National Ambient Air Quality Standards for Ozone

Federal RegisterDec 17, 2014

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Parts 50, 51, 52, 53, and 58

[EPA-HQ-OAR-2008-0699; FRL-9918-43-OAR]

RIN 2060-AP38

National Ambient Air Quality Standards for Ozone

AGENCY:

Environmental Protection Agency.

ACTION:

Proposed rule.

SUMMARY:

Based on its review of the air quality criteria for ozone (O

) and related photochemical oxidants and national ambient air quality standards (NAAQS) for O

, the Environmental Protection Agency (EPA) proposes to make revisions to the primary and secondary NAAQS for O

to provide requisite protection of public health and welfare, respectively. The EPA is proposing to revise the primary standard to a level within the range of 0.065 to 0.070 parts per million (ppm), and to revise the secondary standard to within the range of 0.065 to 0.070 ppm, which air quality analyses indicate would provide air quality, in terms of 3-year average W126 index values, at or below a range of 13-17 ppm-hours. The EPA proposes to make corresponding revisions in data handling conventions for O

and conforming changes to the Air Quality Index (AQI); to revise regulations for the prevention of significant deterioration (PSD) program to add a transition provision for certain applications; and to propose schedules and convey information related to implementing any revised standards. The EPA is proposing changes to the O

monitoring seasons, the Federal Reference Method (FRM) for monitoring O

in the ambient air, Federal Equivalent Method (FEM) procedures for testing, and the Photochemical Assessment Monitoring Stations (PAMS) network.

Along with proposing exceptional event schedules related to implementing any revised O

standards, the EPA is proposing to apply this same schedule approach to other future revised NAAQS and to remove obsolete regulatory language for expired exceptional event deadlines. The EPA is proposing to make minor changes to the procedures and time periods for evaluating potential FRMs and equivalent methods (including making the requirements for nitrogen dioxide consistent with the requirements for O

) and to remove an obsolete requirement for the annual submission of documentation by manufacturers of certain particulate matter monitors. For additional information, see the Executive Summary, section I.A.

DATES:

Written comments on this proposed rule must be received by March 17, 2015.

Public Hearings:

The EPA intends to hold three public hearings on this proposed rule in January 2015. These will be announced in a separate

Federal Register

notice that provides details, including specific dates, times, addresses, and contact information for these hearings.

ADDRESSES:

Submit your comments, identified by Docket ID No. EPA-HQ-OAR-2008-0699, to the EPA by one of the following methods:

•

Federal eRulemaking Portal: http://www.regulations.gov

. Follow the online instructions for submitting comments.

•

Email: A-and-R-Docket@epa.gov

. Include docket ID No. EPA-HQ-OAR-2008-0699 in the subject line of the message.

•

Fax:

(202) 566-9744.

•

Mail:

Environmental Protection Agency, EPA Docket Center (EPA/DC), Mailcode 28221T, Attention Docket ID No. OAR-2008-0699, 1200 Pennsylvania Ave. NW., Washington, DC 20460. Please include a total of two copies.

•

Hand/Courier Delivery:

EPA Docket Center, Room 3334, EPA WJC West Building, 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-2008-0699. 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 email. The

www.regulations.gov

Web site is an “anonymous access” system, which means the EPA will not know your identity or contact information unless you provide it in the body of your comment. If you send an email comment directly to the EPA without going through

www.regulations.gov

your email 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, the 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 the EPA cannot read your comment due to technical difficulties and cannot contact you for clarification, the 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:

The EPA has established dockets for these actions as discussed above. All documents in these dockets are listed on the

www.regulations.gov

Web site. This includes documents in the rulemaking docket (Docket ID No. EPA-HQ-OAR-2008-0699) and a separate docket, established for the Integrated Science Assessment (ISA) (Docket No. EPA-HQ-ORD-2011-0050) that has have been incorporated by reference into the rulemaking docket. 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, is not placed on the Internet and may be viewed, with prior arrangement, at the EPA Docket Center. 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 WJC West Building, 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. For additional information about EPA's public docket visit the EPA Docket Center homepage at:

http://www.epa.gov/epahome/dockets.htm

FOR FURTHER INFORMATION CONTACT:

Ms. Susan Lyon Stone, 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) 541-1146; fax: (919) 541-0237; email:

stone.susan@epa.gov

SUPPLEMENTARY INFORMATION:

General Information

What should I consider as I prepare my comments for EPA?

Submitting CBI.

Do not submit this information to the EPA through

www.regulations.gov

or email. 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.

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.

• 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 ISA for Ozone and Related Photochemical Oxidants is available on the EPA's National Center for Environmental Assessment (NCEA) Web site. To obtain this document, go to

http://www.epa.gov/ncea

, and click on Ozone in the Quick Finder section. This will open a page with a link to the February 2013 ISA. The 2014 Policy Assessment (PA), Health and Welfare Risk and Exposure Assessments (HREA and WREA, respectively), 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 final 2014 PA is available at:

http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_2008_pa.html

, and the final 2014 Health and Welfare Risk and Exposure Assessments and other related technical documents are available at:

http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_2008_rea.html

. These and other related documents are also available for inspection and copying in the EPA docket identified above.

Environmental Justice

Analyses evaluating the potential implications of a revised O

NAAQS for environmental justice populations are discussed in appendix 9A of the Regulatory Impact Analysis (RIA) that accompanies this notice of proposed rulemaking. The RIA is available on the Web, through the EPA's Technology Transfer Network Web site at

http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_index.html

Table of Contents

The following topics are discussed in this preamble:

I. Background

A. Executive Summary

B. Legislative Requirements

C. Related Control Programs To Implement O

Standards

D. Review of Air Quality Criteria and Standards for O

E. Ozone Air Quality

II. Rationale for Proposed Decision on the Primary Standard

A. Approach

B. Health Effects Information

1. Overview of Mechanisms

2. Nature of Effects

3. Adversity of O

Effects

4. Ozone-Related Impacts on Public Health

C. Human Exposure and Health Risk Assessments

1. Air Quality Adjustment

2. Exposure Assessment

3. Quantitative Health Risk Assessments

D. Conclusions on the Adequacy of the Current Primary Standard

1. Summary of Evidence-Based Considerations in the PA

2. Summary of Exposure- and Risk-Based Considerations in the PA

3. Policy Assessment Conclusions on the Current Standard

4. CASAC Advice

5. Administrator's Proposed Conclusions Concerning the Adequacy of the Current Standard

E. Conclusions on the Elements of the Primary Standard

1. Indicator

2. Averaging Time

3. Form

4. Level

F. Proposed Decision on the Primary Standard

III. Communication of Public Health Information

IV. Rationale for Proposed Decision on the Secondary Standard

A. Approach

B. Welfare Effects Information

1. Nature of Effects and Biologically Relevant Exposure Metric

2. Potential Impacts on Public Welfare

C. Exposure and Risk Assessment Information

1. Air Quality Analyses

2. Tree Seedling Growth, Productivity, Carbon Storage and Associated Ecosystem Services

3. Crop Yield

4. Visible Foliar Injury

D. Conclusions on Adequacy of the Current Secondary Standard

1. Evidence- and Exposure/Risk-Based Considerations in the Policy Assessment

2. CASAC Advice

3. Administrator's Proposed Conclusions on Adequacy of the Current Standard

E. Consideration of Alternative Secondary Standards

1. Indicator

2. Consideration of a Cumulative, Seasonal Exposure-based Standard in the Policy Assessment

3. CASAC Advice

4. Air Quality Analyses

5. Administrator's Proposed Conclusions

F. Proposed Decision on the Secondary Standard

V. Appendix U: Interpretation of the Primary and Secondary NAAQS for O

A. Background

B. Data Selection Requirements

C. Data Reporting and Data Handling Requirements

D. Considerations for the Possibility of a Distinct Secondary Standard

E. Exceptional Events Information Submission Schedule

VI. Ambient Monitoring Related to Proposed O

Standards

A. Background

B. Revisions to the Length of the Required O

Monitoring Seasons

C. Revisions to the Photochemical Assessment Monitoring Stations (PAMS)

1. Network Design

2. Speciated VOC Measurements

3. Carbonyl Sampling

4. Nitrogen Oxides Sampling

5. Meteorology Measurements

6. PAMS Season

7. Timing and Other Implementation Issues

D. Addition of a New Federal Reference Method (FRM) for O

E. Revisions to the Procedures for Testing Performance Characteristics and Determining Comparability Between Candidate Methods and Reference Methods

VII. Implementation of Proposed O

Standards

A. NAAQS Implementation Plans

1. Background

2. Timing of Rules and Guidance

3. Section 110 State Implementation Plans

4. Nonattainment Area Requirements

B. Implementing a Distinct Secondary O

NAAQS, if One is Established

C. Designation of Areas

D. Prevention of Significant Deterioration and Nonattainment New Source Review Programs for the Proposed Revised Primary and Secondary O

NAAQS

1. Prevention of Significant Deterioration (PSD)

2. Nonattainment New Source Review

E. Transportation and General Conformity Programs

1. What are transportation and general conformity?

2. Why is the EPA discussing transportation and general conformity in this proposed rulemaking?

3. When would transportation and general conformity apply to areas designated nonattainment for a revised O

NAAQS, if one is established?

4. Will transportation and general conformity apply to a distinct secondary O

NAAQS, if one is established?

5. What impact would the implementation of a revised O

NAAQS have on a State's transportation and/or general conformity SIP?

F. How Background O

Is Addressed in CAA Implementation Provisions

1. Introduction

2. Exceptional Events Exclusions

3. Rural Transport Areas

4. International Transport

VIII. Statutory and Executive Order Reviews

A. Executive Order 12866: Regulatory Planning and Review and Executive Order 13563: Improving Regulation and Regulatory Review

B. Paperwork Reduction Act

C. Regulatory Flexibility Act

D. Unfunded Mandates Reform Act

E. Executive Order 13132: Federalism

F. Executive Order 13175: Consultation and Coordination With Indian Tribal Governments

G. Executive Order 13045: Protection of Children From Environmental Health & Safety Risks

H. Executive Order 13211: Actions That Significantly Affect Energy Supply, Distribution, or Use

I. National Technology Transfer and Advancement Act

J. Executive Order 12898: Federal Actions To Address Environmental Justice in Minority Populations and Low-Income Populations

References

I. Background

A. Executive Summary

This section summarizes information about the purpose of this regulatory action (I.A.1), the major provisions of this proposal (I.A.2), and provisions related to implementation (I.A.3).

1. Purpose of This Regulatory Action

Sections 108 and 109 of the Clean Air Act (CAA) govern the establishment, review, and revision, as appropriate, of the NAAQS to protect public health and welfare. The CAA requires the EPA to periodically review the air quality criteria—the science upon which the standards are based—and the standards themselves. This rulemaking is being conducted pursuant to these statutory requirements. The schedule for completing this review is established by a federal court order, which requires that the EPA sign a proposal by December 1, 2014, and make a final determination by October 1, 2015.

The EPA completed its most recent review of the O

NAAQS in 2008. As a result of that review, EPA took four principal actions: (1) Revised the level of the 8-hour primary O

standard to 0.075 parts per million (ppm); (2) expressed the standard to three decimal places; (3) revised the 8-hour secondary O

standard by making it identical to the revised primary standard; and (4) made conforming changes to the AQI for O

In subsequent litigation, the U.S. Court of Appeals for the District of Columbia Circuit upheld the EPA's 2008 primary O

standard, but remanded the 2008 secondary standard.

State of Mississippi

EPA,

744 F. 3d 1334 (D.C. Cir. 2013). With respect to the primary standard, the court held that the EPA reasonably determined that the existing primary standard, set in 1997, did not protect public health with an adequate margin of safety and required revision. In upholding the EPA's revised primary standard, the court dismissed arguments that the EPA should have adopted a more stringent standard. The court remanded the secondary standard to the EPA after rejecting the EPA's explanation for setting the secondary standard identical to the revised 8-hour primary standard. The court held that because the EPA had failed to identify a level of air quality requisite to protect public welfare, the EPA's comparison between the primary and secondary standards for determining if requisite protection for public welfare was afforded by the primary standard failed to comply with the CAA.

This proposal reflects the Administrator's proposed conclusions based on a review of the O

NAAQS that began in September 2008. In conducting this review, the EPA has carefully evaluated the currently available scientific literature on the health and welfare effects of ozone, focusing particularly on the new literature available since the conclusion of the previous review in 2008. In addition, the EPA has also addressed the remand of the Agency's 2008 decision on the secondary standard. Between 2008 and 2014, the EPA prepared draft and final versions of the Integrated Science Assessment, the Health and Welfare Risk and Exposure Assessments, and the Policy Assessment. Multiple drafts of these documents were available for public review and comment, and as required by the CAA, were peer-reviewed by the Clean Air Scientific Advisory Committee (CASAC), an independent scientific advisory committee established by the CAA and charged with providing advice to the Administrator. The final documents reflect the EPA staff's consideration of the comments and recommendations made by CASAC and the public on draft versions of these documents.

2. Summary of Major Provisions

The EPA is proposing that the current primary O

standard set at a level of 0.075 ppm is not requisite to protect public health with an adequate margin of safety, and that it should be revised to provide increased public health protection. Specifically, the EPA is proposing to retain the indicator (ozone), averaging time (8-hour) and form (annual fourth-highest daily maximum, averaged over 3 years) of the existing primary O

standard and is proposing to revise the level of that standard to within the range of 0.065 ppm to 0.070 ppm. The EPA is proposing this revision to increase public health protection, including for “at-risk” populations such as children, older adults, and people with asthma or other lung diseases, against an array of O

-related adverse health effects. For short-term O

exposures, these effects include decreased lung function, increased respiratory symptoms and pulmonary inflammation, effects that result in serious indicators of respiratory morbidity such as emergency department visits and hospital admissions, and all-cause (total nonaccidental) mortality. For long-term O

exposures, these health effects include a variety of respiratory morbidity effects and respiratory mortality. Recognizing that the CASAC recommended a range of levels from 0.060 ppm to 0.070 ppm, and that levels as low as 0.060 ppm could potentially be supported, the Administrator solicits comment on alternative standard levels below 0.065 ppm, and as low as 0.060 ppm. However, the Administrator notes that setting a standard below 0.065 ppm, down to 0.060 ppm, would inappropriately place very little weight on the uncertainties in the health effects evidence and exposure/risk information. Given alternative views of the currently available evidence and information expressed by some commenters, the EPA is taking comment on both the Administrator's proposed decision to revise the current primary O

standard and the option of retaining that standard.

In addition to proposing changes to the level of the standard, the EPA is

proposing conforming changes to the Air Quality Index (AQI) by proposing to set an AQI value of 100 equal to the level of the 8-hour primary O

standard, and proposing adjustments to the AQI values of 50, 150, 200 and 300.

The EPA also proposes to revise the secondary standard to provide increased protection against vegetation-related effects on public welfare. As an initial matter, the Administrator proposes to conclude that air quality in terms of a three-year average seasonal W126 index value, based on the three consecutive month period within the O

season with the maximum index value, with daily exposures cumulated for the 12-hour period from 8:00 a.m. to 8:00 p.m., within the range from 13 ppm-hrs to 17 ppm-hrs would provide the requisite protection against known or anticipated adverse effects to the public welfare. The EPA solicits comment on this proposed conclusion. In considering how to achieve that level of air quality, the Administrator recognizes that air quality data analyses suggest that air quality in terms of three-year average W126 index values of a range at or below 13 to 17 ppm-hrs would be provided by a secondary standard level within the range of 0.065 to 0.070 ppm, and that to the extent areas need to take action to attain a standard in the range of 0.065 to 0.070 ppm, those actions would also improve air quality as measured by the W126 metric. Thus, the Administrator proposes to revise the level of the current secondary standard to within the range of 0.065 to 0.070 ppm. The EPA solicits comments on this proposed revision of the secondary standard.

