subjects, as well as evidence on
new health endpoints, such as the relationships between ambient
O3 concentrations and school absenteeism and between ambient
O3 and cardiac-related physiological endpoints.
    (5) Several additional studies have been published over the last
decade examining the temporal associations between O3
exposures and emergency department visits for respiratory diseases and
on respiratory-related hospital admissions.
    (6) A large number of newly available epidemiological studies have
examined the effects of acute exposure to PM and O3 on
mortality, notably including large multicity studies that provide much
more robust and credible information than was available in the last
review, as well as recent meta-analyses that have evaluated potential
sources of heterogeneity in O3-mortality associations.
1. Overview of Mechanisms
    Evidence on possible mechanisms by which exposure to O3
may result in acute and chronic health effects is discussed in chapters
5 and 6 of the Criteria Document.\9\ Evidence from dosimetry,
toxicology, and human exposure studies has contributed to an
understanding of the mechanisms that help to explain the biological
plausibility and coherence of evidence for O3-induced
respiratory health effects reported in epidemiological studies. More
detailed information about the physiological mechanisms related to the
respiratory effects of short- and long-term exposure to O3
can be found in section II.A.3.b.i and II.A.3.b.iii, respectively. In
the past, however, little information was available to help explain
potential biological mechanisms which linked O3 exposure to
premature mortality or cardiovascular effects. As discussed more fully
in section II.A.3.b.ii below, since the last review an emerging body of
animal toxicology and human clinical evidence is beginning to suggest
mechanisms that may mediate acute O3 cardiovascular effects.
While much is known about mechanisms that play a role in O3-
related respiratory effects, additional research is needed to more
clearly understand the role that O3 may have in contributing
to cardiovascular effects.
---------------------------------------------------------------------------

    \9\ While most of the available evidence addresses mechanisms
for O3, O3 clearly serves as an indicator for
the total photochemical oxidant mixture found in the ambient air.
Some effects may be caused by one or more components in the overall
pollutant mix, either separately or in combination with
O3.
---------------------------------------------------------------------------

    With regard to the mechanisms related to short-term respiratory
effects, scientific evidence discussed in the Criteria Document
(section 5.2) indicates that reactions of O3 with lipids and
antioxidants in the epithelial lining fluid and the epithelial cell
membranes of the lung can be the initial step in mediating deleterious
health effects of O3. This initial step activates a cascade
of events that lead to oxidative stress, injury, inflammation, airway
epithelial damage and increased alveolar permeability to vascular
fluids. Inflammation can be accompanied by increased airway
responsiveness, which is an increased bronchoconstrictive response to
airway irritants and allergens. Continued respiratory inflammation also
can alter the ability to respond to infectious agents, allergens and
toxins. Acute inflammatory responses to O3 in some healthy
people are well documented, and precursors to lung injury can become
apparent within 3 hours after exposure in humans. Repeated respiratory
inflammation can lead to a chronic inflammatory state with altered lung
structure and lung function and may lead to chronic respiratory
diseases such as fibrosis and emphysema (EPA, 2006a, section 8.6.2).
The severity of symptoms and magnitude of response to acute exposures
depend on inhaled dose, as well as individual susceptibility to
O3, as discussed below. At the same O3 dose,
individuals who are more susceptible to O3 will have a
larger response than those who are less susceptible; among individuals
with similar susceptibility, those who receive a larger dose will have
a larger response to O3.
    The inhaled dose is the product of O3 concentration (C),
minute ventilation or ventilation rate, and duration of exposure (T),
or (C x ventilation rate x T). A large body of data regarding the
interdependent effect of these components of inhaled dose on pulmonary
responses was assessed in the 1986 and 1996 O3 Criteria
Documents. In an attempt to describe O3 dose-response
characteristics, acute responses were modeled as a function of total
inhaled O3 dose which was generally found to be a better
predictor of response than O3 concentration, ventilation
rate, or duration of exposure, alone, or as a combination of any two of
these factors (EPA 2006a, section 6.2). Predicted O3-induced
decrements in lung function have been shown to be a function of
exposure concentration, duration and exercise level for healthy, young
adults (McDonnell et al., 1997). A meta-analysis of 21 studies (Mudway
and Kelly, 2004) showed that markers of inflammation and increased
cellular permeability in healthy subjects are associated with total
O3 dose.
    The Criteria Document summarizes information on potentially
susceptible and vulnerable groups in section 8.7. As described there,
the term susceptibility refers to innate (e.g., genetic or
developmental) or acquired (e.g., personal risk factors, age) factors
that make individuals more likely to experience effects with exposure
to pollutants. A number of population groups have been identified as
potentially susceptible to health effects as a result of O3
exposure, including people with existing lung diseases, including
asthma, children and older adults, and people who have larger than
normal lung function responses that may be due to genetic
susceptibility. In addition, some population groups have been
identified as having increased

vulnerability to O3-related effects due to increased
likelihood of exposure while at elevated ventilation rates, including
healthy children and adults who are active outdoors, for example,
outdoor workers, and joggers. Taken together, the susceptible and
vulnerable groups are more commonly referred to as ``at-risk'' groups
\10\, as discussed more fully below in section II.A.4.b.
---------------------------------------------------------------------------

    \10\ In previous Staff Papers and Federal Register notices
announcing proposed and final decisions on the O3 and
other NAAQS, EPA has used the phrase ``sensitive population groups''
to include both population groups that are at increased risk because
they are more susceptible and population groups that are at
increased risk due to increased vulnerability or exposure. In this
notice, we use the phrase, ``at risk'' populations to include both
types of population groups.
---------------------------------------------------------------------------

