# National Ambient Air Quality Standards for Ozone

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URL: https://www.frixlaw.com/law-library/documents/fr%3AE7-12416

## Record

- **Collection:** Federal Register
- **Document type:** Proposed Rule
- **Published:** July 11, 2007
- **Citation:** 72 FR 37818

## Text

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 (O
3
) and related photochemical oxidants and national ambient air quality standards (NAAQS) for O
3
, EPA proposes to make revisions to the primary and secondary NAAQS for O
3
to provide requisite protection of public health and welfare, respectively, and to make corresponding revisions in data handling conventions for O
3
.

With regard to the primary standard for O
3
, 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 O
3
-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 O
3
, EPA proposes to revise the current 8-hour standard with one of two options to provide increased protection against O
3
-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 O
3
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:

•
www.regulations.gov:
Follow the on-line instructions for submitting comments.

•
E-mail: a-and-r-Docket@epa.gov.

•
Fax:
202-566-1741.

•
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
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
www.regulations.gov
or e-mail. The
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
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
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
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 (202) 566-1744 and the telephone number for the Air and Radiation Docket and Information Center is (202) 566-1742.

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: 919-541-5288; fax: 919-541-0237; e-mail:
mckee.dave@epa.gov.

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
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 O
3

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. O
3
-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 O
3
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 § 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,
” § 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 NO
X
and VOC emissions that contribute to O
3
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 NO
X
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 O
3
season, which are considered natural background emissions.

3
See EPA report,
Evaluating Ozone Control Programs in the Eastern United States: Focus on the NO
X

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 O
3
by decreasing emissions of NO
X
and VOC. These programs complement State and local efforts to improve O
3
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 O
3
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 NO
X
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 NO
X
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 O
3
season NO
X
emissions in that region by about 50 percent and annual NO
X
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 NO
X
and VOC. Current practices that may reduce emissions of NO
X
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 O
3
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 O
3
requirements. The EPA anticipates that certain USDA-approved conservation systems and activities that reduce agricultural emissions of NO
X
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 O
3
NAAQS.

C. Review of Air Quality Criteria and Standards for O
3

Tropospheric (ground-level) O
3
is formed from biogenic and anthropogenic precursor emissions. Naturally occurring O
3
in the troposphere can result from biogenic organic precursors reacting with naturally occurring nitrogen oxides (NO
X
) and by stratospheric O
3
intrusion into the troposphere. Anthropogenic precursors of O
3
, specifically NO
X
and volatile organic compounds (VOC), originate from a wide variety of stationary and mobile sources. Ambient O
3
concentrations produced by these emissions are directly affected by temperature, solar radiation, wind speed and other meteorological factors.

The last review of the O
3
NAAQS was completed on July 18, 1997, based on the 1996 O
3
CD (U.S. EPA, 1996a) and 1996 O
3
Staff Paper (U.S. EPA, 1996b). EPA revised the primary and secondary O
3
standards on the basis of the then latest scientific evidence linking exposures to ambient O
3
to adverse health and welfare effects at levels allowed by the 1-hour average standards (62 FR 38856). The O
3
standards were revised by replacing the existing primary 1-hour average standard with an 8-hour average O
3
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 O
3
standard was changed by making it identical in all respects to the revised primary standard.

Following promulgation of the revised O
3
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 O
3
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 O
3
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 O
3
pollution in shielding the public from the effects of solar ultraviolet (UV) radiation, as well as the direct adverse health effects of O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
(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 O
3
, or for which the Criteria Document judges associations with O
3
to be causal, likely causal, or for which the evidence is highly suggestive that O
3
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 O
3
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 O
3
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 O
3
, 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 O
3
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 O
3
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 O
3
, 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 O
3
-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, O
3
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 O
3
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 O
3
, or for which the Criteria Document judges associations with O
3
to be causal, likely causal, or for which the evidence is highly suggestive that O
3
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 O
3
-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 O
3
levels at and above specific benchmark levels which represent exposure levels at which O
3
-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 O
3
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 O
3
levels.

8
Exposures of concern were also considered in the last review of the O
3
NAAQS, and were judged by EPA to be an important indicator of the public health impacts of those O
3
-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 O
3
-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 O
3
-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 O
3
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 O
3
levels, as well as risk reductions and remaining risks associated with just meeting the current and various alternative O
3
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 O
3
-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 O
3
standards.