The EPA also solicits comments on the alternative approach of revising the secondary standard to a W126-based form, averaged over three years, with a level within the range of 13 ppm-hrs to 17 ppm-hrs. The EPA additionally solicits comments on such a distinct secondary standard with a level within the range extending below 13 ppm-hrs down to 7 ppm-hrs. Further, the EPA solicits comments on retaining the current secondary standard without revision, along with the alternative views of the evidence that would support retaining the current standard.

3. Provisions Related to Implementation

As directed by the CAA, reducing pollution to meet national air quality standards always has been a shared task, one involving the federal government, states, tribes and local air agencies. This partnership has proved effective since the EPA first issued O

standards more than three decades ago, and is evidenced by significantly lower O

levels throughout the country. To provide a foundation that helps air agencies build successful strategies for attaining new O

standards, the EPA will continue to move forward with federal regulatory programs, such as the proposed Clean Power Plan and the final Tier 3 motor vehicle emissions standards. To facilitate the development of CAA-compliant implementation plans and strategies to attain new standards, the EPA intends to issue timely and appropriate implementation guidance and, where appropriate and consistent with the law, new rulemakings to streamline regulatory burdens and provide flexibility in implementation. In addition, given the regional nature of O

air pollution, the EPA will continue to work with states to address interstate transport of O

and O

precursors.

This notice contains several proposed provisions related to implementation of the proposed standards. In addition to revisions to the primary and secondary NAAQS, the EPA is proposing to make corresponding revisions in data handling conventions for O

; to revise regulations for the Prevention of Significant Deterioration (PSD) permitting program to add a provision grandfathering certain pending permits from certain requirements with respect to the proposed revisions to the O

NAAQS; and to convey schedules and information related to implementing any revised standards.

In conjunction with proposing exceptional event schedules related to implementing any revised O

standards, the EPA is also proposing to extend the new schedule approach to other future revised NAAQS and to remove obsolete regulatory language associated with expired exceptional event deadlines for historical standards for both O

and other NAAQS pollutants. The EPA is also proposing to make minor changes to the procedures and time periods for evaluating potential FRMs and equivalent methods, including making the requirements for nitrogen dioxide consistent with the requirements for O

, and removing an obsolete requirement for the annual submission of documentation by manufacturers of certain particulate matter monitors.

B. Legislative Requirements

Two sections of the CAA govern the establishment and revision of the NAAQS. Section 108 (42 U.S.C. 7408) directs the Administrator to identify and list certain air pollutants and then to issue air quality criteria for those pollutants. The Administrator is to list those air pollutants that in her “judgment, cause or contribute to air pollution which may reasonably be anticipated to endanger public health or welfare;” “the presence of which in the ambient air results from numerous or diverse mobile or stationary sources;” and “for which . . . [the Administrator] plans to issue air quality criteria . . . .” Air quality criteria are intended to “accurately reflect the latest scientific knowledge useful in indicating the kind and extent of all identifiable effects on public health or welfare which may be expected from the presence of [a] pollutant in the ambient air . . . .” 42 U.S.C. 7408(b). Section 109 (42 U.S.C. 7409) directs the Administrator to propose and promulgate “primary” and “secondary” NAAQS for pollutants for which air quality criteria are issued. 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.”

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.”

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).

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 provide 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. See

State of Mississippi

EPA,

744 F. 3d 1334, 1353 (D.C. Cir. 2013) (“By requiring an `adequate margin of safety', Congress was directing EPA to build a buffer to protect against uncertain and unknown dangers to human health”); see

also Lead Industries Association

EPA,

647 F.2d 1130, 1154 (D.C. Cir 1980);

American Petroleum Institute

Costle,

665 F.2d 1176, 1186 (D.C. Cir. 1981);

American Farm Bureau Federation

EPA,

559 F. 3d 512, 533 (D.C. Cir. 2009);

Association of Battery Recyclers

EPA,

604 F. 3d 613, 617-18 (D.C. Cir. 2010). 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 provide 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 concentrations, see

Lead Industries

EPA,

647 F.2d at 1156 n.51;

State of Mississippi

EPA,

744 F. 3d at 1351, 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, the EPA considers such factors as the nature and severity of the health effects, the size of sensitive population(s)

at risk, and the kind and degree of the uncertainties that must be addressed. The selection of any particular approach for providing an adequate margin of safety is a policy choice left specifically to the Administrator's judgment. See

Lead Industries Association

EPA,

647 F.2d at 1161-62;

State of Mississippi,

744 F. 3d at 1353.

As used here and similarly throughout this document, the term “population” refers to people having a quality or characteristic in common, including a specific pre-existing illness or a specific age or life stage.

In setting primary and secondary standards that are “requisite” to protect public health and welfare, respectively, as provided in section 109(b), the EPA's task is to establish standards that are neither more nor less stringent than necessary for these purposes. In so doing, the EPA may not consider the costs of implementing the standards. See generally,

Whitman

American Trucking Associations,

531 U.S. 457, 465-472, 475-76 (2001). Likewise, “[a]ttainability and technological feasibility are not relevant considerations in the promulgation of national ambient air quality standards.”

American Petroleum Institute

Costle,

665 F. 2d at 1185.

Section 109(d)(1) 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 . . . .” Since the early 1980's, the Clean Air Scientific Advisory Committee (CASAC) has performed this independent review function.

Lists of CASAC members and of members of the CASAC Ozone Review Panel are available at:

http://yosemite.epa.gov/sab/sabpeople.nsf/WebCommitteesSubCommittees/Ozone%20Review%20Panel

C. Related Control Programs To Implement O

Standards

States are primarily responsible for ensuring attainment and maintenance of ambient air quality standards once the EPA has established them. Under section 110 of the CAA, and related provisions, states are to submit, for the EPA's approval, state implementation plans (SIPs) that provide for the attainment and maintenance of such standards through control programs directed to sources of the pollutants involved. The states, in conjunction with the EPA, also administer the PSD program (CAA sections 160 to 169). In addition, federal programs provide for nationwide reductions in emissions of O

precursors and other air pollutants through the federal motor vehicle and motor vehicle fuel control program under title II of the CAA (sections 202 to 250) which involves controls for emissions from mobile sources and controls for the fuels used by these sources, and new source performance standards for stationary sources under section 111 of the CAA. For some stationary sources, the national emissions standards for hazardous air pollutants under section 112 of the CAA may provide ancillary reductions in O

precursors.

After the EPA establishes a new or revised NAAQS, the CAA directs the EPA and the states to take steps to ensure that the new or revised NAAQS is met. One of the first steps, known as the initial area designations, involves identifying areas of the country that either are attaining or not attaining the new or revised NAAQS along with the nearby areas that contribute to the violations. Upon designation of nonattainment areas, certain states would then be required to develop SIPs to attain the standards. In developing their attainment plans, states would first take into account projected emission reductions from federal and state rules that have been already adopted at the time of plan submittal. A number of significant emission reduction programs that will lead to reductions of O

precursors are in place today or are expected to be in place by the time any new SIPs will be due. Examples of such rules include the Nitrogen Oxides (NO

) SIP Call, Clean Air Interstate Rule (CAIR), and Cross-State Air Pollution Rule (CSAPR),

regulations controlling onroad and nonroad engines and fuels, the utility and industrial boilers hazardous air pollutant rules, and various other programs already adopted by states to reduce emissions from key emissions sources. States would then evaluate the level of additional emission reductions needed for each nonattainment area to attain the O

standards “as expeditiously as practicable,” and adopt new state regulations as appropriate. Section VII of this preamble includes additional discussion of designation and implementation issues associated with any revised O

NAAQS.

The Cross-State Air Pollution Rule was recently upheld by the Supreme Court in

Environmental Protection Agency

EME Homer City Generation,

U.S. (2014). The DC Circuit has since lifted the stay of the rule. Order, Document #1518738,

EME Homer City Generation, L.P.

EPA,

Case #11-1302 (D.C. Cir. Oct. 23, 2014).

D. Review of Air Quality Criteria and Standards for O

The EPA first established primary and secondary NAAQS for photochemical oxidants in 1971 (36 FR 8186, April 30, 1971). The EPA set both primary and secondary standards at a level of 0.08 parts per million (ppm), 1-hr average, total photochemical oxidants, not to be exceeded more than one hour per year. The EPA based the standards on scientific information contained in the 1970

Air Quality Criteria for Photochemical Oxidants

(U.S. DHEW, 1970). The EPA initiated the first periodic review of the NAAQS for photochemical oxidants in 1977. Based on the 1978

Air Quality Criteria for Ozone and Other Photochemical Oxidants

(U.S. EPA, 1978), the EPA published proposed revisions to the original NAAQS in 1978 (43 FR 16962) and final revisions in 1979 (44 FR 8202). At that time, the EPA revised the level of the primary and secondary standards from 0.08 to 0.12 ppm and changed the

indicator from photochemical oxidants to O

and the form of the standards from a deterministic (

i.e.,

not to be exceeded more than one hour per year) to a statistical form. This statistical form defined attainment of the standards as occurring when the expected number of days per calendar year with maximum hourly average concentration greater than 0.12 ppm equaled one or less.

Following the final decision in the 1979 review, the City of Houston challenged the Administrator's decision arguing that the standard was arbitrary and capricious because natural O

concentrations and other physical phenomena in the Houston area made the standard unattainable in that area. The U.S. Court of Appeals for the District of Columbia Circuit (D.C. Circuit) rejected this argument, holding (as noted above) that attainability and technological feasibility are not relevant considerations in the promulgation of the NAAQS. The court also noted that the EPA need not tailor the NAAQS to fit each region or locale, pointing out that Congress was aware of the difficulty in meeting standards in some locations and had addressed this difficulty through various compliance related provisions in the CAA. See

API

Costle,

665 F.2d 1176, 1184-6 (D.C. Cir. 1981).

In 1982, the EPA announced plans to revise the 1978 Air Quality Criteria document (47 FR 11561), and in 1983, the EPA initiated the second periodic review of the O

NAAQS (48 FR 38009). The EPA subsequently published the 1986

Air Quality Criteria for Ozone and Other Photochemical Oxidants

(U.S. EPA, 1986) and the 1989 Staff Paper (U.S. EPA, 1989). Following publication of the 1986 Air Quality Criteria Document (AQCD), a number of scientific abstracts and articles were published that appeared to be of sufficient importance concerning potential health and welfare effects of O

to warrant preparation of a Supplement (U.S. EPA, 1992). On August 10, 1992, under the terms of a court order, the EPA published a proposed decision to retain the existing primary and secondary standards (57 FR 35542). The notice explained that the proposed decision would complete the EPA's review of information on health and welfare effects of O

assembled over a 7-year period and contained in the 1986 AQCD and its 1992 Supplement. The proposal also announced the EPA's intention to proceed as rapidly as possible with the next review of the air quality criteria and standards for O

in light of emerging evidence of health effects related to 6- to 8-hour O

exposures. On March 9, 1993, the EPA concluded the review by affirming its proposed decision to retain the existing primary and secondary standards (58 FR 13008).

In August 1992, the EPA announced plans to initiate the third periodic review of the air quality criteria and O

NAAQS (57 FR 35542). In December 1996, the EPA proposed to replace the then-existing 1-hour primary and secondary standards with 8-hour average O

standards set at a level of 0.08 ppm (equivalent to 0.084 ppm using standard rounding conventions) (61 FR 65716). The EPA also proposed to establish a new distinct secondary standard using a biologically based cumulative, seasonal form. The EPA completed this review on July 18, 1997 (62 FR 38856) by setting the primary standard at a level of 0.08 ppm, based on the annual fourth-highest daily maximum 8-hr average concentration, averaged over three years, and setting the secondary standard identical to the revised primary standard. In reaching this decision, the EPA identified several reasons supporting its decision to reject a potential alternate standard set at 0.07 ppm. Most importantly, the EPA pointed out the scientific uncertainty at lower concentrations and placed significant weight on the fact that no CASAC panel member supported a standard level set lower than 0.08 ppm (62 FR 38868). In addition to noting the uncertainties in the health evidence for exposure concentrations below 0.08 ppm and the advice of CASAC, the EPA noted that a standard set at a level of 0.07 ppm would be closer to peak background concentrations that infrequently occur in some areas due to nonanthropogenic sources of O

precursors (62 FR 38856, 38868; July 18, 1997).

On May 14, 1999, in response to challenges by industry and others to the EPA's 1997 decision, the D.C. Circuit remanded the O

NAAQS to the EPA, finding that section 109 of the CAA, as interpreted by the EPA, effected an unconstitutional delegation of legislative authority.

American Trucking Assoc.

EPA,

175 F.3d 1027, 1034-1040 (D.C. Cir. 1999) (“

ATA I”

). In addition, the court directed that, in responding to the remand, the EPA should consider the potential beneficial health effects of O

pollution in shielding the public from the effects of solar ultraviolet (UV) radiation, as well as adverse health effects.

Id.

at 1051-53. In 1999, the EPA petitioned for rehearing

en banc

on several issues related to that decision. The court granted the request for rehearing in part and denied it in part, but declined to review its ruling with regard to the potential beneficial effects of O

pollution. 195 F.3d 4, 10 (D.C. Cir., 1999) (“

ATA II”

). On January 27, 2000, the EPA petitioned the U.S. Supreme Court for certiorari on the constitutional issue (and two other issues), but did not request review of the ruling regarding the potential beneficial health effects of O

. On February 27, 2001, the U.S. Supreme Court unanimously reversed the judgment of the D.C. Circuit on the constitutional issue.

Whitman

American Trucking Assoc.,

531 U.S. 457, 472-74 (2001) (holding that section 109 of the CAA does not delegate legislative power to the EPA in contravention of the Constitution). The Court remanded the case to the D.C. Circuit to consider challenges to the O

NAAQS that had not been addressed by that court's earlier decisions. On March 26, 2002, the D.C. Circuit issued its final decision on remand, finding the 1997 O

NAAQS to be “neither arbitrary nor capricious,” and so denying the remaining petitions for review.

American Trucking Associations, Inc.

EPA,

283 F.3d 355, 379 (D.C. Cir., 2002) (“

ATA III”

Specifically, in

ATA III,

the D.C. Circuit upheld the EPA's decision on the 1997 O

standard as the product of reasoned decision-making. With regard to the primary standard, the court made clear that the most important support for EPA's decision to revise the standard was the health evidence of insufficient protection afforded by the then-existing standard (“the record is replete with references to studies demonstrating the inadequacies of the old one-hour standard”), as well as extensive information supporting the change to an 8-hour averaging time. 283 F.3d at 378. The court further upheld the EPA's decision not to select a more stringent level for the primary standard noting “the absence of any human clinical studies at ozone concentrations below 0.08 [ppm]” which supported EPA's conclusion that “the most serious health effects of ozone are `less certain' at low concentrations, providing an eminently rational reason to set the primary standard at a somewhat higher level, at least until additional studies become available.”