    Based on new evidence from animal, human clinical and
epidemiological studies the Criteria Document concludes that people
with preexisting pulmonary disease are likely to be among those at
increased risk from O3 exposure. Altered physiological,
morphological and biochemical states typical of respiratory diseases
like asthma, COPD and chronic bronchitis may render people sensitive to
additional oxidative burden induced by O3 exposure (EPA
2006a, section 8.7). Children and adults with asthma are the group that
has been studied most extensively. Evidence from controlled human
exposure studies indicates that asthmatics may exhibit larger lung
function decrements in response to O3 exposure than healthy
controls. As discussed more fully in section II.A.4.b.ii below,
asthmatics present a differential response profile for cellular,
molecular, and biochemical parameters (CD, Figure 8-1) that are altered
in response to acute O3 exposure. They can have larger
inflammatory responses, as manifested by larger increases in markers of
inflammation such as white bloods cells (e.g., PMNs) or inflammatory
cytokines. Asthmatics, and people with allergic rhinitis, are more
likely to mount an allergic-type response upon exposure to
O3, as manifested by increases in white blood cells
associated with allergy (i.e., eosinophils) and related molecules,
which increase inflammation in the airways. The increased inflammatory
and allergic responses also may be associated with the larger late-
phase responses that asthmatics can experience, which can include
increased bronchoconstrictor responses to irritant substances or
allergens and additional inflammation. These more serious responses in
asthmatics and others with lung disease provide biological plausibility
for the respiratory morbidity effects observed in epidemiological
studies.
    Children with and without asthma were found to be particularly
susceptible to O3 effects on lung function and generally
have greater lung function responses than older people. The American
Academy of Pediatrics (2004) notes that children and infants are among
the population groups most susceptible to many air pollutants,
including O3. This is in part because their lungs are still
developing. For example, eighty percent of alveoli are formed after
birth, and changes in lung development continue through adolescence
(Dietert et al., 2000). Moreover, children have high minute ventilation
rates and relatively high levels of physical activity which also
increases their O3 dose (Plunkett et al., 1992). Thus,
children are at risk due to both their susceptibility and
vulnerability.
    Looking more broadly at age-related differences in susceptibility,
several mortality studies have investigated age-related differences in
O3 effects (EPA, 2006a, section <IP_ADDRESS>), primarily in the
older adult population. Among the studies that observed positive
associations between O3 and mortality, a comparison of all
age or younger age (65 years of age) O3-mortality effect
estimates to that of the elderly population (>65 years) indicates that,
in general, the elderly population is more susceptible to O3
mortality effects. There is supporting evidence of age-related
differences in susceptibility to O3 lung function effects.
The Criteria Document concludes that the elderly population (>65 years
of age) appears to be at greater risk of O3-related
mortality and hospitalizations compared to all ages or younger
populations, and children (< 18 years of age) experience other
potentially adverse respiratory health outcomes with increased
O3 exposure (EPA, 2006a, section <IP_ADDRESS>).
    Controlled human exposure studies have also indicated a high degree
of interindividual variability in some of the pulmonary physiological
parameters, such as lung function decrements. The variable effects in
individuals have been found to be reproducible, in other words, a
person who has a large lung function response after exposure to
O3 will likely have about the same response if exposed again
to the same dose of O3 (EPA 2006a, p. 6-2). In human
clinical studies, group mean responses are not representative of this
segment of the population that has much larger than average responses
to O3. Recent studies, discussed in section II.A.4.iv below,
reported a role for genetic polymorphism (i.e., the occurrence together
in the same population of more than one allele or genetic marker at the
same locus with the least frequent allele or marker occurring more
frequently than can be accounted for by mutation alone) in observed
differences in antioxidant enzymes and genes involved in inflammation
to modulate pulmonary function and inflammatory responses to
O3 exposure. These observations suggest a potential role for
these markers in the innate susceptibility to O3, however,
the validity of these markers and their relevance in the context of
prediction to population studies needs additional experimentation.
    Clinical studies that provide information about mechanisms of the
initial response to O3 (e.g., lung function decrements,
inflammation, and injury to the lung) also inform the selection of
appropriate lag times to analyze in epidemiological studies through
elucidation of the time course of these responses (EPA 2006a, section
8.4.3). Based on the results of these studies, it would be reasonable
to expect that lung function decrements could be detected
epidemiologically within lags of 0 (same day) or 1 to 2 days following
O3 exposure, given the rapid onset of lung function changes
and their persistence for 24 to 48 hours among more responsive human
subjects in clinical studies. Other responses take longer to develop
and can persist for longer periods of time. For example, although
asthmatic individuals may begin to experience symptoms soon after
O3 exposure, it may take anywhere from 1 to 3 days after
exposure for these subjects to seek medical attention as a result of
increased airway responsiveness or inflammation that may persist for 2
to 3 days. This may be reflected by epidemiologic observations of
significantly increased risk for asthma-related emergency department
visits or hospital admissions with 1- to 3-day lags, or, perhaps,
enhanced distributed lag risks (combined across 3 days) for such
morbidity indicators. Analogously, one might project increased
mortality within 0 to 3 day lags as a possible consequence of
O3-induced increases in clotting agents arising from the
cascade of events, starting with cell injury described above, occurring
within 12 to 24 hours of O3 exposure. The time course for
many of these initial responses to O3 is highly variable.
Moreover these observations pertain only to the initial response to
O3. Consequent responses can follow. For example,
J[ouml]rres et al., (1996) found that in subjects with

asthma and allergic rhinitis, a maximum percent fall in FEV1
of 27.9% and 7.8%, respectively, occurred 3 days after O3
exposure when they were challenged with the highest common dose of
allergen.
2. Nature of Effects
    The Criteria Document provides new evidence that notably enhances
our understanding of short-term and prolonged exposure effects,
including effects on lung function, symptoms, and inflammatory effects
reported in controlled exposure studies. These studies support and
extend the findings of the previous Criteria Document. There is also a
significant body of new epidemiological evidence of associations
between short-term and prolonged exposure to O3 and effects
such as premature mortality, hospital admissions and emergency
department visits for respiratory (e.g., asthma) causes. Key
epidemiological and controlled human exposure studies are summarized
below and discussed in chapter 3 of the Staff Paper, which is based on
scientific evidence critically reviewed in chapters 5, 6, and 7 of the
Criteria Document, as well as the Criteria Document's integration of
scientific evidence contained in chapter 8.\11\ Conclusions drawn about
O3-related health effects are based upon the full body of
evidence from controlled human exposure, epidemiological and
toxicological data contained in the Criteria Document.
---------------------------------------------------------------------------

    \11\ Health effects discussions are also drawn from the more
detailed information and tables presented in the Criteria Document's
annexes.
---------------------------------------------------------------------------