As discussed below, a substantial amount of new research has been conducted since the last review of the O
3
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 O
3
, 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 O
3
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 O
3
in ambient air. The information highlighted here summarizes: (1) New information available on potential mechanisms for health effects associated with exposure to O
3
; (2) the nature of effects that have been associated directly with exposure to O
3
and indirectly with the presence of O
3
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 O
3
, 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 O
3
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 O
3
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 O
3
-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 O
3
exposure of healthy young adults and increased airway responsiveness to allergens in subjects with allergic asthma and allergic rhinitis exposed to O
3
.

(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 O
3
-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 O
3
concentrations and school absenteeism and between ambient O
3
and cardiac-related physiological endpoints.

(5) Several additional studies have been published over the last decade examining the temporal associations between O
3
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 O
3
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 O
3
-mortality associations.

1. Overview of Mechanisms

Evidence on possible mechanisms by which exposure to O
3
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 O
3
-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 O
3
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 O
3
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 O
3
cardiovascular effects. While much is known about mechanisms that play a role in O
3
-related respiratory effects, additional research is needed to more clearly understand the role that O
3
may have in contributing to cardiovascular effects.

9
While most of the available evidence addresses mechanisms for O
3
, O
3
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 O
3
.

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 O
3
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 O
3
. 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 O
3
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 O
3
, as discussed below. At the same O
3
dose, individuals who are more susceptible to O
3
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 O
3
.

The inhaled dose is the product of O
3
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 O
3
Criteria Documents. In an attempt to describe O
3
dose-response characteristics, acute responses were modeled as a function of total inhaled O
3
dose which was generally found to be a better predictor of response than O
3
concentration, ventilation rate, or duration of exposure, alone, or as a combination of any two of these factors (EPA 2006a, section 6.2). Predicted O
3
-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 O
3
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 O
3
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 O
3
-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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
, 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 O
3
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 O
3
. 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 O
3
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 O
3
effects (EPA, 2006a, section 7.6.7.2), primarily in the older adult population. Among the studies that observed positive associations between O
3
and mortality, a comparison of all age or younger age (65 years of age) O
3
-mortality effect estimates to that of the elderly population (>65 years) indicates that, in general, the elderly population is more susceptible to O
3
mortality effects. There is supporting evidence of age-related differences in susceptibility to O
3
lung function effects. The Criteria Document concludes that the elderly population (>65 years of age) appears to be at greater risk of O
3
-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 O
3
exposure (EPA, 2006a, section 7.6.7.2).

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 O
3
will likely have about the same response if exposed again to the same dose of O
3
(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 O
3
. 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 O
3
exposure. These observations suggest a potential role for these markers in the innate susceptibility to O
3
, 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 O
3
(
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 O
3
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 O
3
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 O
3
-induced increases in clotting agents arising from the cascade of events, starting with cell injury described above, occurring within 12 to 24 hours of O
3
exposure. The time course for many of these initial responses to O
3
is highly variable. Moreover these observations pertain only to the initial response to O
3
. Consequent responses can follow. For example, Jörres
et al.
, (1996) found that in subjects with

asthma and allergic rhinitis, a maximum percent fall in FEV
1
of 27.9% and 7.8%, respectively, occurred 3 days after O
3
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 O
3
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 O
3
-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 O
3
, 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 O
3
, 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 O
3
Exposures

Controlled human exposure studies have shown that O
3
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 O
3
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 O
3
exposure health effects on the respiratory system from short-term O
3
exposures were reviewed in the 1986 and 1996 Criteria Documents (EPA, 1986, 1996). In the last review, 0.50 ppm was the lowest O
3
concentration at which statistically significant reductions in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV
1
) were reported in sedentary subjects. During exercise, spirometric (lung function) and symptomatic responses were observed at much lower O
3
exposures. When minute ventilation was considerably increased by continuous exercise (CE) during O
3
exposures lasting 2 hour or less at ≥ 0.12 ppm, healthy subjects generally experienced decreases in FEV
1
, 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 O
3
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 O
3
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 O
3
exposure relative to young adults; (3) O
3
-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 O
3
, but responses tend to be reproducible within a given individual over a period of several months; (5) subjects exposed repeatedly to O
3
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 O
3
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 O
3
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 O
3
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 3.3.1.1), among the more important of the recent studies that examined changes in FEV
1
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 FEV
1
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 O
3
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, O
3
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 FEV
1
decrements and respiratory symptoms than square-wave exposures (when the overall O
3
doses are equal). These results suggest that peak exposures, reflective of the pattern of ambient O
3
concentrations in some locations, are important in terms of O
3
toxicology.