Id.

(internal citations omitted). The Court also pointed to the significant weight that the EPA properly placed on the advice it received from CASAC.

Id.

at 379. In addition, the court noted that “although relative proximity to peak background O

concentrations did not, in itself, necessitate a level of 0.08 [ppm], EPA could consider that factor when choosing among the three alternative levels.”

Id.

Independently of the litigation, the EPA responded to the court's remand to

consider the potential beneficial health effects of O

pollution in shielding the public from effects of UV radiation. The EPA provisionally determined that the information linking changes in patterns of ground-level O

concentrations to changes in relevant patterns of exposures to UV radiation of concern to public health was too uncertain, at that time, to warrant any relaxation in 1997 O

NAAQS. The EPA also expressed the view that any plausible changes in UV-B radiation exposures from changes in patterns of ground-level O

concentrations would likely be very small from a public health perspective. In view of these findings, the EPA proposed to leave the 1997 8-hour NAAQS unchanged (66 FR 57268, Nov. 14, 2001). After considering public comment on the proposed decision, the EPA published its final response to this remand on January 6, 2003, re-affirming the 8-hour O

NAAQS set in 1997 (68 FR 614).

The EPA initiated the fourth periodic review of the air quality criteria and O

standards in September 2000 with a call for information (65 FR 57810). The schedule for completion of that review was ultimately governed by a consent decree resolving a lawsuit filed in March 2003 by plaintiffs representing national environmental and public health organizations, who maintained that the EPA was in breach of a mandatory legal duty to complete review of the O

NAAQS within a statutorily mandated deadline. On July 11, 2007, the EPA proposed to revise the level of the primary standard within a range of 0.075 to 0.070 ppm (72 FR 37818). Documents supporting this proposed decision included the

Air Quality Criteria for Ozone and Other Photochemical Oxidants

(U.S. EPA, 2006a) and the Staff Paper (U.S. EPA, 2007) and related technical support documents. The EPA also proposed two options for revising the secondary standard: (1) Replace the current standard with a cumulative, seasonal standard, expressed as an index of the annual sum of weighted hourly concentrations cumulated over 12 daylight hours during the consecutive 3-month period within the O

season with the maximum index value, set at a level within the range of 7 to 21 ppm-hrs, or (2) set the secondary standard identical to the proposed primary standard. The EPA completed the review with publication of a final decision on March 27, 2008 (73 FR 16436). In that final rule, the EPA revised the NAAQS by lowering the level of the 8-hour primary O

standard from 0.08 ppm to 0.075 ppm, not otherwise revising the primary standard, and adopting a secondary standard identical to the revised primary standard. In May 2008, state, public health, environmental, and industry petitioners filed suit challenging the EPA's final decision on the 2008 O

standards. On September 16, 2009, the EPA announced its intention to reconsider the 2008 O

standards, and initiated a rulemaking to do so. At the EPA's request, the Court held the consolidated cases in abeyance pending the EPA's reconsideration of the 2008 decision.

On January 19, 2010 (75 FR 2938), the EPA issued a notice of proposed rulemaking to reconsider the 2008 final decision. In that notice, the EPA proposed that further revisions of the primary and secondary standards were necessary to provide a requisite level of protection to public health and welfare. The EPA proposed to decrease the level of the 2008 8-hour primary standard from 0.075 ppm to a level within the range of 0.060 to 0.070 ppm, and to change the secondary standard to a new cumulative, seasonal standard expressed as an annual index of the sum of weighted hourly concentrations, cumulated over 12 hours per day (8 a.m. to 8 p.m.), during the consecutive 3-month period within the O

season with a maximum index value, set at a level within the range of 7 to 15 ppm-hours. The Agency also solicited CASAC review of the proposed rule on January 25, 2010 and solicited additional CASAC advice on January 26, 2011. After considering comments from CASAC and the public, the EPA prepared a draft final rule, which was submitted for interagency review pursuant to Executive Order 12866. On September 2, 2011, consistent with the direction of the President, the Administrator of the Office of Information and Regulatory Affairs (OIRA), Office of Management and Budget (OMB), returned the draft final rule to the EPA for further consideration. In view of this return and the fact that the Agency's next periodic review of the O

NAAQS required under CAA section 109 had already begun (as announced on September 29, 2008), the EPA deferred the decisions involved in the reconsideration until it completed its statutorily required periodic review.

In light of EPA's decision to consolidate the reconsideration with the current review, the D.C. Circuit proceeded with the litigation on the 2008 final decision. On July 23, 2013, the Court upheld the EPA's 2008 primary O

standard, but remanded the 2008 secondary standard to the EPA.

State of Mississippi

EPA,

744 F.3d 1334. With respect to the primary standard, the court first held that the EPA reasonably determined that the existing standard was not requisite to protect public health with an adequate margin of safety, and consequently required revision. Specifically, the court noted that there were “numerous epidemiologic studies linking health effects to exposure to ozone levels below 0.08 ppm and clinical human exposure studies finding a causal relationship between health effects and exposure to ozone levels at and below 0.08 ppm.” 744 F.3d at 1345. The court also specifically endorsed the weight of evidence approach utilized by the EPA in its deliberations.

Id.

at 1344.

The court went on to reject arguments that the EPA should have adopted a more stringent primary standard. Dismissing arguments that a clinical study (as properly interpreted by the EPA) showing effects at 0.06 ppm necessitated a standard level lower than that selected, the court noted that this was a single, limited study.

Id.

at 1350. With respect to the epidemiologic evidence, the court accepted the EPA's argument that there could be legitimate uncertainty that a causal relationship between O

and 8-hour exposures less than 0.075 ppm exists, so that associations at lower levels reported in epidemiologic studies did not necessitate a more stringent standard.

Id.

at 1351-52.

The court cautioned, however, that “perhaps more [clinical] studies like the Adams studies will yet reveal that the 0.060 ppm level produces significant adverse decrements that simply cannot be attributed to normal variation in lung function,” and further cautioned that “agencies may not merely recite the terms `substantial uncertainty' as a justification for their actions.”

Id.

at 1350, 1357 (internal citations omitted).

The court also rejected arguments that an 8-hour primary standard of 0.075 ppm failed to provide an adequate margin of safety, noting that margin of safety considerations involved policy judgments by the agency, and that by setting a standard “appreciably below” the level of the current standard (0.08 ppm), the agency had made a reasonable policy choice.

Id.

Finally, the court rejected arguments that the EPA's decision was inconsistent with CASAC's scientific recommendations because CASAC had been insufficiently clear in its recommendations whether it was providing scientific or policy recommendations, and the EPA had reasonably addressed CASAC's policy recommendations.

Id.

at 1357-58.

With respect to the secondary standard, the court held that because the EPA had failed to identify a level of air quality requisite to protect public welfare, the EPA's comparison between

the primary and secondary standards for determining if requisite protection for public welfare was afforded by the primary standard did not comply with the CAA. The court thus rejected the EPA's explanation for setting the secondary standard identical to the revised 8-hour primary standard, and remanded the secondary standard to the EPA.

Id.

at 1360-62.

At the time of the court's decision, the EPA had already completed significant portions of its next statutorily required periodic review of the O

NAAQS. On September 29, 2008, the EPA announced the initiation of a new periodic review of the air quality criteria for O

and related photochemical oxidants and issued a call for information in the

Federal Register

(73 FR 56581, Sept. 29, 2008). A wide range of external experts, as well as the EPA staff, representing a variety of areas of expertise (

e.g.,

epidemiology, human and animal toxicology, statistics, risk/exposure analysis, atmospheric science, ecology, biology, plant science, ecosystem services) participated in a workshop. This workshop was held on October 28-29, 2008 in Research Triangle Park, NC. The workshop provided an opportunity for a public discussion of the key policy-relevant issues around which the EPA would structure this O

NAAQS review and the most meaningful new science that would be available to inform our understanding of these issues.

Based in part on the workshop discussions, the EPA developed a draft Integrated Review Plan (IRP) outlining the schedule, process, and key policy-relevant questions that would guide the evaluation of the air quality criteria for O

and the review of the primary and secondary O

NAAQS. A draft of the IRP was released for public review and comment in September 2009. This IRP was the subject of a consultation with the CASAC on November 13, 2009 (74 FR 54562; October 22, 2009).

The EPA considered comments received from that consultation and from the public in finalizing the plan and in beginning the review of the air quality criteria. The EPA's overall plan and schedule for this review is presented in the

Integrated Review Plan for the Ozone National Ambient Air Quality Standards.

See

http://yosemite.epa.gov/sab/sabproduct.nsf/WebProjectsbyTopicCASAC!OpenView

for more information on CASAC activities related to the current O

NAAQS review.

EPA 452/R-11-006; April 2011; Available:

http://www.epa.gov/ttn/naaqs/standards/ozone/data/2011_04_OzoneIRP.pdf.

As part of the process of preparing the O

ISA, the EPA's NCEA hosted a workshop to review and discuss preliminary drafts of key sections of the ISA on August 6, 2010 (75 FR 42085, July 20, 2010). The CASAC and the public reviewed the first external review draft ISA (U.S. EPA, 2011a; 76 FR 10893, February 28, 2011) at a meeting held in May 19-20, 2011 (76 FR 23809; April 28, 2011). Based on CASAC and public comments, NCEA prepared a second draft ISA (U.S. EPA, 2011b; 76 FR 60820, September 30, 2011). CASAC and the public reviewed this draft at a January 9-10, 2012 (76 FR 236, December 8, 2011) meeting. Based on CASAC and public comments, NCEA prepared a third draft ISA (U.S. EPA 2012a; 77 FR 36534; June 19, 2012), which was reviewed at a CASAC meeting in September 2012. The EPA released the final ISA (EPA/600/R-10/076F) in February 2013.

The EPA presented its plans for conducting the Risk and Exposure Assessments (REAs) that build on the scientific evidence presented in the ISA, in two planning documents titled

Ozone National Ambient Air Quality Standards: Scope and Methods Plan for Health Risk and Exposure Assessment

and

Ozone National Ambient Air Quality Standards: Scope and Methods Plan for Welfare Risk and Exposure Assessment

(henceforth, Scope and Methods Plans).

These planning documents outlined the scope and approaches that staff planned to use in conducting quantitative assessments, as well as key issues that would be addressed as part of the assessments. The EPA released these documents for public comment in April 2011, and consulted with CASAC on May 19-20, 2011 (76 FR 23809; April 28, 2011). In designing and conducting the initial health risk and welfare risk assessments, the EPA considered CASAC comments (Samet, 2011) on the Scope and Methods Plans and also considered public comments. In May 2012, the EPA issued a memo titled

Updates to Information Presented in the Scope and Methods Plans for the Ozone NAAQS Health and Welfare Risk and Exposure Assessments

that described changes to elements of the scope and methods plans and provided a brief explanation of each change and the reason for it.

EPA-452/P-11-001 and -002; April 2011; Available:

http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_2008_pd.html.

In July 2012, the EPA made the first drafts of the Health and Welfare REAs available for CASAC review and public comment (77 FR 42495, July 19, 2012). The first draft PA

was made available for CASAC review and public comment in August 2012. These documents were reviewed by the CASAC O

Panel at a public meeting in September 2012. The second draft REAs and PA, made available by the EPA in January 2014 (79 FR 4694, January 29, 2014), were prepared with consideration of advice from CASAC (Frey and Samet, 2012a, 2012b) and comments from the public. These drafts were reviewed by the CASAC O

Panel at a public meeting on March 25-27, 2014. The CASAC issued final reports on the second drafts of the HREA on July 1, 2014 (Frey, 2014a), and the WREA on June 18, 2014 (Frey, 2014b), respectively. The CASAC issued a final report on the second draft PA on June 26, 2014 (Frey, 2014c). The final versions of the HREA (U.S. EPA 2014a), WREA (U.S. EPA, 2014b), and PA (U.S. EPA, 2014c) were made available by the EPA in August, 2014. These documents reflect staff's consideration of the comments and recommendations made by CASAC, as well as comments made by members of the public, in their review of the draft versions of these documents.

The PA is prepared by the staff in the EPA's Office of Air Quality Planning and Standards (OAQPS). It presents a staff evaluation of the policy implications of the key scientific and technical information in the ISA and REAs for the EPA's consideration. The PA provides a transparent evaluation, and staff conclusions, regarding policy considerations related to reaching judgments about the adequacy of the current standards, and if revision is considered, what revisions may be appropriate to consider. The PA is intended to help “bridge the gap” between the agency's scientific assessments presented in the ISA and REAs, and the judgments required of the EPA Administrator in determining whether it is appropriate to retain or revise the NAAQS.

E. Ozone Air Quality

Ozone is formed near the Earth's surface due to chemical interactions involving solar radiation and precursor pollutants including volatile organic compounds (VOCs), nitrogen oxides (NO

), methane (CH

) and carbon monoxide (CO). The precursor emissions leading to O

formation can result from both man-made sources (

e.g.,

motor vehicles and electric power generation) and natural sources (

e.g.,

vegetation and wildfires). Occasionally, O

that is created naturally in the stratosphere can also contribute to O

levels near the surface. Once formed, O

can be transported by winds before eventually being removed from the atmosphere via chemical reactions or deposition to surfaces. In sum, O

concentrations are influenced by complex interactions between precursor emissions, meteorological conditions, and surface characteristics.

In order to continuously assess O

air pollution levels, state and local environmental agencies operate O

monitors at various locations and

subsequently submit the data to the EPA. At present, there are approximately 1,400 monitors across the U.S. reporting hourly O

averages during the times of the year when local O

pollution can be important. Much of this monitoring is focused on O

measurements in urban areas where precursor emissions tend to be largest, as well as locations directly downwind of these areas, but there are also over 100 sites in rural areas where high levels of O

can periodically exist due to transport from upwind sources. Based on data from this national network, the EPA estimates that approximately 133 million Americans live in counties where O

concentrations were above the level of the existing health-based NAAQS of 0.075 ppm at least 4 days in 2012. High O

values can occur almost anywhere within the contiguous 48 states, although locations in California, Texas, and the Northeast Corridor are especially subject to poor O

air quality. From a temporal perspective, the highest daily peak O

concentrations generally tend to occur during the afternoon within the warmer months due to higher solar radiation and other conducive meteorological conditions during these times. The exceptions to this general rule include: (1) Some rural sites where transport of O

from upwind areas of regional production can occasionally result in high nighttime levels of O

, (2) high-elevation sites periodically influenced by stratospheric intrusions, and (3) certain locations in the western U.S. where large quantities of O

precursors emissions associated with oil and gas development can be trapped by strong inversions associated with snow cover during the colder months and efficiently converted to O

One of the challenging aspects of developing plans to reduce emissions leading to high O

concentrations is that the response of O

to precursor reductions is nonlinear. In particular, NO

causes both the formation and destruction of O

. The net impact of NO

emissions on O

concentrations depends on the local quantities of NO

, VOC, and sunlight which interact in a set of complex chemical reactions. In some areas, such as urban centers where NO

emissions typically are high, NO

leads to the net destruction of O

, making O

levels lower in the immediate vicinity. This phenomenon is particularly pronounced under conditions that lead to low O

concentrations (

i.e.

during cool, cloudy weather and at night when photochemical activity is limited or nonexistent). However, while NO

can initially destroy O

near the emission sources, these same NO

emissions eventually do react to form more O

downwind. Photochemical model simulations suggest that the additional expected reductions in NO

emissions will slightly increase O

concentrations on days with lower O

concentrations in areas in close proximity to NO

sources, while at the same time decreasing the highest O

concentrations in outlying areas. See generally, U.S. EPA, 2014a (section 2.2.1).