a. Morbidity
    This section summarizes scientific information on the effects of
inhalation of O3, including public health effects of short-
term, prolonged, and long-term exposures on respiratory morbidity and
cardiovascular system effects, as discussed in chapters 6, 7 and 8 of
the Criteria Document and chapter 3 of the Staff Paper. This section
also summarizes the uncertainty about the potential indirect effects on
public health associated with changes due to increases in UV-B
radiation exposure, such as UV-B radiation-related skin cancers, that
may be associated with reductions in ambient levels of ground-level
O3, as discussed in chapter 10 of the Criteria Document and
chapter 3 of the Staff Paper.
i. Effects on the Respiratory System From Short-Term and Prolonged
O3 Exposures
    Controlled human exposure studies have shown that O3
induces a variety of health effects, including: lung function
decrements, respiratory symptoms, increased airway responsiveness,
respiratory inflammation and permeability, increased susceptibility to
respiratory infection, and acute morphological effects. Epidemiology
studies have reported associations between O3 exposures
(i.e., 1-hour, 8-hour and 24-hour) and a wide range of respiratory-
related health effects including: Pulmonary function decrements;
respiratory symptoms; increased asthma medication use; increased school
absences; increased emergency department visits and hospital
admissions.
(a) Pulmonary Function Decrements, Respiratory Symptoms, and Asthma
Medication Use
(i) Results From Controlled Human Exposure Studies
    A large number of studies published prior to 1996 that investigated
short-term O3 exposure health effects on the respiratory
system from short-term O3 exposures were reviewed in the
1986 and 1996 Criteria Documents (EPA, 1986, 1996). In the last review,
0.50 ppm was the lowest O3 concentration at which
statistically significant reductions in forced vital capacity (FVC) and
forced expiratory volume in 1 second (FEV1) were reported in
sedentary subjects. During exercise, spirometric (lung function) and
symptomatic responses were observed at much lower O3
exposures. When minute ventilation was considerably increased by
continuous exercise (CE) during O3 exposures lasting 2 hour
or less at >= 0.12 ppm, healthy subjects generally experienced
decreases in FEV1, FVC, and other measures of lung function;
increases in specific airway resistance (sRaw), breathing frequency,
and airway responsiveness; and symptoms such as cough, pain on deep
inspiration, shortness of breath, throat irritation, and wheezing. When
exposures were increased to 4 to 8 hours in duration, statistically
significant lung function and symptom responses were reported at
O3 concentrations as low as 0.08 ppm and at lower minute
ventilation (i.e., moderate rather than high level exercise) than the
shorter duration studies.
    The most important observations drawn from studies reviewed in the
1996 Criteria Document were that: (1) Young healthy adults exposed to
O3 concentrations >= 0.080 ppm develop significant,
reversible, transient decrements in pulmonary function if minute
ventilation or duration of exposure is increased sufficiently; (2)
children experience similar lung function responses but report lesser
symptoms from O3 exposure relative to young adults; (3)
O3-induced lung function responses are decreased in the
elderly relative to young adults; (4) there is a large degree of
intersubject variability in physiological and symptomatic responses to
O3, but responses tend to be reproducible within a given
individual over a period of several months; (5) subjects exposed
repeatedly to O3 for several days show an attenuation of
response upon successive exposures, but this attenuation is lost after
about a week without exposure; and (6) acute O3 exposure
initiates an inflammatory response which may persist for at least 18 to
24 hours post exposure.
    The development of these respiratory effects is time-dependent
during both exposure and recovery periods, with great overlap for
development and disappearance of the effects. In healthy human subjects
exposed to typical ambient O3 levels near 0.120 ppm, lung
function responses largely resolve within 4 to 6 hours post-exposure,
but cellular effects persist for about 24 hours. In these healthy
subjects, small residual lung function effects are almost completely
gone within 24 hours, while in hyperresponsive subjects, recovery can
take as much as 48 hours to return to baseline. The majority of these
responses are attenuated after repeated consecutive exposures, but such
attenuation to O3 is lost one week post-exposure.
    Since 1996, there have been a number of studies published
investigating lung function and symptomatic responses that generally
support the observations previously drawn. Recent studies for acute
exposures of 1 to 2 hours and 6 to 8 hours in duration are compiled in
the Staff Paper (Appendix 3C). As summarized in more detail in the
Staff Paper (section <IP_ADDRESS>), among the more important of the recent
studies that examined changes in FEV1 in large numbers of
subjects over a range of 1-2 hours at exposure levels of 0.080 to 0.40
ppm were studies by McDonnell et al. (1997) and Ultman et al. (2004).
These studies observed considerable intersubject variability in
FEV1 decrements, which was consistent with findings in the
1996 Criteria Document.
    For prolonged exposures (4 to 8 hours) in the range of 0.080 to
0.160 ppm O3 using moderate intermittent exercise and
typically using square-

wave exposure patterns (i.e., a constant exposure level during time of
exposure), several pre- and post-1996 studies (Folinsbee et al., 1988,
1994; Horstman et al., 1990; Adams, 2002, 2003a, 2006) have reported
statistically significant lung function responses and increased
symptoms in healthy adults with increasing duration of exposure,
O3 concentration, and minute ventilation. Studies that
employed triangular exposure patterns (i.e., integrated exposures that
begin at a low level, rise to a peak, and return to a low level during
the exposure) (Hazucha et al., 1992; Adams 2003a, 2006) suggest that
the triangular exposure pattern can potentially lead to greater
FEV1 decrements and respiratory symptoms than square-wave
exposures (when the overall O3 doses are equal). These
results suggest that peak exposures, reflective of the pattern of
ambient O3 concentrations in some locations, are important
in terms of O3 toxicology.
    McDonnell (1996) used data from a series of studies to investigate
the frequency distributions of FEV1 decrements following 6.6
hour exposures and found statistically significant but relatively small
group mean decreases in average FEV1 responses (between 5
and 10 percent) at 0.080 ppm O3.\12\ Notably, about 26
percent of the 60 exposed subjects had lung function decrements >10
percent, including about 8 percent of the subjects that experienced
large decrements (>20 percent) (EPA, 2007, Figure 3-1A). These results
(which were not corrected for exercise in filtered air responses)
demonstrate that while average responses may be relatively small at the
0.080 ppm exposure level, some individuals experience more severe
effects that may be clinically significant. Similar results at the
0.080 ppm exposure level (for 6.6 hours during intermittent exercise)
were seen in more recent studies of 30 healthy young adults by Adams
(2002, 2006).\13\ In these studies, relatively small but statistically
significant lung function decrements and respiratory symptom responses
were found (for both square-wave and triangular exposure patterns),
with 17 percent of the subjects (5 of 30) experiencing >= 10 percent
FEV1 decrements (comparing pre- and post-exposures) when the
results were not corrected for the effects of exercise alone in
filtered air (EPA, 2007, Figure 3-1B) and with 23 percent of subjects
(7 of 30) experiencing such effects when the results were corrected
(EPA, 2007, p. 3-6).\14\
---------------------------------------------------------------------------

    \12\ This study and other studies (Folinsbee et al., 1988;
Horstman et al., 1990; and McDonnell et al., 1991), conducted in
EPA's clinical research facility in Chapel Hill, NC, measured ozone
concentrations to within +/-5 percent or +/-0.004 ppm at the 0.080
ppm exposure level.
    \13\ These studies, conducted at a facility at the University of
California, in Davis, CA, reported O3 concentrations to
be accurate within +/-0.003 ppm over the range of concentrations
included in these studies.
    \14\ These distributional results presented in the Criteria
Document and Staff Paper for the Adams studies are based on study
data that were not included in the publication but were obtained
from the author.
---------------------------------------------------------------------------

    These studies by Adams (2002, 2006) are notable in that they are
the only available controlled exposure human studies that examine
respiratory effects associated with prolonged O3 exposures
at levels below 0.080 ppm, which was the lowest exposure level that had
been examined in the last review. The Adams (2006) study investigated a
range of exposure levels (0.000, 0.040, 0.060, and 0.080 ppm
O3) using square-wave and triangular exposure patterns. The
study was designed to examine multiple comparisons of pulmonary
function (FEV1) and respiratory symptom responses (total
subjective symptoms (TSS) and pain on deep inspiration (PDI)) between
these various exposure protocols at six different time points within
the exposure periods. At the 0.060 ppm exposure level, the author
reported no statistically significant differences for FEV1
decrements nor for most respiratory symptoms responses; statistically
significant responses were reported only for TSS for the triangular
exposure pattern toward the end of the exposure period, with the PDI
responses being noted as following a closely similar pattern (Adams,
2006, p. 131-132). EPA's reanalysis of the data from the Adams (2006)
study, comparing FEV1 responses pre- and post-exposure at
the 0.060 ppm exposure level, found small group mean differences from
responses to filtered air that were statistically significant.\15\
Notably, these studies report a small percentage of subjects
experiencing lung function decrement (>= 10 percent) at the 0.060 ppm
exposure level.\16\
---------------------------------------------------------------------------

    \15\ Brown, J.S. (2007). EPA Office of Research and Development
memorandum to Ozone NAAQS Review Docket (OAR-2005-0172); Subject:
The effects of ozone on lung function at 0.06 ppm in healthy adults,
June 14, 2007.
    \16\ Based on study data (Adams, 2006) provided by the author, 7
percent of the subjects (2 of 30 subjects) experienced notable
FEV1 decrements >= 10 percent) with the square wave
exposure pattern at the 0.060 ppm exposure level (comparing pre- and
post-exposures) when the results were corrected for the effects of
exercise alone in filtered air (EPA, 2007, p. 3-6).
---------------------------------------------------------------------------