McDonnell (1996) used data from a series of studies to investigate the frequency distributions of FEV
1
decrements following 6.6 hour exposures and found statistically significant but relatively small group mean decreases in average FEV
1
responses (between 5 and 10 percent) at 0.080 ppm O
3
.
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 FEV
1
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 O
3
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 O
3
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 O
3
) using square-wave and triangular exposure patterns. The study was designed to examine multiple comparisons of pulmonary function (FEV
1
) 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 FEV
1
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 FEV
1
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 FEV
1
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 O
3
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 FEV
1
or peak expiratory flow (PEF), and respiratory symptoms in healthy adults and asthmatic children are closely correlated to ambient O
3
concentrations. Pre-1996 field studies focused primarily on children attending summer camps and found O
3
-related impacts on measures of lung function, but not respiratory symptoms, in healthy children. The newer studies have expanded to evaluate O
3
-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 O
3
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 O
3
exposures were estimated by averaging hourly O
3
concentrations from ambient monitors located at the base and summit. The mean 8-hour average O
3
concentration was 0.040 ppm (8-hour average concentration range of 0.021 ppm to 0.074 ppm O
3
). Decreased lung function was associated with O
3
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 O
3
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 O
3
-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 O
3
for a 5-day cumulative lag, suggesting that O
3
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 O
3
was 0.048 ppm across the 8 cities. Excluding days when 8-hour average O
3
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 O
3
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 O
3
-related reductions in PEF, with variations in effect depending on lag time and time of day. Mean 1-hour maximum O
3
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 O
3
exposure and reduced PEF in asthmatics, other studies did not, possibly due to low levels of O
3
exposure. EPA concludes that these studies collectively indicate that O
3
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 O
3
.

Most of the panel studies which have investigated associations between O
3
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 O
3
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 O
3
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 O
3
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 O
3
and 8-hour max O
3
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 O
3
were observed on a variety of respiratory symptoms only in the medication user group. Both daily 1-hour max and 8-hour max O
3
concentrations were similarly related to symptoms such as chest tightness and shortness of breath. Effects of O
3
, but not PM
2.5
, remained significant and even increased in magnitude in two-pollutant models. Some of the associations were noted at 1-hour max O
3
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 O
3
, and provides supportive evidence for effects of O
3
independent of PM
2.5
. 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 O
3
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 O
3
exposure, these studies had less statistical power and/or were conducted in areas with relatively low 1-hour maximum average O
3
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 O
3
primary standard.

School absenteeism is another potential surrogate for the health implications of O
3
exposure in children. The association between school absenteeism and ambient O
3
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 PM
10
and CO concentrations) and found that ambient O
3
concentrations with a distributed lag of 14 days were statistically significantly associated with an increased rate of school absences. Gilliland
et al.
(2001) studied O
3
-related absences among about 2,000 4th grade students in 12 southern California communities and found statistically significant associations between 8-hour average O
3
concentrations (with a distributed lag out to 30 days) and all absence categories, and particularly for respiratory causes. Neither PM
10
nor NO
2
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 O
3
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 O
3
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 3.3.1.1.2), 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 O
3
causes an increase in airway responsiveness as indicated by a reduction in the concentration of stimuli required to produce a given reduction in FEV
1
or airway obstruction. Increased airway responsiveness is an important consequence of exposure to O
3
because its presence means that the airways are predisposed to narrowing on inhalation of various stimuli, such as specific allergens, cold air or SO
2
. 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 O
3
(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 O
3
(0.160 ppm for 7.6 hours) was observed. These observations, based on O
3
exposures to levels much higher than the current standard level suggest that O
3
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, O
3
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 O
3
can induce increased airway responsiveness in asthmatic subjects to O
3
, who typically have increased airway responsiveness at baseline. A subsequent study (Jörres
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 O
3
levels; other studies reported similar results. According to one study (Folinsbee and Hazucha, 2000), changes in airway responsiveness after O
3
exposure resolve more slowly than changes in FEV
1
or respiratory symptoms. Other studies of repeated exposure to O
3
suggest that changes in airway responsiveness tend to be somewhat less affected by attenuation with consecutive exposures than changes in FEV
1
(EPA, 2006a, p. 6-31).

The Criteria Document (section 6.8) concludes that O
3
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 O
3
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 O
3
exposure represents a plausible link between O
3
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 O
3
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 3.3.1.3 of the Staff Paper). Some of these prior studies suggest that inflammatory responses may be detected in some individuals following O
3
exposures in the absence of O
3
-induced pulmonary decrements in those subjects. These studies also demonstrate that short-term exposures to O
3
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 O
3
causes these effects.