At present, both the primary and secondary NAAQS use the annual fourth-highest daily maximum 8-hour concentration, averaged over 3 years, as the form of the standard. An additional air quality metric, referred to as W126, is often used to assess cumulative impact of O

exposure on ecosystems and vegetation. W126 is a seasonal aggregate of weighted hourly O

values observed between 8 a.m. and 8 p.m. As O

precursor emissions have decreased across the U.S., O

design values

have concurrently shown a modest downward trend. Ozone design values decreased by approximately 9% on average between 2000 and 2012. Air quality model simulations estimate that peak O

levels will continue to improve over the next decade as additional reductions in O

precursors from power plants, motor vehicles, and other sources are realized.

A design value is a statistic that describes the air quality status of a given location relative to the level of the NAAQS.

In addition to being affected by changing emissions, future O

concentrations will also be affected by climate change. Modeling studies in EPA's Interim Assessment (U.S. EPA, 2009b) and cited in support of the 2009 Endangerment Finding (74 FR 66,496; Dec. 15, 2009) show that, while the impact is not uniform, climate change has the potential to cause increases in summertime O

concentrations over substantial regions of the country, with increases tending to occur during higher peak pollution episodes in the summer, if offsetting emissions reductions are not made. Increases in temperature are expected to be the principal factor in driving any ozone increases, although increases in stagnation frequency may also contribute (Jacob and Winner, 2009). These increases in O

pollution over broad areas of the U.S., including in the largest metropolitan areas with the worst O

problems, increase the risk of morbidity and mortality. Children, people with asthma or other lung diseases, older adults, and people who are active outdoors, including outdoor workers, are among the most vulnerable to these O

-related health effects. If unchecked, climate change has the potential to offset some of the improvements in O

air quality, and therefore some of the improvements in public health, that are expected from reductions in emissions of O

precursors.

Another challenging aspect of the O

issue is the involvement of sources of O

and O

precursors beyond those from domestic, anthropogenic sources. Modeling analyses have suggested that nationally the majority of O

exceedances are predominantly caused by anthropogenic emissions from within the U.S. However, observational and modeling analyses have concluded that O

concentrations in some locations in the U.S. can be substantially influenced by sources that may not be suited to domestic control measures. In particular, certain high-elevation sites in the western U.S. are impacted by a combination of non-local sources like international transport, stratospheric O

, and O

originating from wildfire emissions. Ambient O

from these non-local sources is collectively referred to as background O

. See generally section 2.4 of the Policy Assessment (U.S. EPA, 2014c). The analyses suggest that, at these locations, there can be episodic events with substantial background contributions where O

concentrations approach or exceed the level of the current NAAQS (

i.e.,

75 ppb). These events are relatively infrequent and the EPA has policies that allow for the exclusion of air quality monitoring data from design value calculations when they are substantially affected by certain background influences. Wildfires pose a direct threat to air quality and public safety—threats that can be mitigated through management of wildland vegetation. The use of wildland prescribed fire can influence the occurrence of catastrophic wildfires which may help manage the contribution of wildfires to background O

levels and periodic peak O

events. Prescribed fire mimics a natural process necessary to manage and maintain fire-adapted ecosystems and climate change adaptation, while reducing risk of uncontrolled emissions from catastrophic wildfires. Wildfire emissions may make it more challenging to meet the NAAQS. However, the CAA requires the EPA to set the NAAQS at levels requisite to protect public health and welfare without regard to the source of the pollutant.

API,

665 F. 2d at 1185-86. The EPA may consider proximity to background levels as a factor in the decision whether and how to revise the NAAQS when considering levels within the range of reasonable values

supported by the air quality criteria and judgments of the Administrator.

ATA III,

283 F. 3d at 379. It is in the implementation process that states and the EPA can address how to develop effective public policy in locations in which background sources contribute substantially to high O

. Section VII.F provides more detail about how background O

can be addressed via CAA implementation provisions.

II. Rationale for Proposed Decision on the Primary Standard

This section presents the Administrator's rationale for her proposed decision to revise the existing primary O

standard by lowering the level of the standard to within the range of 0.065 to 0.070 ppm. As discussed more fully below, this rationale draws from the thorough review in the ISA of the available scientific evidence, published through July 2011, on human health effects associated with the presence of O

in the ambient air. This rationale also takes into account: (1) Analyses of O

air quality, human exposures to O

, and O

-associated health risks, as presented and assessed in the HREA; (2) the EPA staff assessment of the most policy-relevant scientific evidence and exposure/risk information in the PA; (3) CASAC advice and recommendations, as reflected in discussions of drafts of the ISA, REA, and PA at public meetings, in separate written comments, and in CASAC's letters to the Administrator; and (4) public input received during the development of these documents, either in connection with CASAC meetings or separately.

Section II.A below provides an overview of the approaches used to consider the scientific evidence and exposure/risk information as it relates to the primary O

standard. This includes summaries of the approach adopted by the Administrator in the 2008 review of the O

NAAQS and of the approach adopted in the PA in the current review. Section II.B summarizes the body of evidence for health effects attributable to short- or long-term O

exposures, with a focus on effects for which the ISA judges that there is a “causal” or a “likely to be causal” relationship with O

exposures. Section II.C summarizes the HREA's quantitative estimates of O

exposures and health risks, including key results and uncertainties. Sections II.D and II.E present the Administrator's proposed conclusions on the adequacy of the current primary O

standard and alternative primary standards, respectively.

A. Approach

In the 2008 review of the O

NAAQS, Administrator Stephen L. Johnson revised the level of the 8-hour primary O

standard from 0.08 ppm

to 0.075 ppm (75 parts per billion (ppb)

). This decision was based on his consideration of the available scientific evidence and exposure/risk information, the advice and recommendations of CASAC, and comments from the public. The Administrator placed primary emphasis on the body of available scientific evidence, while viewing the results of exposure and risk assessments as providing supporting information. Specifically, he judged that a standard set at 75 ppb would be appreciably below the concentration at which adverse effects had been demonstrated in the controlled human exposure studies available at that time (

i.e.,

80 ppb), and would provide a significant increase in protection compared to the then-current standard. The Administrator further concluded that the body of evidence did not support setting a lower standard level, given the increasing uncertainty in the evidence at lower O

concentrations (U.S. EPA, 2014c, Chapter 1).

Due to rounding convention, the 1997 standard level of 0.08 ppm corresponded to 0.084 ppm (84 ppb).

The level of the O

standard is specified as 0.075 ppm rather than 75 ppb. However, in the PA we refer to ppb, which is most often used in the scientific literature and in the ISA, in order to avoid the confusion that could result from switching units when discussing the evidence in relation to the standard level. Similarly, in the preamble to this notice we refer to ppb.

In the current review, the EPA's approach to informing decisions on the primary O

standard builds upon the general approach used in the last review and reflects the broader body of scientific evidence, updated exposure/risk information, and advances in O

air quality modeling now available. This approach, described in detail in the PA (U.S. EPA, 2014c, section 1.3.1), is based most fundamentally on using the EPA's assessment of the available scientific evidence and associated quantitative analyses to inform the Administrator's judgments regarding a primary standard for O

that is “requisite” (

i.e.,

neither more nor less stringent than necessary) to protect public health with an adequate margin of safety. Specifically, it is based on consideration of the available body of scientific evidence assessed in the ISA (U.S. EPA, 2013a), exposure and risk analyses presented in the HREA (U.S. EPA, 2014a), advice and recommendations from CASAC (Frey, 2014a, c), and public comments. Based on the application of this approach, the PA assesses and integrates the evidence and information, and reaches conclusions for the Administrator's consideration about the range of policy options that could be supported. The remainder of this section describes the PA's approach to reviewing the primary O

standard, and to informing the Administrator's proposed decisions on the current and alternative standards.

As an initial matter, the PA recognizes that the final decision to retain or revise the current primary O

standard is a public health policy judgment to be made by the Administrator and will draw upon the available scientific evidence for O

-attributable health effects and on analyses of population exposures and health risks, including judgments about the appropriate weight to assign the range of uncertainties inherent in the evidence and analyses. The PA's general approach to informing these public health policy judgments recognizes that the available health effects evidence reflects a continuum from relatively higher O

concentrations, at which scientists generally agree that health effects are likely to occur, through lower concentrations, at which the likelihood and magnitude of a response become increasingly uncertain. Therefore, the conclusions in the PA reflect an interpretation of the available scientific evidence and exposure/risk information that, in the views of the EPA staff, neither overstates nor understates the strengths and limitations of that evidence and information.

This approach is consistent with the requirements of sections 108 and 109 of the CAA, as well as with how the EPA and the courts have historically interpreted the CAA.

Draft versions of the PA were subject to review by CASAC and the final PA reflects consideration of the advice received from CASAC during the review process. CASAC concluded that “Overall, we find the Second Draft PA to be adequate for its intended purpose of providing a strong scientific basis for findings regarding the inadequacy of current primary and secondary ozone air quality standards” (Frey, 2014c, p. v).

The PA draws upon an integrative synthesis of the entire body of available scientific evidence for O

-related health effects, including the evidence newly available in the current review and the evidence from previous reviews, as presented in the ISA (U.S. EPA, 2013a). Consideration of the scientific evidence is based fundamentally on information from controlled human exposure and epidemiologic studies, supplemented by information from animal toxicology studies. In the PA, such evidence informs the consideration of the health

endpoints and at-risk populations

on which to focus the current review, and the consideration of the O

concentrations at which various health effects can occur.

In this review, the term “at-risk population” is used to encompass populations or lifestages that have a greater likelihood of experiencing health effects related to exposure to an air pollutant due to a variety of factors; other terms used in the literature include susceptible, vulnerable, and sensitive. These factors may be intrinsic, such as genetic factors, lifestage, or the presence of preexisting diseases, or they may be extrinsic, such as socioeconomic status (SES), activity pattern and exercise level, or increased pollutant exposures (U.S. EPA 2013, p. lxx, 8-1, 8-2). The courts and the CAA's legislative history refer to these at-risk subpopulations as “susceptible” or “sensitive” populations. See,

e.g., American Lung Ass'n

EPA,

134 F. 3d 388, 389 (D.C. Cir. 1998) (“NAAQS must protect not only average health individuals, but also `sensitive citizens'—children, for example, or people with asthma, emphysema, or other conditions rendering them particularly vulnerable to air pollution” (quoting S. Rep. No. 91-1196 at 10).

Since the 2008 review of the O

NAAQS, the EPA has developed formal frameworks for characterizing the strength of the scientific evidence with regard to health effects associated with exposures to O

in ambient air and factors that may increase risk in some populations or lifestages. These frameworks provide the basis for robust, consistent, and transparent processes for evaluating the scientific evidence, including uncertainties in the evidence, and for drawing weight-of-evidence conclusions on air pollution-related health effects and at-risk populations. These frameworks for characterizing the strength of the scientific evidence are discussed in detail in the ISA (U.S. EPA, 2013a, Preamble; Chapter 8).

With regard to characterization of health effects, the ISA uses a five-level hierarchy to classify the overall weight of evidence into one of the following categories: causal relationship, likely to be a causal relationship, suggestive of a causal relationship, inadequate to infer a causal relationship, and not likely to be a causal relationship (U.S. EPA, 2013a, Preamble Table II). In using the 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

, confidence increases as the number of studies consistently reporting a particular health endpoint grows and as other factors, such as biological plausibility and the strength, consistency, and coherence of evidence, increase. Conclusions about biological plausibility and about the consistency and coherence of O

-related health effects are drawn from the integration of epidemiologic studies with mechanistic information from controlled human exposure and animal toxicological studies, as discussed in the ISA (U.S. EPA, 2013a, EPA Framework for Causal Determination, p. 1viii). The PA places the greatest weight on the health effects for which the evidence has been judged in the ISA to support a “causal” or a “likely to be causal” relationship with O

exposures.

The PA further considers the evidence base assessed in the ISA with regard to the types and levels of exposure at which health effects are indicated. This consideration of the evidence, which directly informs conclusions regarding the adequacy of current or alternative standards, differs from consideration of the evidence in the ISA with regard to overarching determinations of causality. Therefore, studies that inform determinations of causality may or may not be concluded to be informative with regard to the adequacy of the current or alternative standards.

For example, the PA judges that health studies evaluating exposure concentrations near or below the level of the current standard and epidemiologic studies conducted in locations meeting the current standard are particularly informative when considering the adequacy of the public health protection provided by the current standard (U.S. EPA, 2014c, Chapters 3 and 4).

As with health endpoints, the ISA's characterization of the weight of evidence for potential at-risk populations is based on the evaluation and synthesis of evidence from across scientific disciplines. The ISA uses the collective evidence to examine the coherence of effects across disciplines and to determine the biological plausibility of reported effects. Based on this approach, the ISA characterizes the evidence for a number of “factors” that have the potential to place populations at increased risk for O

-related effects. The categories considered in evaluating the evidence for these potential at-risk factors are “adequate evidence,” “suggestive evidence,” “inadequate evidence,” and “evidence of no effect.” For the “adequate evidence” category, the ISA concludes that this category is appropriate when multiple high-quality studies show “there is substantial, consistent evidence within a discipline to conclude that a factor results in a population or lifestage being at increased risk of air pollutant-related health effect(s) relative to some reference population or lifestage” (U.S. EPA, 2013a, p. 8-2). In addition, where applicable, the “adequate evidence” category reflects a conclusion that there is coherence in the evidence across disciplines. The other categories reflect greater uncertainty in the evidence. In this review, the PA focuses on those factors for which the ISA judges there is adequate evidence of increased risk (U.S. EPA, 2013a, Table 8-5). At-risk populations are discussed in more detail in section 3.1.5 of the PA (U.S. EPA, 2014c) and these categories are discussed in more detail in the ISA (U.S. EPA, 2013a, chapter 8, Table 8-1).

Using the available scientific evidence to inform conclusions on the current and alternative standards is complicated by the recognition that a population-level threshold has not been identified below which it can be concluded with confidence that O

-attributable effects do not occur (U.S. EPA, 2013a, section 2.5.4.4). In the absence of a discernible threshold, the PA's general approach to considering the available O

health evidence involves characterizing confidence in the extent to which O

-attributable effects occur, and the extent to which such effects are adverse, over the ranges of O

exposure concentrations evaluated in controlled human exposure studies and over the distributions of ambient O

concentrations in locations where epidemiologic studies have been conducted. As noted above, the PA recognizes that the available health effects evidence reflects a continuum from relatively high O

concentrations, at which scientists generally agree that adverse health effects are likely to occur, through lower concentrations, at which the likelihood and magnitude of a response become increasingly uncertain. Aspects of the approach used in this review to evaluate evidence from controlled human exposure and epidemiologic studies, respectively, are discussed below.