(ii) Results of Epidemiological and Field Studies
    A relatively large number of field studies investigating the
effects of ambient O3 concentrations, in combination with
other air pollutants, on lung function decrements and respiratory
symptoms have been published over the last decade that support the
major findings of the 1996 Criteria Document that lung function
changes, as measured by decrements in FEV1 or peak
expiratory flow (PEF), and respiratory symptoms in healthy adults and
asthmatic children are closely correlated to ambient O3
concentrations. Pre-1996 field studies focused primarily on children
attending summer camps and found O3-related impacts on
measures of lung function, but not respiratory symptoms, in healthy
children. The newer studies have expanded to evaluate O3-
related effects on outdoor workers, athletes, the elderly, hikers,
school children, and asthmatics. Collectively, these studies confirm
and extend clinical observations that prolonged (i.e., 6-8 hour)
exposure periods, combined with elevated levels of exertion or
exercise, increase the dose of O3 to the lungs at a given
ambient exposure level and result in larger lung function effects. The
results of one large study of hikers (Korrick et al., 1998), which
reported outcome measures stratified by several factors (e.g., gender,
age, smoking status, presence of asthma) within a population capable of
more than normal exertion, provide useful insight. In this study, lung
function was measured before and after hiking, and individual
O3 exposures were estimated by averaging hourly
O3 concentrations from ambient monitors located at the base
and summit. The mean 8-hour average O3 concentration was
0.040 ppm (8-hour average concentration range of 0.021 ppm to 0.074 ppm
O3). Decreased lung function was associated with
O3 exposure, with the greatest effect estimates reported for
the subgroup that reported having asthma or wheezing, and for those who
hiked for longer periods of time.
    Asthma panel studies conducted both in the U.S. and in other
countries have reported that decrements in PEF are associated with
routine O3 exposures among asthmatic and healthy persons.
One large U.S. multicity study, the National Cooperative Inner City
Asthma Study or NCICAS, (Mortimer et al., 2002) examined O3-
related changes in PEF in 846 asthmatic children from 8 urban areas and
reported that the incidence of >= 10 percent decrements in morning PEF
are associated with increases in 8-hour average O3 for a 5-
day cumulative lag, suggesting that O3 exposure may be
associated with clinically significant changes in PEF in

asthmatic children; however, no associations were reported with evening
PEF. The mean 8-hour average O3 was 0.048 ppm across the 8
cities. Excluding days when 8-hour average O3 was greater
than 0.080 ppm (less than 5 percent of days), the associations with
morning PEF remained statistically significant. Mortimer et al. (2002)
discussed potential biological mechanisms for delayed effects on
pulmonary function in asthma, which included increased nonspecific
airway responsiveness secondary to airway inflammation due to
O3 exposure. Two other panel studies (Romieu et al., 1996,
1997) carried out simultaneously in northern and southwestern Mexico
City with mildly asthmatic school children reported statistically
significant O3-related reductions in PEF, with variations in
effect depending on lag time and time of day. Mean 1-hour maximum
O3 concentrations in these locations ranged from 0.190 ppm
(SD 80) in northern Mexico City to 0.196 ppm (SD 78) in southwestern
Mexico City. While several studies report statistically significant
associations between O3 exposure and reduced PEF in
asthmatics, other studies did not, possibly due to low levels of
O3 exposure. EPA concludes that these studies collectively
indicate that O3 may be associated with short-term declines
in lung function in asthmatic individuals and that the Mortimer et al.
(2002) study showed statistically significant effect at concentrations
in the range below 0.080 ppm O3.
    Most of the panel studies which have investigated associations
between O3 exposure and respiratory symptoms or increased
use of asthma medication are focused on asthmatic children. Two large
U.S. studies (Mortimer et al., 2002; Gent et al., 2003) have reported
associations between ambient O3 concentrations and daily
symptoms/asthma medication use, even after adjustment for copollutants.
Results were more mixed, meaning that a greater proportion of studies
were not both positive and statistically significant, across smaller
U.S. and international studies that focused on these health endpoints.
    The NCICAS reported morning symptoms in 846 asthmatic children from
8 U.S. urban areas to be most strongly associated with a cumulative 1-
to 4-day lag of O3 concentrations (Mortimer et al., 2002).
The NCICAS used standard protocols that included instructing caretakers
of the subjects to record symptoms (including cough, chest tightness,
and wheeze) in the daily diary by observing or asking the child. While
these associations were not statistically significant in several
cities, when the individual data are pooled from all eight cities,
statistically significant effects were observed for the incidence of
symptoms. The authors also reported that the odds ratios remained
essentially the same and statistically significant for the incidence of
morning symptoms when days with 8-hour O3 concentrations
above 0.080 ppm were excluded. These days represented less than 5
percent of days in the study.
    Gent and colleagues (2003) followed 271 asthmatic children under
age 12 and living in southern New England for 6 months (April through
September) using a daily symptom diary. They found that mean 1-hour max
O3 and 8-hour max O3 concentrations were 0.0586
ppm (SD 19.0) and 0.0513 ppm (SD 15.5), respectively. The data were
analyzed for two separate groups of subjects, those who used
maintenance asthma medications during the follow-up period and those
who did not. The need for regular medication was considered to be a
proxy for more severe asthma. Not taking any medication on a regular
basis and not needing to use a bronchodilator would suggest the
presence of very mild asthma. Statistically significant effects of 1-
day lag O3 were observed on a variety of respiratory
symptoms only in the medication user group. Both daily 1-hour max and
8-hour max O3 concentrations were similarly related to
symptoms such as chest tightness and shortness of breath. Effects of
O3, but not PM2.5, remained significant and even
increased in magnitude in two-pollutant models. Some of the
associations were noted at 1-hour max O3 levels below 0.060
ppm. In contrast, no effects were observed among asthmatics not using
maintenance medication. In terms of person days of follow-up, this is
one of the larger studies currently available that address symptom
outcomes in relation to O3, and provides supportive evidence
for effects of O3 independent of PM2.5. Study
limitations include the post-hoc nature of the population
stratification by medication use. Also, the study did not account for
all of the important meteorological factors that might influence these
results, such as relative humidity or dew point.
    The multicity study by Mortimer et al. (2002), which provides an
asthmatic population representative of the United States, and several
single-city studies indicate a robust association of O3
concentrations with respiratory symptoms and increased medication use
in asthmatics. While there are a number of well-conducted, albeit
relatively smaller, U.S. studies which showed only limited or a lack of
evidence for symptom increases associated with O3 exposure,
these studies had less statistical power and/or were conducted in areas
with relatively low 1-hour maximum average O3 levels, in the
range of 0.03 to 0.09 ppm. Even so, the evidence has continued to
expand since 1996 and now is considered to be much stronger than in the
previous review. The Criteria Document concludes that the asthma panel
studies, as a group, and the NCICAS in particular, indicate a positive
association between ambient concentrations and respiratory symptoms and
increased medication use in asthmatics. The evidence has continued to
expand since 1996 and now is considered to be much stronger than in the
previous review of the O3 primary standard.
    School absenteeism is another potential surrogate for the health
implications of O3 exposure in children. The association
between school absenteeism and ambient O3 concentrations was
assessed in two relatively large field studies. Chen et al. (2000)
examined total daily school absenteeism in about 28,000 elementary
school students in Nevada over a 2-year period (after adjusting for
PM10 and CO concentrations) and found that ambient
O3 concentrations with a distributed lag of 14 days were
statistically significantly associated with an increased rate of school
absences. Gilliland et al. (2001) studied O3-related
absences among about 2,000 4th grade students in 12 southern California
communities and found statistically significant associations between 8-
hour average O3 concentrations (with a distributed lag out
to 30 days) and all absence categories, and particularly for
respiratory causes. Neither PM10 nor NO2 were
associated with any respiratory or nonrespiratory illness-related
absences in single pollutant models. The Criteria Document concludes
that these studies of school absences suggest that ambient
O3 concentrations, accumulated over two to four weeks, may
be associated with school absenteeism, and particularly illness-related
absences, but further replication is needed before firm conclusions can
be reached regarding the effect of O3 on school absences. In
addition, more research is needed to help shed light on the
implications of variation in the duration of the lag structures (i.e.,
1 day, 5 days, 14 days, and 30 days) found both across studies and
within data sets by health endpoint and exposure metric.