Lung inflammation and increased permeability, which are distinct events controlled by different mechanisms, are two commonly observed effects of O
3
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 O
3
. In addition to their role in inflammation, many of these compounds have bronchoconstrictive properties and may be involved in increased airway responsiveness following O
3
exposure. An in vitro study of epithelial cells from nonatopic and atopic asthmatics exposed to 0.010 to 0.100 ppm O
3
showed significantly increased permeability compared to cells from normal persons. This indicates a potentially inherent susceptibility of cells from asthmatic individuals for O
3
-induced permeability.

17
Graham and Koren (1990) compared inflammatory mediators present in NL and BAL fluids of humans exposed to 0.4 ppm O
3
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) O
3
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 O
3
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 O
3
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 O
3
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 O
3
exposures at 0.080 and 0.100 ppm. To provide some perspective on the public health impact for these effects, the Staff Paper (section 3.3.1.1.3) 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 O
3
-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 O
3
dose (product of O
3
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 O
3
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, O
3
reactivity is not eliminated at environmentally relevant exposures (Criteria Document, p. 8-24). Further, antioxidant reactivity with O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
effects, the effects of particles, and respiratory infections (EPA, 2006a, p. 8-26).

(e) Morphological Effects

The 1996 Criteria Document found that short-term O
3
exposures cause similar alterations in lung morphology in all laboratory animal species studied, including primates. As discussed in the Staff Paper (section 3.3.1.1.5), 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 O
3
-induced damage (epithelial cell necrosis and remodeling of respiratory bronchioles), possibly because epithelium in this region receives the greatest dose of O
3
delivered to the lower respiratory tract. Following chronic O
3
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 O
3
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 O
3
dose. The potential impacts of repeated short-term and chronic morphological effects of O
3
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 O
3
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 O
3
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 O
3
. As discussed in section 3.3.1.1.6 of the Staff Paper, numerous studies conducted in various locations in the U.S. and Canada consistently have shown a relationship between ambient O
3
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 O
3
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 O
3
NAAQS, the Criteria Document evaluated emergency department visits and hospital admissions as possible outcomes following exposure to O
3
(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 O
3
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 O
3
) and at higher levels (above 0.120 ppm 1-hour max O
3
), 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 O
3
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 O
3
, after adjustment for possible confounding effects of temperature and copollutants. Overall, the 1996 Criteria Document concluded that there was strong evidence that ambient O
3
exposures can cause significant exacerbations of preexisting respiratory disease in the general public. Excess respiratory-related hospital admissions associated with O
3
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 O
3
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 O
3
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 O
3
.

In reviewing evidence for associations between emergency department visits for asthma and short-term O
3
exposures, the Criteria Document notes that in general, O
3
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 O
3
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 O
3
concentrations, length of the study period, and statistical methods used to control confounding by seasonal patterns and copollutants appear to affect the observed O
3
effect on emergency department visits. Thus, the Criteria Document has concluded that stratified analyses by season generally supported a positive association between O
3
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 O
3
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 O
3
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 O
3
concentrations and respiratory hospital admissions in the warm season. However, not all studies found a statistically significant relationship with O
3
, possibly because of very low ambient O
3
levels. Analyses for confounding using multipollutant regression models suggest that copollutants generally do not confound the association between O
3
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 O
3
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 O
3
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 O
3
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 O
3
Exposures

The 1996 Criteria Document concluded that there was insufficient evidence from the limited number of studies to determine whether long-term O
3
exposures resulted in chronic health effects at ambient levels observed in the U.S. However, the aggregate evidence suggested that O
3
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 O
3
exposure is associated with smaller growth-related increases in lung function in children than they would have experienced living in areas with lower O
3
levels and that there is some limited, as yet uncertain, evidence that seasonal O
3
also may affect lung function in young adults, although the uncertainty about the role of copollutants makes it difficult to attribute the effects to O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
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 O
3
(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 O
3
levels were associated with decreases in FVC, FEV
1
, PEF and forced expiratory flow (FEF
25-75
) (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 O
3
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 O
3
levels also experienced smaller increases in various lung function parameters. The strongest relationship with O
3
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 O
3
and NO
2
were significant joint predictors of FEV
1
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 O
3
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 O
3
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 O
3
exposures on lung function development.

Evidence for a significant relationship between long-term O
3
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 O
3
exposures during childhood. A similar study of college freshmen at University of California at Berkeley also reported significant effects of long-term O
3
exposures on lung function (Künzli
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 O
3
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 O
3
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 O
3
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 O
3
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 chil

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3AE7-12416. Public record. Not legal advice.