Controlled human exposure studies provide direct evidence of relationships between pollutant exposures and human health effects (U.S. EPA, 2013a, p.lx). 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. Such studies are particularly useful in defining the specific conditions under which pollutant exposures can result in health impacts, including the exposure concentrations, durations, and ventilation rates under which effects can occur. As discussed in the ISA, controlled human exposure studies provide clear and compelling evidence for an array of human health effects that are directly attributable to acute exposures to O

per se

(

i.e.,

as opposed to O

and other photochemical oxidants, for which O

is an indicator, or other co-occurring pollutants) (U.S. EPA, 2013a, Chapter 6). Together with animal toxicological studies, which can provide

information about more serious health outcomes as well as the effects of long-term exposures and mode of action, controlled human exposure studies also help to provide biological plausibility for health effects observed in epidemiologic studies.

The PA considers the evidence from controlled human exposure studies in two ways. First, the PA considers the extent to which controlled human exposure studies provide evidence for health effects following exposures to different O

concentrations, down to the lowest-observed-effects levels in those studies. Second, the PA uses these studies to help evaluate the extent to which there is confidence in health effect associations reported in epidemiologic studies down through lower ambient O

concentrations, where the likelihood and magnitude of O

-attributable effects become increasingly uncertain.

The PA considers the range of O

exposure concentrations evaluated in controlled human exposure studies, including concentrations near or below the level of the current standard. The PA considers both group mean responses, which provide insight into the extent to which observed changes are due to O

exposures rather than to chance alone, and interindividual variability in responses, which provides insight into the fraction of the population that might be affected by such O

exposures (U.S. EPA, 2013a, section 6.2.1.1). When considering the relative weight to place on various controlled human exposure studies, the discussion in the PA focuses on the exposure conditions evaluated (

e.g.,

exercising versus resting, exposure duration); the nature, magnitude, and likely adversity of effects over the range of reported O

exposure concentrations; the statistical precision of reported effects; and the consistency of results across studies for a given health endpoint and exposure concentration. In addition, because controlled human exposure studies typically involve healthy individuals and do not evaluate the most sensitive individuals in the population (U.S. EPA, 2013a, Preamble p. lx), when considering the implications of these studies for evaluation of the current and alternative standards, the PA also considers the extent to which reported effects are likely to reflect the magnitude and/or severity of effects in at-risk groups.

The PA also considers epidemiologic studies of short- and long-term O

concentrations in ambient air. Epidemiologic studies provide information on associations between variability in ambient O

concentrations and variability in various health outcomes, including lung function decrements, respiratory symptoms, school absences, hospital admissions, emergency department visits, and premature mortality (U.S. EPA, 2013a, Chapters 6 and 7). Epidemiologic studies can inform understanding of the effects in the study population (which may include at-risk groups) of real-world exposures to the range of O

concentrations in ambient air, as well as provide evidence of associations between ambient O

levels and more serious acute and chronic health effects 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 (

e.g.

, effects modifiers such as averting behavior) affects the level of confidence that the health effects being investigated are attributable to O

exposures, alone and in combination with copollutants.

Available epidemiologic studies have generally not indicated a discernible population threshold below which O

is no longer associated with health effects (U.S. EPA, 2013a, section 2.5.4.4). However, the currently available epidemiologic evidence indicates decreased confidence in reported concentration-response relationships for O

concentrations at the lower ends of ambient distributions due to the low density of data in this range (U.S. EPA, 2013a, section 2.5.4.4). As discussed more fully in Chapter 1 of the PA (U.S. EPA, 2014c), the general approach to considering the results of epidemiologic studies within the context of the current and alternative standards focuses on characterizing the range of ambient O

concentrations over which studies indicate the most confidence in O

-associated health effects, and the concentrations below which confidence in such health effect associations becomes appreciably lower.

In placing emphasis on specific epidemiologic studies, as in past reviews, the discussion in the PA focuses on the epidemiologic studies conducted in the U.S. and Canada. Such studies reflect air quality and exposure patterns that are likely more typical of the U.S. population, since studies conducted outside the U.S. and Canada may well reflect different demographic and air pollution characteristics.

The PA also focuses on studies reporting associations with effects judged in the ISA (U.S. EPA, 2013a) to be robust to confounding by other factors, including co-occurring air pollutants.

Though the PA recognizes that a broader body of studies, including international studies, informs the causal determinations in the ISA.

To put staff conclusions about O

-related health effects into a broader public health context, the PA also considers exposure and risk estimates from the HREA, which develops and applies models to estimate human exposures to O

and O

-related health risks in urban study areas across the United States (U.S. EPA, 2014a). The HREA estimates exposures of concern, based on interpreting quantitative exposure estimates within the context of controlled human exposure study results; lung function risks, based on applying exposure-response relationships from controlled human exposure studies to quantitative estimates of exposures; and epidemiologic-based risk estimates, based on applying concentration-response relationships drawn from epidemiologic studies to adjusted air quality. Each of these types of assessments is discussed briefly below.

As in the 2008 review, the HREA estimates exposures at or above benchmark concentrations of 60, 70, and 80 ppb, reflecting exposure concentrations of concern based on the available health evidence.

Estimates of exposures of concern, defined as personal exposures while at moderate or greater exertion to 8-hour average ambient O

levels, at or above these discrete benchmark concentrations provide perspective on the public health risks of O

-related health effects that have been demonstrated in controlled human exposure and toxicological studies. However, because of a lack of exposure-response information across a range of exposure concentrations in these studies, these risks cannot be assessed using a quantitative risk assessment. Though this analysis is conducted using discrete benchmark concentrations, information from the broad body of evidence indicates that health-relevant exposures are more appropriately viewed as a continuum with greater confidence and certainty about the existence of health effects at higher O

exposure concentrations and less confidence and certainty at lower exposure concentrations. This approach recognizes that there is no sharp breakpoint within the exposure-response relationship for exposure concentrations at and above 80 ppb down to 60 ppb.

For example, see 75 FR 2945-2946 (January 19, 2010) and 73 FR 16441-16442 (March 27, 2008) discussing “exposures of concern.”

Within the context of this continuum, estimates of exposures of concern at these discrete benchmark

concentrations provide some perspective on the public health impacts of O

-related health effects, such as pulmonary inflammation, that are plausibly linked to the more serious effects seen in epidemiologic studies but cannot be evaluated in quantitative risk assessments. They also help elucidate the extent to which such impacts may be reduced by meeting the current and alternative standards. 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 due to individual variability in responsiveness. Only a subset of individuals can be expected to experience such adverse health effects, and at-risk populations or lifestages, such as people with asthma or children, are expected to be affected more by such exposures than healthy adults.

The HREA also generates quantitative estimates of O

health risks for air quality adjusted to just meet the current

and alternative standards. One approach to estimating O

health risks is to combine modeled exposure estimates with exposure-response relationships derived from controlled human exposure studies of O

-induced health effects. The HREA uses this approach to estimate the occurrence of O

-induced lung function decrements in at-risk populations, including school-age children, school-age children with asthma, adults with asthma, and older adults. The available exposure-response information does not support this approach for other endpoints evaluated in controlled human exposure studies (U.S. EPA, 2014a, section 2.3).

For purposes of the exposure and risk estimates with adjusted air quality, the REA considered any value <76 ppb to be “just meeting” the current 75 ppb standard (U.S. EPA, 2014a).

The other approach used in this review to estimate O

-associated health risks is to apply concentration-response relationships derived from short- and/or long-term epidemiologic studies to air quality adjusted to just meet current and alternative standards. The concentration-response relationships drawn from epidemiologic studies are based on population exposure surrogates, such as 8-hour concentrations averaged across monitors and over more than one day (U.S. EPA, 2013a, Chapter 6). The HREA presents epidemiologic-based risk estimates for O

-associated mortality, hospital admissions, emergency department visits, and respiratory symptoms (U.S. EPA, 2014a, section 2.3). These estimates are derived from the full distributions of ambient O

concentrations estimated for the study locations.

In addition, the HREA estimates mortality risks associated with various portions of distributions of short-term O

concentrations (U.S. EPA, 2014a). The PA considers risk estimates based on the full distributions of ambient O

concentrations and, when available, estimates of the risk associated with various portions of those ambient distributions.

In doing so, the PA takes note of the ISA conclusions regarding confidence in linear concentration-response relationships over distributions of ambient concentrations (see above), and of the extent to which health effect associations at various ambient O

concentrations are supported by the evidence from experimental studies for effects following specific O

exposures.

In previous reviews, including the 2008 review and reconsideration, such risks were separately estimated for O

concentrations characterized as above policy-relevant background concentrations. Policy-relevant background concentrations were defined as the distribution of O

concentrations attributable to sources other than anthropogenic emissions of O

precursor emissions (

e.g.,

VOC, CO, NO

) in the U.S., Canada, and Mexico. The decision in this review to estimate total risk across the full range of O

concentrations reflects consideration of advice from CASAC (Frey and Samet, 2012b).

In a series of sensitivity analyses, the HREA also evaluates a series of threshold models for respiratory mortality associated with long-term O

concentrations. The PA considers these risk estimates based on threshold models, in addition to HREA core estimates based on the linear model (U.S. EPA, 2014a, sections 3.2.3.2, 4.4.2.3).

B. Health Effects Information

This section outlines key information contained in the ISA (U.S. EPA, 2013a, Chapters 4 to 8) and in the PA (U.S. EPA, 2014c, Chapters 3 and 4) on the known or potential effects on public health which may be expected from the presence of O

in the ambient air. The information highlighted here summarizes: (1) New information available on potential mechanisms for health effects associated with exposure to O

(II.B.1); (2) the nature of effects that have been associated directly with both short- and long-term exposure to O

and indirectly with the presence of O

in ambient air (II.B.2); (3) considerations related to the adversity of O

-attributable health effects (II.B.3); and (4) considerations in characterizing the public health impact of O

including the identification of “at risk” populations (II.B.4).

The decision in the 2008 rulemaking emphasized the large number of epidemiologic studies published since the 1997 review that continued to report associations with respiratory hospital admissions and emergency department visits, as well as additional health endpoints, including the effects of acute (short-term and prolonged) and chronic exposures to O

on lung function decrements and enhanced respiratory symptoms in asthmatic individuals, school absences, and premature mortality. It also emphasized controlled human exposure studies showing respiratory effects with prolonged O

exposures at levels below 80 ppb, changes in lung host defenses, and increased airway responsiveness, and animal toxicology studies that provided information about mechanisms of action.

The ISA (U.S. EPA, 2013a) prepared for this review emphasizes a large number of new epidemiologic studies published since the last review on effects associated with both short- and long-term exposures, including new epidemiologic studies about risk factors. It also emphasizes important new information from controlled human exposure, dosimetry and toxicology studies. Highlights of the new evidence included:

(1) Two controlled human exposure studies new since the 2008 review are now available that examine respiratory effects associated with prolonged, 6.6-hour, O

exposures to levels of 72 ppb

and 60 ppb. These studies observed effects in healthy adults, including lung function decrements combined with respiratory symptoms at 72 ppb, and lung function decrements and pulmonary inflammation at 60 ppb. These studies expand on evidence of lung function decrements with O

exposure at 60 ppb available in the last review, and provide new evidence of airway inflammation, a mechanism by which O

may cause other more serious respiratory effects (

e.g.

, asthma exacerbations).

As noted below, for the 70 ppb exposure concentration, Schelegle et al. (2009) reported that the actual mean exposure concentration was 72 ppb.

(2) Recent multicity and single city epidemiologic studies continue to report associations between short-term O

exposures and respiratory hospital admissions and respiratory emergency department visits. Recent multicity studies and a multi-continent study have reported consistent positive associations between short-term O

exposure and total (nonaccidental) mortality, expanding upon evidence available in the last review. They also observed associations between O

exposure and cardiovascular and respiratory mortality.

The consideration of ambient O

concentrations in the locations of these epidemiologic studies are discussed in sections II.D.1.b and II.E.4.a below, for the current standard and alternative standards, respectively.

(3) Recent controlled human exposure studies reporting systemic inflammation and cardiac changes provide support for the expanded body of epidemiologic evidence for

cardiovascular mortality, although lack of coherence with epidemiologic studies of cardiovascular morbidity remains an important uncertainty.

(4) New epidemiologic studies provide expanded evidence for respiratory effects associated with long-term or repeated O

concentrations (

e.g.

, seasonal average of 1- or 8-hour daily max concentrations). Recent studies report interactions between exercise or different genetic variants and both new-onset asthma in children and increased respiratory symptom effects in individuals with asthma; additional studies of respiratory morbidity and mortality support the association between long-term exposure to O

and a range of respiratory health effects.

(5) New evidence of risk factors (

i.e.,

people with certain genetic variants related to antioxidant status or inflammation, and people with reduced intake of antioxidant nutrients) strengthens our understanding of the potential modes of action from O

-induced effects.

1. Overview of Mechanisms

The purpose of this section is to describe the ISA's characterization of the key events and pathways that contribute to health effects resulting from both short-term and long-term exposures to O

. The information in this section draws from section 5.3 of the ISA (U.S. EPA, 2013a). Mode of action refers to a sequence of key events and processes that result in a given toxic effect. Elucidation of mechanisms provides a more detailed understanding of these key events and processes. Experimental evidence elucidating modes of action and/or mechanisms contributes to our understanding of the biological plausibility of adverse O

-related health effects, including respiratory effects and effects outside the respiratory system (U.S. EPA, 2013a, Chapters 6 and 7).

Figure 3.1 in the PA (U.S. EPA, 2014c) shows the current understanding of key events in the toxicity pathway of O

, based on the available evidence. These key events are described briefly here and in more detail in section 3.1.1 of the PA. The initial key event is the formation of secondary oxidation products in the respiratory tract (U.S. EPA, 2013a, section 5.3). This mainly involves direct reactions with components of the extracellular lining fluid (ELF). Although the ELF has inherent capacity to quench (based on individual antioxidant capacity), this capacity can be overwhelmed, especially with exposure to elevated concentrations of O

. The resulting secondary oxidation products transmit signals to the epithelium, pain receptive nerve fibers and, if present, immune cells (

i.e.,

eosinophils, dendritic cells and mast cells) involved in allergic responses. Thus, the available evidence indicates that the effects of O

are mediated by components of ELF and by the multiple cell types found in the respiratory tract. Further, oxidative stress is an implicit part of this initial key event.

It is well understood that secondary oxidation products initiate numerous responses at the cellular, tissue, and whole organ level of the respiratory system. These responses include the activation of neural reflexes leading to lung function decrements, airway obstruction, and extrapulmonary effects such as slow resting heart rate; initiation of inflammation; alteration of barrier epithelial function; sensitization of bronchial smooth muscle; modification of lung host defenses; and airways remodeling (U.S. EPA, 2013a, section 5.3.10, Figure 5-8). Each of these effects is discussed in more detail in section 3.1.1 of the PA (U.S. EPA, 2014c).

Persistent inflammation and injury, which are observed in animal models of chronic and intermittent exposure to O

, are associated with airways remodeling (see Section 7.2.3 of the ISA, U.S. EPA 2013). Chronic intermittent exposure to O

has also been shown to result in effects on the developing lung and immune system. Systemic inflammation and vascular oxidative/nitrosative stress are also key events in the toxicity pathway of O

. Extrapulmonary effects of O

occur in numerous organ systems, including the cardiovascular, central nervous, reproductive, and hepatic systems (U.S. EPA, 2013a, sections 6.3 to 6.5 and sections 7.3 to 7.5).