(b) Increased Airway Responsiveness
    As discussed in more detail in the Criteria Document (section 6.8)
and Staff Paper (section <IP_ADDRESS>.2), increased airway responsiveness,
also known as airway hyperresponsiveness (AHR) or bronchial
hyperreactivity, refers to a condition in which the propensity for the
airways to bronchoconstrict due to a variety of stimuli (e.g., exposure
to cold air, allergens, or exercise) becomes augmented. This condition
is typically quantified by measuring the decrement in pulmonary
function after inhalation exposure to specific (e.g., antigen,
allergen) or nonspecific (e.g., methacholine, histamine)
bronchoconstrictor stimuli. Exposure to O3 causes an
increase in airway responsiveness as indicated by a reduction in the
concentration of stimuli required to produce a given reduction in
FEV1 or airway obstruction. Increased airway responsiveness
is an important consequence of exposure to O3 because its
presence means that the airways are predisposed to narrowing on
inhalation of various stimuli, such as specific allergens, cold air or
SO2. Statistically significant and clinically relevant
decreases in pulmonary function have been observed in early phase
allergen response in subjects with allergic rhinitis after consecutive
(4-day) 3-hour exposures to 0.125 ppm O3 (Holz et al.,
2002). Similar increased airway responsiveness in asthmatics to house
dust mite antigen 16 to 18 hours after exposure to a single dose of
O3 (0.160 ppm for 7.6 hours) was observed. These
observations, based on O3 exposures to levels much higher
than the current standard level suggest that O3 exposure may
be a clinically important factor that can exacerbate the response to
ambient bronchoconstrictor substances in individuals with preexisting
allergic asthma or rhinitis. Further, O3 may have an
immediate impact on the lung function of asthmatics as well as
contribute to effects that persist for longer periods.
    Kreit et al. (1989) found that O3 can induce increased
airway responsiveness in asthmatic subjects to O3, who
typically have increased airway responsiveness at baseline. A
subsequent study (J[ouml]rres et al., 1996) suggested an increase in
specific (i.e., allergen-induced) airway reactivity in subjects with
allergic asthma, and to a lesser extent in subjects with allergic
rhinitis after short-term exposure to higher O3 levels;
other studies reported similar results. According to one study
(Folinsbee and Hazucha, 2000), changes in airway responsiveness after
O3 exposure resolve more slowly than changes in
FEV1 or respiratory symptoms. Other studies of repeated
exposure to O3 suggest that changes in airway responsiveness
tend to be somewhat less affected by attenuation with consecutive
exposures than changes in FEV1 (EPA, 2006a, p. 6-31).
    The Criteria Document (section 6.8) concludes that O3
exposure is linked with increased airway responsiveness. Both human and
animal studies indicate that increased airway responsiveness is not
mechanistically associated with inflammation, and does not appear to be
strongly associated with initial decrements in lung function or
increases in symptoms. As a result of increased airway responsiveness
induced by O3 exposure, human airways may be more
susceptible to a variety of stimuli, including antigens, chemicals, and
particles. Because asthmatic subjects typically have increased airway
responsiveness at baseline, enhanced bronchial response to antigens in
asthmatics raises potential public health concerns as they could lead
to increased morbidity (e.g., medication usage, school absences,
emergency room visits, hospital admissions) or to more persistent
alterations in airway responsiveness (Criteria Document, p. 8-21). As
such, increased airway responsiveness after O3 exposure
represents a plausible link between O3 exposure and
increased hospital admissions.
(c) Respiratory Inflammation and Increased Permeability
    Based on evidence from the previous review, acute inflammatory
responses in the lung have been observed subsequent to 6.6 hour
O3 exposures to the lowest tested level--0.080 ppm--in
healthy adults engaged in moderately high exercise (section 6.9 of the
Criteria Document and section <IP_ADDRESS> of the Staff Paper). Some of
these prior studies suggest that inflammatory responses may be detected
in some individuals following O3 exposures in the absence of
O3-induced pulmonary decrements in those subjects. These
studies also demonstrate that short-term exposures to O3
also can cause increased permeability in the lungs of humans and
experimental animals. Inflammatory responses and epithelial
permeability have been seen to be independent of spirometric responses.
Not only are the newer lung inflammation and increased cellular
permeability findings discussed in the Criteria Document (pp. 8-21 to
8-24) consistent with the previous review, but they provide better
characterization of the physiological mechanisms by which O3
causes these effects.
    Lung inflammation and increased permeability, which are distinct
events controlled by different mechanisms, are two commonly observed
effects of O3 exposure observed in all of the species
studied. Increased cellular permeability is a disruption of the lung
barrier that leads to leakage of serum proteins, influx of
polymorphonuclear leukocytes (neutrophils or PMNs), release of
bioactive mediators, and movement of compounds from the airspaces into
the blood.
    A number of controlled human exposure studies have analyzed
bronchoalveolar lavage (BAL) and nasal lavage (NL)\17\ fluids and cells
for markers of inflammation and lung damage (EPA, 2006a, Annex AX6).
Increased lung inflammation is demonstrated by the presence of
neutrophils found in BAL fluid in the lungs, which has long been
accepted as a hallmark of inflammation. It is apparent, however, that
inflammation within airway tissues may persist beyond the point that
inflammatory cells are found in the BAL fluid. Soluble mediators of
inflammation, such as cytokines and arachidonic acid metabolites have
been measured in the BAL fluid of humans exposed to O3. In
addition to their role in inflammation, many of these compounds have
bronchoconstrictive properties and may be involved in increased airway
responsiveness following O3 exposure. An in vitro study of
epithelial cells from nonatopic and atopic asthmatics exposed to 0.010
to 0.100 ppm O3 showed significantly increased permeability
compared to cells from normal persons. This indicates a potentially
inherent susceptibility of cells from asthmatic individuals for
O3-induced permeability.
---------------------------------------------------------------------------

    \17\ Graham and Koren (1990) compared inflammatory mediators
present in NL and BAL fluids of humans exposed to 0.4 ppm
O3 for 2 hours and found similar increases in PMNs in
both fluids, suggesting a qualitative correlation between
inflammatory changes in the lower airways (BAL) and upper
respiratory tract (NL).
---------------------------------------------------------------------------

    In the 1996 Criteria Document, assessment of controlled human
exposure studies indicated that a single, acute (1 to 4 hours)
O3 exposure (>= 0.080 to 0.100 ppm) of subjects engaged in
moderate to heavy exercise could induce a number of cellular and
biochemical changes suggestive of pulmonary inflammation and lung
permeability (EPA, 2006a, p. 8-22). These changes persisted for at
least 18 hours. Markers from BAL fluid following both 2-hour and 4-hour
O3 exposures repeated up to 5 days indicate that there is
ongoing cellular damage irrespective of attenuation of

some cellular inflammatory responses of the airways, pulmonary
function, and symptom scores (EPA, 2006a, p. 8-22). Acute airway
inflammation was shown in Devlin et al. (1990) to occur among adults
exposed to 0.080 ppm O3 for 6.6 hours with exercise. McBride
et al. (1994) reported that asthmatic subjects were more sensitive than
non-asthmatics to upper airway inflammation for O3 exposures
that did not affect pulmonary function (EPA, 2006a, p. 6-33). However,
the public health significance of these changes is not entirely clear.
    The studies reporting inflammatory responses and markers of lung
injury have clearly demonstrated that there is significant variation in
response of subjects exposed, especially to 6.6 hours O3
exposures at 0.080 and 0.100 ppm. To provide some perspective on the
public health impact for these effects, the Staff Paper (section
<IP_ADDRESS>.3) notes that one study (Devlin et al., 1991) showed that
roughly 10 to 50 percent of the 18 young healthy adult subjects
experienced notable increases (i.e., >= 2 fold increase) in most of the
inflammatory and cellular injury indicators analyzed, associated with
6.6-hour exposures at 0.080 ppm. Similar, although in some cases
higher, fractions of the population of 10 healthy adults tested saw > 2
fold increases associated with 6.6-hour exposures to 0.100 ppm. The
authors of this study expressed the view that ``susceptible
subpopulations such as the very young, elderly, and people with
pulmonary impairment or disease may be even more affected'' (Devlin et
al., 1991).
    Since 1996, a substantial number of human exposure studies have
been published which have provided important new information on lung
inflammation and epithelial permeability. Mudway and Kelly (2004)
examined O3-induced inflammatory responses and epithelial
permeability with a meta-analysis of 21 controlled human exposure
studies and showed that an influx in neutrophils and protein in healthy
subjects is associated with total O3 dose (product of
O3 concentration, exposure duration, and minute ventilation)
(EPA, 2006a, p. 6-34). Results of the analysis suggest that the time
course for inflammatory responses (including recruitment of neutrophils
and other soluble mediators) is not clearly established, but there is
evidence that attenuation profiles for many of these parameters are
different (EPA, 2006a, p. 8-22).
    The Criteria Document (chapter 8) concludes that interaction of
O3 with lipid constituents of epithelial lining fluid (ELF)
and cell membranes and the induction of oxidative stress is implicated
in injury and inflammation. Alterations in the expression of cytokines,
chemokines, and adhesion molecules, indicative of an ongoing oxidative
stress response, as well as injury repair and regeneration processes,
have been reported in animal toxicology and human in vitro studies
evaluating biochemical mediators implicated in injury and inflammation.
While antioxidants in ELF confer some protection, O3
reactivity is not eliminated at environmentally relevant exposures
(Criteria Document, p. 8-24). Further, antioxidant reactivity with
O3 is both species-specific and dose-dependent.
(d) Increased Susceptibility to Respiratory Infection
    As discussed in more detail in the Criteria Document (sections
5.2.2, 6.9.6, and 8.4.2), short-term exposures to O3 have
been shown to impair physiological defense capabilities in experimental
animals by depressing alveolar macrophage (AM) functions and by
altering the mucociliary clearance of inhaled particles and microbes
resulting in increased susceptibility to respiratory infection. Short-
term O3 exposures also interfere with the clearance process
by accelerating clearance for low doses and slowing clearance for high
doses. Animal toxicological studies have reported that acute
O3 exposures suppress alveolar phagocytosis and immune
system functions. Dysfunction of host defenses and subsequent increased
susceptibility to bacterial lung infection in laboratory animals has
been induced by short-term exposures to O3 levels as low as
0.080 ppm.
    A single controlled human exposure study reviewed in the 1996
Criteria Document reported that exposure to 0.080 to 0.100 ppm
O3 for 6.6 hours (with moderate exercise) induced decrements
in the ability of AMs to phagocytose microorganisms (EPA, 2006a, p. 8-
26). Integrating the recent animal study results with human exposure
evidence available in the 1996 Criteria Document, the Criteria Document
concludes that available evidence indicates that short-term
O3 exposures have the potential to impair host defenses in
humans, primarily by interfering with AM function. Any impairment in AM
function may lead to decreased clearance of microorganisms or nonviable
particles. Compromised AM functions in asthmatics may increase their
susceptibility to other O3 effects, the effects of
particles, and respiratory infections (EPA, 2006a, p. 8-26).
(e) Morphological Effects
    The 1996 Criteria Document found that short-term O3
exposures cause similar alterations in lung morphology in all
laboratory animal species studied, including primates. As discussed in
the Staff Paper (section <IP_ADDRESS>.5), cells in the centriacinar region
(CAR) of the lung (the segment between the last conducting airway and
the gas exchange region) have been recognized as a primary target of
O3-induced damage (epithelial cell necrosis and remodeling
of respiratory bronchioles), possibly because epithelium in this region
receives the greatest dose of O3 delivered to the lower
respiratory tract. Following chronic O3 exposure, structural
changes have been observed in the CAR, the region typically affected in
most chronic airway diseases of the human lung (EPA, 2006a, p. 8-24).
    Ciliated cells in the nasal cavity and airways, as well as Type I
cells in the gas-exchange region, are also identified as targets. While
short-term O3 exposures can cause epithelial cell
proliferation and fibrolitic changes in the CAR, these changes appear
to be transient with recovery time after exposure, depending on species
and O3 dose. The potential impacts of repeated short-term
and chronic morphological effects of O3 exposure are
discussed below in the section on effects from long-term exposures.
Long-term or prolonged exposure has been found to cause chronic lesions
similar to early lesions of respiratory bronchiolitis, which have the
potential to progress to fibrotic lung disease (Criteria Document, p.
8-25).
    Recent studies continue to show that short-term and sub-chronic
exposures to O3 cause similar alterations in lung structure
in a variety of experimental animal species. For example, a series of
new studies that used infant rhesus monkeys and simulated seasonal
ambient exposure (0.5 ppm 8 hours/day for 5 days, every 14 days for 11
episodes) reported remodeling in the distal airways; abnormalities in
tracheal basement membrane; eosinophil accumulation in conducting
airways; and decrements in airway innervation (Criteria Document, p. 8-
25). Based on evidence from animal toxicological studies, short-term
and sub-chronic exposures to O3 can cause morphological
changes in the respiratory systems, particularly in the CAR, of a
number of laboratory animal species (EPA, 2006a, section 5.2.4).