Responses to O

exposure are variable within the population. Studies have shown a large range of pulmonary function (

i.e.,

spirometric) responses to O

among healthy young adults, while responses within an individual are relatively consistent over time. Other responses to O

have also been characterized by a large degree of interindividual variability. For example, a 3- to 20-fold difference among subjects in their studies in airways inflammation (

i.e.,

neutrophilia influx) following O

exposure has been reported (Schelegle et al., 1991 and Devlin et al., 1991, respectively). Reproducibility of an individual's inflammatory response to O

exposure in humans, measured as sputum neutrophilia, was demonstrated by Holz et al (1999). Since individual inflammatory responses were relatively consistent across time, it was thought that inflammatory responsiveness reflected an intrinsic characteristic of the subject (Mudway and Kelly, 2000). While the basis for the observed interindividual variability in responsiveness to O

is not clear, section 5.4.2 of the ISA discusses mechanisms that may underlie the variability in responses seen among individuals. Certain functional genetic polymorphisms, pre-existing conditions or diseases, nutritional status, lifestages, and co-exposures contribute to altered risk of O

-induced effects. Experimental evidence for such O

-induced changes contributes to our understanding of the biological plausibility of adverse O

-related health effects, including a range of respiratory effects as well as effects outside the respiratory system (

e.g.,

cardiovascular effects) (U.S. EPA, 2013a, Chapters 6 and 7).

2. Nature of Effects

The health effects of O

are described in detail and assessed in the ISA (U.S. EPA, 2013a). Based on this assessment, the ISA determined that a “causal” relationship exists between short-term exposure to O

in ambient air

and effects on the respiratory system and that a “likely to be causal” relationship

exists between long-term exposure to O

in ambient air and respiratory effects (U.S. EPA 2013a, pp. 1-6 to 1-7). As stated in the ISA, “[c]ollectively, a very large amount of evidence spanning several decades supports a relationship between exposure to O

and a broad range of respiratory effects” (US. EPA, 2013a, p. 1-6). The ISA summarizes the longstanding body of evidence for O

respiratory effects as follows (U.S. EPA, 2013a, p. 1-5):

In determining that a causal relationship exists for O

with specific health effects, the EPA has concluded that “[e]vidence is sufficient to conclude that there is a causal relationship with relevant pollutant exposures” (U.S. EPA, 2013a, p. lxiv).

In determining a “likely to be a causal” relationship exists for O

with specific health effects, the EPA has concluded that “[e]vidence is sufficient to conclude that a causal relationship is likely to exist with relevant pollutant exposures, but important uncertainties remain” (U.S. EPA, 2013a, p. lxiv).

The clearest evidence for health effects associated with exposure to O

is provided by studies of respiratory effects. Collectively, a very large amount of evidence spanning several decades supports a relationship between exposure to O

and a broad range of respiratory effects (see Section 6.2.9 and Section 7.2.8). The majority of this evidence is derived from studies investigating short-term exposures (

i.e.,

hours to weeks) to O

, although animal toxicological studies and recent epidemiologic evidence demonstrate that long-term exposure (

i.e.,

months to years) may also harm the respiratory system.

Additionally, the ISA determined that the relationships between short-term exposures to O

in ambient air and both total mortality and cardiovascular effects are likely to be causal, based on expanded evidence bases in the current review (U.S. EPA, 2013a, pp. 1-7 to 1-

8). In the ISA, the EPA additionally determined that the currently available evidence for additional endpoints is “suggestive” of causal relationships between short-term (central nervous system effects) and long-term exposure (cardiovascular effects, reproductive and developmental effects, central nervous system effects and total mortality) to ambient O

Consistent with emphasis in past reviews on O

health effects for which the evidence is strongest, in this review the EPA places the greatest emphasis on studies of health effects that have been judged in the ISA to be caused by, or likely to be caused by, O

exposures (U.S. EPA, 2013a, section 2.5.2). This section discusses the evidence for health effects attributable to O

exposures, with a focus on respiratory morbidity and mortality effects attributable to short- and long-term exposures, and cardiovascular system effects (including mortality) and total mortality attributable to short-term exposures. This section focuses particularly on considering the extent to which the scientific evidence available in the current review has been strengthened since the last review, and the extent to which important uncertainties and limitations in the evidence from the last review have been addressed.

a. Respiratory Effects—Short-Term

The 2006 O

AQCD concluded that there was clear, consistent evidence of a causal relationship between short-term O

exposure and respiratory effects (U.S. EPA, 2006a). This conclusion was substantiated by evidence from controlled human exposure and toxicological studies indicating a range of respiratory effects in response to short-term O

exposures, including pulmonary function decrements and increases in respiratory symptoms, lung inflammation, lung permeability, and airway hyperresponsiveness. Toxicological studies provided additional evidence for O

-induced impairment of host defenses. Combined, these findings from experimental studies provided support for epidemiologic evidence, in which short-term increases in ambient O

concentration were consistently associated with decreases in lung function in populations with increased outdoor exposures, especially children with asthma and healthy children; increases in respiratory symptoms and asthma medication use in children with asthma; and increases in respiratory-related hospital admissions and asthma-related emergency department visits (U.S. EPA, 2013a, pp. 6-1 to 6-2).

As discussed in detail in the ISA (U.S. EPA, 2013a, section 6.2.9), studies evaluated since the completion of the 2006 O

AQCD support and expand upon the strong body of evidence that, in the last review, indicated a causal relationship between short-term O

exposures and respiratory health effects. Recent controlled human exposure studies conducted in young, healthy adults with moderate exertion have reported forced expiratory volume in 1 second (FEV

) decrements and pulmonary inflammation following prolonged exposures to O

concentrations as low as 60 ppb, and respiratory symptoms following exposures to concentrations as low as 72 ppb (based on group mean responses).

Epidemiologic studies provide evidence that increases in ambient O

exposures are associated with lung function decrements, increases in respiratory symptoms, and pulmonary inflammation in children with asthma; increases in respiratory-related hospital admissions and emergency department visits; and increases in respiratory mortality. Some of these studies report such associations even for O

concentrations at the low end of the distribution of daily concentrations. Recent epidemiologic studies report that associations with respiratory morbidity and mortality are stronger during the warm/summer months and remain robust after adjustment for copollutants. Recent toxicological studies reporting O

-induced inflammation, airway hyperresponsiveness, and impaired lung host defense continue to support the biological plausibility and modes of action for the O

-induced respiratory effects observed in the controlled human exposure and epidemiologic studies. Further support is provided by recent studies that found O

-associated increases in indicators of airway inflammation and oxidative stress in children with asthma (U.S. EPA, 2013a, section 6.2.9). Together, epidemiologic and experimental studies support a continuum of respiratory effects associated with O

exposure that can result in respiratory-related emergency department visits, hospital admissions, and/or mortality (U.S. EPA, 2013a, section 6.2.9).

Schelegle et al. (2009) reported a statistically significant increase in respiratory symptoms in healthy adults at a target O

exposure concentration of 70 ppb, averaged over the study period. For this 70 ppb target exposure concentration, Schelegle et al. (2009) reported that the actual mean exposure concentration was 72 ppb.

Across respiratory endpoints, evidence indicates antioxidant capacity may modify the risk of respiratory morbidity associated with O

exposure (U.S. EPA, 2013a, section 6.2.9, p. 6-161). The potentially elevated risk of populations with diminished antioxidant capacity and the reduced risk of populations with sufficient antioxidant capacity is supported by epidemiologic studies and from controlled human exposure studies. Additional evidence characterizes O

-induced decreases in antioxidant levels as a key event in the mode of action for downstream effects.

Key aspects of this evidence are discussed below with regard to lung function decrements; pulmonary inflammation, injury, and oxidative stress; airway hyperresponsiveness; respiratory symptoms and medication use; lung host defense; allergic and asthma-related responses; hospital admissions and emergency department visits; and respiratory mortality.

CASAC concurred that these were “the kinds of identifiable effects on public health that are expected from the presence of ozone in the ambient air” (Frey 2014c, p. 3).

i. Lung Function Decrements

In the 2008 review, a large number of controlled human exposure studies

reported O

-induced lung function decrements in young, healthy adults engaged in intermittent, moderate exertion following 6.6 hour exposures to O

concentrations at or above 80 ppb. Although two studies also reported effects following exposures to lower concentrations, an important uncertainty in the last review was the extent to which exposures to O

concentrations below 80 ppb result in lung function decrements. In addition, in the last review epidemiologic panel studies had reported O

-associated lung function decrements in a variety of different populations (

e.g.,

children, outdoor workers) likely to experience increased exposures. In the current review, additional controlled human exposure studies are available that have evaluated exposures to O

concentrations of 60 or 72 ppb. The available evidence from controlled human exposure and panel studies is

assessed in detail in the ISA (U.S. EPA, section 6.2.1) and is summarized below.

The controlled human exposure studies emphasized in the PA utilize only healthy adult subjects. In the near absence of controlled human exposure data for children, HREA estimates of lung function decrements are based on the assumption that children exhibit the same lung function responses following O

exposures as healthy 18 year olds (U.S. EPA, 2014a, section 6.2.4 and 6.5). This assumption is justified in part by the findings of McDonnell et al. (1985), who reported that children (8-11 years old) experienced FEV

responses similar to those observed in adults (18-35 years old). Thus, the conclusions about the occurrence of lung function decrements that follow generally apply to children as well as to adults.

Controlled exposures to O

concentrations that can be found in the ambient air can result in a number of lung function effects, including decreased inspiratory capacity, mild bronchoconstriction, and rapid, shallow breathing patterns during exercise. Reflex inhibition of inspiration results in a decrease in forced vital capacity (FVC) and total lung capacity (TLC) and, in combination with mild bronchoconstriction, contributes to a decrease in FEV

(U.S. EPA, 2013a, section 6.2.1.1). Accumulating evidence indicates that such effects are mediated by activation of sensory nerves, resulting in the involuntary truncation of inspiration and a mild increase in airway obstruction due to bronchoconstriction (U.S. EPA, 2013a, section 5.3.10).

Data from controlled human exposure studies show that increasing the duration of O

exposures and increasing ventilation rates decreases the O

exposure concentrations required to impair lung function. Ozone exposure concentrations well above those typically found in ambient air are required to impair lung function in healthy resting adults, while exposure to O

concentrations at or below those in the ambient air have been reported to impair lung function in healthy adults exposed for longer durations while undergoing intermittent, moderate exertion (U.S. EPA, 2013a, section 6.2.1.1). With repeated O

exposures over several days, FEV

responses become attenuated in both healthy adults and adults with mild asthma, though this attenuation of response is lost after about a week without exposure (U.S. EPA, 2013a, section 6.2.1.1; p. 6-27).

When considering controlled human exposure studies of O

-induced lung function decrements, the ISA and PA evaluate both group mean changes in lung function and the interindividual variability in the magnitude of responses. An advantage of O

controlled human exposure studies (

i.e.

, compared to the epidemiologic panel studies discussed below) is that reported effects necessarily result from exposures to O

itself.

To the extent studies report statistically significant decrements in mean lung function following O

exposures after controlling for other factors, these studies provide greater confidence that measured decrements are due to the O

exposure itself, rather than to chance alone. As discussed below, group mean changes in lung function are often small, especially following exposures to relatively low O

concentrations (

e.g.

, 60 ppb). However, even when group mean decrements in lung function are small, some individuals could experience decrements that are “clinically meaningful” (Pellegrino et al., 2005; ATS, 1991) with respect to criteria for spirometric testing, and/or that could be considered adverse with respect to public health policy decisions (see section II.B.3, below).

The ISA notes that the use of filtered air responses as a control for the assessment of responses following O

exposure in controlled human exposure studies serves to eliminate alternative explanations other than O

itself in causing the measured responses (U.S. EPA, 2013a, section 6.2.1.1).

At the time of the last review, a number of controlled human exposure studies had reported lung function decrements in young, healthy adults following prolonged (6.6-hour) exposures while at moderate exertion to O

concentrations at and above 80 ppb. In addition, there were two controlled human exposure studies by Adams (2002, 2006) that examined lung function effects following exposures to 60 ppb O

. The EPA's analysis of the data from the Adams (2006) study reported a small but statistically significant O

-induced decrement in group mean FEV

following exposures of young, healthy adults to 60 ppb O

while at moderate exertion, when compared with filtered air controls (Brown et al., 2008).

Further examination of the post-exposure FEV

data, and mean data for other time points and other concentrations, indicated that the temporal pattern of the response to 60 ppb O

was generally consistent with the temporal patterns of responses to higher O

concentrations in this and other studies (75 FR 2950, January 19, 2010). This suggested a pattern of response following exposures to 60 ppb O

that was consistent with a dose-response relationship, rather than random variability. See also

State of Mississippi

EPA

, F. 3d at 1347 (upholding EPA's interpretation of the Adams studies).

Adams (2006) did not find effects on FEV

at 60 ppb to be statistically significant. In an analysis of the Adams (2006) data, Brown et al. (2008) showed that even after removal of potential outliers, the average effect on FEV

at 60 ppb was small, but highly statistically significant (p <0.002) using several common statistical tests.

Figure 6-1 in the ISA summarizes the currently available evidence from multiple controlled human exposure studies evaluating group mean changes in FEV

following prolonged O

exposures (

i.e.

, 6.6 hours) in young, healthy adults engaged in moderate levels of physical activity (U.S. EPA, 2013a, section 6.2.1.1). With regard to the group mean changes reported in these studies, the ISA specifically notes the following (U.S. EPA, 2013a, section 6.2.1.1, Figure 6-1):

1. Prolonged exposure to 40 ppb O

results in a small decrease in group mean FEV

that is not statistically different from responses following exposure to filtered air (Adams, 2002; Adams, 2006).

2. Prolonged exposure to an average O

concentration of 60 ppb results in group mean FEV

decrements ranging from 1.8% to 3.6% (Adams 2002; Adams, 2006;

Schelegle et al., 2009;

Kim et al., 2011). Based on data from multiple studies, the weighted average group mean decrement was 2.7%. In some analyses, these group mean decrements in lung function were statistically significant (Brown et al., 2008; Kim et al., 2011), while in other analyses they were not (Adams, 2006; Schelegle et al., 2009).

Adams (2006); (2002) both provide data for an additional group of 30 healthy subjects that were exposed via facemask to 60 ppb (square-wave) O

for 6.6 hours with moderate exercise (V

= 23 L/min per m

BSA). These subjects are described on page 133 of Adams (2006) and pages 747 and 761 of Adams (2002). The FEV

decrement may be somewhat increased due to a target V

of 23 L/min per m

BSA relative to other studies having the target V

of 20 L/min per m

BSA. The facemask exposure is not expected to affect the FEV

responses relative to a chamber exposure.

For the 60 ppb target exposure concentration, Schelegle et al. (2009) reported that the actual mean exposure concentration was 63 ppb.

Adams (2006) did not find effects on FEV

at 60 ppb to be statistically significant. In an analysis of the Adams (2006) data, Brown et al. (2008) addressed the more fundamental question of whether there were statistically significant differences in responses before and after the 6.6 hour exposure period and found the average effect on FEV

at 60 ppb to be small, but highly statistically significant using several common statistical tests, even after removal of potential outliers. Schelegle et al. (2009) reported that, compared to filtered air, the largest change in FEV

for the 60 ppb protocol occurred after the sixth (and final) exercise period.

3. Prolonged exposure to an average O

concentration of 72 ppb results in a statistically significant group mean decrement in FEV

of about 6% (Schelegle et al., 2009).

As noted above, for the 70 ppb exposure group, Schelegle et al. (2009) reported that the actual mean exposure concentration was 72 ppb.

4. Prolonged square-wave exposure to average O

concentrations of 80 ppb, 100 ppb, or 120 ppb O

results in statistically significant group mean decrements in FEV

ranging from 6 to 8%, 8 to 14%, and 13 to 16%, respectively (Folinsbee et al., 1988; Horstman et al., 1990; McDonnell et al., 1991; Adams, 2002; Adams, 2003; Adams, 2006).

As illustrated in Figure 6-1 of the ISA, there is a smooth dose-response

curve without evidence of a threshold for exposures between 40 and 120 ppb O

(U.S. EPA, 2013a, Figure 6-1). When these data are taken together, the ISA concludes that “mean FEV

is clearly decreased by 6.6-hour exposures to 60 ppb O

and higher concentrations in [healthy, young adult] subjects performing moderate exercise” (U.S. EPA, 2013a, p. 6-9).

With respect to interindividual variability in lung function, in an individual with relatively “normal” lung function, with recognition of the technical and biological variability in measurements, within-day changes in FEV

of ≥5% are clinically meaningful (Pellegrino et al., 2005; ATS, 1991). The ISA (U.S. EPA, 2013a, section 6.1.) focuses on individuals with >10% decrements in FEV

for two reasons. A 10% FEV

decrement is accepted by the American Thoracic Society (ATS) as an abnormal response and a reasonable criterion for assessing exercise-induced bronchoconstriction (Dryden et al., 2010; ATS, 2000). (U.S. EPA, 2013a, section 6.2.1.1). Also, some individuals in the Schelegle et al. (2009) study experienced 5-10% FEV

decrements following exposure to filtered air.

In previous NAAQS reviews, the EPA has made judgments regarding the potential implications for individuals experiencing FEV

decrements of varying degrees of severity.

For people with lung disease, the EPA judged that moderate functional decrements (

e.g.,

FEV

decrements >10% but <20%, lasting up to 24 hours) would likely interfere with normal activity for many individuals, and would likely result in more frequent use of medication (75 FR 2973, January 19, 2010). In previous reviews CASAC has endorsed these conclusions. In the context of standard setting, in the last review of the O

NAAQS CASAC indicated that it is appropriate to focus on the lower end of the range of moderate functional responses (

e.g.,

FEV

decrements ≥10%) when estimating potentially adverse lung function decrements in people with lung disease, especially children with asthma (Henderson, 2006c; transcript of CASAC meeting, day 8/24/06, page 149). More specifically, CASAC stated that “[a] 10% decrement in FEV

can lead to respiratory symptoms, especially in individuals with pre-existing pulmonary or cardiac disease. For example, people with chronic obstructive pulmonary disease have decreased ventilatory reserve (

i.e.,

decreased baseline FEV

) such that a ≥10% decrement could lead to moderate to severe respiratory symptoms” (Samet, 2011). In this review, CASAC reiterated its support for this conclusion, stating that “[a]n FEV1 decrement of ≥10% is a scientifically relevant surrogate for adverse health outcomes for people with asthma and lung disease” (Frey, 2014c p. 3). Therefore, in considering interindividual variability in O

-induced lung function decrements in the current review, the EPA also focuses on the extent to which individuals were reported to experience FEV

decrements of 10% or greater.

Such judgments have been made for decrements in FEV

as well as for increased airway responsiveness and symptomatic responses (

e.g.,

cough, chest pain, wheeze). Ranges of pulmonary responses and their associated potential impacts are presented in Tables 3-2 and 3-3 of the 2007 Staff Paper (U.S. EPA, 2007).

The approach to using results from controlled human exposure studies conducted in healthy adults to provide perspective on the potential public health impacts of O

-related respiratory health effects is discussed in section II.A above, and in sections II.C.2 and II.C.3 below.

New studies (Schelegle et al., 2009; Kim et al., 2011) add to the previously available evidence for interindividual variability in the responses of healthy adults following exposures to O

. Following prolonged exposures to 80 ppb O

while at moderate exertion, the proportion of healthy adults experiencing FEV

decrements greater than 10% was 17% by Adams (2006), 26% by McDonnell (1996), and 29% by Schelegle et al. (2009). Following exposures to 60 ppb O

, that proportion was 20% by Adams (2002), 3% by Adams (2006), 16% by Schelegle et al. (2009), and 5% by Kim et al. (2011). Across these studies, the weighted average proportion (

i.e.,

based on numbers of subjects in each study) of young, healthy adults with >10% FEV

decrements is 25% following exposure to 80 ppb O

and 10% following exposure to 60 ppb O

, for 6.6 hours at moderate exertion (U.S. EPA, 2013a, page 6-18 and 6-19).

The ISA notes that responses within an individual tend to be reproducible over a period of several months, indicating that interindividual differences reflect differences in intrinsic responsiveness. Given this, the ISA concludes that “[t]hough group mean decrements are biologically small and generally do not attain statistical significance, a considerable fraction of exposed individuals experience clinically meaningful decrements in lung function” when exposed for 6.6 hours to 60 ppb O

during quasi continuous, moderate exertion (U.S. EPA, 2013a, section 6.2.1.1, p. 6-20).

The ISA notes that by considering responses uncorrected for filtered air exposures, during which lung function typically improves (which would increase the size of the change, pre-and post-exposure), 10% is an underestimate of the proportion of healthy individuals that are likely to experience clinically meaningful changes in lung function following exposure for 6.6 hours to 60 ppb O

during intermittent moderate exertion (U.S. EPA, 2012, section 6.2.1.1).

Based on the data available at 60 ppb, 1% of subjects experienced decrements >20% (also uncorrected for filtered air exposures).

This review has marked an advance in the ability to make reliable quantitative predictions of the potential lung function response to ozone exposure, and thus to reasonably predict the degree of interindividual response of lung function to that exposure. McDonnell et al. (2012) and Schelegle et al. (2012) developed models using data on O

exposure concentrations, ventilation rates, duration of exposures, and lung function responses from a number of controlled human exposure studies. See section 6.2.1.1 of the ISA (U.S. EPA 2013a, p. 6-15). The McDonnell et al. (2012) and Schelegle et al. (2012) studies analyzed large datasets to fit compartmental models that included the concept of a dose of onset in lung function response or a response threshold based upon the inhaled O

dose. The McDonnell et al. (2012) model was fit to a dataset consisting of the FEV

responses of 741 young, healthy adults (18-35 years of age) from 23 individual controlled exposure studies. Concentrations across individual studies ranged from 40 ppb to 400 ppb,

activity level ranged from rest to heavy exercise, duration of exposure was from 2 to 7.6 hours. The extension of the McDonnell et al. (2012) model to children and older adults is discussed in section 6.2.4 of the HREA (U.S. EPA, 2014a). Schelegle et al. (2012) also analyzed a large dataset with substantial overlap to that used by McDonnell et al. (2012). The Schelegle et al. (2012) model was fit to the FEV

responses of 220 young healthy adults (taken from a dataset of 704 individuals) from 21 individual controlled exposure studies. The resulting empirical models can estimate the frequency distribution of individual responses for any exposure scenario as well as summary measures of the distribution such as the mean or median response and the proportions of individuals with FEV

decrements >10%, 15%, and 20%.

Responses to O

in these studies were adjusted for responses observed following exposure to filtered air.

The predictions of the McDonnell and Schelegle models are consistent with the observed results from the individual studies of O

-induced FEV

decrements. Specifically, McDonnell et al. (2012) estimated that 9% of healthy exercising adults would experience FEV

decrements greater than 10% following

6.6 hour exposure to 60 ppb O

, and that 22% would experience such decrements following exposure to 80 ppb O

(U.S. EPA, 2013a, p. 6-18 and Figure 6-3).

Schelegle et al. (2012) estimated that, for a prolonged (6.6 hours) O

exposure with moderate, quasi-continuous exercise, the average dose of onset for FEV

decrement would be reached following 4 to 5 hours of exposure to 60 ppb, and following 3 to 4 hours of exposure to 80 ppb. However, 14% of the individuals were estimated to have a dose of onset that was less than 40% of the average. Those individuals were estimated to reach their dose of onset following 1 to 2 hours of exposure to 50 to 80 ppb O

(U.S. EPA, 2013a, p. 6-16), which is consistent with the threshold FEV

responses reported by McDonnell et al. (2012).

Also consistent with the data from published studies (see above), this model predicts that 1% of people would experience FEV

decrements >20% following 6.6 hour exposure to 60 ppb O

CASAC agreed that these models mark a significant technical advance over the exposure-response modeling approach used in the last review (Frey, 2014a), stating that “the comparison of the MSS [McDonnell-Stewart-Smith] model results to those obtained with the exposure-response (E-R) model is of tremendous importance. Typically, the MSS model gives results about a factor of three higher than the E-R model for school-aged children, which is expected because the MSS model includes responses for a wider range of exposure protocols (under different levels of exertion, lengths of exposure, and patterns of exposure concentrations) than the E-R model” (Frey, 2014a, p. 7). CASAC explicitly found “the updated and expanded lung finds the MSS model to be scientifically and biologically defensible.” (Frey, 2014a, pp. 2, 8).

As discussed above and in the ISA (U.S EPA, 2013a, Section 5.3.2), secondary oxidation products formed following O

exposures can activate neural reflexes leading to decreased lung function. The McDonnell and Schelegle models included mathematical approaches to simulate the potential protective effect of antioxidants in the ELF at lower ambient O

concentrations, and include a dose threshold below which changes in lung function do not occur.

Epidemiologic studies

have consistently linked short-term increases in ambient O

concentrations with lung function decrements in diverse populations and lifestages, including children attending summer camps, adults exercising or working outdoors, and groups with pre-existing respiratory diseases such as asthmatic children (U.S. EPA, 2013a, section 6.2.1.2). Some of these studies reported O

-associated lung function decrements accompanied by respiratory symptoms

in asthmatic children (Just et al., 2002; Mortimer et al., 2002; Ross et al., 2002; Gielen et al., 1997; Romieu et al., 1997; Thurston et al., 1997; Romieu et al., 1996). In contrast, studies of children in the general population have reported similar O

-associated lung function decrements but without accompanying respiratory symptoms (Ward et al., 2002; Gold et al., 1999; Linn et al., 1996) (U.S. EPA, 2013a, section 6.2.1.2).

Unless otherwise specified, the epidemiologic studies discussed in the PA evaluate only adults.

Reversible loss of lung function in combination with the presence of symptoms meets the ATS definition of adversity (ATS, 2000).

Several epidemiologic panel studies

reported statistically significant associations with lung function decrements at relatively low ambient O

concentrations. For outdoor recreation or exercise, associations were reported in analyses restricted to 1-hour average O

concentrations less than 80 ppb (Spektor et al., 1988a; Spektor et al., 1988b), 60 ppb (Brunekreef et al., 1994; Spektor et al., 1988a), and 50 ppb (Brunekreef et al., 1994). Among outdoor workers, Brauer et al. (1996) found a robust association with daily 1-hour max O

concentrations less than 40 ppb. Ulmer et al. (1997) found a robust association in schoolchildren with 30-minute maximum O

concentrations less than 60 ppb. For 8-hour average O

concentrations, associations with lung function decrements in children with asthma were found to persist at concentrations less than 80 ppb in a U.S. multicity study (Mortimer et al., 2002) and less than 51 ppb in a study conducted in the Netherlands (Gielen et al., 1997).

Panel studies include repeated measurements of health outcomes, such as respiratory symptoms, at the individual level (U.S. EPA, 2013a, p. 1x).

Epidemiologic panel studies investigating the effects of short-term exposure to O

provided information on potential confounding by copollutants such as particulate matter with a median aerodynamic diameter less than or equal to 2.5 microns (PM

2.5

), particulate matter with a median aerodynamic diameter less than or equal to 10 microns (PM

), nitrogen dioxide (NO

), or sulfur dioxide (SO

). These studies varied in how they evaluated confounding. Some studies of subjects exercising outdoors indicated that ambient concentrations of copollutants such as NO

, SO

, or acid aerosol were low, and thus not likely to confound associations observed for O

(Hoppe et al., 2003; Brunekreef et al., 1994; Hoek et al., 1993). In other studies of children with increased outdoor exposures, O

was consistently associated with decreases in lung function, whereas other pollutants such as PM

2.5

, sulfate, and acid aerosol individually showed variable associations across studies (Thurston et al., 1997; Castillejos et al., 1995; Berry et al., 1991; Avol et al., 1990; Spektor et al., 1988a). Studies that conducted copollutant modeling generally found O

-associated lung function decrements to be robust (

i.e.,

most copollutant-adjusted effect estimates fell within the 95% confidence interval (CI) of the single-pollutant effect estimates) (U.S. EPA, 2013a, Figure 6-10 and Table 6-14). Most O

effect estimates for lung function were robust to adjustment for temperature, humidity, and copollutants such as PM

2.5

, PM

, NO

, or SO

. Although examined in only a few epidemiologic studies, O

also remained associated with decreases in lung function with adjustment for pollen or acid aerosols (U.S. EPA, 2013a, section 6.2.1.2).

Several epidemiologic studies demonstrated the protective effects of vitamin E and vitamin C supplementation, and increased dietary antioxidant intake, on O

-induced lung function decrements (Romieu et al., 2002) (U.S. EPA, 2013a, Figure 6-7 and Table 6-8).

These results provide support for the new, quantitative models (McDonnell et al., 2012; Schelegle et al., 2012), discussed above, which make use of the concept of oxidant stress to estimate the occurrence of lung function decrements following exposures to relatively low O

concentrations.

Evidence from controlled human exposure studies is mixed, suggesting that supplementation may be ineffective in the absence of antioxidant deficiency (U.S. EPA, 2013a, p. 5-63).

In conclusion, new information from controlled human exposure studies considerably strengthens the evidence and reduces the uncertainties, relative to the evidence that was available at the time of the 2008 review, regarding the presence and magnitude of lung function decrements in healthy adults following prolonged exposures to O

concentrations below 80 ppb. As discussed in Section 6.2.1.1 in the ISA (U.S. EPA, 2013, p. 6-12), there is information available from four separate studies that evaluated exposures to 60 ppb O

(Kim et al., 2011; Schelegle et al., 2009; Adams 2002; 2006). Although not consistently statistically significant, group mean FEV

decrements following exposures to 60 ppb O

are consistent

among these studies. Moreover, as is illustrated in Figure 6-1 of the ISA (U.S. EPA, 2013a), the group mean FEV

responses at 60 ppb fall on a smooth intake dose-response curve for exposures between 40 and 120 ppb O

. Based on the data in these studies, 10% of young, healthy adults experience clinically meaningful decrements in lung function when exposed for 6.6 hours to 60 ppb O

during intermittent, moderate exertion. One recent study has also reported statistically significant decrements following exposures to 72 ppb O

(Schelegle et al., 2009). Predictions from newly developed quantitative models are consistent with these experimental results. Additionally, as discussed in more detail in section II.B.4 below, epidemiologic studies continue to provide evidence of lung function decrements in people who are active outdoors, including people engaged in outdoor recreation or exercise, children, and outdoor workers, at low ambient O

concentrations. While few new epidemiologic studies of O

-associated lung function decrements are available in this review, previously available studies have reported associations with decrements, including at relatively low ambient O

concentrations.

ii. Pulmonary Inflammation, Injury, and Oxidative Stress

Ozone exposures result in increased respiratory tract inflammation and epithelial permeability. Inflammation is a host response to injury, and the induction of inflammation is evidence that injury has occurred. Oxidative stress has been shown to play a key role in initiating and sustaining O

-induced inflammation. Secondary oxidation products formed as a result of reactions between O

and components of the ELF can increase the expression of molecules (

i.e.,

cytokines, chemokines, and adhesion molecules) that can enhance airway epithelium permeability (U.S. EPA, 2013a, sections 5.3.3 and 5.3.4). As discussed in detail in the ISA (U.S. EPA, 2013a, section 6.2.3), O

exposures can initiate an acute inflammatory response throughout the respiratory tract that has been reported to persist for at least 18-24 hours after exposure.