(f) Emergency Department Visits/Hospital Admissions for Respiratory
Causes
    Increased summertime emergency department visits and hospital
admissions for respiratory causes have been associated with ambient
exposures to O3. As discussed in section <IP_ADDRESS>.6 of the
Staff Paper, numerous studies conducted in various locations in the
U.S. and Canada consistently have shown a relationship between ambient
O3 levels and increased incidence of emergency department
visits and hospital admissions for respiratory causes, even after
controlling for modifying factors, such as weather and copollutants.
Such associations between elevated ambient O3 during summer
months and increased hospital admissions have a plausible biological
basis in the human and animal evidence of functional, symptomatic, and
physiologic effects discussed above and in the increased susceptibility
to respiratory infections observed in laboratory animals.
    In the last review of the O3 NAAQS, the Criteria
Document evaluated emergency department visits and hospital admissions
as possible outcomes following exposure to O3 (EPA, 2006a,
section 7.3). The evidence was limited for emergency department visits,
but results of several studies generally indicated that short-term
exposures to O3 were associated with respiratory emergency
department visits. The strongest and most consistent evidence, at both
lower levels (i.e., below 0.120 ppm 1-hour max O3) and at
higher levels (above 0.120 ppm 1-hour max O3), was found in
the group of studies which investigated summertime\18\ daily hospital
admissions for respiratory causes in different eastern North American
cities. These studies consistently demonstrated that ambient
O3 levels were associated with increased hospital admissions
and accounted for about one to three excess respiratory hospital
admissions per million persons with each 0.100 ppm increase in 1-hour
max O3, after adjustment for possible confounding effects of
temperature and copollutants. Overall, the 1996 Criteria Document
concluded that there was strong evidence that ambient O3
exposures can cause significant exacerbations of preexisting
respiratory disease in the general public. Excess respiratory-related
hospital admissions associated with O3 exposures for the New
York City area (based on Thurston et al., 1992) were included in the
quantitative risk assessment in the prior review and are included in
the current assessment along with estimates for respiratory-related
hospital admissions in Cleveland, Detroit, and Los Angeles based on
more recent studies (Staff Paper, chapter 5). Significant uncertainties
and the difficulty of obtaining reliable baseline incidence numbers
resulted in emergency department visits not being used in the
quantitative risk assessment in either the last or the current
O3 NAAQS review.
---------------------------------------------------------------------------

    \18\ Discussion of the reasons for focusing on warm season
studies is found in the section 2.A.3.a below.
---------------------------------------------------------------------------

    In the past decade, a number of studies have examined the temporal
pattern associations between O3 exposures and emergency
department visits for respiratory causes (EPA, 2006a, section 7.3.2).
These studies are summarized in the Criteria Document (chapter 7 Annex)
and some are shown in Figure 1 (in section II.A.3). Respiratory causes
for emergency department visits include asthma, bronchitis, emphysema,
pneumonia, and other upper and lower respiratory infections, such as
influenza, but asthma visits typically dominate the daily incidence
counts. Most studies report positive associations. Among studies with
adequate controls for seasonal patterns, many reported at least one
significant positive association involving O3.
    In reviewing evidence for associations between emergency department
visits for asthma and short-term O3 exposures, the Criteria
Document notes that in general, O3 effect estimates from
summer only analyses tended to be positive and larger compared to
results from cool season or all year analyses (Figure 7-8, EPA, 2006a,
p. 7-68). Several of the studies reported significant associations
between O3 concentrations and emergency department visits
for respiratory causes, in particular asthma. However, inconsistencies
were observed which were at least partially attributable to differences
in model specifications and analysis approach among various studies.
For example, ambient O3 concentrations, length of the study
period, and statistical methods used to control confounding by seasonal
patterns and copollutants appear to affect the observed O3
effect on emergency department visits. Thus, the Criteria Document has
concluded that stratified analyses by season generally supported a
positive association between O3 concentrations and emergency
department visits for asthma in the warm season.
    Hospital admissions studies focus specifically on unscheduled
admissions because unscheduled hospital admissions occur in response to
unanticipated disease exacerbations and are more likely than scheduled
admissions to be affected by variations in environmental factors, such
as daily O3 levels. Results of a fairly large number of
these studies published during the past decade are summarized in
Criteria Document (chapter 7 Annex), and results of U.S. and Canadian
studies are shown in Figure 1 below (in section II.A.3). As a group,
these hospital admissions studies tend to be larger geographically and
temporally than the emergency department visit studies and provide
results that are generally more consistent. The strongest associations
of respiratory hospital admissions with O3 concentrations
were observed using short lag periods, in particular for a 0-day lag
(same day exposure) and a 1-day lag (previous day exposure). Most
studies in the United States and Canada indicated positive,
statistically significant associations between ambient O3
concentrations and respiratory hospital admissions in the warm season.
However, not all studies found a statistically significant relationship
with O3, possibly because of very low ambient O3
levels. Analyses for confounding using multipollutant regression models
suggest that copollutants generally do not confound the association
between O3 and respiratory hospitalizations. Ozone effect
estimates were robust to PM adjustment in all-year and warm-season only
data.
    Overall, the Criteria Document concludes that positive and robust
associations were found between ambient O3 concentrations
and various respiratory disease hospitalization outcomes, when focusing
particularly on results of warm-season analyses. Recent studies also
generally indicate a positive association between O3
concentrations and emergency department visits for asthma during the
warm season (EPA, 2006a, p. 7-175). These positive and robust
associations are supported by the human clinical, animal toxicological,
and epidemiological evidence for lung function decrements, increased
respiratory symptoms, airway inflammation, and increased airway
responsiveness. Taken together, the overall evidence supports a causal
relationship between acute ambient O3 exposures and
increased respiratory morbidity outcomes resulting in increased
emergency department visits and hospitalizations during the warm season
(EPA, 2006a, p. 8-77).