Inflammation induced by exposure of humans to O

can have several potential outcomes: (1) Inflammation induced by a single exposure (or several exposures over the course of a summer) can resolve entirely; (2) continued acute inflammation can evolve into a chronic inflammatory state; (3) continued inflammation can alter the structure and function of other pulmonary tissue, leading to diseases such as asthma; (4) inflammation can alter the body's host defense response to inhaled microorganisms, particularly in potentially at-risk populations or lifestages such as the very young and old; and (5) inflammation can alter the lung's response to other agents such as allergens or toxins (U.S. EPA, 2013a, section 6.2.3). Thus, lung injury and the resulting inflammation provide a mechanism by which O

may cause other more serious morbidity effects (

e.g.,

asthma exacerbations).

CASAC also addressed this issue: “The CASAC believes that these modest changes in FEV

are usually associated with inflammatory changes, such as more neutrophils in the bronchoalveolar lavage fluid. Such changes may be linked to the pathogenesis of chronic lung disease” (Frey, 2014a p. 2).

In the last review, controlled human exposure studies reported O

-induced airway inflammation following exposures at or above 80 ppb and animal toxicological studies provided evidence for increases in inflammation and permeability in rabbits at levels as low as 100 ppb O

. In the current review, the link between O

exposures and airway inflammation and injury has been evaluated in additional controlled human exposure studies, as well as in recent epidemiologic studies. Controlled human exposure studies have generally been conducted in young, healthy adults or in adults with asthma using lavage (proximal airway and bronchoalveolar), bronchial biopsy, and more recently, induced sputum. These studies have evaluated one or more indicators of inflammation, including neutrophil

(PMN) influx, markers of eosinophilic inflammation, increased permeability of the respiratory epithelium, and/or prevalence of proinflammatory molecules (U.S. EPA, 2013a, section 6.2.3.1). Epidemiologic studies have generally evaluated associations between ambient O

and markers of inflammation and/or oxidative stress, which plays a key role in initiating and sustaining inflammation (U.S. EPA, 2013a, section 6.2.3.2).

Referred to as either neutrophils or polymorphonuclear neutrophils (or PMNs), these are the most abundant type of white blood cells in mammals. PMNs are recruited to the site of injury following trauma and are the hallmark of acute inflammation. The presence of PMNs in the lung has long been accepted as a hallmark of inflammation and is an important indicator that O

causes inflammation in the lungs. Neutrophilic inflammation of tissues indicates activation of the innate immune system and requires a complex series of events, that then are normally followed by processes that clear the evidence of acute inflammation.

There is an extensive body of evidence from controlled human exposure studies indicating that short-term exposures to O

can cause pulmonary inflammation. A single acute exposure (1-4 hours) of humans to moderate concentrations of O

(200-600 ppb) while exercising at moderate to heavy intensities resulted in a number of cellular and biochemical changes in the lung, including inflammation characterized by increased numbers of PMNs, increased permeability of the epithelial lining of the respiratory tract, cell damage, and production of proinflammatory molecules (

i.e.,

cytokines and prostaglandins, U.S. EPA, 2006a). A meta-analysis of 21 controlled human exposure studies (Mudway and Kelly, 2004) using varied experimental protocols (80-600 ppb O

exposures; 1-6.6 hours exposure duration; light to heavy exercise; bronchoscopy at 0-24 hours post-O

exposure) reported that PMN influx in healthy subjects is linearly associated with total O

dose.

Several studies, including one published since the last review (Alexis et al., 2010), have reported O

-induced increases in PMN influx and permeability following exposures at or above 80 ppb (Alexis et al., 2010; Peden et al., 1997; Devlin et al., 1991), and eosinophilic inflammation following exposures at or above 160 ppb (Scannell et al., 1996; Peden et al., 1997; Hiltermann et al., 1999; Vagaggini et al., 2002). In addition, one recent controlled human exposure study has reported O

-induced PMN influx following exposures of healthy adults to 60 ppb O

(Kim et al., 2011), the lowest concentration at which inflammatory responses have been evaluated in human studies.

As with FEV

responses to O

, inflammatory responses to O

are generally reproducible within individuals, with some individuals experiencing more severe O

-induced airway inflammation than indicated by group averages (Holz et al., 2005; Holz et al., 1999). Unlike O

-induced decrements in lung function, which are attenuated following repeated exposures over several days (U.S. EPA, 2013a, section 6.2.1.1), some markers of O

-induced inflammation and tissue damage remain elevated during repeated exposures, indicating ongoing damage to the respiratory system (U.S. EPA, 2013a, section 6.2.3.1).

Most controlled human exposure studies have reported that asthmatics experience larger O

-induced inflammatory responses than non-asthmatics.

Specifically, asthmatics

exposed to 200 ppb O

for 4-6 hours with exercise show significantly more neutrophils in bronchoalveolar lavage fluid (BALF) than similarly exposed healthy individuals (Scannell et al., 1996; Basha et al., 1994). Bosson et al. (2003) reported significantly greater expression of a variety of pro-inflammatory cytokines in asthmatics, compared to healthy subjects, following exposure to 200 ppb O

for 2 hours. In addition, research available in the last review, combined with a recent study newly available in this review, indicates that pretreatment of asthmatics with corticosteroids can prevent the O

-induced inflammatory response in induced sputum, though pretreatment did not prevent FEV

decrements (Vagaggini et al., 2001; 2007). In contrast, Stenfors et al. (2002) did not detect a difference in the O

-induced increases in neutrophil numbers between 15 subjects with mild asthma and 15 healthy subjects by bronchial wash at the 6 hours postexposure time point, although the neutrophil increase in the asthmatic group was on top of an elevated baseline.

When evaluated, these studies have also reported O

-induced respiratory symptoms in asthmatics. Specifically, Scannell et al. (1996), Basha et al. (1994), and Vagaggini et al. (2001, 2007)

reported increased symptoms in addition to inflammation.

In people with allergic airway disease, including people with rhinitis and asthma, evidence available in the last review indicated that proinflammatory mediators also cause accumulation of eosinophils in the airways (Jorres et al., 1996; Peden et al., 1995 and 1997; Frampton et al., 1997; Hiltermann et al., 1999; Holz et al., 2002; Vagaggini et al., 2002). The eosinophil, which increases inflammation and allergic responses, is the cell most frequently associated with exacerbations of asthma (72 FR 37846, July 11, 2007).

Studies reporting inflammatory responses and markers of lung injury have clearly demonstrated that there is important variation in the responses of exposed subjects (72 FR 37831, July 11, 2007). Some individuals also appear to be intrinsically more susceptible to increased inflammatory responses from O

exposure (Holz et al., 2005). In healthy adults exposed to each 80 and 100 ppb O

, Devlin et al. (1991) observed group average increases in neutrophilic inflammation of 2.1- and 3.8-fold, respectively. However, there was a 20-fold range in inflammatory responses between individuals at both concentrations. Relative to an earlier, similar study conducted at 400 ppb (Koren et al., 1989), Devlin et al. (1991) noted that although some of the study population showed little or no increase in inflammatory and cellular injury indicators analyzed after exposures to lower levels of O

(

i.e.,

80 and 100 ppb), others had changes that were as large as those seen when subjects were exposed to 400 ppb O

. The study authors concluded that, “while the population as a whole may have a small inflammatory response to near-ambient levels of ozone, there may be a significant subpopulation that is very sensitive to these low levels” (Devlin et al., 1991).

A number of studies report that O

exposures increase epithelial permeability. Increased BALF protein, suggesting O

-induced changes in epithelial permeability, has been reported at 1 hour and 18 hours postexposure (Devlin et al., 1997; Balmes et al., 1996). A meta-analysis of results from 21 publications (Mudway and Kelly, 2004) for varied experimental protocols (80-600 ppb O

; 1-6.6 hours duration; light to heavy exercise; bronchoscopy at 0-24 hours post-O

exposure; healthy subjects), showed that increased BALF protein is associated with total inhaled O

dose. As noted in the 2009 PM ISA (U.S. EPA, 2009a), it has been postulated that changes in permeability associated with acute inflammation may provide increased access of inhaled antigens, particles, and other inhaled substances deposited on lung surfaces to the smooth muscle, interstitial cells, immune cells underlying the epithelium, and the blood (U.S. EPA, 2013a, sections 5.3.4, 5.3.5). As has been observed with FEV

responses, within individual changes in permeability are correlated with changes following sequential O

exposures (Que et al., 2011). Changes in permeability and AHR apear to be mediated by different pathways. Animal toxicology studies have provided some support for this hypothesis (Adamson and Prieditis, 1995; Chen et al., 2006), though these studies did not specifically evaluate O

exposures (U.S. EPA, 2009a).

The limited epidemiologic evidence reviewed in the 2006 O

AQCD (U.S. EPA, 2006a) reported associations between short-term increases in ambient O

concentrations and airways inflammation in children (1-hour max O

of approximately 100 ppb). In the 2006 O

AQCD (U.S. EPA, 2006a), there was limited evidence for increases in nasal lavage levels of inflammatory cell counts and molecules released by inflammatory cells (

i.e.,

eosinophilic cationic protein, and myeloperoxidases). Since 2006, as a result of the development of less invasive methods, there has been a large increase in the number of studies assessing ambient O

-associated changes in airway inflammation and oxidative stress, the types of biological samples collected, and the types of indicators. Most of these recent studies have evaluated biomarkers of inflammation or oxidative stress in exhaled breath, nasal lavage fluid, or induced sputum (U.S. EPA, 2013a, section 6.2.3.2). These recent studies form a larger database to establish coherence with findings from controlled human exposure and animal studies that have measured the same or related biological markers. Additionally, results from these studies provide further biological plausibility for the associations observed between ambient O

concentrations and respiratory symptoms and asthma exacerbations.

A number of epidemiologic studies provide evidence that short-term increases in ambient O

exposure increase pulmonary inflammation and oxidative stress in children, including those with asthma (Sienra-Monge et al., 2004; Barraza-Villarreal et al., 2008; Romieu et al., 2008; Berhane et al., 2011). Multiple studies examined and found increases in exhaled nitric oxide (eNO)

(Berhane et al., 2011; Khatri et al., 2009; Barraza-Villarreal et al., 2008). In some studies of subjects with asthma, increases in ambient O

concentration at the same lag were associated with both increases in pulmonary inflammation and respiratory symptoms (Khatri et al., 2009; Barraza-Villarreal et al., 2008). Although more limited in number, epidemiologic studies also found associations with cytokines such as IL-6 or IL-8 (Barraza-Villarreal et al., 2008; Sienra-Monge et al., 2004), eosinophils (Khatri et al., 2009), antioxidants (Sienra-Monge et al., 2004), and indicators of oxidative stress (Romieu et al., 2008) (U.S. EPA, 2013a, section 6.2.3.2). Because associations with inflammation were attenuated with higher antioxidant intake in the study by Sienra-Monge et al. (2004), this study provides additional evidence that inhaled O

is likely to be an important source of reactive oxygen species in airways and/or may increase pulmonary inflammation via oxidative stress-mediated mechanisms among all age groups. Limitations in some recent studies have contributed to inconsistent results in adults (U.S. EPA, 2013a, section 6.2.3.2).

Exhaled NO has been shown to be a useful biomarker for airway inflammation in large population-based studies (Linn et al., 2009) (U.S. EPA, 2013a, section 7.2.4).

Exposure to ambient O

on multiple days can result in larger increases in pulmonary inflammation and oxidative stress, as discussed in section 6.2.3.2 of the ISA (U.S. EPA, 2013a). In studies that examined multiple O

lags,

multiday averages of 8-hour maximum or 8-hour average concentrations were associated with larger increases in pulmonary inflammation and oxidative stress (Berhane et al., 2011; Delfino et al., 2010; Sienra-Monge et al., 2004), consistent with controlled human exposure (U.S. EPA, 2013a, section 6.2.3.1) and animal studies (U.S. EPA, 2013a, section 6.2.3.3) reporting that some markers of pulmonary inflammation remain elevated with O

exposures repeated over multiple days. Evidence from animal toxicological studies also clearly indicates that O

exposures result in damage and inflammation in the lung (U.S. EPA, 2013a, section 5.3). In the few studies that evaluated the potential for confounding, O

effect estimates were not confounded by temperature or humidity, and were robust to adjustment for PM

2.5

or PM

(Barraza-Villarreal et al., 2008; Romieu et al., 2008; Sienra-Monge et al., 2004).

In conclusion, a relatively small number of controlled human exposure studies evaluating O

-induced airway inflammation have become available since the last review. For purposes of reviewing the current O

NAAQS, the most important of these recent studies reported a statistically significant increase in airway inflammation in healthy adults at moderate exertion following exposures to 60 ppb O

, the lowest concentration that has been evaluated for inflammation. In addition, a number of recent epidemiologic studies report O

-associated increases in markers of pulmonary inflammation, particularly in children. Thus, recent studies continue to support the evidence for airway inflammation and injury that was available in previous reviews, with new evidence for such effects following exposures to lower concentrations than had been evaluated previously.

iii. Airway Hyperresponsiveness

Airway hyperresponsiveness (AHR) refers to a condition in which the conducting airways undergo enhanced bronchoconstriction in response to a variety of stimuli. Airway hyperresponsiveness is an important consequence of exposure to ambient O

because its presence reflects a change in airway smooth muscle reactivity, and indicates that the airways are predisposed to narrowing upon inhalation of a variety of ambient stimuli including specific triggers (

i.e.,

allergens) and nonspecific triggers (

e.g.,

, and cold air). People with asthma are generally more sensitive to bronchoconstricting agents than those without asthma, and the use of an airway challenge to inhaled bronchoconstricting agents is a diagnostic test in asthma (U.S. EPA, 2013, section 6.2.2). Standards for airway responsiveness testing have been developed for the clinical laboratory (ATS, 2000), although variation in the methodology for administering the bronchoconstricting agent may affect the results (Cockcroft et al., 2005). There is a wide range of airway responsiveness in people without asthma, and responsiveness is influenced by a number of factors, including cigarette smoke, pollutant exposures, respiratory infections, occupational exposures, and respiratory irritants. Dietary antioxidants have been reported to attenuate O

-induced bronchial hyperresponsiveness in people with asthma (Trenga et al., 2001).

Evidence for airway hyperresponsiveness (AHR) following O

exposures is derived primarily from controlled human exposure and toxicological studies (U.S. EPA, 2013a, section 6.2.2). Airway responsiveness is often quantified by measuring changes in pulmonary function

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