ii. Effects on the Respiratory System of Long-Term O3
Exposures
    The 1996 Criteria Document concluded that there was insufficient
evidence from the limited number of studies to determine whether long-
term O3 exposures resulted in chronic health effects at
ambient levels observed in the U.S. However, the aggregate evidence
suggested that O3 exposure, along with other environmental
factors, could be responsible for health effects in exposed
populations. Animal toxicological studies carried out in the 1980's and
1990's demonstrated that long-term exposures can result in a variety of
morphological effects, including permanent changes in the small airways
of the lungs, including remodeling of the distal airways and CAR and
deposition of collagen, possibly representing fibrotic changes. These
changes result from the damage and repair processes that occur with
repeated exposure. Fibrotic changes were also found to persist after
months of exposure providing a potential pathophysiologic basis for
changes in airway function observed in children in some recent
epidemiological studies. It appears that variable seasonal ambient
patterns of exposure may be of greater concern than continuous daily
exposures.
    Several studies published since 1996 have investigated lung
function changes over seasonal time periods (EPA, 2006a, section
7.5.3). The Criteria Document (p. 7-114) summarizes these studies
collectively indicate that seasonal O3 exposure is
associated with smaller growth-related increases in lung function in
children than they would have experienced living in areas with lower
O3 levels and that there is some limited, as yet uncertain,
evidence that seasonal O3 also may affect lung function in
young adults, although the uncertainty about the role of copollutants
makes it difficult to attribute the effects to O3 alone.
    Lung capacity grows during childhood and adolescence as body size
increases, reaches a maximum during the twenties, and then begins to
decline steadily and progressively with age. Long-term exposure to air
pollution has long been thought to contribute to slower growth in lung
capacity, diminished maximally attained capacity, and/or more rapid
decline in lung capacity with age (EPA, 2006a, section 7.5.4).
Toxicological findings evaluated in the 1996 Criteria Document
demonstrated that repeated daily exposure of rats to an episodic
profile of O3 caused small, but significant, decrements in
growth-related lung function that were consistent with early indicators
of focal fibrogenesis in the proximal alveolar region, without overt
fibrosis. Because O3 at sufficient concentrations is a
strong respiratory irritant and has been shown to cause inflammation
and restructuring of the respiratory airways, it is plausible that
long-term O3 exposures might have a negative impact on
baseline lung function, particularly during childhood when these
exposures might have long-term risks.
    Several epidemiological studies published since 1996 have examined
the relationship between lung function development and long-term
O3 exposure. The most extensive and robust study of
respiratory effects in relation to long-term air pollution exposures
among children in the U.S. is the Children's Health Study carried out
in 12 communities of southern California starting in 1993. One analysis
(Peters et al., 1999a) examined the relationship between long-term
O3 exposures and self-reports of respiratory symptoms and
asthma in a cross sectional analysis and found a limited relationship
between outcomes of current asthma, bronchitis, cough and wheeze and a
0.040 ppm increase in 1-hour max O3 (EPA, 2006a, p. 7-115).
Another analysis (Peters et al., 1999b) examined the relationship
between lung function at baseline and levels of air pollution in the
community. They reported evidence that annual mean O3 levels
were associated with decreases in FVC, FEV1, PEF and forced
expiratory flow (FEF25-75) (the latter two being
statistically significant) among females but not males. In a separate
analysis (Gauderman et al., 2000) of 4th, 7th, and 10th grade students,
a longitudinal analysis of lung function development over four years
found no association with O3 exposure. The Children's Health
Study enrolled a second cohort of more than 1500 fourth graders in 1996
(Gauderman et al., 2002). While the strongest associations with
negative lung function growth were observed with acid vapors in this
cohort, children from communities with higher 4-year average
O3 levels also experienced smaller increases in various lung
function parameters. The strongest relationship with O3 was
with PEF. Specifically, children from the least-polluted community had
a small but statistically significant increase in PEF as compared to
those from the most-polluted communities. In two-pollutant models, only
8-hour average O3 and NO2 were significant joint
predictors of FEV1 and maximal midexpiratory flow (MMEF).
Although results from the second cohort of children are supportive of a
weak association, the definitive 8-year follow-up analysis of the first
cohort (Gauderman et al., 2004a) provides little evidence that long-
term exposure to ambient O3 at current levels is associated
with significant deficits in the growth rate of lung function in
children. Avol et al. (2001) examined children who had moved away from
participating communities in southern California to other states with
improved air quality. They found that a negative, but not statistically
significant, association was observed between O3 and lung
function parameters. Collectively, the results of these reports from
the children's health cohorts provide little evidence to support an
impact of long-term O3 exposures on lung function
development.
    Evidence for a significant relationship between long-term
O3 exposures and decrements in maximally attained lung
function was reported in a nationwide study of first year Yale students
(Kinney et al., 1998; Galizia and Kinney, 1999) (EPA, 2006a, p. 7-120).
Males had much larger effect estimates than females, which might
reflect higher outdoor activity levels and correspondingly higher
O3 exposures during childhood. A similar study of college
freshmen at University of California at Berkeley also reported
significant effects of long-term O3 exposures on lung
function (K[uuml]nzli et al., 1997; Tager et al., 1998). In a
comparison of students whose city of origin was either Los Angeles or
San Francisco, long-term O3 exposures were associated with
significant changes in mid- and end-expiratory flow measures, which
could be considered early indicators for pathologic changes that might
progress to COPD.
    There have been a few studies that investigated associations
between long-term O3 exposures and the onset of new cases of
asthma (EPA, 2006a, section 7.5.6). The Adventist Health and Smog
(AHSMOG) study cohort of about 4,000 was drawn from nonsmoking, non-
Hispanic white adult Seventh Day Adventists living in California (Greer
et al., 1993; McDonnell et al., 1999). During the ten-year follow-up in
1987, a statistically significant increased relative risk of asthma
development was observed in males, compared to a nonsignificant
relative risk in females (Greer et al., 1993). In the 15-year follow-up
in 1992, it was reported that for males, there was a statistically
significant increased relative risk of developing asthma associated
with 8-hour average O3 exposures, but there was no evidence
of an association in females. Consistency of results in the two studies
with different follow-up

times provides supportive evidence of the potential for an association
between long-term O3 exposure and asthma incidence in adult
males; however, representativeness of this cohort to the general U.S.
population may be limited (EPA, 2006a, p. 7-125).
    In a similar study (McConnell et al., 2002) of incident asthma
among children (ages 9 to 16 at enrollment), annual surveys of 3,535
children initially without asthma were used to identify new-onset
asthma cases as part of the Children's Health Study. Six high-
O3 and six low-O3 communities were identified
where the children resided. There were 265 children who reported new-
onset asthma during the follow-up period. Although asthma risk was no
higher for all residents of the six high-O3 communities
versus the six low-O3 communities, asthma risk was 3.3 times
greater for children who played three or more sports as compared with
children who played no sports within the high-O3
communities. This association was absent in the communities with lower
O3 concentrations. No other pollutants were found to be
associated with new-onset asthma (EPA, 2006a, p. 7-125). Playing sports
may result in extended outdoor activity and exposure occurring during
periods when O3 levels are higher. It should be noted,
however, that the results of the Children's Health Study were based on
a small number of new-onset asthma cases among children who played
three or more sports. Future replication of these findings in other
cohorts would help determine whether a causal interpretation is
appropriate.
    In animal toxicology studies, the progression of morphological
effects reported during and after a chronic exposure in the range of
0.50 to 1.00 ppm O3 is complex, with inflammation peaking
over the first few days of exposure, then dropping, then plateauing,
and finally, largely disappearing (EPA, 2006a, section <IP_ADDRESS>). By
contrast, fibrotic changes in the tissue increase very slowly over
months of exposure, and, after exposure ceases, the changes sometimes
persist or increase. Epithelial hyperplasia peaks soon after the
inflammatory response but is usually maintained in both the nose and
lungs with continuous exposure; it also does not return to pre-exposure
levels after the end of exposure. Patterns of exposure in this same
concentration range determine effects, with 18 months of daily
exposure, causing less morphologic damage than exposures on alternating
months. This is important as environmental O3 exposure is
typically seasonal. Long-term studies by Plopper and colleagues (Evans
et al., 2003; Schelegle et al., 2003; Chen et al., 2003; Plopper and
Fanucchi, 2000) investigated infant rhesus monkeys exposed to
simulated, seasonal O3 and demonstrated: (1) Remodeling in
the distal airways, (2) abnormalities in tracheal basement membrane;
(3) eosinophil accumulation in conducting airways; and (4) decrements
in airway innervation (EPA, 2006a, p. 5-45). These findings provide
additional information regarding possible injury-repair processes
occurring with long-term O3 exposures suggesting that these
processes are only partially reversible and may progress following
cessation of O3 exposure. Further, these processes may lead
to nonreversible structural damage to lung tissue; however, there is
still too much uncertainty to characterize the significance of these
findings to human exposure profiles and effect levels (EPA, 2006a, p.
8-25).
    In summary, in the past decade, important new longitudinal studies
have examined the effect of chronic O3 exposure on